Andrea De Gaetano

Roux-en-Y gastric bypass and biliopancreatic diversion can markedly ameliorate diabetes in morbidly obese patients, often resulting in disease remission. Prospective, randomized trials comparing these procedures with medical therapy for the treatment of diabetes are needed.In this single-center, nonblinded, randomized, controlled trial, 60 patients between the ages of 30 and 60 years with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 35 or more, a history of at least 5 years of diabetes, and a glycated hemoglobin level of 7.0% or more were randomly assigned to receive conventional medical therapy or undergo either gastric bypass or biliopancreatic diversion. The primary end point was the rate of diabetes remission at 2 years (defined as a fasting glucose level of <100 mg per deciliter [5.6 mmol per liter] and a glycated hemoglobin level of <6.5% in the absence of pharmacologic therapy).At 2 years, diabetes remission had occurred in no patients in the medical-therapy group versus 75% in the gastric-bypass group and 95% in the biliopancreatic-diversion group (P<0.001 for both comparisons). Age, sex, baseline BMI, duration of diabetes, and weight changes were not significant predictors of diabetes remission at 2 years or of improvement in glycemia at 1 and 3 months. At 2 years, the average baseline glycated hemoglobin level (8.65±1.45%) had decreased in all groups, but patients in the two surgical groups had the greatest degree of improvement (average glycated hemoglobin levels, 7.69±0.57% in the medical-therapy group, 6.35±1.42% in the gastric-bypass group, and 4.95±0.49% in the biliopancreatic-diversion group).In severely obese patients with type 2 diabetes, bariatric surgery resulted in better glucose control than did medical therapy. Preoperative BMI and weight loss did not predict the improvement in hyperglycemia after these procedures. (Funded by Catholic University of Rome; ClinicalTrials.gov number, NCT00888836.).

Randomised controlled trials have shown that bariatric surgery is more effective than conventional treatment for the short-term control of type-2 diabetes. However, published studies are characterised by a relatively short follow-up. We aimed to assess 5 year outcomes from our randomised trial designed to compare surgery with conventional medical treatment for the treatment of type 2 diabetes in obese patients.We did our open-label, randomised controlled trial at one diabetes centre in Italy. Patients aged 30-60 years with a body-mass index of 35 kg/m(2) or more and a history of type 2 diabetes lasting at least 5 years were randomly assigned (1:1:1), via a computer-generated randomisation procedure, to receive either medical treatment or surgery by Roux-en-Y gastric bypass or biliopancreatic diversion. Participants were aware of treatment allocation before the operation and study investigators were aware from the point of randomisation. The primary endpoint was the rate of diabetes remission at 2 years, defined as a glycated haemaglobin A1c (HbA1c) concentration of 6·5% or less (≤47·5 mmol/mol) and a fasting glucose concentration of 5·6 mmol/L or less without active pharmacological treatment for 1 year. Here we analyse glycaemic and metabolic control, cardiovascular risk, medication use, quality of life, and long-term complications 5 years after randomisation. Analysis was by intention to treat for the primary endpoint and by per protocol for the 5 year follow-up. This study is registered with ClinicalTrials.gov, number NCT00888836.Between April 27, 2009, and Oct 31, 2009, we randomly assigned 60 patients to receive either medical treatment (n=20) or surgery by gastric bypass (n=20) or biliopancreatic diversion (n=20); 53 (88%) patients completed 5 years' follow-up. Overall, 19 (50%) of the 38 surgical patients (seven [37%] of 19 in the gastric bypass group and 12 [63%] of 19 in the bilipancreatic diversion group) maintained diabetes remission at 5 years, compared with none of the 15 medically treated patients (p=0·0007). We recorded relapse of hyperglycaemia in eight (53%) of the 15 patients who achieved 2 year remission in the gastric bypass group and seven (37%) of the 19 patients who achieved 2 year remission in the biliopancreatic diversion group. Eight (42%) patients who underwent gastric bypass and 13 (68%) patients who underwent biliopancreatic diversion had an HbA1c concentration of 6·5% or less (≤47·5 mmol/mol) with or without medication, compared with four (27%) medically treated patients (p=0·0457). Surgical patients lost more weight than medically treated patients, but weight changes did not predict diabetes remission or relapse after surgery. Both surgical procedures were associated with significantly lower plasma lipids, cardiovascular risk, and medication use. Five major complications of diabetes (including one fatal myocardial infarction) arose in four (27%) patients in the medical group compared with only one complication in the gastric bypass group and no complications in the biliopancreatic diversion group. No late complications or deaths occurred in the surgery groups. Nutritional side-effects were noted mainly after biliopancreatic diversion.Surgery is more effective than medical treatment for the long-term control of obese patients with type 2 diabetes and should be considered in the treatment algorithm of this disease. However, continued monitoring of glycaemic control is warranted because of potential relapse of hyperglycaemia.Catholic University of Rome.

Oxygen is commonly administered after extubation. Although several devices are available, data about their clinical efficacy are scarce.To compare the effects of the Venturi mask and the nasal high-flow (NHF) therapy on PaO2/FiO2SET ratio after extubation. Secondary endpoints were to assess effects on patient discomfort, adverse events, and clinical outcomes.Randomized, controlled, open-label trial on 105 patients with a PaO2/FiO2 ratio less than or equal to 300 immediately before extubation. The Venturi mask (n = 52) or NHF (n = 53) were applied for 48 hours postextubation.PaO2/FiO2SET, patient discomfort caused by the interface and by symptoms of airways dryness (on a 10-point numerical rating scale), interface displacements, oxygen desaturations, need for ventilator support, and reintubation were assessed up to 48 hours after extubation. From the 24th hour, PaO2/FiO2SET was higher with the NHF (287 ± 74 vs. 247 ± 81 at 24 h; P = 0.03). Discomfort related both to the interface and to airways dryness was better with NHF (respectively, 2.6 ± 2.2 vs. 5.1 ± 3.3 at 24 h, P = 0.006; 2.2 ± 1.8 vs. 3.7 ± 2.4 at 24 h, P = 0.002). Fewer patients had interface displacements (32% vs. 56%; P = 0.01), oxygen desaturations (40% vs. 75%; P < 0.001), required reintubation (4% vs. 21%; P = 0.01), or any form of ventilator support (7% vs. 35%; P < 0.001) in the NHF group.Compared with the Venturi mask, NHF results in better oxygenation for the same set FiO2 after extubation. Use of NHF is associated with better comfort, fewer desaturations and interface displacements, and a lower reintubation rate. Clinical trial registered with www.clinicaltrials.gov (NCT 01575353).

In Brief Objective: To compare diabetes remission after bariatric surgery in subjects with body mass index (BMI) of 35 kg/m2 or more or BMI of less than 35 kg/m2 to determine which predictors are best. Background: BMI is currently the only selection criterion for bariatric surgery in diabetic subjects. Many studies have challenged BMI for predicting diabetes remission. Methods: Data sources were PubMed, Cochrane Library, and EMBASE databases from January 1980 to June 2013. The selected studies were randomized controlled trials, controlled clinical trials, or cohort studies with 10 or more patients per arm. Of 1437 screened articles, 94 studies were included with 94,579 patients undergoing surgical procedures (4944 with type 2 diabetes mellitus). Weight, BMI, glycated hemoglobin A1c, fasting glucose, and insulin were abstracted by 2 independent reviewers. The effect size was the percent diabetes remission. Results: Meta-analysis was performed for BMI less than 35 kg/m2 (group 1) and BMI 35 kg/m2 or more (group 2). Diabetes remission was 72% [95% confidence interval (CI), 65–80] in group 1 and 71% (95% CI, 65–77) in group 2. Diabetes resolution was 89% (95% CI, 83–94) after biliopancreatic diversion, 77% (95% CI, 72–82) after Roux-en-Y bypass, 62% (95% CI, 46–79) after gastric banding, and 60% (95% CI, 51–70) after sleeve gastrectomy. The only significant predictor of glycated hemoglobin A1c reduction was waist circumference, lower baseline waist associating with higher reduction. Conclusions: Bariatric surgery determines similar diabetes remission rates in patients with BMI of 35 kg/m2 or more or BMI of less than 35 kg/m2. Baseline BMI is unrelated to diabetes remission. The association of baseline waist circumference with glycated hemoglobin A1c reduction is likely due to selection bias. Bariatric or metabolic effects of the surgical procedures appear independent, and different indices are needed to predict them. This meta-analysis study compares diabetes outcome after bariatric surgery in subjects with body mass index of 35 kg/m2 or more or body mass index of less than 35 kg/m2 to determine which predictors of diabetes remission are best in the 2 groups. Differences in type 2 diabetes mellitus remission after different bariatric surgery procedures were also studied.

Eligibility criteria for bariatric surgery in diabetes include BMI ≥35 kg/m(2) and poorly controlled glycemia. However, BMI does not predict diabetes remission, and thus, predictors need to be identified.Seven hundred twenty-seven patients were included in a database merged from the Swedish Obese Subjects (SOS) study and two randomized controlled studies, with 415 surgical and 312 medical patients in total. Bariatric operations were divided into gastric only (GO) and gastric plus diversion (GD).Sixty-four percent of patients in the surgical arm and 15.0% in the medical arm experienced diabetes remission (P < 0.001). GO yielded 60% remission, and GD yielded 76% remission. The best predictors of diabetes remission were lower baseline glycemia and shorter diabetes duration. However, when operation type was considered, GD predicted a higher likelihood of remission and greater weight loss. Patients in remission (responders) lost more weight (25% vs. 17%) and waist circumference (18% vs. 13%) and experienced better insulin sensitivity than nonresponders.Surgery is more effective than medical treatment in achieving diabetes remission and tighter glycemic control. Shorter diabetes duration, lower fasting glycemia before surgery, and GD versus GO procedures independently predict higher rates of remission, whereas baseline HbA1c and waist circumference predict improved glycemic control. The results show the advantage of an early operation together with better controlled glycemia on diabetes remission independently of BMI.

Objective: Acute respiratory distress syndrome (ARDS) is frequently associated with increased pulmonary vascular resistance and thus with systolic load of the right ventricle. We hypothesized that levosimendan, a new calcium sensitizer with potential pulmonary vasodilator properties, improves hemodynamics by unloading the right ventricle in patients with ARDS. Design: Prospective, randomized, placebo-controlled, pilot study. Setting: Twenty-two-bed multidisciplinary intensive care unit of a university hospital. Patients: Thirty-five patients with ARDS in association with septic shock. Interventions: Patients were randomly allocated to receive a 24-hr infusion of either levosimendan 0.2 μg/kg/min (n = 18) or placebo (n = 17). Data from right heart catheterization, cardiac magnetic resonance, arterial and mixed venous oxygen tensions and saturations, and carbon dioxide tensions were obtained before and 24 hrs after drug infusion. Measurements and Main Results: At a mean arterial pressure between 70 and 80 mm Hg (sustained with norepinephrine infusion), levosimendan increased cardiac index (from 3.8 ± 1.1 to 4.2 ± 1.0 L/min/m2) and decreased mean pulmonary artery pressure (from 29 ± 3 to 25 ± 3 mm Hg) and pulmonary vascular resistance index (from 290 ± 77 to 213 ± 50 dynes/s/cm5/m2; each p < .05). Levosimendan also decreased right ventricular end-systolic volume and increased right ventricular ejection fraction (p < .05). In addition, levosimendan increased mixed venous oxygen saturation (from 63 ± 8 to 70 ± 8%; p < .01). Conclusions: This study provides evidence that levosimendan improves right ventricular performance through pulmonary vasodilator effects in septic patients with ARDS. A large multiple-center trial is needed to investigate whether levosimendan is able to improve the overall prognosis of patients with sepsis and ARDS.

OBJECTIVE Inflammation is associated with pancreatic β-cell apoptosis and reduced insulin sensitivity. Literature suggests that interleukin (IL)-1β may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed to determine the efficacy, safety, and tolerability of LY2189102, a neutralizing IL-1β antibody, in T2DM patients. RESEARCH DESIGN AND METHODS Phase II, randomized, double-blind, parallel, placebo-controlled study of subcutaneous LY2189102 (0.6, 18, and 180 mg) administered weekly for 12 weeks in T2DM patients on diet and exercise, with or without approved antidiabetic medications. RESULTS LY2189102 reduced HbA1c at 12 weeks (adjusted mean differences versus placebo: −0.27, −0.38 and −0.25% for 0.6, 18 and 180 mg doses, respectively), and fasting glucose at multiple time points compared with placebo. LY2189102 also reduced postprandial glycemia, and inflammatory biomarkers, including hs-CRP and IL-6. LY2189102 was generally well tolerated. CONCLUSIONS Weekly subcutaneous LY2189102 for 12 weeks was well tolerated, modestly reduced HbA1c and fasting glucose, and demonstrated significant anti-inflammatory effects in T2DM patients. Neutralizing IL-1β holds promise as a convenient adjuvant treatment for T2DM.

The surgical option could represent a valid alternative to medical therapy in some diabetic patients. However, no data are available on long-term effects of metabolic surgery on diabetic complications. We aimed to determine whether patients with newly diagnosed type 2 diabetes who underwent bilio-pancreatic diversion (BPD) had less micro- and macrovascular complications than those who received conventional therapy.This was an unblinded, case-controlled trial with 10-years' follow-up, conducted from July 1998 through October 2009 at the Day Hospital of Metabolic Diseases, Catholic University, Rome, Italy. A consecutive sample of 110 obese patients (BMI >35 kg/m(2)) with newly diagnosed type 2 diabetes was enrolled. The study was completed by 50 subjects. The main outcome measure was long-term effects (10 years) of BPD versus those associated with conventional therapy on microvascular outcome, micro- and macroalbuminuria, and glomerular filtration rate (GFR). Secondary measures included macrovascular outcomes, type 2 diabetes remission, glycated hemoglobin, and hyperlipidemia.Ten-year GFR variation was -45.7 ± 18.8% in the medical arm and 13.6 ± 24.5% in the surgical arm (P < 0.001). Ten-year hypercreatininemia prevalence was 39.3% in control subjects and 9% in BPD subjects (P = 0.001). After 10 years, all BPD subjects recovered from microalbuminuria, whereas microalbuminuria appeared or progressed to macroalbuminuria in control subjects. Three myocardial infarctions, determined by electrocardiogram, and one stroke occurred in control subjects. After the 10-year follow-up, coronary heart disease (CHD) probability was 0.22 ± 0.10 and 0.05 ± 0.04 in the medical and surgical groups, respectively (P < 0.001). Remission from type 2 diabetes was observed in all patients within 1 year of surgery. Surgical and medical subjects had lost 34.60 ± 10.25 and 0.38 ± 6.10% of initial weight at the 10-year follow-up (P < 0.001).Renal and cardiovascular complications were dramatically reduced in the surgical arm, indicating long-term benefits of BPD on diabetic complications, at least in the case of morbid obesity with decompensated type 2 diabetes.

Mathematical modeling of the glucose-insulin feedback system is necessary to the understanding of the homeostatic control, to analyze experimental data, to identify and quantify relevant biophysical parameters, to design clinical trials and to evaluate diabetes prevention or disease modification therapies. Much work has been made over the last 30years, and the time now seems ripe to provide a comprehensive review. The one here proposed is focused on the most important clinical/experimental tests performed to understand the mechanism of glucose homeostasis. The review proceeds from models of pancreatic insulin production, with a coarser/finer level of detail ranging over cellular and subcellular scales, to short-term organ/tissue models accounting for the intra-venous and the oral glucose tolerance tests as well as for the euglycemic hyperinsulinemic clamp, to total-body, long-term diabetes models aiming to represent disease progression in terms of β-cell population dynamics over a long period of years.

ContextWe compared the incidence of hypoglycemia after Roux-en-Y gastric bypass (RYGB) vs sleeve gastrectomy (SG).

A close relationship between elevated plasma free fatty acid (FFA) levels and insulin resistance is commonly reported in obese subjects. The aim of the present study was to evaluate the role of intramuscular triglyceride (mTG) and FFA levels in insulin sensitivity in 30 nondiabetic normal-weight or obese subjects (18 with body mass index [BMI] = 21.8 ± 3.3 kg/m2 and 12 with BMI = 34.6 ± 2.7 kg/m2) who underwent minor abdominal surgery. Body composition was estimated by isotopic dilution, substrate oxidation by indirect calorimetry, and whole-body glucose uptake by euglycemic-hyperinsulinemic clamp (EHC). Glucose uptake (M) value negatively correlated with the MTG level (R2 = −.56, P < .0001), which was increased in obese different in the 2 groups: an increased concentration of saturated fat was present in obese patients (unsaturated to saturated ratio, 1.89 ± 0.40 v 2.19 ± 0.07, P < .0001). Stepwise linear regression analysis of total mTGs and palmitic and oleic fractions on the M value showed that only TGs and plamitic acid were significantly related to glucose uptake (R2 = .66, P < .0001). Furthermore, among the other anthropometric variables, only the BMI was significantly correlated with MTGs (R2 = .71, P < .0001). In conclusion, not only the MTG concentration but also the FFA pattern seems to affect insulin-mediated glucose uptake. A pivotal role might be played by a high saturated fatty acid content in the TGs. A close relationship between elevated plasma free fatty acid (FFA) levels and insulin resistance is commonly reported in obese subjects. The aim of the present study was to evaluate the role of intramuscular triglyceride (mTG) and FFA levels in insulin sensitivity in 30 nondiabetic normal-weight or obese subjects (18 with body mass index [BMI] = 21.8 ± 3.3 kg/m2 and 12 with BMI = 34.6 ± 2.7 kg/m2) who underwent minor abdominal surgery. Body composition was estimated by isotopic dilution, substrate oxidation by indirect calorimetry, and whole-body glucose uptake by euglycemic-hyperinsulinemic clamp (EHC). Glucose uptake (M) value negatively correlated with the MTG level (R2 = −.56, P < .0001), which was increased in obese different in the 2 groups: an increased concentration of saturated fat was present in obese patients (unsaturated to saturated ratio, 1.89 ± 0.40 v 2.19 ± 0.07, P < .0001). Stepwise linear regression analysis of total mTGs and palmitic and oleic fractions on the M value showed that only TGs and plamitic acid were significantly related to glucose uptake (R2 = .66, P < .0001). Furthermore, among the other anthropometric variables, only the BMI was significantly correlated with MTGs (R2 = .71, P < .0001). In conclusion, not only the MTG concentration but also the FFA pattern seems to affect insulin-mediated glucose uptake. A pivotal role might be played by a high saturated fatty acid content in the TGs.

Objective: Acute renal failure is common in septic patients. Fenoldopam, a dopamine-1 receptor agonist, increases renal blood flow and may, therefore, reduce the risk of acute renal failure in such patients. Accordingly, we sought to determine the safety and efficacy of fenoldopam for the prevention of acute renal failure in septic patients. Design: Prospective, double-blind, placebo-controlled trial. Setting: Three multidisciplinary intensive care units at a university hospital. Patients: Three hundred septic patients with baseline serum creatinine concentrations <150 μmol/L. Interventions: We randomized patients to a continuous infusion of either fenoldopam (n = 150) at 0.09 μg·kg−1·min−1 or placebo (n = 150) while in the intensive care unit. The primary outcome measure was the incidence of acute renal failure, defined as a serum creatinine concentration increase to >150 μmol/L, during study drug infusion. Measurements and main results: The incidence of acute renal failure was significantly lower in the fenoldopam group compared with the control group (29 vs. 51 patients; p = .006). The odds ratio of developing acute renal failure for patients treated with fenoldopam was estimated to be 0.47 (p = .005). The difference in the incidence of severe acute renal failure (creatinine >300 μmol/L), however, failed to achieve statistical significance (10 vs. 21; p = .056). The length of intensive care unit stay in surviving patients was significantly lower in the fenoldopam group compared with the control group (10.64 ± 9.3 vs. 13.4 ± 14.0; p < .001). There were no complications of fenoldopam infusion. A direct effect of treatment on the probability of death, beyond its effect on acute renal failure, was not significant (odds ratio = 0.68, p = .1). Conclusions: Compared with placebo, low-dose fenoldopam resulted in a smaller increase in serum creatinine in septic patients. The clinical significance of this finding is uncertain. A large multiple-center trial is now needed to confirm these findings.

To determine the effects of an intravenous bolus dose of a vasopressin analogue, terlipressin (1 mg), on systemic haemodynamic parameters and gastric mucosal perfusion (GMP) in patients with catecholamine-treated septic shock using a gastric tonometry and laser-Doppler flowmetry technique.Prospective open label study.Two multidisciplinary intensive care units.Fifteen patients with norepinephrine-treated septic shock.Every patient with mean arterial pressure between 50 and 55 mmHg treated with high dose norepinephrine received an intravenous bolus dose of terlipressin as last resort therapy. A laser-Doppler probe and tonometer were introduced into the gastric lumen.Terlipressin produced a decrease in cardiac output ( p<0.05), a progressive increase in mean arterial pressure ( p<0.05) and in GMP, detected by laser-Doppler flowmetry ( p<0.05) over 30 min and sustained for at least 24 h. The ratio of GMP to systemic oxygen delivery increased after terlipressin bolus dose ( p<0.05). The gradient between gastric mucosal and arterial PCO(2) tended to be lower after terlipressin, and the difference was statistically significant ( p<0.05) after 8 h. Terlipressin administration significantly increased ( p<0.05) urine output compared to baseline and higher values were found at each set of measurement. The terlipressin-induced increase in urine output was associated with a significantly increased creatinine clearance ( p<0.05). Reduction of the high-dose norepinephrine was observed in all patients ( p<0.05).Our findings showed that, in patients with norepinephrine-treated septic shock, terlipressin increased GMP, urine output and creatinine clearance by an increase in mean arterial pressure.

Polycystic ovary syndrome (PCOS) and menopausal subjects are characterized by an increased cardiovascular and type 2 diabetes mellitus risk, at least partially related to insulin disturbances. The evaluation of insulin resistance in these patients could be useful as primary prevention. The aim of the study was to verify the validity of several indexes of insulin sensitivity in PCOS and menopausal subjects by comparing the data obtained by these indexes to those of euglycemic-hyperinsulinemic clamp studies.One hundred PCOS and 110 menopausal subjects were analyzed; all subjects underwent an oral glucose tolerance test (75 g) and euglycemic-hyperinsulinemic clamp study. Seven PCOS patients and 13 menopausal subjects had impaired glucose tolerance or type 2 diabetes mellitus and were excluded from the study. After analysis of correlation coefficients between the evaluated indexes and the clamp studies, the sensitivity and specificity of different cut-off values for each parameter were analyzed by receiver operating characteristic (ROC) curves.The best correlation coefficients with clamp studies were obtained with the Avignon insulin sensitivity index (SiM) (R(s) = 0.7812) in PCOS patients and the Matsuda and De Fronzo index (R(s) = 0.6178) in menopausal patients. The best predictive index of insulin resistance in PCOS was a Avignon insulin sensitivity basal index (SibB) value of 62 or less (78% sensitivity, 95% specificity) and an insulin area under the curve (AUC) of 7,000 microIU/ml or more (>/=50,225 pmol/liter) x 120 min (83% sensitivity, 90% specificity). In the menopausal population, the best predictive performance was obtained by an insulin AUC of 10,000 microIU/ml or more (>/=71,750 pmol/liter) x 240 min (70% sensitivity, 88% specificity).The presence of high correlation coefficients does not necessarily mean that the indexes of insulin resistance have an optimal predictive performance; this is probably due to the presence of many borderline values. The simple evaluation of insulin AUC seems to effectively replace the euglycemic-hyperinsulinemic clamp in routine clinical practice, allowing results superimposable to those obtained by minimal model analysis.

Silver-impregnated central venous catheters (CVCs) have been proposed as a means for preventing CVC colonization and related bloodstream infections (CRBSIs).To evaluate the efficacy of CVCs impregnated with silver nanoparticles in a large group of critically ill patients.A prospective, randomized clinical trial was conducted in five intensive care units (ICUs). Three hundred and thirty-eight adult patients requiring CVCs between April 2006 and November 2008 were randomized to receive AgTive silver-nanoparticle-impregnated (SC) or conventional (CC) CVCs. Primary endpoints were CVC colonization (growth of ≥15 colony-forming units from the catheter tip) and incident CRBSIs (meeting the definitions of the Centers for Disease Control and Prevention). Infection-free time (days from initial CVC insertion to initial blood culture positivity) and ICU mortality rates were measured as secondary endpoints.The SC group (N = 135) and CC group (N = 137) were similar in terms of clinical and laboratory parameters at baseline, reasons for ICU admission, complications during CVC insertion, and total time with CVC (mean ± standard deviation; SC 13 ± 24 vs CC 15 ± 37 days). No significant intergroup differences were found in CVC colonization rates (SC 32.6% vs CC 30%; P = 0.7), CRBSI incidence rates (3.36 infections per 1000 catheter-days in both groups), infection-free times (SC 13 ± 34 vs CC 12 ± 12 days; P = 0.85) or ICU mortality (SC 46% vs CC 43%; P = 0.7).In critically ill patients, use of AgTive(®) silver-nanoparticle-impregnated CVCs had no significant effect on CVC colonization, CRBSI incidence or ICU mortality. These CVCs cannot be recommended as an adjunctive tool for control of CRBSIs.

Ifosfamide and cisplatin cause urinary loss of carnitine, which is a fundamental molecule for energy production in mammalian cells. We investigated whether restoration of the carnitine pool might improve chemotherapy-induced fatigue in non-anaemic cancer patients. Consecutive patients with low plasma carnitine levels who experienced fatigue during chemotherapy were considered eligible for study entry. Patients were excluded if they had anaemia or other conditions thought to be causing asthenia. Fatigue was assessed by the Functional Assessment of Cancer Therapy-Fatigue quality of life questionnaire. Treatment consisted of oral levocarnitine 4 g daily, for 7 days. Fifty patients were enrolled; chemotherapy was cisplatin-based in 44 patients and ifosfamide-based in six patients. In the whole group, baseline mean Functional Assessment of Cancer Therapy-Fatigue score was 19.7 (+/-6.4; standard deviation) and the mean plasma carnitine value was 20.9 microM (+/-6.8; standard deviation). After 1 week, fatigue ameliorated in 45 patients and the mean Functional Assessment of Cancer Therapy-Fatigue score was 34.9 (+/-5.4; standard deviation) (P<.001). All patients achieved normal plasma carnitine levels. Patients maintained the improved Functional Assessment of Cancer Therapy-Fatigue score until the next cycle of chemotherapy. In selected patients, levocarnitine supplementation may be effective in alleviating chemotherapy-induced fatigue. This compound deserves further investigations in a randomised, placebo-controlled study.

Due to the increasing importance of identifying insulin resistance, a need exists to have a reliable mathematical model representing the glucose/insulin control system. Such a model should be simple enough to allow precise estimation of insulin sensitivity on a single patient, yet exhibit stable dynamics and reproduce accepted physiological behavior.A new, discrete Single Delay Model (SDM) of the glucose/insulin system is proposed, applicable to Intra-Venous Glucose Tolerance Tests (IVGTTs) as well as to multiple injection and infusion schemes, which is fitted to both glucose and insulin observations simultaneously. The SDM is stable around baseline equilibrium values and has positive bounded solutions at all times. Applying a similar definition as for the Minimal Model (MM) SI index, insulin sensitivity is directly represented by the free parameter KxgI of the SDM. In order to assess the reliability of Insulin Sensitivity determinations, both SDM and MM have been fitted to 40 IVGTTs from healthy volunteers. Precision of all parameter estimates is better with the SDM: 40 out of 40 subjects showed identifiable (CV < 52%) KxgI from the SDM, 20 out of 40 having identifiable SI from the MM. KxgI correlates well with the inverse of the HOMA-IR index, while SI correlates only when excluding five subjects with extreme SI values. With the exception of these five subjects, the SDM and MM derived indices correlate very well (r = 0.93).The SDM is theoretically sound and practically robust, and can routinely be considered for the determination of insulin sensitivity from the IVGTT. Free software for estimating the SDM parameters is available.

Few attempts have been made to model mathematically the progression of type 2 diabetes. A realistic representation of the long-term physiological adaptation to developing insulin resistance is necessary for effectively designing clinical trials and evaluating diabetes prevention or disease modification therapies. Writing a good model for diabetes progression is difficult because the long time span of the disease makes experimental verification of modeling hypotheses extremely awkward. In this context, it is of primary importance that the assumptions underlying the model equations properly reflect established physiology and that the mathematical formulation of the model give rise only to physically plausible behavior of the solutions. In the present work, a model of the pancreatic islet compensation is formulated, its physiological assumptions are presented, some fundamental qualitative characteristics of its solutions are established, the numerical values assigned to its parameters are extensively discussed (also with reference to available cross-sectional epidemiologic data), and its performance over the span of a lifetime is simulated under various conditions, including worsening insulin resistance and primary replication defects. The differences with respect to two previously proposed models of diabetes progression are highlighted, and therefore, the model is proposed as a realistic, robust description of the evolution of the compensation of the glucose-insulin system in healthy and diabetic individuals. Model simulations can be run from the authors' web page.

High levels of indoor NO2 are associated with increased asthma symptoms and decreased expiratory peak flows in children. We investigated the association of exposure to domestic indoor NO2, objectively measured in winter and spring, with respiratory symptoms and lung function in a sample of adolescents from a southern Mediterranean area.From a large school population sample (n=2150) participating in an epidemiological survey in the urban area of the City of Palermo (southern Italy), a sub-sample of 303 adolescents was selected which furnished an enriched sample for cases of current asthma. All subjects were evaluated by a health questionnaire, skin prick tests and spirometry. One-week indoor NO2 monitoring of their homes was performed by diffusive sampling during spring and again during winter.We found that about 25% of subjects were exposed to indoor NO2 levels higher than the 40µg/m(3) World Health Organization limit, during both spring and winter. Moreover, subjects exposed to the highest indoor NO2 concentrations had increased frequency of current asthma (p=0.005), wheeze episodes in the last 12 months (p<0.001), chronic phlegm (p=0.013), and rhinoconjunctivitis (p=0.008). Finally, subjects with a personal history of wheeze ever had poorer respiratory function (FEF25-75%, p=0.01) when exposed to higher indoor NO2 concentrations.Home exposure to high indoor NO2 levels frequently occurs in adolescents living in a southern Mediterranean urban area and is significantly associated with the risks for increased frequency of both respiratory symptoms and reduced lung function.

The aim of this article is to show the good performance obtained by the state observer applied to a delay differential equations (DDE) model of the glucose-insulin system recently used in the artificial pancreas (AP) framework. Validation is carried out by real clinical measurements available from 20 healthy subjects who underwent an intravenous glucose tolerance test (IVGTT). The results show that the observer behavior is robust with respect to the initial conditions, which have been set according to a pair of very critical cases of under- and overestimation. Also, the robustness of the observer with respect to some model parameters, such as the delay in the pancreatic insulin production, is discussed.

PURPOSE The aim of the study was to investigate the role of squamous cell carcinoma antigen (SCC) in the management of patients with locally advanced cervical cancer treated by neoadjuvant chemotherapy and radical surgery. PATIENTS AND METHODS SCC assay was performed with a radioimmunoassay kit in a series of 102 patients with locally advanced cervical cancer. The values of 2.5, 5, and 7 ng/mL were used to define SCC antigen positivity. The chi 2 and Fisher's exact test and the stepwise logistic regression were used to evaluate the distribution of marker values. Analysis of survival was performed using the Kaplan and Meier test and Cox multivariate regression analysis. RESULTS SCC levels were elevated in 65%, 45%, and 32% of patients with primary tumors for cutoff values of 2.5, 5, and 7 ng/mL, respectively. SCC pretreatment levels correlated with stage, tumor volume and lymph node status. In the multivariate analysis, SCC expression proved to be an independent predictor of response to neoadjuvant chemotherapy. SCC posttreatment levels were strongly related to chemotherapy response. Moreover, the overall correlation between the clinical course of the disease and the variation of SCC levels was 83%. In patients with squamous cell tumors, survival was significantly longer in SCC-negative cases compared with SCC-positive cases (P = .04). Moreover, in patients undergoing surgery after response to neoadjuvant chemotherapy, low SCC values were associated with better prognosis (P = .02). In the multivariate analysis, parametrial involvement and SCC status proved to retain an independent prognostic value. CONCLUSION Our data show that SCC assay may provide useful information to improve the prognostic characterization and disease monitoring of patients with locally advanced cervical cancer undergoing neoadjuvant chemotherapy.

The problem of tracking a desired plasma glucose evolution is considered, for cases of basal hyperglycemia. A time-delay model is used to describe the glucose–insulin regulatory system, aiming to detail the endogenous pancreatic insulin release, which is not negligible in Type 2 diabetic patients. Insulin is assumed to be administered by means of intra-venous infusions. Only measurements of glycemia are considered: to this aim a nonlinear observer for time-delay systems is used to estimate the plasma insulin concentration. In the spirit of the separation theorem, a nonlinear control law is proposed, based on the exact input/output feedback linearization, which makes use of the observer estimates instead of the full state measurements. The local convergence of the tracking error to zero is theoretically proved. Simulations are performed in a virtual environment, taking into account the standard technology concerning blood glucose sensors and insulin delivery devices. Numerical results show the robustness of the proposed approach with respect to the uncertainties of the model parameters, as well as to the glucose measurement errors and insulin pump malfunctioning.

Background Positive end-expiratory pressure (PEEP) benefits in acute respiratory distress syndrome are driven by lung dynamic strain reduction. This depends on the variable extent of alveolar recruitment. The recruitment-to-inflation ratio estimates recruitability across a 10–cm H2O PEEP range through a simplified maneuver. Whether recruitability is uniform or not across this range is unknown. The hypotheses of this study are that the recruitment-to-inflation ratio represents an accurate estimate of PEEP-induced changes in dynamic strain, but may show nonuniform behavior across the conventionally tested PEEP range (15 to 5 cm H2O). Methods Twenty patients with moderate-to-severe COVID-19 acute respiratory distress syndrome underwent a decremental PEEP trial (PEEP 15 to 13 to 10 to 8 to 5 cm H2O). Respiratory mechanics and end-expiratory lung volume by nitrogen dilution were measured the end of each step. Gas exchange, recruited volume, recruitment-to-inflation ratio, and changes in dynamic, static, and total strain were computed between 15 and 5 cm H2O (global recruitment-to-inflation ratio) and within narrower PEEP ranges (granular recruitment-to-inflation ratio). Results Between 15 and 5 cm H2O, median [interquartile range] global recruitment-to-inflation ratio was 1.27 [0.40 to 1.69] and displayed a linear correlation with PEEP-induced dynamic strain reduction (r = –0.94; P &amp;lt; 0.001). Intraindividual recruitment-to-inflation ratio variability within the narrower ranges was high (85% [70 to 109]). The relationship between granular recruitment-to-inflation ratio and PEEP was mathematically described by a nonlinear, quadratic equation (R2 = 0.96). Granular recruitment-to-inflation ratio across the narrower PEEP ranges itself had a linear correlation with PEEP-induced reduction in dynamic strain (r = –0.89; P &amp;lt; 0.001). Conclusions Both global and granular recruitment-to-inflation ratio accurately estimate PEEP-induced changes in lung dynamic strain. However, the effect of 10 cm H2O of PEEP on lung strain may be nonuniform. Granular recruitment-to-inflation ratio assessment within narrower PEEP ranges guided by end-expiratory lung volume measurement may aid more precise PEEP selection, especially when the recruitment-to-inflation ratio obtained with the simplified maneuver between PEEP 15 and 5 cm H2O yields intermediate values that are difficult to interpret for a proper choice between a high and low PEEP strategy. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

The Intra Venous Glucose Tolerance Test (IVGTT) is a simple and established experimental procedure in which a challenge bolus of glucose is administered intra-venously and plasma glucose and insulin concentrations are then frequently sampled. The modeling of the measured concentrations has the goal of providing information on the state of the subject's glucose/insulin control system: an open problem is to construct a model representing simultaneously the entire control system with a physiologically believable qualitative behavior. A previously published single-distributed-delay differential model was shown to have desirable properties (positivity, boundedness, global stability of solutions) under the hypothesis of a specific, square-wave delay integral kernel. The present work extends the previous results to a family of models incorporating a generic non- negative, square integrable normalized kernel. Every model in this family describes the rate of glucose concentration variation as due to both insulin-dependent and insulin-independent net glucose tissue uptake, as well as to constant liver glucose production. The rate of variation of plasma insulin concentration depends on insulin catabolism and on pancreatic insulin secretion. Pancreatic insulin secretion at time $t$ is assumed to depend on the earlier effects of glucose concentrations, up to time $t$ (distributed delay). We consider a non-negative, square integrable normalized weight function $\omega$ on $R^+ =[0, \infty)$ as the fraction of maximal pancreatic insulin secretion at a given glucose concentration. No change in local asymptotic stability is introduced by the time delay. Considering an appropriate Lyapunov functional, it is found that the system is globally asymptotically stable if the average time delay has a parameter- dependent upper bound. An example of good model fit to experimental data is shown using a specific delay kernel.

Background: Botulinum toxin is a powerful, long‐acting inhibitor of muscular contractions in both voluntary and smooth muscle. It acts by blocking the release of the neurotransmitter acetylcholine. In the stomach, propulsive contractions of the antrum are necessary for the gastric contents to pass into the duodenum. Aims: To investigate whether intramuscular injections of botulinum toxin type A into the gastric antrum of rats would cause a reduction in food intake and hence body weight, by inhibition of gastric emptying. Materials and methods: This was a prospective, randomized, 3‐way parallel group study in rats. The first group was anaesthetized, laparotomized and given 20 U of botulinum toxin type A by intramuscular injection into the gastric antrum (botulinum toxin type A group, n =14). The second group was anaesthetized, laparotomized and injected with saline (sham group, n =14) and the third group did not have any intervention (control group, n =5). Food intake was measured daily for 7 weeks and body weight was measured daily for 10 weeks. Results: There was a significant difference in loss of body weight between the two treated groups (14.0 ± 8.2% botulinum toxin type A group, 4.4 ± 2.7% sham group; P &lt; 0.001). Further, the time to reach the weight nadir was significantly longer in the botulinum toxin type A group (8.7 ± 3.9 days) compared with the sham group (5.3 ± 3.8 days; P &lt; 0.04). There were no significant differences between the sham and control groups for any of the body weight parameters. The minimum dietary intake was significantly lower in the botulinum toxin type A group than in the sham group (37.8 ± 21.8% of the basal value in the botulinum toxin type A group, vs. 65.5 ± 32.0 in the sham group, P &lt; 0.05). In addition, the time to reach the nadir was significantly prolonged (8.2 ± 3.5 days, botulinum toxin type A group vs. 4.9 ± 1.7 days, sham group, P &lt; 0.001). Conclusions: The parallel reduction of body weight and food intake in botulinum toxin type A treated animals is consistent with a long lasting inhibition of the antral pump. This is probably due to slowed gastric emptying leading to early satiety. Patients with morbid obesity might benefit from endoscopic injections of botulinum toxin type A into the stomach wall.

Terlipressin has been suggested as the ideal drug to treat anesthesia-induced hypotension in patients under long-term renin-angiotensin system inhibitor treatment for arterial hypertension. The authors compared the effects of terlipressin and norepinephrine on systemic hemodynamic parameters and gastric mucosal perfusion using a laser Doppler flowmetry technique in patients treated with renin-angiotensin system inhibitors who experienced hypotension at induction of anesthesia.Thirty-two patients scheduled for carotid endarterectomy under general anesthesia and treated with renin-angiotensin system inhibitors had hypotension after induction of general anesthesia. They were randomized to receive 1 mg of terlipressin (n = 16) or norepinephrine infusion (n = 16) to counteract anesthesia-induced hypotension. A laser Doppler probe was introduced into the gastric lumen. All measurements were performed just before surgery, during hypotension, at 30 min, and at 4 h.Terlipressin produced an increase in mean arterial pressure and a decrease in gastric mucosal perfusion detected by laser Doppler flowmetry (P < 0.05) over 30 min that were sustained for 4 h. During the infusion, norepinephrine produced an increase in mean arterial pressure and in gastric mucosal perfusion detected by laser Doppler flowmetry (P < 0.05). If compared to norepinephrine, terlipressin reduced oxygen delivery and oxygen consumption (P < 0.05) and increased arterial lactate concentrations (P < 0.05).This study showed the efficacy of terlipressin in the treatment of hypotension episodes in anesthetized patients chronically treated with renin-angiotensin system inhibitors, angiotensin converting-enzyme inhibitors, and angiotensin II receptor antagonists. However, the negative effects on gastric mucosal perfusion and the risk of iatrogenic oxygen supply dependency of terlipressin need to be taken into account.

Background Abnormally low plasma levels of coenzyme Q10 (CoQ10) have been found in patients with cancer of the breast, lung, or pancreas. Objective A prospective study of patients with melanoma was conducted to assess the usefulness of CoQ10 plasma levels in predicting the risk of metastasis and the duration of the metastasis-free interval. Methods Between January 1997 and August 2004, plasma CoQ10 levels were measured with high-performance liquid chromatography in 117 consecutive melanoma patients without clinical or instrumental evidence of metastasis according to American Joint Committee on Cancer criteria and in 125 matched volunteers without clinically suspect pigmented lesions. Patients taking CoQ10 or cholesterol-lowering medications and those with a diagnosis of diabetes mellitus were excluded from the study. Multiple statistical methods were used to evaluate differences between patients and control subjects and between patients who did (32.5%) and did not (67.5%) develop metastases during follow-up. Results CoQ10 levels were significantly lower in patients than in control subjects (t test: P < .0001) and in patients who developed metastases than in the metastasis-free subgroup (t test: P < .0001). Logistic regression analysis indicated that plasma CoQ10 levels were a significant predictor of metastasis (P = .0013). The odds ratio for metastatic disease in patients with CoQ10 levels that were less than 0.6 mg/L (the low-end value of the range measured in a normal population) was 7.9, and the metastasis-free interval was almost double in patients with CoQ10 levels 0.6 mg/L or higher (Kaplan-Meier analysis: P < .001). Limitations A study with a larger sample, which is currently being recruited, and a longer follow-up will doubtlessly increase the statistical power and enable survival statistics to be obtained. Conclusions Analysis of our findings suggests that baseline plasma CoQ10 levels are a powerful and independent prognostic factor that can be used to estimate the risk for melanoma progression. Abnormally low plasma levels of coenzyme Q10 (CoQ10) have been found in patients with cancer of the breast, lung, or pancreas. A prospective study of patients with melanoma was conducted to assess the usefulness of CoQ10 plasma levels in predicting the risk of metastasis and the duration of the metastasis-free interval. Between January 1997 and August 2004, plasma CoQ10 levels were measured with high-performance liquid chromatography in 117 consecutive melanoma patients without clinical or instrumental evidence of metastasis according to American Joint Committee on Cancer criteria and in 125 matched volunteers without clinically suspect pigmented lesions. Patients taking CoQ10 or cholesterol-lowering medications and those with a diagnosis of diabetes mellitus were excluded from the study. Multiple statistical methods were used to evaluate differences between patients and control subjects and between patients who did (32.5%) and did not (67.5%) develop metastases during follow-up. CoQ10 levels were significantly lower in patients than in control subjects (t test: P < .0001) and in patients who developed metastases than in the metastasis-free subgroup (t test: P < .0001). Logistic regression analysis indicated that plasma CoQ10 levels were a significant predictor of metastasis (P = .0013). The odds ratio for metastatic disease in patients with CoQ10 levels that were less than 0.6 mg/L (the low-end value of the range measured in a normal population) was 7.9, and the metastasis-free interval was almost double in patients with CoQ10 levels 0.6 mg/L or higher (Kaplan-Meier analysis: P < .001). A study with a larger sample, which is currently being recruited, and a longer follow-up will doubtlessly increase the statistical power and enable survival statistics to be obtained. Analysis of our findings suggests that baseline plasma CoQ10 levels are a powerful and independent prognostic factor that can be used to estimate the risk for melanoma progression.

The purpose was to compare the dosimetric results observed in 201 breast cancer patients submitted to tangential forward intensity‐modulated radiation therapy (IMRT) with those observed in 131 patients treated with a standard wedged 3D technique for postoperative treatment of whole breast, according to breast size and supraclavicular node irradiation. Following dosimetric parameters were used for the comparison: and for the irradiated volume; and for the ipsilateral lung; and for the heart. Stratification was made according to breast size and supraclavicular (SCV) nodal irradiation. As respect to irradiated volume, a significant reduction of (mean values: versus ) and (mean % values: versus ), and an increase of (mean % values: versus ) were observed with forward IMRT. The homogeneity of dose distribution to target volume significantly improved with forward IMRT in all patient groups, irrespective of breast size or supraclavicular nodal irradiation. When patients treated with supraclavicular nodal irradiation were excluded from the analysis, forward IMRT slightly reduced (mean values: versus ) and (mean values versus ) of the ipsilateral lung. The dose to the heart tended to be lower with IMRT but this difference was not statistically significant. Tangential forward IMRT in postoperative treatment of whole breast improved dosimetric parameters in terms of homogeneity of dose distribution to the target in a large sample of patients, independent of breast size or supraclavicular nodal irradiation. Lung irradiation was slightly reduced in patients not undergoing to supraclavicular irradiation. PACS numbers: 87.53.Kn; 87.55.de

Little information is available in the literature on the effect of L-carnitine to improve glucose disposal in healthy control subjects and type 2 diabetic patients. No data are reported on the pharmacological properties of acetyl-L-carnitine (ALC) in type 2 diabetes mellitus. The present study evaluates glucose uptake and oxidation rates with either ALC or placebo administration in 18 type 2 diabetic patients. On different days, each patient received both a primed-constant infusion of ALC (5 mg/kg body weight [BW] priming bolus and either 0.025, 0.1, or 1.0 mg/kg BW/min constant infusion) and a comparable placebo formulation. During the infusion period, continuous indirect calorimetric monitoring and a euglycemic-hyperinsulinemic clamp (EHC) study were performed. The total end-clamp glucose tissue uptake (M value) was significantly increased by the administration of ALC (from 3.8 to 5.2 mg/kg/min, P = .006), and the dose dependence of this effect reached borderline statistical significance (P = .037). The increase in the M/I ratio was also highly significant after ALC administration (from 3.9 to 5.8 x 10(-2) mg/kg/min/(microUI/mL, P < .001), while no statistically significant effect was attributable to the different dosages. The increase in the M value was related to increased glucose storage (highly significant effect of ALC) rather than increased glucose oxidation (no statistical significance). In conclusion, the effect of ALC on glucose disposal has no relationship to the amount administered. This could be due to an effect of ALC on the enzymes involved in both the glycolytic and gluconeogenetic pathways, and a possible reversibility of glycogen synthase inhibition in diabetic subjects.

The Minimal Model, (MM), used to assess insulin sensitivity (IS) from Intra-Venous Glucose-Tolerance Test (IVGTT) data, suffers from frequent lack of identifiability (parameter estimates with Coefficients of Variation (CV) less than 52%). The recently proposed Single Delay Model (SDM) is evaluated as a practical alternative. The SDM was applied to 74 IVGTTs from lean (19), overweight (22), obese (22) and morbidly obese (11) subjects. Estimates from the SDM (KxgI) were compared with the corresponding MM (SI), 1/HOMA-IR index and Euglycemic-Hyperinsulinemic Clamp (M-EHC over 7 subjects) estimates. KxgI was identifiable in 73 out of 74 subjects (CV = 69% in the 74th subject) and ranged from 1.25 × 10-5 to 4.36 × 10-4min-1pM-1; SI CV was >52% in 36 subjects (up to 2.36 × 109%) and presented 18 extreme values (≤ 1.5 × 10-12 or ≥ 3.99). KxgI correlated well with 1/HOMA-IR (r = 0.56, P < 0.001), whereas the correlations KxgI-SI and 1/HOMA-IR-SI were high (r = 0.864 and 0.52 respectively) and significant (P < 0.001 in both cases) only in the non-extreme SI sub-sample (56 subjects). Correlations KxgI vs. M-EHC and SI vs. M-EHC were positive (r = 0.92, P = 0.004 and r = 0.83, P = 0.02 respectively). KxgI decreased for higher BMI's (P < 0.001), SI significantly so only over the non-extreme-SI sub-sample. The Acute Insulin Response Index was also computed and the expected inverse (hyperbolic) relationship with the KxgI observed. Precise estimation of insulin sensitivity over a wide range of BMI, stability of all other model parameters, closer adherence to accepted physiology make the SDM a useful alternative tool for the evaluation of insulin sensitivity from the IVGTT.

Diabetes mellitus has become a prevalent disease in the world. Diagnostic protocol for the onset of diabetes mellitus is the initial step in the treatments. The intravenous glucose tolerance test (IVGTT) has been considered as the most accurate method to determine the insulin sensitivity and glucose effectiveness. It is well known that there exists a time delay in insulin secretion stimulated by the elevated glucose concentration level. However, the range of the length of the delay in the existing IVGTT models are not fully discussed and thus in many cases the time delay may be assigned to a value out of its reasonable range. In addition, several attempts had been made to determine when the unique equilibrium point is globally asymptotically stable. However, all these conditions are delay-independent. In this paper, we discuss the range of the time delay and provide easy-to-check delay-dependent conditions for the global asymptotic stability of the equilibrium point for a recent IVGTT model through Liapunov function approach. Estimates of the upper bound of the delay for global stability are given in corollaries. In addition, the numerical simulation in this paper is fully incorporated with functional initial conditions, which is natural and more appropriate in delay differential equation systems.

Closed-loop devices delivering medical treatments in an automatic fashion clearly require a thorough preliminary phase according to which the proposed control law is tested and validated as realistically as possible, before arranging in vivo experiments in a clinical setting. The present note develops a virtual environment aiming to validate a recently proposed model-based glucose control law on a solid simulation framework. From a theoretical viewpoint, the artificial pancreas has been designed by suitably exploiting a minimal set of delay differential equations modeling the glucose–insulin regulatory system; on the other hand, the validation platform makes use of a different, multi-compartmental model to build up a population of virtual patients. Simulations are carried out by properly addressing the available technological limits and the unavoidable uncertainties in real-time continuous glucose sensors as well as possible malfunctioning on the insulin delivery devices. The results show the robustness of the proposed control law that turns out to be efficient and extremely safe on a heterogenous population of virtual patients.

In order to provide a method for precise identification of insulin sensitivity from clinical Oral Glucose Tolerance Test (OGTT) observations, a relatively simple mathematical model (Simple Interdependent glucose/insulin MOdel SIMO) for the OGTT, which coherently incorporates commonly accepted physiological assumptions (incretin effect and saturating glucose-driven insulin secretion) has been developed. OGTT data from 78 patients in five different glucose tolerance groups were analyzed: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), IFG+IGT, and Type 2 Diabetes Mellitus (T2DM). A comparison with the 2011 Salinari (COntinuos GI tract MOdel, COMO) and the 2002 Dalla Man (Dalla Man MOdel, DMMO) models was made with particular attention to insulin sensitivity indices ISCOMO, ISDMMO and kxgi (the insulin sensitivity index for SIMO). ANOVA on kxgi values across groups resulted significant overall (P<0.001), and post-hoc comparisons highlighted the presence of three different groups: NGT (8.62×10−5±9.36×10−5 min−1pM−1), IFG (5.30×10−5±5.18×10−5) and combined IGT, IFG+IGT and T2DM (2.09×10−5±1.95×10−5, 2.38×10−5±2.28×10−5 and 2.38×10−5±2.09×10−5 respectively). No significance was obtained when comparing ISCOMO or ISDMMO across groups. Moreover, kxgi presented the lowest sample average coefficient of variation over the five groups (25.43%), with average CVs for ISCOMO and ISDMMO of 70.32% and 57.75% respectively; kxgi also presented the strongest correlations with all considered empirical measures of insulin sensitivity. While COMO and DMMO appear over-parameterized for fitting single-subject clinical OGTT data, SIMO provides a robust, precise, physiologically plausible estimate of insulin sensitivity, with which habitual empirical insulin sensitivity indices correlate well. The kxgi index, reflecting insulin secretion dependency on glycemia, also significantly differentiates clinically diverse subject groups. The SIMO model may therefore be of value for the quantification of glucose homeostasis from clinical OGTT data.

Several models of Gastric Emptying (GE) have been employed in the past to represent the rate of delivery of stomach contents to the duodenum and jejunum. These models have all used a deterministic form (algebraic equations or ordinary differential equations), considering GE as a continuous, smooth process in time. However, GE is known to occur as a sequence of spurts, irregular both in size and in timing. Hence, we formulate a simple stochastic process model, able to represent the irregular decrements of gastric contents after a meal. The model is calibrated on existing literature data and provides consistent predictions of the observed variability in the emptying trajectories. This approach may be useful in metabolic modeling, since it describes well and explains the apparently heterogeneous GE experimental results in situations where common gastric mechanics across subjects would be expected.

In this paper we deal with the problem of tracking a desired plasma glucose concentration by means of intra-venous insulin administration, for Type 2 diabetic patients exhibiting basal hyperglycemia.A nonlinear time-delay model is used to describe the glucose-insulin regulatory system, according to which a model-based approach is exploited to design a semiglobal sampled-data dynamic output feedback controller.It is shown that emulation, by Euler approximation, of a proposed continuous-time control law yields stabilization in the sampleand-hold sense to the closed-loop system.The glucose regulator makes use of only sampled glucose measurements.Theoretical results are validated through a virtual environment broadly accepted as a substitute to animal trials for the preclinical testing of control strategies in plasma glucose regulation.Numerical results are encouraging and pave the way to further clinical verifications.

In this paper, we study the nonexistence of global solutions for certain classes of nonlinear fractional differential inequalities involving weighted fractional derivatives and a singular potential function. Namely, using the test function method with a judicious choice of the test function, we obtain sufficient criteria depending on the parameters of the considered problems, under which we have absence of global solutions. Next, some special cases of the potential function are discussed.

When a subject is at rest and meals have not been eaten for a relatively long time (e.g. during the night), presumably near-constant, zero-order glucose production occurs in the liver. Glucose elimination from the bloodstream may be proportional to glycemia, with an apparently first-order, linear elimination rate. Besides glycemia itself, unobserved factors (insulinemia, other hormones) may exert second and higher order effects. Random events (sleep pattern variations, hormonal cycles) may also affect glycemia. The time-course of transcutaneously, continuously measured glycemia (CGM) thus reflects the superposition of different orders of control, together with random system error. The problem may be formalized as a fractional random walk, or fractional Brownian motion. In the present work, the order of this fractional stochastic process is estimated on night-time CGM data from one subject.

Several hypotheses have been proposed to explain the nutritional deficiencies seen in Crohn disease patients, including inadequate food intake, decreased assimilation and increased loss of nutrients, and increased energy expenditure. To assess the effect of steroid therapy on body composition, energy expenditure, and fuel selection in Crohn disease, we compared 12 patients (6 men and 6 women) with biopsy-proven ileal Crohn disease with 11 healthy volunteers (6 men and 5 women). Five patients [Crohn's disease activity index (CDAI) = 98.4 +/- 3.78] took no medication and seven patients (CDAI = 283.9 +/- 22.5) were administered 29 +/- 18 mg prednisone/d. Body composition was evaluated by isotopic dilution and bioelectrical impedance analysis, and 24-h energy expenditure and basal metabolic rate were measured in a respiratory chamber. Fat-free mass was not significantly different among groups, whereas fat mass was lower in patients than in control subjects. Energy intake was higher in treated patients than in both untreated patients (P = 0.004) and control subjects (P = 0.005). Fecal losses were not significantly different between untreated patients and control subjects, but were higher (and proportional to the CDAI) in treated patients than in control subjects (P = 0.001). Metabolizable energy was not significantly different among groups, whereas energy balance was significantly higher in treated patients than in both control subjects (P = 0.0057) and untreated patients (P = 0.018). Nitrogen balance was mildly negative in treated patients compared with both control subjects and untreated patients, but not significantly so. In conclusion, prednisone treatment in Crohn disease patients stimulates food intake, promoting an overall positive energy balance despite large fecal nutrient losses.

To better understand the long-term weight stability of postobese patients who underwent biliopancreatic diversion (BPD), we studied 24-h energy and nutrient balance in eight women at least 3 yr after surgery (PO) and compared the results to those obtained in eight normal never-obese control women (C), matched by age and weight. Body composition was measured by dual-energy x-ray absorptiometry (DXA). All the patients were on an ad libitum diet; 24-h energy and nutrient intake were measured on the experimental day. Twenty-four-hour energy expenditure (EE) and 24-h nutrient oxidation rates were measured in a respiratory chamber, and energy and nutrient balances were calculated after correcting for 24-h fecal nutrient loss. No differences in body composition were found between PO and C. PO had a higher gross energy intake than C (10.6 ± 3.4 vs. 8.0 ± 2.2 MJ/d; p < 0.05); however, due to the higher energy fecal loss in PO as compared to C (2.4 ± 1.3 vs. 0.09 ± 0.01 MJ/day; p < 0.01), 24-h metabolizable energy intake (MEI) was not different in the two groups. The energy fecal loss in the PO patients was mostly in the form of lipid. EE at 24 h was not different in PO as compared to C. Therefore energy balance, computed as the difference between 24-h MEI and 24-h EE, was similar in the two groups. Respiratory quotient was significantly higher in PO than in C (1.00 ± 0.08 vs. 0.83 ± 0.03; p < 0.01). Carbohydrate (−135 ± 37 g/d in PO vs. 63 ± 23 g/d in C; p < 0.001), and lipid (48 ± 14 g/d in PO vs. −23 ± 6 g/d in C; p < 0.001) balances were different in the two groups. We conclude that chronic lipid malabsorption was the main metabolic abnormality explaining the achievement of energy balance in postobese subjects after biliopancreatic diversion. A chronic reduction of lipid absorption seems to play a key role in the long-term weight stability of this group of postobese subjects.

A novel supervised neural network-based algorithm is designed to reliably distinguish in electrocardiographic (ECG) records between normal and ischemic beats of the same patient. The basic idea behind this paper is to consider an ECG digital recording of two consecutive R-wave segments (RRR interval) as a noisy sample of an underlying function to be approximated by a fixed number of Radial Basis Functions (RBF). The linear expansion coefficients of the RRR interval represent the input signal of a feed-forward neural network which classifies a single beat as normal or ischemic. The system has been evaluated using several patient records taken from the European ST-T database. Experimental results show that the proposed beat classifier is very reliable, and that it may be a useful practical tool for the automatic detection of ischemic episodes.

This note investigates the problem of plasma glucose regulation by means of subcutaneous insulin administration. A discrete delay differential equation model of the glucose-insulin regulatory system has been considered, which properly takes into account also the pancreatic insulin release, in such a way to allow insulin therapies for both Type I and Type II diabetes (in this latter case the endogenous insulin delivery is not negligible). The method of exact input/output feedback linearization and stabilization is used, in order to ensure the local convergence of the tracking error to zero. Simulations are performed in a virtual environment, and numerical results show the effectiveness of the proposed approach.

The main aim of this research was to test if fractional-order differential equation models could give better fits than integer-order models to continuous glucose monitoring (CGM) data from subjects with type 1 diabetes. In this research, real continuous glucose monitoring (CGM) data was analyzed by three mathematical models, namely, a deterministic first-order differential equation model, a stochastic first-order differential equation model with Brownian motion, and a deterministic fractional-order model. CGM data was analyzed to find optimal values of parameters by using ordinary least squares fitting or maximum likelihood estimation using a kernel-density approximation. Matlab and R programs have been developed for each model to find optimal values of the parameters to fit observed data and to test the usefulness of each model. The fractional-order model giving the best fit has been estimated for each subject. Although our results show that fractional-order models can give better fits to the data than integer-order models in some cases, it is clear that the models need further improvement before they can give satisfactory fits.

As only 1% of clinically eligible subjects choose to undergo surgical treatment for obesity, other options should be investigated. This study aimed to assess the effects of intensive lifestyle modification (ILM) with or without 3-mg liraglutide daily vs. sleeve gastrectomy (SG) on BMI after 1 year. In this study performed at an Italian university hospital, non-diabetic patients eligible for bariatric surgery were recruited from a weight-loss clinic and had the option to choose from three possible weight-loss programmes up to an allocation of 25 subjects in each arm matched by BMI and age. ILM consisted in 813 kcal of a very low-calorie diet (VLCD) for 1 month, followed by a diet of 12 kcal/kg body weight of high protein and high fat for 11 months plus 30 min of brisk walking daily and at least 3 h of aerobic exercise weekly. SG patients followed a VLCD for 1 month and a free diet thereafter. Patients were evaluated at baseline and at 1, 3, 6, 9 and 12 months. A total of 75 patients were enrolled; retention was 100% in the SG and 85% in the two medical arms. SG reduced BMI by 32% (P < 0.001 vs. medical arm), while ILM + liraglutide and ILM led to BMI reductions of 24% and 14%, respectively (P < 0.001). More women allocated themselves to the ILM + liraglutide group. Weight loss was 43 kg with SG, 26 kg with ILM + liraglutide and 15 kg with ILM alone. Lean body mass reductions were −11.6 kg with SG, −6.3 kg with ILM and −8.3 kg with ILM + liraglutide. Prevalence of prediabetes was significantly lower with ILM + liraglutide, and insulin resistance was reduced by about 70% by both ILM + liraglutide and SG vs. 39% by ILM alone. Cardiometabolic risk factors were greatly reduced in all three groups. At least in the short-term, liraglutide 3.0 mg once daily associated with drastic calorie-intake restriction and intensive physical activity promoted a 24% weight loss, which was almost two times greater than ILM alone and only about 25% less than with SG, while preserving lean body mass. Although this study was non-randomised, it was designed to explore the efficacy of medical treatments for obesity in everyday clinical practice.

American Journal of Medical GeneticsVolume 87, Issue 4 p. 366-368 Letter to the Editor Double-blind, placebo-controlled study of L-acetylcarnitine for the treatment of hyperactive behavior in fragile X syndrome M.G. Torrioli, Corresponding Author M.G. Torrioli mgtorrioli@pcg.it Cattedra di Neuropsichiatria Infantile, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalyCattedra di Neuropsichiatria Infantile, Policlinico A. Gemelli, Università Cattolica del S. Cuore, Largo A. Gemelli 8, 00168 Roma, ItalySearch for more papers by this authorS. Vernacotola, S. Vernacotola Cattedra di Neuropsichiatria Infantile, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalySearch for more papers by this authorP. Mariotti, P. Mariotti Cattedra di Neuropsichiatria Infantile, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalySearch for more papers by this authorE. Bianchi, E. Bianchi Cattedra di Neuropsichiatria Infantile, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalySearch for more papers by this authorM. Calvani, M. Calvani Sigma-tau S.p.A., Pomezia, ItalySearch for more papers by this authorA. De Gaetano, A. De Gaetano Centro di Fisiopatologia dello Shock, Consiglio Nazionale delle Ricerche, Roma, ItalySearch for more papers by this authorP. Chiurazzi, P. Chiurazzi Istituto di Genetica Medica, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalySearch for more papers by this authorG. Neri, G. Neri Istituto di Genetica Medica, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalySearch for more papers by this author M.G. Torrioli, Corresponding Author M.G. Torrioli mgtorrioli@pcg.it Cattedra di Neuropsichiatria Infantile, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalyCattedra di Neuropsichiatria Infantile, Policlinico A. Gemelli, Università Cattolica del S. Cuore, Largo A. Gemelli 8, 00168 Roma, ItalySearch for more papers by this authorS. Vernacotola, S. Vernacotola Cattedra di Neuropsichiatria Infantile, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalySearch for more papers by this authorP. Mariotti, P. Mariotti Cattedra di Neuropsichiatria Infantile, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalySearch for more papers by this authorE. Bianchi, E. Bianchi Cattedra di Neuropsichiatria Infantile, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalySearch for more papers by this authorM. Calvani, M. Calvani Sigma-tau S.p.A., Pomezia, ItalySearch for more papers by this authorA. De Gaetano, A. De Gaetano Centro di Fisiopatologia dello Shock, Consiglio Nazionale delle Ricerche, Roma, ItalySearch for more papers by this authorP. Chiurazzi, P. Chiurazzi Istituto di Genetica Medica, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalySearch for more papers by this authorG. Neri, G. Neri Istituto di Genetica Medica, Facoltà di Medicina “A. Gemelli”, Università Cattolica, Roma, ItalySearch for more papers by this author First published: 07 December 1999 https://doi.org/10.1002/(SICI)1096-8628(19991203)87:4<366::AID-AJMG18>3.0.CO;2-FCitations: 34AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume87, Issue43 December 1999Pages 366-368 RelatedInformation

The Euglycemic Hyperinsulinemic Clamp (EHC) is the most widely used experimental procedure for the determination of insulin sensitivity. In the present study, 16 subjects with BMI between 18.5 and 63.6 kg/m2 have been studied with a long-duration (5 hours) EHC. In order to explain the oscillations of glycemia occurring in response to the hyperinsulinization and to the continuous glucose infusion at varying speeds, we first hypothesized a system of ordinary differential equations (ODEs), with limited success. We then extended the model and represented the experiment using a system of stochastic differential equations (SDEs). The latter allow for distinction between (i) random variation imputable to observation error and (ii) system noise (intrinsic variability of the metabolic system), due to a variety of influences which change over time. The stochastic model of the EHC was fitted to data and the system noise was estimated by means of a (simulated) maximum likelihood procedure, for a series of different hypothetical measurement error values. We showed that, for the whole range of reasonable measurement error values: (i) the system noise estimates are non-negligible; and (ii) these estimates are robust to changes in the likely value of the measurement error. Explicit expression of system noise is physiologically relevant in this case, since glucose uptake rate is known to be affected by a host of additive influences, usually neglected when modeling metabolism. While in some of the studied subjects system noise appeared to only marginally affect the dynamics, in others the system appeared to be driven more by the erratic oscillations in tissue glucose transport rather than by the overall glucose-insulin control system. It is possible that the quantitative relevance of the unexpressed effects (system noise) should be considered in other physiological situations, represented so far only with deterministic models.

Stochastic leaky integrate-and-fire (LIF) neuronal models are common theoretical tools for studying properties of real neuronal systems. Experimental data of frequently sampled membrane potential measurements between spikes show that the assumption of constant parameter values is not realistic and that some (random) fluctuations are occurring. In this letter, we extend the stochastic LIF model, allowing a noise source determining slow fluctuations in the signal. This is achieved by adding a random variable to one of the parameters characterizing the neuronal input, considering each interspike interval (ISI) as an independent experimental unit with a different realization of this random variable. In this way, the variation of the neuronal input is split into fast (within-interval) and slow (between-intervals) components. A parameter estimation method is proposed, allowing the parameters to be estimated simultaneously over the entire data set. This increases the statistical power, and the average estimate over all ISIs will be improved in the sense of decreased variance of the estimator compared to previous approaches, where the estimation has been conducted on each individual ISI. The results obtained on real data show good agreement with classical regression methods.

The seminal publication of the Diabetes Prevention Program (DPP) results in 2002 has provided insight into the impact of major therapies on the development of diabetes over a time span of a few years. In the present work, the publicly available DPP data set is used to calibrate and evaluate a recently developed mechanistic mathematical model for the long-term development of diabetes to assess the model's ability to predict the natural history of disease progression and the effectiveness of preventive interventions. A general population is generated from which virtual subject samples corresponding to the DPP enrollment criteria are selected. The model is able to reproduce with good fidelity the observed time courses of both diabetes incidence and average glycemia, under realistic hypotheses on evolution of disease and efficacy of the studied therapies, for all treatment arms. Model-based simulations of the long-term evolution of the disease are consistent with the transient benefits observed with conventional therapies and with promising effects of radical improvement of insulin sensitivity (as by metabolic surgery) or of β-cell protection. The mechanistic diabetes progression model provides a credible tool by which long-term implications of antidiabetic interventions can be evaluated.

Obesity is characterized by decreased insulin-stimulated glucose uptake in muscle and shift from glucose to lipid oxidation, the so-called metabolic inflexibility. Biliopancreatic diversion (BPD), a mainly malabsorptive bariatric operation, determines a prompt improvement of insulin resistance, but the mechanisms are still unclear.We aimed to estimate the response of glucose transporter 4 (GLUT4) and hexokinase-II (HKII) gene expression to hyperinsulinemia before and after surgical treatment with a BPD or dietary-induced weight loss. The association with 24-hour energy expenditure and its different components-diet-induced thermogenesis (DIT), resting energy expenditure, physical activity (PA) of daily living, and physical exercise-was also determined. DESIGN, SETTING, AND MAIN OUTCOME MEASURES: Case-control study: 20 subjects, BPD vs diet-induced weight loss. Four subjects withdrew in the surgical arm and 1 subject withdrew in the dietary arm. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp. Energy expenditure was assessed by indirect calorimetry over 24 hours. Muscle biopsies were obtained during the clamp to measure gene expression: GLUT4 and HKII.Insulin sensitivity increased significantly (P < .01) only after BPD (0.101 ± 0.012 to 0.204 ± 0.033 μmol/kg/min/pM). Enhanced GLUT4 and HKII mRNA levels were observed after surgery (P < .0001 and P = .021, respectively), whereas they were not affected by diet-induced weight loss. Carbohydrate oxidation (P = .0027), DIT (P = .033), PA (P = .036), and energy expenditure during the exercise (P = .017) increased only in the BPD group.BPD improved impaired glucose metabolism and insulin resistance through increased glucose uptake, glycogen synthesis, and glucose oxidation. Furthermore, the concomitant increase in DIT, PA, and exercise in BPD patients may partly explain their ability to sustained long-term weight loss and may contribute to the improved insulin sensitivity.

In this work some advances in the theory of curvature of two-dimensional probability manifolds corresponding to families of distributions are proposed. It is proved that location-scale distributions are hyperbolic in the Information Geometry sense even when the generatrix is non-even or non-smooth. A novel formula is obtained for the computation of curvature in the case of exponential families: this formula implies some new flatness criteria in dimension 2. Finally, it is observed that many two parameter distributions, widely used in applications, are locally hyperbolic, which highlights the role of hyperbolic geometry in the study of commonly employed probability manifolds. These results have benefited from the use of explainable computational tools, which can substantially boost scientific productivity.

The use of mechanical ventilators is widespread within Intensive Care Units, both in patients with normal respiratory function (e.g., post-operative patients) and in subjects with pathologic conditions influencing ventilation mechanics.In particular heart failure, the decreased capacity of the heart to pump blood through the systemic and pulmonary circulation, is clinically known to adversely affect ventilation.Depending on gravity, different areas of the lungs receive different quotas of the pulmonary blood flow, and their alveoli are ventilated to different degrees: the ventilation/perfusion ratio (V/Q) captures this relationship and is normally higher at the apexes and lower at the bases of the lungs (normal distribution of the ratio).Maldistribution of V/Q occurs when these differences are accentuated, and leads to inefficient gas exchange and diminished arterial oxygen saturation.In this work, we introduce a mathematical model of mechanical ventilation and pulmonary blood perfusion, incorporating a representation of the lungs by vertically stacked functional layers.Numerical simulations readily show how progressive degrees of heart pump decompensation are associated with worsening distribution of the ventilation/perfusion ratio, even in the absence of other complicating factors, such as pulmonary edema.

Obesity and diabetes are a progressively more and more deleterious hallmark of modern, well fed societies. In order to study the potential impact of strategies designed to obviate the pathological consequences of detrimental lifestyles, a model for the development of Type 2 diabetes geared towards large population simulations would be useful. The present work introduces such a model, representing in simplified fashion the interplay between average glycemia, average insulinemia and functional beta-cell mass, and incorporating the effects of excess food intake or, conversely, of physical activity levels. Qualitative properties of the model are formally established and simulations are shown as examples of its use.

Pharmacokinetics of s.c. administered insulin preparations have been widely studied, mostly using descriptive measures such as AUC, time to peak, or the peak plasma concentration. Several compartmental modelling studies of single-bolus s.c. insulin pharmacokinetics have also appeared, with contrasting results regarding the feasibility of insulin pharmacokinetics modelling and the appropriate level of detail for such models. In this paper, we used compartmental models to study the pharmacokinetics of biphasic insulin aspart administered by multiple s.c. injections. The main objective was to assess the magnitude of the inter-and intra-subject variation in the kinetics.Analyses were performed on 24-h serum insulin concentrations measured in 20 type 1 diabetes subjects given three daily s.c. injections of biphasic insulin aspart.Preliminary analysis of the AUC:dose ratio showed that the apparent kinetics are not constant throughout the three daily injections of the compound. A simple and robust compartmental model was shown to be appropriate for interpreting the observations, provided that one of its parameters (the first-order rate constant for transfer from the s.c. depot to plasma) is allowed to vary between injections.Population estimates of the chosen model show that intra-subject variations between injections is of the same order of magnitude as inter-subject variation, partially explaining the difficulties encountered when individually tailoring intensified insulin therapy. We conclude that the explicit consideration of a rather simple kinetic model will allow better experimental designs in the future study of s.c. insulin preparations.

Recently P. Palumbo, S. Panunzi and A. De Gaetano analyzed a delay model of the glucose–insulin system. They proved its persistence, the existence of a unique positive equilibrium point, as well as the local stability of this point. In this paper we consider further the uniform persistence of such equilibrium solutions and their global stability. Using the omega limit set of a persistent solution and constructing a full time solution, we also investigate the effect of delays in connection with the behavior of oscillating solutions to the system. The model is shown to admit global stability under certain conditions of the parameters. It is also shown that the model admits slowly oscillating behavior, which demonstrates that the model is physiologically consistent and actually applicable to diabetological research.

The paper investigates the problem of tracking a desired plasma glucose evolution by means of intra-venous insulin administration.A modelbased approach is followed.A recent model of the glucose/insulin regulatory system which consists of discrete-delay nonlinear differential equations is used.A disturbance is added to the insulin kinetics in order to model uncertainties concerning both the insulin delivery rate and the mechanism actuating the insulin pump.A feedback control law which yields input-to-state stability of the closed loop error system with respect to the disturbance is provided.Such control law depends on the glucose and insulin measurements at the present and at a delayed time.In silico simulations validate the theoretical results.

Several models for the long-term development of T2DM already exist, focusing on the dynamics of the interaction between glycemia, insulinemia and β-cell mass. Current models consider representative (fasting or daily average) glycemia and insulinemia as characterizing the compensation state of the subject at some instant in slow time. This implies that only these representative levels can be followed through time and that the role of fast glycemic oscillations is neglected. An improved model (DPM15) for the long-term progression of T2DM is proposed, introducing separate peripheral and hepatic (liver and kidney) insulin actions. The DPM15 model no longer uses near-equilibrium approximation to separate fast and slow time scales, but rather describes, at each step in slow time, a complete day in the life of the virtual subject in fast time. The model can thus represent both fasting and postprandial glycemic levels and describe the effect of interventions acting on insulin-enhanced tissue glucose disposal or on insulin-inhibited hepatic glucose output, as well as on insulin secretion and β-cell replicating ability. The model can simulate long-term variations of commonly used clinical indices (HOMA-B, HOMA-IR, insulinogenic index) as well as of Oral Glucose Tolerance or Euglycemic Hyperinsulinemic Clamp test results. The model has been calibrated against observational data from the Diabetes Prevention Program study: it shows good adaptation to observations as a function of very plausible values of the parameters describing the effect of such interventions as Placebo, Intensive LifeStyle and Metformin administration.

We evaluated the metabolic response to a standard (75-g) oral-glucose-tolerance test (OGTT) in eight postobese women (PO) who underwent biliopancreatic diversion and in eight healthy control women (C). All subjects had been weight-stable for ≥ 2 y. Blood samples for glucose, insulin, C-peptide, and nonesterified free fatty acids were taken at baseline and during 180 min after the glucose load. Plasma glucose and insulin concentrations at baseline and during the OGTT were similar in the two groups, suggesting the absence of an insulin-resistant state in the PO. Continuous indirect calorimetry was performed throughout the test. Glucose-induced thermogenesis (GIT) was higher in PO than in C (8.6 ± 2.6 vs 4.3 ± 1.9%; P < 0.01). These data indicate that GIT and insulin-glucose metabolism are not impaired in postobese patients when a near ideal body weight is reached and maintained after weight loss; this suggests that thermogenic deficiencies and hyperinsulinemia-insulin resistance are alterations secondary to obesity.

Early surgical intervention remains the most successful therapy for melanoma. Despite better outcomes observed in soft tissue and lymph node metastases, the results of pharmacological therapies are still disappointing. Currently, there is no standard adjuvant therapy for melanoma. Low concentrations of coenzyme Q10 have been demonstrated in melanoma cell lines and in sera of melanoma patients. These data and the results of clinical trials of patients with other advanced cancers prompted this study of the long-term administration of an optimized dose of recombinant interferon α-2b and coenzyme Q10 to patients with stage I and II melanoma. A 3-year trial envisaging uninterrupted treatment with low-dose recombinant interferon α-2b (9 000 000 000 IU weekly) administered twice daily and coenzyme Q10 (400 mg/day) was conducted in patients with stage I and II melanoma (American Joint Committee on Cancer criteria 2002) and surgically removed lesions. Treatment efficacy was evaluated as incidence of recurrences at 5 years. All patients completed the treatment and the follow-up. Significantly different rates of disease progression were observed in the interferon+coenzyme Q10 and the interferon group for both stages. No patient withdrew from the study owing to side effects. Long-term administration of an optimized dose of recombinant interferon α-2b in combination with coenzyme Q10 seemed to induce significantly decreased rates of recurrence and had negligible adverse effects. A survival study could not be undertaken owing to the small patient sample and the short duration of follow-up.

Consensus exists that several bariatric surgery procedures produce a rapid improvement of glucose homeostasis in obese diabetic patients, improvement apparently uncorrelated with the degree of eventual weight loss after surgery. Several hypotheses have been suggested to account for these results: among these, the anti-incretin, the ghrelin and the lower-intestinal dumping hypotheses have been discussed in the literature. Since no clear-cut experimental results are so far available to confirm or disprove any of these hypotheses, in the present work a mathematical model of the glucose-insulin-incretin system has been built, capable of expressing these three postulated mechanisms. The model has been populated with critically evaluated parameter values from the literature, and simulations under the three scenarios have been compared.The modeling results seem to indicate that the suppression of ghrelin release is unlikely to determine major changes in short-term glucose control. The possible existence of an anti-incretin hormone would be supported if an experimental increase of GIP concentrations were evident post-surgery. Given that, on the contrary, collected evidence suggests that GIP concentrations decrease post-surgery, the lower-intestinal dumping hypothesis would seem to describe the mechanism most likely to produce the observed normalization of Type 2 Diabetes Mellitus (T2DM) after bariatric surgery.The proposed model can help discriminate among competing hypotheses in a context where definitive data are not available and mechanisms are still not clear.

The secretion of insulin by the pancreas has been the object of much attention over the past several decades. Insulin is known to be secreted by pancreatic β-cells in response to hyperglycemia: its blood concentrations however exhibit both high-frequency (period approx. 10 minutes) and low-frequency oscillations (period approx. 1.5 hours). Furthermore, characteristic insulin secretory response to challenge maneuvers have been described, such as frequency entrainment upon sinusoidal glycemic stimulation; substantial insulin peaks following minimal glucose administration; progressively strengthened insulin secretion response after repeated administration of the same amount of glucose; insulin and glucose characteristic curves after Intra-Venous administration of glucose boli in healthy and pre-diabetic subjects as well as in Type 2 Diabetes Mellitus. Previous modeling of β-cell physiology has been mainly directed to the intracellular chain of events giving rise to single-cell or cell-cluster hormone release oscillations, but the large size, long period and complex morphology of the diverse responses to whole-body glucose stimuli has not yet been coherently explained. Starting with the seminal work of Grodsky it was hypothesized that the population of pancreatic β-cells, possibly functionally aggregated in islets of Langerhans, could be viewed as a set of independent, similar, but not identical controllers (firing units) with distributed functional parameters. The present work shows how a single model based on a population of independent islet controllers can reproduce very closely a diverse array of actually observed experimental results, with the same set of working parameters. The model’s success in reproducing a diverse array of experiments implies that, in order to understand the macroscopic behaviour of the endocrine pancreas in regulating glycemia, there is no need to hypothesize intrapancreatic pacemakers, influences between different islets of Langerhans, glycolitic-induced oscillations or β-cell sensitivity to the rate of change of glycemia.

In 1978, Thomas J. Sorensen defended a thesis in chemical engineering at the University of California, Berkeley, where he proposed an extensive model of glucose-insulin control, model which was thereafter widely employed for virtual patient simulation. The original model, and even more so its subsequent implementations by other Authors, presented however a few imprecisions in reporting the correct model equations and parameter values. The goal of the present work is to revise the original Sorensen’s model, to clearly summarize its defining equations, to supplement it with a missing gastrio-intestinal glucose absorption and to make an implementation of the revised model available on-line to the scientific community.

It is a common understanding that fat-free mass (FFM) increases with body weight. However, limited information is available as to the relationship between weight increase and changes in body composition. We performed the present study to determine quantitatively the relationship between body composition, total body weight, age, and sex. Body composition data were obtained by isotopic dilution on 273 subjects ranging in body mass index (BMI) from about 13 to 70 kg/m(2). Adipose free tissue (AFT) was modeled as a nonlinear, increase-limited function of body weight. Model parameters were evaluated as functions of sex, age, and height. The relationship between AFT and body weight was very well approximated by means of the nonlinear model (R(2) =.95), with maximal AFT being determined by both sex and height and with AFT growth rate determined only by sex. AFT clearly shows a nonlinear behavior, tending to increase less and less with progressively increasing body weight. With the proposed model, an asymptotic maximal AFT may be postulated. The organism seems to have an intrinsic limitation to how much skeletal muscle development may take place to accommodate the necessities of an ever-increasing load. These limits are different between the sexes, with women tending to approach more rapidly than men a lower maximal AFT for the same height.

BackgroundIn gastric juice, high levels of the carcinoembryonic antigen (CEA) and the carbohydrate antigen 19-9 (CA 19-9) have been found to correlate with precancerous lesions and gastric cancer. So far, sampling of gastric juice has required upper endoscopy. In place of this invasive procedure, we investigated a new tool for the quantitation of tumor markers in gastric juice.Materials and methodsThe study population consisted of healthy controls and consecutive subjects with suspected gastric cancer or dyspepsia/epigastric distress. Patients were asked to swallow a small gelatine capsule (14 mm in length and 5 mm in diameter) containing a pierced plastic cover and surrounding a piece of absorbent paper. The capsule was left in the gastric cavity for 60 min to allow saturation of the absorbent paper with gastric juice. A 45–50 cm length of nylon thread connected to the inner capsule was used to remove the device from the gastric cavity. After processing the absorbent paper for radioimmunoassay, CEA and CA 19-9 levels were correlated to the findings of upper endoscopy and biopsies of gastric mucosa or suspected lesions.ResultsThe endogastric capsule did not cause any side-effects and 62 participants were fully compliant to the procedure. Assessable gastric juice samples were taken from 23 patients with gastric cancer, 15 patients with intestinal metaplasia or dysplasia, 12 patients with gastritis and 12 controls without gastric diseases. In the 12 samples of gastric juice from control patients, mean values of CEA and CA 19-9 were 1.1 ± 0.9 ng/ml and 16 ± 7.5 ng/ml, respectively. The mean levels of both markers were found to increase according to the severity of gastric lesions and in patients with cancer, mean CEA and CA 19-9 levels were 513 ± 627 ng/ml and 545 ± 510 ng/ml, respectively. Patients with precancerous lesions and cancer showed higher levels of CEAand CA 19-9 than patients with normal findings or gastritis (P <0.001).ConclusionsThe endogastric capsule is a simple, non-invasive tool for the measurement of CEA and CA 19-9 levels in gastric juice. These values may discriminate between normal or minor pathologic changes and precancerous lesions or carcinomas. Further investigations are warranted, since this may represent a new method for gastric cancer screening.

A closed-loop therapy for diabetic patients is proposed, by suitably exploiting a discrete Delay Differential Equation (DDE) model of the glucose-insulin system. To this aim, plasma glucose concentration is regulated by means of subcutaneous insulin administration, in order to track a desired glucose profile. The method of exact input/output feedback linearization and stabilization is used, in order to ensure the local convergence of the tracking error to zero. The use of a state observer for delay systems makes it so that the control law requires only glucose measurements, which are easily achievable according to the present technology. Even if exogenous insulin administration is standardly used for Type I diabetic patients (who do not have a pancreatic insulin release), the use of a DDE model allows to extend the proposed treatment also to Type II diabetes. Performed simulations show the effectiveness of the proposed approach.

Exogenous insulin administration is the basic way to face the widespread disease of Diabetes Mellitus. To this aim, closed-loop approaches, though theoretically realizable according to the control theory results and to the recent technology concerning continuous glucose measurements and affordable insulin infusion pumps, require a careful and thorough testing ground on a virtual environment before arranging an in-vivo clinical setting of experiments. In this work, a model-based control law for the plasma glycemia, recently published by the same authors, is evaluated by closing the loop on a virtual patient, whose model equations are different from the ones used to synthesize the control law. That means: a minimal model of the glucose-insulin system to design the insulin therapy, and a different, more detailed, comprehensive model to test in silico the control scheme. Uncertainties on the blood glucose measurements, as well as malfunctioning on the insulin delivery devices are considered, according to the standard technology, in order to obtain an effective benchmark for the closed-loop control and to show in fact the robustness of the proposed approach.

In this paper we deal with the problem of tracking a desired plasma glucose evolution by means of intra-venous insulin administration, for Type 2 diabetic patients exhibiting basal hyperglycemia. A nonlinear time-delay model is used to describe the glucose-insulin regulatory system, and a modelbased approach is exploited in order to design a global sampleddata control law for such system. Sontag's universal formula is designed to obtain a steepest descent feedback induced by a suitable control Lyapunov-Krasovskii functional. Such a feedback is a stabilizer in the sample-and-hold sense. Furthermore, the input-to-state stability redesign method is used in order to attenuate the effects of bounded actuation disturbances and observation errors, which can appear for uncertainties in the instruments. The proposed control law depends on sampled glucose and insulin measurements. Theoretical results are validated through simulations.

Dodecanedioic acid (C12), a saturated, aliphatic dicarboxylic acid with 12 carbon atoms, was given as an intravenous bolus (800 μmol/kg of body weight [kg BW ]) in male Wistar rats to study its pharmacokinetic profile. Because total plasma C12, which results from the sum of both free and albumin binding fractions, was measured by high‐performance liquid chromatography, an in vitro experimental session was carried out to determine the binding curve of C12 in rat plasma. These data were then used to calculate the plasma C12 free fraction in in vivo experiments. The best fit obtained for the experimental data of albumin binding was obtained with the equation of reversible, saturable binding to one, two, or three classes of noninteracting equivalent sites. Only a single binding site was clearly identified with a dissociation constant of 147 μmol/L and a maximal predicted binding of 1.57 mol/mol albumin. The urinary excretion of C12 was 3.90 ± 1.62% of the administered dose. The pharmacokinetic analysis was performed by one‐compartment model with linear transfer to the tissues, taking into account simultaneously both plasma concentration and urine excretion data. The apparent volume of distribution of C12 was 0.248 ± 0.035 L/kg BW , the apparent first order rate constant to the tissues was 0.0535 ± 0.0123 min −1 and that from plasma to urine was 0.00206 ± 0.00051 min −1 . The C12 plasma half‐life was 12.47 minutes. Renal clearance was 0.00051 L/kg BW per minute, whereas the systemic clearance was 0.0138 L/kg BW per minute. Because the renal clearance was much less than the rat inulin clearance reported in literature, the presence of C12 passive back‐diffusion was hypothesized. ( Journal of Parenteral and Enteral Nutrition 18:225–230, 1994)

Inadequate splanchnic perfusion in septic shock is associated with increased morbidity and mortality. As result of splanchnic ischemia, mucosal permeability increases. Considering the implication of improved mucosal perfusion in terms of maintenance of mucosal barrier integrity, dopamine-1 receptor stimulation could be helpful in septic shock. The goal of the current study was to determine the effects of fenoldopam on systemic hemodynamic parameters and gastric mucosal perfusion in patients with septic shock. Furthermore, the authors tested the hypothesis that the addition of fenoldopam (0.1 microg x kg(-1) x min(-1)) to a combination of norepinephrine and dobutamine (5 microg x kg(-1) x min(-1)) may improve gastric mucosal perfusion in septic shock.Patients with septic shock were randomized to a double-blind 2-h infusion of fenoldopam (n = 20) or placebo (n = 20). Each group received dobutamine (5 microg x kg(-1) x min(-1)), and the dosage of norepinephrine was adjusted to achieve a mean arterial pressure between 70 and 80 mmHg. A laser-Doppler probe and tonometer were introduced into the gastric lumen.A significant increase in gastric mucosal perfusion, detected by laser-Doppler flowmetry, was observed in the group treated with fenoldopam (P < 0.05). In addition, this increase in microcirculatory flow occurred despite the fact that systemic flow remained unchanged. Differences in gastroarterial partial pressure of carbon dioxide values were not statistically significant in the fenoldopam and placebo groups.The study showed that, for the same mean arterial pressure, short-term fenoldopam infusion increased gastric mucosal perfusion in patients with septic shock.

The aim of this study was to compare intensity-modulated radiation therapy (IMRT) with 3D conformal technique (3D-CRT), with respect to target coverage and irradiation of organs at risk for high dose postoperative radiotherapy (PORT) of the prostate fossa. 3D-CRT and IMRT treatment plans were compared with respect to dose to the rectum and bladder. The dosimetric comparison was carried out in 15 patients considering 2 different scenarios: (1) exclusive prostate fossa irradiation, and (2) pelvic node irradiation followed by a boost on the prostate fossa. In scenario (1), a 3D-CRT plan (box technique) and an IMRT plan were calculated and compared for each patient. In scenario (2), 3 treatment plans were calculated and compared for each patient: (a) 3D-CRT box technique for both pelvic (prophylactic nodal irradiation) and prostate fossa irradiation (3D-CRT only); (b) 3D-CRT box technique for pelvic irradiation followed by an IMRT boost to the prostatic fossa (hybrid 3D-CRT and IMRT); and (c) IMRT for both pelvic and prostate fossa irradiation (IMRT only). For exclusive prostate fossa irradiation, IMRT significantly reduced the dose to the rectum (lower Dmean, V50%, V75%, V90%, V100%, EUD, and NTCP) and the bladder (lower Dmean, V50%, V90%, EUD and NTCP). When prophylactic irradiation of the pelvis was also considered, plan C (IMRT only) performed better than plan B (hybrid 3D-CRT and IMRT) as respect to both rectum and bladder irradiation (reduction of Dmean, V50%, V75%, V90%, equivalent uniform dose [EUD], and normal tissue complication probability [NTCP]). Plan (b) (hybrid 3D-CRT and IMRT) performed better than plan (a) (3D-CRT only) with respect to dose to the rectum (lower Dmean, V75%, V90%, V100%, EUD, and NTCP) and the bladder (Dmean, EUD, and NTCP). Postoperative IMRT in prostate cancer significantly reduces rectum and bladder irradiation compared with 3D-CRT.

Objective: In this article we provide evidence of a significant spontaneous humoral response in cancer patients. Methods: A panel of tumor-associated antigens, previously identified through serological screening of phage-displayed cDNA libraries from solid human tumors, breast carcinoma cell lines and human testis by employing breast cancer patient sera, was used in this study to survey sera from 182 patients with known disease histories and clinical stages. Results: This analysis reveals a statistically significant association between tumor disease and presence in peripheral blood of IgG antibodies against four autoantigens. One of these antigens (D7-1) is particularly interesting in that the antibody response against it grows with cancer progression from stages I through IV, with an incidence of 13.2, 13.5, 18.2 and 27%, respectively. The significance of this stage-dependent increase in the incidence is confirmed by the Mantel–Haenszel Chi-squared test (P = 0.001). Conclusions: Our data confirm association between breast cancer diagnosis of patients and presence in their peripheral blood of antibodies against several autoantigens identified by phage display.

Dicarboxylic acids have been proposed as an alternate lipid energetic substrate for total parenteral nutrition. No data are yet available on the possible effect of dicarboxylic acids on glucose metabolism in humans. Thus, we examined the effect of a continuous intravenous infusion of the sodium salt of the 10-carbon atom alyphatic dicarboxylic acid, sebacate (Sb), on insulin-dependent glucose metabolism in four control subjects, four patients with insulin-dependent diabetes mellitus, and four obese subjects. All subjects received a constant 5-hour infusion of saline or sebacate (6.6 g/h), in a randomized order on two different days. After 3 hours of infusion, a 120-minute euglycemic, hyperinsulinemic clamp procedure was performed (insulin infusion rate = 40 mU/m2 per minute). Glucose uptake, plasma sebacate, insulin, glucagon, C-peptide, and ketone bodies were measured. No significant differences in insulinemia were found among groups either during the saline infusion or the sebacate infusion. On the contrary, glucose uptake (molar) was significantly reduced during the sebacate vs the saline day in all three groups: 6.7 +/- 0.04 vs 3.7 +/- 1.3 in control subjects (p < .001), 4.6 +/- 0.4 vs 2.5 +/- 1.2 in patients with insulin-dependent diabetes mellitus (p < .001), and 4.8 +/- 0.5 vs 2.7 +/- 0.2 mg/kg per minute in obese subjects (p < .001). In conclusion, Sb administration was associated with a glucose-sparing effect as shown by the reduced glucose uptake in all patients studied. Sebacate did not stimulate insulin secretion, inasmuch as no modification of C-peptide plasma levels was observed after 3 hours of Sb infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

To test the potential effects of dexfenfluramine (dF) on enhancing free fatty acid (FFA) turnover and oxidation rates, 11 obese female non-insulin-dependent diabetes mellitus (NIDDM) outpatients (age, 52.5 +/- 1.5 years; weight, 81.3 +/- 3.2 kg; height, 158 +/- 3.04 cm; body mass index, 32.4 +/- 0.7 kg/m2) received a primed-constant infusion of 1-14C-palmitate. The waist to hip ratio (WHR) was 0.91 +/- 0.04. Fat body mass and lean body mass, assessed by dual-energy x-ray densitometry, were 32.0 +/- 1.5 and 49.30 +/- 2.67 kg, respectively. All patients had an average hemoglobin A1 of 6.3% +/- 0.3% in the month preceding the study and had not received oral hypoglycemic agents. Gas exchange was measured both basally and during a ventilated-hood system, indirect-calorimetry session. The protocol was a randomized, placebo-controlled, single-blind design. Subjects received dF 30 mg acutely (n = 6) or a placebo (n = 5). A dose of dF 15 mg twice daily or placebo was then administered over 15 days (chronic). To obtain serum peak level of the drug, dF was administered 2 hours before starting palmitate infusion. A free diet was allowed throughout the study, and the group treated with dF lost approximately 0.5 kg body weight. Acute and chronic dF administration resulted in a significant increase in FFA oxidation, expressed as a percentage of the dose of radiocarbon (respectively, 11.47% +/- 0.46% v 9.50% +/- 0.46% [P < .01] and 12.06% +/- 0.71% v 9.88% +/- 0.62% [P < .01]). FFA turnover rate was higher after both acute and chronic dF administration (respectively, 10.71 +/- 2.18 v 7.79 +/- 1.48 mumol/kg/min [P < .05] and 11.92 +/- 2.74 v 8.43 +/- 1.86 mumol/kg/min [P < .05]). Serum FFA concentration during both acute and chronic dF administration increased, but not significantly. Mean serum glucose level decreased after acute dF from 114.3 +/- 8.6 to 86.5 +/- 5.1 mg/dL (P < .001) and after chronic dF from 120.3 +/- 7.3 to 89.8 +/- 5.8 mg/dL (P < .001). Serum insulin was not affected by dF administration. In conclusion, oral acute and chronic dF administration increase FFA turnover and oxidation rates in NIDDM obese patients. This may play an important role in weight reduction. In addition, dF shows a weight-independent effect on glucose metabolism, reducing serum glucose levels without acting on insulin secretion.

Weight loss and malnutrition are commonly reported in inflammatory bowel disease (IBD), but differences between Crohn's disease (CD) and ulcerative colitis (UC) patients have rarely been pointed out. In this regard, a sample of 102 consecutive patients with a diagnosis of either CD (n = 63, 33 males) or UC (n = 39, 25 males) based on previously reported clinical, morphologic, and histopathologic criteria were studied. Twenty-six anthropometric and metabolic variables were measured upon admission. Body composition was assessed by both anthropometry and bioimpedance measurements, and energy expenditure and substrate oxidation were assessed by indirect calorimetry. The data were subjected to principal-component analysis and to factor rotation to derive a set of a few basic independent descriptors of the metabolic features of each subject. Six descriptors were found to be responsible for greater than 86% of the total sample variability and to associate very well with mutually disjoint subsets of the original variables. The six summarizing factors are listed in order of decreasing percentage of explained variation (size 41.8%, fatness 17.9%, fuel 12.2%, shape 5.4%, energy 5.2%, and steroid 3.9%). CD and UC patients differed significantly with respect to fatness (CD lower, P = .004) and carbohydrate (CHO) fuel preference (CD lower, P = .030). Hence, CD patients showed a reduced fat mass (FM) compared with UC patients, and from a metabolic point of view, too, CD and UC are not superimposable. In fact, the lower CHO oxidation (CHOox) rate and consequent preferential lipid utilization found in CD patients may be taken into account as a contributing cause of lipid tissue wasting and in planning therapeutic enteral regimens.

Many modern techniques for the diagnosis of pathological states in humans and for their subsequent treatment can be posed as nonlinear identification problems of essentially nonlinear dynamic systems or as nonlinear optimal control problems. It can be shown that the linearised versions of such models are inadequate and do not represent at all well the complexity of the problem. Thus, nonlinear estimation and control techniques are required for progress to be made in this field. The aim of this review is to examine some models suggested in the medical literature for the modelling of certain medical treatments and diagnoses. Then examine how these models can be enriched by using Operational Research techniques so that a better control is provided on the diagnosis and the treatment, as well as the formulation of more precise models of the phenomenon. The review will present some applications both therapeutic and diagnostic that have appeared in the literature. Special interest will be bestowed on hyperthermic systems in oncological treatment and glucose–insulin dynamics for diabetic patients, while heart dynamics and magnetic resonance imaging will also receive attention. These applications are good examples to show the advantages of Operational Research methods in this field of endeavour. The outline of the paper is the following. After the introduction, in section two a brief description of nonlinear system models of phenomena will be given, for definitional and descriptive purposes. In section three a discussion of how to apply System theory in the medical field will be presented, together with an analysis of the possible benefits. In section four some applications of dynamical models to medical diagnosis and treatment will be described, while in section five the appropriate conclusions will be stated.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death in the world. Despite many diagnostic and therapeutic tools are now available to improve survival and reduce its recurrence, prognosis is closely conditioned by the time of diagnosis. Surveillance and early diagnosis are crucial for a successful therapy. We report a clinical case from the HCC archive of the Hepatocatt meetings held in Ge-melli Hospital (Catholic University of Rome). The case describes a tumor progression in a multistep process from a small liver nodule to overt HCC and its management by a multidisciplinary team.

The effects on oxygen consumption and carbon dioxide production of a constant intravenous infusion of 0.15 g of disodium sebacate (Sb), the sodic salt of a medium‐chain dicarboxylic acid with 10 carbon atoms, per kilogram of body weight per hour over 5 hours and of a 50% mixture of medium‐and long‐chain triglycerides (MCT/LCT) were compared in 10 healthy men. Oxygen consumption and carbon dioxide production were measured by indirect calorimetry. Mean oxygen consumption was about 19% higher than the basal oxygen consumption at the end of MCT/LCT infusion but was only 5% higher than the basal oxygen consumption when Sb was infused. There was an eightfold increase in plasma β‐hydroxybutyrate and acetoacetate concentrations and a threefold increase in serum insulin levels during MCT/LCT infusion, but no significant change in ketone bodies and insulin from basal values was observed during and after Sb infusion. Pharmacokinetic parameters were also computed, showing an average apparent volume of distribution of 167 mL/kg of body weight for MCTs and 112 mL/kg of body weight for Sb. The t ½ of MCTs was 50 minutes and that of Sb was 78 minutes. Urinary excretion of Sb and its β‐oxidative by‐product, suberic acid, globally accounted for 48% of the given amount of Sb. In spite of its urinary loss and slower tissue uptake compared with MCTs, Sb avoided ketone body formation or elevation in insulin levels and did not induce a significant increase in oxygen consumption. The Sb caloric equivalent was 6.643 kcal/g, and the remaining amount of Sb administered (approximately 5.2 g/h in a 70‐kg subject) seemed to be energetically useful by furnishing 34.54 kcal/h, ie, 829 kcal over 24 hours. This caloric support is equivalent to or even higher than that usually given as MCTs; however, formation of ketone bodies and interference with glucose metabolism are avoided. ( Journal of Parenteral and Enteral Nutrition 17 :257–264, 1993)

The paper investigates the problem of tracking a desired plasma glucose evolution by means of intra-venous insulin administration. A model-based approach is followed. Only measurements of glycemia are considered. A nonlinear observer for delay differential systems is used for the estimation of insulinemia. In the spirit of the separation theorem, a nonlinear control law is proposed, based on the feedback linearization, which makes use of the observer estimations instead of the full state measurements. The local convergence of the tracking error to zero is theoretically proved. In silico simulations, which also take into account input saturation, show the very good performance of the proposed control technique.

A partial differential Progressive Tubular Reabsorption (PTR) model, describing renal tubular glucose reabsorption and urinary glucose excretion following a glucose load perturbation, is proposed and fitted to experimental data from five subjects. For each subject the Glomerular Filtration Rate was estimated and both blood and urine glucose were sampled following an Intra-Venous glucose bolus. The PTR model was compared with a model representing the conventional Renal Threshold Hypothesis (RTH). A delay bladder compartment was introduced in both formulations. For the RTH model, the average threshold for glycosuria varied between 9.90±4.50 mmol/L and 10.63±3.64 mmol/L (mean ± Standard Deviation) under different hypotheses; the corresponding average maximal transport rates varied between 0.48±0.45 mmol/min (86.29±81.22 mg/min) and 0.50±0.42 mmol/min (90.62±76.15 mg/min). For the PTR Model, the average maximal transports rates varied between 0.61±0.52 mmol/min (109.57±93.77 mg/min) and 0.83±0.95 mmol/min (150.13±171.85 mg/min). The time spent by glucose inside the tubules before entering the bladder compartment varied between 1.66±0.73 min and 2.45±1.01 min. The PTR model proved much better than RTH at fitting observations, by correctly reproducing the delay of variations of glycosuria with respect to the driving glycemia, and by predicting non-zero urinary glucose elimination at low glycemias. This model is useful when studying both transients and steady-state glucose elimination as well as in assessing drug-related changes in renal glucose excretion.

Dicarboxylic acids are water-soluble, contrary to monocarboxylic acids, and have a metabolic pathway intermediate between those of lipids and carbohydrates. Our goal was to investigate the plasma turnover and oxidation rate of dodecanedioic acid (C12) in eight healthy male volunteers.A simultaneous infusion of both cold (0.24 mmol/min corresponding to 0.396 kcal/min) and radiolabeled (1.62 microCi/min) C12 free acid was performed. Blood specimens were sampled over a period of 360 minutes, and 24-hour urine samples were collected to measure the levels of C12 by high-performance liquid chromatography and liquid scintillation. Indirect calorimetry was continuously performed, and expired 14CO2 was collected. Binding of C12 in human plasma was determined in separate experiments using equilibrium dialysis.A linear one-compartment model was used to describe the kinetics of labeled C12. Its volume of distribution was 139.02 +/- 10.84 mL/kgbw (mean +/- SE), and its plasma elimination constant was 0.01 +/- 0.004 min-1. The 24-hour urinary excretion of C12 was 3.14 +/- 0.96 mmol, corresponding to about 7% of the administered dose. The amount of C12 oxidized, expressed as percent oxidation, was equal to 35.44 +/- 1.64%. The mean basal value of npRQ (0.80 +/- 0.006) significantly (p < .02) decreased during the infusion to 0.78 +/- 0.01, which is a value close to that theoretically calculated (0.77). The oxidation of free fatty acids was significantly increased at the end of the C12 infusion, whereas the glucose oxidation was reduced to about 50%.The experimental data suggest that C12 might represent a fuel substrate immediately available for tissue energy requirements, because a relevant amount of C12 is promptly oxidized. Its prompt oxidation and its conversion to succinic acid support the use of dodecanedioic acid in parenteral nutrition, especially in insulin-resistance conditions in which glucose uptake and oxidation is impaired.

One of the questions involved in the formulation of a new model for a physiological phenomenon, when the model represents a dynamical system, is that concerning its qualitative behavior. The determination of the stability of a particular dynamical system is usually made analytically, from a linearization of the system around an equilibrium point. This analytic proof may often be very complex or impossible, leading to the imposition of conditions on the relative magnitude of the structural model parameters or to other partial results. We discuss a general technique whereby a probabilistic judgment is made on the stability of a dynamical system, and we apply it to the study of a particular delay differential system modelling the relationship between insulin secretion and glucose uptake. This technique is applicable in case experimental material is available from which to estimate the dispersion of the model parameters. A stability criterion is obtained via the usual linearization around an equilibrium point, it is approximated as a Taylor series in the parameters truncated after the first term, and its variance is then computed from the dispersion of the parameters. While the conclusion is probabilistic in nature, it can be obtained for a wide class of models and from either sample or individual experimental subject's parameter estimates.

There exists a huge variety in the occurrence and characteristics of major incidents. Incident management stakeholders and in particular emergency health service providers have to deal with two basic challenges: The disproportion between the needs and the available human/material resources in the response capacity and the inherent time constraints of an emergency. These critical factors play a seminal role in the decision-making process during a crisis event, which affects all levels of command & control (strategic, operational, and tactical). The drawback with current health emergency management systems lies with the command & control operations that should coordinate the actions of the separate services and turn them into an effective, multi-faceted crisis response mechanism. IMPRESS improves the efficiency of decision making in emergency health operations, which has a direct impact on the quality of services provided to citizens. Furthermore it provides a consolidated concept of operations, to effectively manage medical resources, prepare and coordinate response activities, supported by a Decision Support System, using data from multiple heterogeneous sources. The proposed solution facilitates communication between Health Services (and Emergency Responders) at all levels of response and the crisis cycle with the necessary health care systems support, supervision and management of participating organizations. It will assist health services in becoming more proactive, better prepared and interoperable with other emergency response organizations.

Dicarboxylic acids (DA) are alternate lipid substrates recently proposed in parenteral nutrition. Two new derivatives of DA, a triglyceride of sebacic (TGC10) and one of dodecanedioic (TGC12) acid have been synthesised in order to reduce the amount of sodium given with the unesterified forms. The present paper describes a rapid and direct high-performance liquid chromatographic method (HPLC) for the analysis of these substances in both plasma and urine. Thirty-six male Wistar rats were rapidly injected with 64 mg of TGC10 or 53 mg of TGC12. The triglycerides and their products of hydrolysis were measured in plasma samples taken at different times. For the dose of 500 ng the intra-assay variations ranged from 6. 80+/-0.35% for TGC10 to 18.6+/-3.20% for TGC12 and the inter-assay variations were from 4.44+/-2.21% for TGC10 to 15.0+/-6.72% for TGC12. The detection limit for both triglycerides was 5 ng. This rapid and direct HPLC method could have practical implications in monitoring the concentration of both triglycerides and free forms of DA in biological samples of patients who might benefit from the administration of these substances during parenteral nutrition regimens.

The possibility of computing Diet Induced Thermogenesis (DIT) is an important feature of metabolic investigations. However, methodological problems have affected the determination of DIT in the indirect calorimetric chamber. DIT has been commonly estimated by regressing energy expenditure on a measure of physical activity. Although used for many years as the only feasible approach to calculate DIT in a respiratory chamber, this traditional method has been criticized because of an apparent underestimation of the DIT, but no alternative method has been suggested so far. The present work proposes to estimate DIT directly by means of a mathematical model. This approach also allows to simultaneously estimate other parameters, namely resting energy expenditure (REE), physical activity (PA) and physical exercise (PE).

Dicarboxylic acids with an even number of carbon atoms have been proposed as an alternate energy substrate for enteral or parenteral nutrition in the acutely ill patient, due to their water solubility and their yielding TCA cycle intermediates upon beta-oxidation. In the present work, a nonlinear compartmental model of the kinetics of dodecanedioic acid is developed, and its parameters are estimated from time concentration experimental observations obtained from six healthy volunteers undergoing a per os administration of 3 g of the substance. Although the model is linear in the transfer of the free substance from plasma to the tissues, the exchange between gut and plasma compartments is represented as a saturable function. Albumin binding is then incorporated to obtain the final model in terms of the measured total concentrations. Estimates of the model's structural parameters were computed for each experimental subject, and the usual single-subject approximate confidence regions for the parameters were derived by inversion of the Hessian at the optimum. To verify the applicability of this approximation, the nonlinearity of the expectation surface at the optimum was measured by computing the normal (intrinsic) component of curvature. Because the model curvature was excessive in all subjects, the usual approximation could not be trusted to provide acceptable approximations to the parameter confidence regions. A suitable Monte Carlo simulation yielded empirical joint parameter distributions from which the approximate parameter variances could finally be obtained.

In this work we consider the local sampled-data stabilization of human plasma glycemia. It is proved theoretically that the implementation by sampling and holding, for suitable small sampling period, of a state feedback which is shown in the literature to yield local stabilization when applied in a continuous time basis, yields local practical stabilization, with arbitrarily small final target ball. The model of the system is given by a nonlinear retarded functional differential equation and the above state feedback is provided by standard tools of differential geometry for time-delay systems. The proposed theoretical result proves an important property for the digital implementation of the controller, which has been shown in past literature to perform very well when checked in closed-loop with well known computer simulators of diabetic patients approved by the Food and Drug Administration as a substitute of animal trials.

A composite model, describing the glucose/insulin dynamics following daily food administration and insulin injections in Type 1 Diabetes Mellitus patients is presented. Three daily meals have been simulated, food intake representing four different types of foodstuffs, along with three rapid-acting insulin injections and one long-acting insulin injection. Three different scenarios (depending on whether food intake and/or administration times were fixed or random) were hypothesized: simulations show a very realistic time-course for both glucose and insulin dynamics over long (20 days) and short (one day) time periods.

Mathematical models of the cardiovascular system and of cerebral autoregulation (CAR) have been employed for several years in order to describe the time course of pressures and flows changes subsequent to postural changes. The assessment of the degree of efficiency of cerebral auto regulation has indeed importance in the prognosis of such conditions as cerebro-vascular accidents or Alzheimer. In the quest for a simple but realistic mathematical description of cardiovascular control, which may be fitted onto non-invasive experimental observations after postural changes, the present work proposes a first version of an empirical Stochastic Delay Differential Equations (SDDEs) model. The model consists of a total of four SDDEs and two ancillary algebraic equations, incorporates four distinct delayed controls from the brain onto different components of the circulation, and is able to accurately capture the time course of mean arterial pressure and cerebral blood flow velocity signals, reproducing observed auto-correlated error around the expected drift.

Exogenous insulin administration is the standard way to regulate hyperglycemia in diabetic patients and, in the recent decades, the challenging task to design an artificial pancreas has been addressed with the aim to synthesize a closedloop control law by means of sampled glucose measurements.Model-based control law allow to explicitly exploit the glucoseinsulin mathematical model, but need to cope with different sources of uncertainties and disturbances affecting the system.The present note investigates the framework of the H∞ control as a tool to attenuate the effect of a meal, modeled as an unknown disturbance.To this end an LMI-based feedback control law is synthesized, by properly exploiting a Delay Differential Equation model of the glucose-insulin system, that makes use of only glucose measurements, to avoid the use of insulin measurements, known to be slower and more cumbersome to obtain, more expensive and also less accurate than glucose measurements.It is shown by simulations that, besides to regulate plasma glycemia onto a desired level starting from a hyperglycemic state, the control law efficiently constrains the post-prandial increase of glycemia on a very tight control, preventing dangerous oscillations.

To determine the hydrolysis rate of medium‐chain triglycerides (MCTs) to medium‐chain free fatty acids (MCFAs) and the disposition rate of MCFAs, five healthy volunteers (H) and eight surgically stressed patients (S) received 0.5 mL of Lipofundin 20% per kilogram body weight as an intravenous bolus. Serum MCTs (C8 and C10) and MCFAs were measured by high‐performance liquid chromatography during the 120 minutes postinjection. A linear two‐compartment model was found to be descriptive and robust: the apparent volumes of distribution were found to be similar in healthy and surgical subjects for both MCTs and MCFAs. The first‐order transformation rate constant (hydrolysis) from MCTs to MCFAs was not significantly different between the H and S groups (overall 0.112 ± 0.022/min, C8; 0.078 ± 0.020/min, C10). The rate constant for tissue MCFA uptake from plasma was significantly different between S and H subjects both for C10 alone (H: 0.0337 ± 0.0078; S: 0.1194 ± 0.0240; p =.020) and for C8 and C10 together (H: 0.0382 ± 0.0054; S: 0.1012 ± 0.0168; p =.008), whereas it failed to attain significance when C8 alone was considered (H: 0.047 ± 0.0077; S: 0.0829 ± 0.0230; p =.210). These results show that use of MCTs is increased in surgical patients because of enhanced tissue uptake of the corresponding free fatty acids, whereas there does not seem to be an increase of MCT hydrolysis in response to acute disease. This would indicate that the stressed patient is in fact able to effectively use this alternative lipid substrate in the face of increased metabolic demand. ( Journal of Parenteral and Enteral Nutrition 18 :134–140, 1994)

Dodecanedioic acid (C12), a saturated aliphatic dicarboxylic acid with twelve C atoms, was given as an intraperitoneal bolus to male Wistar rats, with the aim of evaluating C12 suitability as an energy substrate for parenteral nutrition. The 24 h urinary excretion of C12 was 3.9% of the administered dose. C12 kinetics were investigated by a one-compartment model with saturable tissue uptake and reversible binding to plasma albumin. The analysis of plasma concentration and urinary excretion data from different animals yielded the population means of the kinetic parameters: renal clearance was 0.72 ml/min per kg body weight (BW) (much smaller than inulin clearance in the rat), and maximal tissue uptake was 17.8 mumol/min per kg BW corresponding to 123.7 J/min per kg BW. These results encourage the consideration of C12 as a possible substrate for parenteral nutrition. To investigate the effect of C12 administration on glucose kinetics, two other groups of rats, one treated with an intraperitoneal bolus of C12 and the other with saline, were subsequently given an intravenous injection of D[-U-14C]glucose in a tracer amount. Radioactivity data of both control and C12-treated rats were analysed by means of a two-compartment kinetic model which takes into account glucose recycling. The estimates of glucose pool size (2.3 mmol/kg BW) and total-body rate of disappearance (82.1 mumol/min per kg BW) in control rats agreed with published values. In C12-treated rats, the rate of disappearance appeared to be reduced to 36.7 mumol/min per kg BW and the extent of recycling appeared to be negligible.

Glucose-induced pancreatic insulin release is the fundamental mechanism responsible for glucose homeostasis, its failure determining the clinical picture of Diabetes Mellitus. The details of the feedback loop controlling glycemia through insulin secretion have been an important subject of investigation and modeling for decades. In this note, a recently published population model is considered, whose purpose is to replicate in silico different observed phenomena such as low frequency glycemia-insulinemia oscillations, as well as concordant induction of high-frequency insulin oscillations. The basic idea underlying this model is that the pancreas behaves like a population of independent controllers (each consisting of a fundamental secreting unit, a pancreatic islet), all reacting to the same glucose stimulus, but with varying performance characteristics. This idea has been supported by a relatively wide range of simulations, aiming to replicate most important in vivo experiments concerning pancreatic insulin release. It will be shown in this note that the same mathematical structure can also replicate a set of in vitro experiments, provided that the model context is adapted to the structure of the different experiments to be simulated. More in details, the model will be shown to reproduce the double phase of insulin release during a prolonged glucose stimulus: a first phase of impulsive insulin release, immediately upon glucose administration, and a second phase of more gradual release, dependent on the potentiation effect of the secretory units.

A glucose control problem is considered, with the aim to regulate a basal hyperglycemic state down to a safe euglycemic level. A discrete Delay Differential Equation (DDE) model of the glucose-insulin system is considered, that properly takes into account also the pancreatic insulin release, not negligible in Type 2 diabetic patients. Insulin is supposed to be administered subcutaneously. A geometric approach is considered, according to which the feedback linearization with delay cancelation theory is applied. In order to use only glucose measurements to synthesize the control law an observer for nonlinear delay systems is exploited, and the local convergence of the tracking error to zero is theoretically proven. Simulations are performed in a virtual environment, that properly takes into account input saturation: numerical results show the effectiveness of the proposed approach as well as that of the observer.