Jeffrey Fessel

Visceral adipose tissue accumulates during antiretroviral therapy in many patients who are infected with the human immunodeficiency virus (HIV); this process is associated with an increased cardiovascular risk. We assessed the use of a growth hormone–releasing factor analogue, tesamorelin, to decrease visceral adiposity.

Ibalizumab, a humanized IgG4 monoclonal antibody, blocks the entry of human immunodeficiency virus type 1 (HIV-1) by noncompetitive binding to CD4.In this single-group, open-label, phase 3 study, we enrolled 40 adults with multidrug-resistant (MDR) HIV-1 infection in whom multiple antiretroviral therapies had failed. All the patients had a viral load of more than 1000 copies of HIV-1 RNA per milliliter. After a 7-day control period in which patients continued to receive their current therapy, a loading dose of 2000 mg of ibalizumab was infused; the viral load was quantified 7 days later. Through week 25 of the study, patients received 800 mg of ibalizumab every 14 days, combined with an individually optimized background regimen including at least one fully active agent. The primary end point was the proportion of patients with a decrease in viral load of at least 0.5 log10 copies per milliliter from baseline (day 7) to day 14.A total of 31 patients completed the study. The mean baseline viral load was 4.5 log10 copies per milliliter, and the mean CD4 count was 150 per microliter. Of the 40 patients in the intention-to-treat population, 33 (83%) had a decrease in viral load of at least 0.5 log10 copies per milliliter from baseline (P<0.001 for the comparison with the control period). The mean viral-load decrease was 1.1 log10 copies per milliliter. During the control period, 1 patient, who received the optimized background regimen prematurely, had a decrease in viral load of 0.5 log10 copies per milliliter. At week 25, patients who had received ibalizumab plus an optimized background regimen had a mean decrease of 1.6 log10 copies per milliliter from baseline; 43% of the patients had a viral load of less than 50 copies per milliliter, and 50% had a viral load of less than 200 copies per milliliter. Among 10 patients who had virologic failure or rebound, in vitro testing identified 9 who had a lower degree of susceptibility to ibalizumab than at baseline. The most common adverse event was diarrhea (in 20% of patients). Four patients died from causes related to underlying illnesses; 1 had a serious adverse event (the immune reconstitution inflammatory syndrome) that was deemed to be related to ibalizumab therapy.In patients with MDR HIV-1 infection who had advanced disease and limited treatment options, ibalizumab had significant antiviral activity during a 25-week study. Evidence of the emergence of diminished ibalizumab susceptibility was observed in vitro in patients who had virologic failure. (Funded by the Orphan Products Clinical Trials Grants Program of the Food and Drug Administration and TaiMed Biologics; TMB-301 ClinicalTrials.gov number, NCT02475629 .).

The relationship between self-reported quality of life and disability and disease severity was evaluated in subjects with treatment-failure gout (n = 110) in a prospective, 52-week, observational study.Subjects had symptomatic crystal-proven gout of at least 2 years' duration and intolerance or refractoriness to conventional urate-lowering therapy. Serum uric acid (sUA) concentration, swollen and tender joint counts, frequency and severity of gout flares, tophus assessments, comorbidities, and patient-reported outcomes data [Medical Outcomes Study Short Form-36 (SF-36), Health Assessment Questionnaire-Damage Index] were collected. Analyses included correlations of patient-reported outcomes with clinical variables and changes in clinical status.Mean age of study subjects was 59 years. Mean scores on SF-36 physical functioning subscales were 34.2-46.8, analogous to persons aged >or= 75 years in the general population. Subjects with more severe gout at baseline had worse health-related quality of life (HRQOL) in all areas (p < 0.02 for all measures), compared to patients with mild-moderate disease. Number of flares reported in past year, number of tender joints, swollen joints, and tophi correlated significantly with some or all HRQOL and disability measures. sUA was not significantly correlated with any HRQOL or disability measure. Subjects with comorbidities experienced worse physical, but not mental, functioning.Severe gout is associated with poor HRQOL and disability, especially for patients who experience more gout flares and have a greater number of involved joints. Subject perceptions of gout-related functioning and pain severity appear to be highly sensitive indicators of HRQOL and disability.

The frequency of HLA-DQ antigens in AIDS patients with toxoplasmic encephalitis (TE) were examined. HLA-DQ3 was significantly more frequent in white North American AIDS patients with TE (85.0%) than in the general white population (51.8%; P = .007, corrected P = .028) or randomly selected control AIDS patients who had not developed TE (40.0%; P = .016). In contrast, the frequency of HLA-DQ1 was lower in TE patients than in healthy controls (40.0% vs. 66.5%, P = .027), but this difference did not reach statistical significance when corrected for the number of variables tested (corrected P = .108 for the general white population). HLA-DQ3 thus appears to be a genetic marker of susceptibility to development of TE in AIDS patients, and DQ1 may be a resistance marker. These HLA associations with disease indicate that development of TE in AIDS patients is affected by a gene or genes in the HLA complex and that HLA-DQ typing may help in decisions regarding TE prophylaxis.

Multiple genetic, metabolic, and environmental abnormalities are known to contribute to the pathogenesis of Alzheimer’s dementia (AD). If all of those abnormalities were addressed it should be possible to reverse the dementia; however, that would require a suffocating volume of drugs. Nevertheless, the problem may be simplified by using available data to address, instead, the brain cells whose functions become changed as a result of the abnormalities, because at least eleven drugs are available from which to formulate a rational therapy to correct those changes. The affected brain cell types are astrocytes, oligodendrocytes, neurons, endothelial cells/pericytes, and microglia. The available drugs include clemastine, dantrolene, erythropoietin, fingolimod, fluoxetine, lithium, memantine, minocycline, pioglitazone, piracetam, and riluzole. This article describes the ways by which the individual cell types contribute to AD’s pathogenesis and how each of the drugs corrects the changes in the cell types. All five of the cell types may be involved in the pathogenesis of AD; of the 11 drugs, fingolimod, fluoxetine, lithium, memantine, and pioglitazone, each address all five of the cell types. Fingolimod only slightly addresses endothelial cells, and memantine is the weakest of the remaining four. Low doses of either two or three drugs are suggested in order to minimize the likelihood of toxicity and drug–drug interactions (including drugs used for co-morbidities). Suggested two-drug combinations are pioglitazone plus lithium and pioglitazone plus fluoxetine; a three-drug combination could add either clemastine or memantine. Clinical trials are required to validate that the suggest combinations may reverse AD.

Human cytomegalovirus (CMV) DNA copy number in white blood cells from both human immunodeficiency virus (HIV)-seronegative and HIV-seropositive patients was amplified from the immediate-early region of CMV DNA and quantified by colorimetric detection of the hybridization of the amplification product to a detector oligonucleotide probe in microtiter wells. By Mann-Whitney U test, significantly higher (P < .05, two-tailed) copy numbers of CMV DNA were detected in HIV-seropositive patients with retinitis than in either patients with < 100 CD4 cells/mm3 and no symptomatic CMV disease or HIV-seropositive patients with > 100 CD4 cells/mm3. By prospective monitoring for increases in CMV DNA copy number, it may be possible to identify HIV-seropositive patients who are at imminent risk for development of symptomatic CMV retinitis.

Abstract A few anti‐amyloid trials offer a slight possibility of preventing progression of cognitive loss, but none has reversed the process. A possible reason is that amyloid may be necessary but insufficient in the pathogenesis of AD, and other causal factors may need addressing in addition to amyloid. It is argued here that drugs addressing myelination and synaptogenesis are the optimum partners for anti‐amyloid drugs, since there is much evidence that early in the process that leads to AD, both neural circuits and synaptic activity are dysfunctional. Evidence to support this argument is presented. Evidence is also presented that clemastine, fingolimod, and rolipram, benefit both myelination and synaptogenesis. It is suggested that a regimen that includes one of them plus an anti‐amyloid drug, could reverse AD.

Objective: Treatment of HIV patients with daily tesamorelin, a growth hormone-releasing factor analogue, for 26 weeks resulted in a significant decrease in visceral adipose tissue (VAT) and improvement in lipids. The objective of the 26-week extension phase was to evaluate long-term safety and effects of tesamorelin. Design: HIV patients with central fat accumulation in the context of antiretroviral therapy were randomized to tesamorelin 2 mg (n = 273) or placebo (n = 137) s.c. daily for 26 weeks. At week 26, patients originally on tesamorelin were rerandomized to 2 mg tesamorelin (T–T group, n = 154) or placebo (T–P group, n = 50), whereas patients originally on placebo were switched to tesamorelin (P–T group, n = 111). Methods: Safety included adverse events and glucose parameters. Results: Tesamorelin was generally well tolerated. The prevalence of adverse events and serious adverse events during the extension phase was comparable with the initial phase. Changes in glucose parameters over 52 weeks were not clinically significant and similar to those after 26 weeks. The change in VAT was sustained at −18% over 52 weeks of treatment (P < 0.001 versus baseline) as was the change in triglycerides (−51 mg/dl, P < 0.001 versus baseline). Similar sustained beneficial effects were seen for total cholesterol, but high-density lipoprotein decreased minimally over 52 weeks. Upon discontinuation of tesamorelin, VAT reaccumulated. Conclusion: Treatment with tesamorelin was generally well tolerated and resulted in sustained decreases in VAT and triglycerides over 52 weeks without aggravating glucose. Though effects on VAT are sustained during treatment for 52 weeks, these effects do not last beyond the duration of treatment.

A puzzling feature of schizophrenia, is the long latency between the beginning of neuropathological changes and the clinical presentation that may be two decades later. Abnormalities in oligodendrocyte function may explain this latency, because mature oligodendrocytes produce myelination, and if myelination were abnormal from the outset, it would cause the synaptic dysfunction and abnormal neural tracts that are underpinning features of schizophrenia. The hypothesis is that latency is caused by events that occur in some patients as early as in-utero or infancy, because clones of abnormal, myelinating oligodendrocytes may arise at that time; their number doubles every ~2 years, so their geometric increase between birth and age twenty, when clinical presentation occurs, is about 1000-fold plus the effect of compounding. For those patients in particular, the long latency is because of a small but ongoing increase in volume of the resulting, abnormally myelinated neural tracts until, after a long latent interval, a critical mass is reached that allows the full clinical features of schizophrenia. During latency, there may be behavioral aberrancies because of abnormally myelinated neural tracts but they are insufficiently numerous for the clinical syndrome. The occurrence of behavioral symptoms during the long latent period, substantiates the hypothesis that abnormal oligodendrocytes explain the latency in some patients. Treatment with fingolimod or siponimod benefits both oligodendrocytes and neural tracts. Clinical trial would validate their potential benefit in appropriate patients with schizophrenia and, concurrently, would validate the hypothesis.

Pharmacotherapy for most psychiatric conditions was developed from serendipitous observations of benefit from drugs prescribed for different reasons. An algorithmic approach to formulating pharmacotherapy is proposed, based upon which combination of changed activities by brain cell-types is dominant for any particular condition, because those cell-types contain and surrogate for genetic, metabolic and environmental information, that has affected their function. The algorithm performs because functions of some or all the affected cell-types benefit from several available drugs: clemastine, dantrolene, erythropoietin, fingolimod, fluoxetine, lithium, memantine, minocycline, pioglitazone, piracetam, and riluzole PROCEDURES/FINDINGS: Bipolar disorder, major depressive disorder, schizophrenia, Alzheimer's disease, and post-traumatic stress disorder, illustrate the algorithm; for them, literature reviews show that no single combination of altered cell-types accounts for all cases; but they identify, for each condition, which combination occurs most frequently, i.e., dominates, as compared with other possible combinations. Knowing the dominant combination of altered cell-types in a particular condition, permits formulation of therapy with combinations of drugs taken from the above list. The percentage of patients who might benefit from that therapy, depends upon the frequency with which the dominant combination occurs in patients with that particular condition.Knowing the dominant combination of changed cell types in psychiatric conditions, permits an algorithmically formulated, rationally-based treatment. Different studies of the same condition often produce discrepant results; all might be correct, because identical clinical phenotypes result from different combinations of impaired cell-types, thus producing different results. Clinical trials would validate both the proposed concept and choice of drugs.

Used as a supplement to psychotherapy, pharmacotherapy that addresses all of the known metabolic and genetic contributions to the pathogenesis of psychiatric conditions caused by stressors would require an inordinate number of drugs. Far simpler is to address the abnormalities caused by those metabolic and genetic changes in the cell types of the brain that mediate the behavioral abnormality. Relevant data regarding the changed brain cell types are described in this article and are derived from subjects with the paradigmatic behavioral abnormality of PTSD and from subjects with traumatic brain injury or chronic traumatic encephalopathy. If this analysis is correct, then therapy is required that benefits all of the affected brain cell types; those are astrocytes, oligodendrocytes, synapses and neurons, endothelial cells, and microglia (the pro-inflammatory (M1) subtype requires switching to the anti-inflammatory (M2) subtype). Combinations are advocated using several drugs, erythropoietin, fluoxetine, lithium, and pioglitazone, that benefit all of the five cell types, and that should be used to form a two-drug combination, suggested as pioglitazone with either fluoxetine or lithium. Clemastine, fingolimod, and memantine benefit four of the cell types, and one chosen from those could be added to the two-drug combination to form a three-drug combination. Using low doses of chosen drugs will limit both toxicity and drug-drug interactions. A clinical trial is required to validate both the advocated concept and the choice of drugs.

Two hundred and forty-six patients infected with human immunodeficiency virus (HIV) who also had disseminated Mycobacterium avium complex received either azithromycin 250 mg every day, azithromycin 600 mg every day, or clarithromycin 500 mg twice a day, each combined with ethambutol, for 24 weeks. Samples drawn from patients were cultured and clinically assessed every 3 weeks up to week 12, then monthly thereafter through week 24 of double-blind therapy and every 3 months while on open-label therapy through the conclusion of the trial. The azithromycin 250 mg arm of the study was dropped after an interim analysis showed a lower rate of clearance of bacteremia. At 24 weeks of therapy, the likelihood of patients' developing 2 consecutive negative cultures (46% vs. 56%, P=.24) or 1 negative culture (59% vs. 61%, P=.80) was similar for azithromycin 600 mg (n=68) and clarithromycin (n=57), respectively. The likelihood of relapse was 39% versus 27% (P=.21) on azithromycin compared with clarithromycin, respectively. Of the 6 patients who experienced relapse, none of those randomized to receive azithromycin developed isolates resistant to macrolides, compared with 2 of 3 patients randomized to receive clarithromycin [corrected]. Mortality was similar in patients comprising each arm of the study (69% vs. 63%; hazard, 95.1% confidence interval, 1.1 [0.7, 1.7]). Azithromycin 600 mg, when given in combination with ethambutol, is an effective agent for the treatment of disseminated M. avium disease in patients infected with HIV.

Abstract Several hundred clinical trials of initially promising drugs have failed to produce meaningful clinical improvement of Alzheimer's disease (AD), which is probably because there are at least 25 biochemical pathways known to be aberrant that underpin the disease, and unless there is a single drug that addresses all or most of them, even promising drugs if given alone are unlikely to succeed. Because so many pathways are potentially at fault, it is quite possible that no treatment might succeed. However, because amnestic mild cognitive impairment (aMCI) often precedes AD and, assuming that those with aMCI who progress to AD commence with insufficient risk factors for AD but accrue them later, then it is likely that fewer pathways need addressing in aMCI than in AD to either prevent progression of aMCI to AD or effect its reversion. Published reports show that eight drugs, that is, dantrolene, erythropoietin, lithium, memantine, minocycline, piracetam, riluzole, and silymarin, address many of the pathways underlying MCI and AD. Among those eight drugs, combinations between either two or three of them have combined nonoverlapping actions that benefit enough of the approximately 25 pathways at fault so that their convergent efficacy has the potential to prevent aMCI from progressing to AD. The combinations should be subjected to a clinical trial in persons with aMCI to establish their safety and efficacy.

Hydrogen sulfide (H2S) is one of the three known gas signal transducers, and since its potential physiological role was reported, the literature on H2S has been increasing. H2S is involved in processes such as vasodilation, neurotransmission, angiogenesis, inflammation, and the prevention of ischemia-reperfusion injury, and its mechanism remains to be further studied. At present, the role of post-translational processing of proteins has been considered as a possible mechanism for the involvement of H2S in a variety of physiological processes. Current studies have shown that H2S is involved in S-sulfhydration, phosphorylation, and S-nitrosylation of proteins, etc. This paper focuses on the effects of protein modification involving H2S on physiological and pathological processes, looking forward to providing guidance for subsequent research.

Abstract Prevention is better than cure and prevention of Alzheimer's disease (AD) may be possible. In elderly persons who are cognitively normal, synaptic hypometabolism as shown by reduced cerebral uptake of fluorodeoxyglucose ( 18 F‐FDG), provides a premonitory signal of potential, future loss of cognition if those individuals also have present evidence of amyloid deposition seen in the Pittsburgh compound B positron emission tomography (PIB‐PET) scan for amyloid. Those are the persons who should be targeted if one aims to prevent AD. The synaptic hypometabolism implies that the brain's availability of adenosine triphosphate (ATP) is inadequate for performance of all required synaptic functions. This review first describes the basis for asserting that reduced cerebral uptake of 18 F‐FDG accurately reflects synaptic hypometabolism; second, explains the basis for asserting that hypometabolism implies inadequate ATP; third, shows that amyloid beta (Aβ) itself, Aβ modified by pyroglutamate to become a molecule termed pE(3)Aβ, and cyclophilin‐D, in concert are the main contributors to inadequate synaptic ATP and that, therefore, reducing all of their levels would neutralize their combined effect and correct the hypometabolism. pE(3)Aβ is more neurotoxic than unmodified Aβ; and cyclophilin D inhibits ATP synthase and reduces ATP formation. Finally, this review describes an mRNA self‐replicating vaccine that will raise brain levels of ATP by reducing Aβ, pyroglutamate‐modified Aβ, and cyclophilin‐D, and thereby—in cognitively normal elderly persons who have synaptic hypometabolism—prevent initiation of the process that terminates in AD.

The goal of the treatment for Alzheimer's dementia (AD) is the cure of dementia. A literature review revealed 18 major elements causing AD and 29 separate medications that address them. For any individual with AD, one is unlikely to discern which major causal elements produced dementia. Thus, for personalized, precision medicine, all causal elements must be treated so that each individual patient will have her or his causal elements addressed. Twenty-nine drugs cannot concomitantly be administered, so triple combinations of drugs taken from that list are suggested, and each triple combination can be administered sequentially, in any order. Ten combinations given over 13 weeks require 2.5 years, or if given over 26 weeks, they require 5.0 years. Such sequential treatment addresses all 18 elements and should cure dementia. In addition, any comorbid risk factors for AD whose first presence or worsening was within ±1 year of when AD first appeared should receive appropriate, standard treatment together with the sequential combinations. The article outlines a randomized clinical trial that is necessary to assess the safety and efficacy of the proposed treatments; it includes a triple-drug Rx for equipoise. Clinical trials should have durations of both 2.5 and 5.0 years unless the data safety monitoring board (DSMB) determines earlier success or futility since it is uncertain whether three or six months of treatment will be curative in humans, although studies in animals suggest that the briefer duration of treatment might be effective and restore defective neural tracts.

The aim of this study is to examine the hypotheses stating the importance of amyloid or of its oligomers in the pathogenesis of Alzheimer's disease (AD).Published studies were examined.The importance of amyloid in the pathogenesis of AD is well established, yet accepting it as the main cause for AD is problematic, because amyloid-centric treatments have provided no clinical benefit and about one-third of cognitively normal, older persons have cerebral amyloid plaques. Also problematic is the alternative hypothesis that, instead of amyloid plaques, it is oligomers of amyloid precursor protein that cause AD.Evidence is presented suggesting amyloid/oligomers as necessary but insufficient causes of the dementia and that, for dementia to develop, requires the addition of cofactors known to be associated with AD. Those cofactors include several subcellular processes: mitochondrial impairments; the Wnt signaling system; the unfolded protein response; the ubiquitin proteasome system; the Notch signaling system; and tau, calcium, and oxidative damage.A modified amyloid/oligomer hypothesis for the pathogenesis of AD is that activation of one or more of the aforementioned cofactors creates a burden of functional impairments that, in conjunction with amyloid/oligomers, now crosses a threshold of dysfunction that results in clinical dementia. Of considerable importance, several treatments that might reverse the activation of some of the subcellular processes are available, for example, lithium, pioglitazone, erythropoietin, and prazosin; they should be given in combination in a clinical trial to test their safety and efficacy. © 2017 John Wiley & Sons, Ltd.

After the midninth decade of age, the incidence rates of Alzheimer's disease (AD) and the presence of active TGF-β1 show comparable increases. The hypothesis is proposed that the reason why advanced age is a major risk factor for AD is a progressive decrease with advancing age in the numbers of TGFR2 receptors in the brain, with the consequence of a decline in the neurotrophic efficacy of TGF-β1 and 2 despite their already increased levels in older persons. Alternative, possible reasons are discussed but rejected because either those reasons may also affect young persons or because they cannot be validated in a clinical trial. The proposed hypothesis may be validated in persons with aMCI after raising their brain levels of TGF-β1 and 2 by using a combination of three drugs, lithium, memantine, plus either glatiramer or venlafaxine, and then assessing their progression to AD.

A paradox regarding Alzheimer's dementia (AD) and mild cognitive impairment (MCI) is thats spontaneous cure of AD has never been reported, whereas spontaneous cure for MCI occurs fequently. This article analyzes what accounts for this difference. It holds that it is not merely because, for any condition, a stage is reached beyond which it cannot be reversed, since even widely metastatic cancer would be curable were there effective chemotherapy and rheumatoid arthritis became controllable when immune-suppressant treatment was introduced; thus, so could AD be reversible via effective therapy. The analysis presented leads to an explanation of the paradox that is in four categories: (1) levels of transforming growth factor-β are significantly reduced after the transition from MCI to AD; (2) levels of Wnt/β-catenin are significantly reduced after the transition; (3) there is altered epidermal-mesenchymal transition (EMT) in neurons after the transition; (4) there may be risk factors that are either newly operative or pre-existing but worsened at the time of transition, that are particular to individual patients. It is suggested that addressing and ameliorating all of those four categories might cure AD. Medications to address and ameliorate each of the four categories are described.

There are two generic approaches to curing any medical condition. The first treats every patient for all of the known possible causes that contribute to pathogenesis; the second individualizes potentially curative therapy by identifying in each separate patient only those components of pathogenesis that are actually operative, and treating those. This article adopts the second approach for formulating a cure of Alzheimer’s dementia (AD). Components of AD’s pathogenesis are, in alphabetical order: circadian rhythm disturbances, depression, diabetes and insulin resistance, dyslipidemia, hypertension, inflammation, metabolic syndrome, mitochondrial dysfunction, nutritional deficiencies, TGF-β deficiency, underweight, vascular abnormalities, and Wnt/β-catenin deficiency. For each component, data are described that show the degree by which its prevalence is more in the patients with mild cognitive impairment (MCI) who did not revert to having normal cognition than in those who did, because the former group is the pool of patients from among which future AD may develop. Addressing only those components that are present in a particular individual, is potentially a curative strategy. Published data indicate that curative therapy requires that the number of such components to address should be ≥3. Although structural brain changes cannot be directly addressed, the impaired neural tracts result from many of the reversible causal elements, so correcting them will benefit those tract

There are two generic approaches to curing any medical condition. The first one treats every patient for all the known possible causes that contribute to pathogenesis; the second one individualizes potentially curative therapy by only identifying in each separate patient the components of pathogenesis that are actually operative and treating those. This article adopts the second approach for formulating a cure for Alzheimer's dementia (AD). The components of AD's pathogenesis are, in alphabetical order, as follows: circadian rhythm disturbances, depression, diabetes and insulin resistance, dyslipidemia, hypertension, inflammation, metabolic syndrome, mitochondrial dysfunction, nutritional deficiencies, TGF-β deficiency, underweight, vascular abnormalities, and Wnt/β-catenin deficiency. For each component, data are described that show the degree to which its prevalence is higher in patients with mild cognitive impairment (MCI) who did not revert to having normal cognition than in those who did because the former group is the pool of patients in which future AD may develop. Only addressing the components that are present in a particular individual potentially is a curative strategy. Published data indicate that curative therapy requires the number of such components that are addressed to be ≥3. Although structural brain changes cannot be directly addressed, the impaired neural tracts result from many of the reversible causal elements, so correcting them will benefit these tracts.

Atraumatic osteonecrosis is a common complication of SLE and is seen in other connective tissue diseases, in patients treated with high doses of CSs, in HIV-infected patients and in alcoholic patients. Standard care is confined to analgesia, core decompression if the condition is early and affects the femoral head and joint replacement. However, consideration of the underlying biological mechanisms leads to the recognition of many potential therapies that might either prevent progression or, even, reverse the process if it is not yet too far advanced. These potential therapies merit detailed consideration. Critical points are that (i) histopathological evidence shows that the initial cellular event is apoptosis of osteocytes; and (ii) another requisite, as homeostasis requires that death and rebirth of osteocytes be balanced, is an accompanying inadequate proliferative capacity of osteoblasts. Thus, a logical approach to treatment includes measures that (i) reduce apoptosis of osteocytes and (ii) enhance proliferation of osteoblasts/pre-osteoblasts. Measures to reduce the ongoing apoptosis of osteocytes require reinforcing the effects of members of the Bcl-2 family (Bcl-2 itself and Mcl-1), the Wnt/catenin pathways (using an available sclerostin antibody) and HSPs (by application of local heat using US, deep wave diathermy or infrared), as well as administration of bisphosphonates and nitrates. Measures to enhance proliferation of osteoblasts/pre-osteoblasts include the use of stem cells, extracorporeal shock wave therapy, aspirin, the proteosome inhibitor bortezomib, melatonin and application of local heat. Use of VEGF would encourage proliferation of blood vessels and osteogenesis. Certain drugs that inhibit osteoblast proliferation should be avoided, including NSAIDs, serotonin reuptake inhibitors and thiazolidinediones.

Abstract Elderly persons with currently normal cognition who have cerebral hypometabolism as shown by low uptake of 18 fluorine‐fluorodeoxyglucose ( 18 F‐FDG), are at risk of future loss of cognition and, thus, of future Alzheimer's dementia (AD). Reduction of either 18 F‐FDG or cognition is assumed to reflect synaptic dysfunction, since synapses account for the majority of glucose use by the brain and cognition depends upon accurate synaptic function. The chronology of the connection between reduced cerebral synaptic function and hypometabolism is, therefore, a critical question, because if synaptic dysfunction came first, then correcting the hypometabolism would likely not benefit synaptic function; but if hypometabolism came first, then correcting the hypometabolism probably would benefit synaptic function. That correction might prevent initiation of the cognitive loss that eventuates in AD and, thereby, would benefit the vast numbers of persons in their eighth to tenth decades of life who are at risk for AD. Among the many citations reviewed in this presentation, seven show hypometabolism that precedes synaptic dysfunction, and two show the reverse. Thus the preponderance of evidence, 78%, suggests that the initiating event is synaptic hypometabolism and that it is 3.5‐fold less likely that synaptic dysfunction is the initiator. In addition, it is inherently unlikely that synaptic dysfunction causes hypometabolism. This conclusion could be tested by a clinical trial whose primary objective would be to assess the benefit to cognition of improving synaptic metabolism in patients who are at risk for cognitive loss.

Abstract It is better to attempt stopping Alzheimer's disease (AD) before it starts than trying to cure it after it has developed. A cerebral scan showing deposition of either amyloid or tau identifies those elderly persons whose cognition is currently normal but who are at risk of subsequent cognitive loss that may develop into AD. Synaptic hypometabolism is usually present in such at‐risk persons. Although inadequate adenosine triphosphate (ATP) may cause synaptic hypometabolism, that may not be the entire cause because, in fact, measurements in some of the at‐risk persons have shown normal ATP levels. Thiamine deficiency is often seen in elderly, ambulatory persons in whom thiamine levels correlate with Mini‐Mental State Examination scores. Thiamine deficiency has many consequences including hypometabolism, mitochondrial depression, oxidative stress, lactic acidosis and cerebral acidosis, amyloid deposition, tau deposition, synaptic dysfunction and abnormal neuro‐transmission, astrocyte function, and blood brain barrier integrity, all of which are features of AD. Although the clinical benefits of administering supplementary thiamine to patients with AD or mild cognitive impairment have been mixed, it is more likely to succeed at preventing the onset of cognitive loss if administered at an earlier time, when the number of aberrant biochemical pathways is far fewer. Providing a thiamine supplement to elderly persons who still have normal cognition but who have deposition of either amyloid or tau, may prevent subsequent cognitive loss and eventual dementia. A clinical trial is needed to validate that possibility.

(1) To summarize the mental conditions that may accompany persistent symptoms following acute infection by SARS-CoV-2, often termed Long Covid; (2) to formulate treatment based upon the brain cells that are dominantly affected.(1) Review the reports relating to the mental symptoms occurring in Long Covid. (2) Review the drugs that address the brain cells affected in Long Covid, and suggest pharmacotherapy for those patients whose response to psychotherapy is suboptimal.Long Covid affects ~ 10% of patients infected by SARS-CoV-2, and mental symptoms affect ~ 20% of persons with Long Covid. The brain cell-types that have been demonstrated as dominantly affected in Long Covid are astrocytes, oligodendrocytes, neurons, endothelial cells/pericytes, and microglia. Lithium and fluoxetine each address all of those four cell-types. Low dosage of each is likely to be well-tolerated and to cause neither clinically important adverse events (AE) nor serious adverse events (SAE).For those patients whose response to psychotherapy is suboptimal, lithium and fluoxetine should be administered in combination for both depth of benefit and reduction of dosages.

Although drugs may slow its progression, authentic cure of AD has never been accomplished. Here, six approaches are suggested that might achieve genuine cure. The six therapies include: 1) treatments addressing levels of TGF-β and Wnt/β-catenin, that become significantly reduced after MCI transitions to AD, and addressing also the impaired epithelial-to-mesenchymal transition (EMT) in AD's pathogenesis; 2) and 3) are two formulations that address the inadequate counter-responses to initial loss of cognition; 4) treatments addressing the brain cells whose impaired functions result in MCI and dementia; 5) the need for using partner drugs even when a particular drug addresses a single pathogenetic cause such as amyloid deposition; 6) enhancing the likelihood of genuine cure by using combinations of approaches chosen from the foregoing. Briefly, genuine cure of AD is possible; however, since AD denotes not one but multiple, phenotypically similar conditions, no one therapy can be generalized to all cases.

In a well-conducted study involving more than 9000 patients and pancreatitis events from 2001 to 2006, the EuroSIDA investigators report in this issue of AIDS a ‘low overall rate of pancreatitis’ (1.27 cases of pancreatitis per 1000 patient-years) and no increased risk of pancreatitis among HIV-infected patients treated with antiretroviral drugs, or among patients who received 2′,3′-dideoxyinosine (didanosine) or 2′,3′-didehydro-3′-deoxythymidine (stavudine) whether singly or in combination. The only risk factors for pancreatitis found after controlling for confounding were high viral load, lower CD4 cell level, and more advanced disease. Those of us who have been treating HIV-infected patients since the earliest days of the epidemic, and saw much pancreatitis in those early days, will find the EuroSIDA data interesting and quite surprising, particularly in the light of other reports, including one citing data from as recently as 2001, which described rates that are much higher than those from EuroSIDA. Dutta et al.[1] analysed 321 patients seen in the period 1993–1994; 45 (14%) developed pancreatitis. Among 8451 subjects enrolled in 20 AIDS Clinical Trials Group studies in 1989–1999, Reisler et al.[2] reported an overall pancreatitis rate that was almost five times that in EuroSIDA, i.e. 6.1 per 1000 person-years. In a separate report, Reisler et al.[3] saw pancreatitis in 8.5 per 1000 person-years during the later period, 1996–2001. As the EuroSIDA investigators mention, previous studies used various methods applied to a variety of patients and report a range of rates. It is unfortunate, however, that the EuroSIDA data do not extend further back in time to show whether their current low rates reflect a decline from previous years or whether their rates have always been low. The EuroSIDA findings led us to examine our own experience with a large group of HIV-infected individuals treated in the facilities of the Kaiser Permanente Medical Care Program in Northern California during the years 1996–2006, when the number of HIV patients in care ranged between 4000 and 6000 annually. We looked to see whether the data for 2001–2006 show a similarly low annual incidence of pancreatitis as reported by EuroSIDA, and whether there was a decline in these later years (2001–2006) compared with earlier years (1996–2000). We counted as incident pancreatitis events (‘presumptive’ by EuroSIDA standards) the first occurrences of plasma lipase greater than four times the upper limit of normal, amylase greater than six times the upper limit of normal (this level of amylase is unlikely to represent a non-specific increase), or a diagnosis of pancreatitis as captured in the electronic medical record. Figure 1 shows that the annual incidence of pancreatitis according to these criteria was approximately five times that seen by EuroSIDA, and approximately the same as occurred in the 8451 patients reported by Reisler et al.[2]. Furthermore, we observed very little, if any, decline in incidence over the 11-year period.Fig. 1: Incidence (first per patient) of pancreatitis: Kaiser Permanente Northern California, 1996–2006. An event is defined as lipase greater than four times the upper limit of normal, amylase greater than six times the upper limit of normal, or a diagnosis of pancreatitis (hospital or outpatient International Classification of Diseases, version 9, code 577.xx).Equally puzzling in the EuroSIDA report (and something we have not yet analysed in our own data) is the absence of a role for didanosine or stavudine in the etiology of pancreatitis despite the fact that 43% of the EuroSIDA patients used these drugs either singly or in combination at baseline. Pancreatitis was recognized as a complication of didanosine therapy even in the phase 1 studies and its occurrence was clearly related to dosage: whereas only 6.3% of those receiving less than 500 mg/day developed pancreatitis, this increased to 13.3% of those receiving 500–750 mg/day, and rose to 50% of those taking more than 750 mg/day [4]. Another early study of 51 men with AIDS treated with didanosine 10–12 mg/kg per day showed clinical pancreatitis in 12 and asymptomatic elevations of amylase and lipase in another 10 men [5]. Pancreatitis caused by stavudine is also a well-established phenomenon. Among 2163 patients receiving one or both of didanosine and stavudine, the rate was 10 per 1000 person-years for stavudine, eight per 1000 person-years for didanosine and 60 per 1000 person-years for stavudine combined with didanosine [6]. What might account for the four to fivefold lower rate observed at EuroSIDA sites compared with north America, and for the absence of an association with exposure to didanosine and stavudine? These are intriguing questions that deserve further study. Is the lower incidence of pancreatitis an issue of different drugs besides antiretroviral agents that were used and might exert synergistic or antagonistic effects with antiretroviral therapy vis a vis harm or protection of the pancreas? For example, pentamidine causes pancreatitis and was widely used in inhalation therapy as prophylaxis against pneumocystis pneumonia before the efficacy of sulfamethoxazole/trimethoprim was recognized. If this were the explanation, there should be far fewer cases in the years since 2000 than in earlier years, but Fig. 1 does not show this difference nor did the two reports of Reisler and colleagues [2,3]. Is there a difference in the prevalence of gallstones in the two continents that might be reflected in different rates of pancreatitis? Is the form of alcohol consumed by Europeans different from that which north Americans drink? Does the north American diet cause more hypertriglyceridemia than the European diet? As regards the absent association of didanosine and stavudine with pancreatitis in the EuroSIDA studies, these drugs are used less in recent years because of their several toxicities. Our own findings show little if any lowering of the incidence of pancreatitis in those recent years (Fig. 1). Concomitant use of methadone reduced the measured areas under the time-concentration curve of didanosine by 63% and of stavudine by 25% [7]; was methadone more widely used by European than north American patients? Were more of the north Americans than the Europeans receiving treatment for hepatitis C? Among 22 patients infected with HIV and treated for hepatitis C with interferon and ribavirin, five developed pancreatitis; four of these were taking both didanosine and stavudine, one was taking stavudine without didanosine [8]. In brief, the EuroSIDA observations of a low rate of pancreatitis and a minimal role for didanosine and stavudine are discordant with experience from north America. The reasons for these unexpected findings are unclear and require further study. Conflicts of interest: None.

Abstract One of the puzzling observations concerning mild cognitive impairment (MCI) and Alzheimer's disease (AD), is that many gene expressions in MCI may be in the opposite direction of those seen in AD. Several examples of this paradox are provided. The likely explanation lies in in the control mechanisms of gene transcription. These mechanisms include (1) modification of DNA and histones by methylation or acetylation, affecting the balance between the Compass group of proteins that enhances mRNA formation, and the Polycomb group that suppresses it; (2) compensation for the loss of one gene's function by another gene with overlapping functions; (3) reduced control of the entire neural RNA production; and (4) response to microRNAs (miRNA). Although data are inadequate to exclude with certainty any one of the indicated mechanisms, the available evidence favors overall reduced control of neural mRNA production, including the effect of miRNA. The switch occurs at a specific stage, somewhere between Braak 0‐1 and Braak 2‐3, in the progression from MCI to AD, which reduces the number of its likely causes. Two strong but related candidates are the repressor element‐1 silencing transcription factor (REST), which in adult neurons impairs plasticity; and a miRNA, for example, miRNA124, that represses REST. Another possible explanation is that only those patients with MCI who will not progress to AD are the ones that have gene expressions in the opposite direction as in AD. The solution to the paradox may have pragmatic value.

Abstract Reduced functionality of transforming growth factor β (TGF‐β) is a major pathogenetic component of Alzheimer's disease (AD). The reduction is caused by an ≈50% decrease in the AD brain of the TGF‐β receptor, TGFBR, causing a bottleneck effect that reduces the downstream actions of TGF‐β, which is highly disadvantageous for brain function. Degradation of TGFBR occurs in caveolae with participation by caveolin‐1 (Cav‐1) and CD109. Mechanisms for this are discussed. In the cerebral microcirculation, endothelial cells (which are rich in caveolae) carry CD109 as a surface marker that co‐precipitates with Cav‐1. Atorvastatin reduced Cav‐1 by 75% and, because Cav‐1 and CD109 co‐immunoprecipitate reciprocally, atorvastatin would also reduce the level of CD109. Administration of atorvastatin as a component of combination therapy would diminish the degradation of TGFBR and thereby benefit patients with AD.

Abstract In the process that eventuates in mild cognitive impairment (MCI) and ultimately in Alzheimer's dementia, the earliest identifiable change is in the function of synapses. If started at that early point in time, when there is subjective but not objective memory loss plus abnormal brain imaging with fluorodeoxyglucose and Pittsburgh compound B, treatment with a single drug directed at synaptic dysfunction might prevent development of cognitive impairment. Each of four drugs, dantrolene, lithium, minocycline, and piracetam, benefits synaptic impairment. This presentation has two sections. In the first, evidence is discussed at length, for abnormality in the axo‐spinous synapse as being the earliest change before objective cognitive decline. The second section explains the benefits to synapses provided by the four mentioned drugs. Dantrolene and lithium perhaps have the strongest supporting data for use as single agents: their efficacy should be subjected to clinical trial.

MycosesVolume 49, Issue 1 p. 68-69 Smoking and cryptococcosis in AIDS patients Gary D. Friedman, Gary D. Friedman Division of Research, Kaiser Permanente Medical Care Program Department of Health Research and Policy, Stanford University School of Medicine, OaklandSearch for more papers by this authorJeffrey Fessel, Jeffrey Fessel Department of Medicine, Kaiser Permanente Medical Center, San Francisco, CA, USASearch for more papers by this authorNatalia Udaltsova, Natalia Udaltsova Division of Research, Kaiser Permanente Medical Care ProgramSearch for more papers by this authorLeo B. Hurley, Leo B. Hurley Division of Research, Kaiser Permanente Medical Care ProgramSearch for more papers by this author Gary D. Friedman, Gary D. Friedman Division of Research, Kaiser Permanente Medical Care Program Department of Health Research and Policy, Stanford University School of Medicine, OaklandSearch for more papers by this authorJeffrey Fessel, Jeffrey Fessel Department of Medicine, Kaiser Permanente Medical Center, San Francisco, CA, USASearch for more papers by this authorNatalia Udaltsova, Natalia Udaltsova Division of Research, Kaiser Permanente Medical Care ProgramSearch for more papers by this authorLeo B. Hurley, Leo B. Hurley Division of Research, Kaiser Permanente Medical Care ProgramSearch for more papers by this author First published: 30 November 2005 https://doi.org/10.1111/j.1439-0507.2005.01178.xCitations: 2 Gary D. Friedman, MD, Kaiser Permanente Division of Research, 2000 Broadway, Oakland, CA 94612, USA. Tel.: +1 510 891 3542. Fax: +1 510 891 3606. E-mail: gdf@dor.kaiser.org Read the full textAboutPDF 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 Volume49, Issue1January 2006Pages 68-69 RelatedInformation

Abstract If it is correct that ineffective levels of transforming growth factors beta and their receptor account for old age being a risk factor for Alzheimer's disease (AD), then increasing TGFBR2 might be therapeutic. Pacltaxel is a direct way to increase TGFBR2 levels. Indirect ways that will increase TGFBR2, include decreasing the levels of c‐myc because that will lower the miRNA cluster 17‐92, particularly its miR‐17 and miR‐20a components; and raising EGFR because that also will increase TGFBR2. Metformin and desferrioxamine are drugs that decrease c‐myc; and statins increase levels of EGF. Clinical trials using those drugs, would demonstrate whether they decrease the progression from amnestic mild cognitive impairment to AD.

The goal of treatment for Alzheimer's dementia (AD) is the restoration of normal cognition. No drug regimen has ever achieved this. This article suggests that curing AD may be achieved by combination therapy as follows. First, with intranasal insulin to augment the body's natural counter-reaction to the changes in brain cell-types that produced the dementia. Second, with edaravone to decrease free radicals, which are increased and causal in AD. Third, as described elsewhere, with one or two drugs from among pioglitazone, fluoxetine, and lithium, which address the brain cell-types whose changed functions cause the dementia. Insulin restores cerebral glucose, which is the main nutrient for brain neurons whose depletion is responsible for the dementia; and edaravone decreases ROS, which are intrinsic causes of neuropathology in AD. This combination of drugs is a potential cure for many patients with AD, and should be tested in a clinical trial.

Objective The objective of this study was to determine whether a triple therapy regimen incorporating twice-daily saquinavir is as effective as a three-times daily regimen. Methods This was an open-label, Phase III, multicentre, 48-week study involving 837 HIV-1-infected patients randomised to one of the following: saquinavir soft gel capsule (SGC) 1200 mg three-times daily, plus two nucleoside reverse transcriptase inhibitors (NRTIs) (arm A); saquinavir SGC 1600 mg twice-daily, plus two NRTIs (arm B); saquinavir SGC 1200 mg twice-daily and nelfinavir 1250 mg twice-daily, plus a single NRTI (arm C). The primary outcome measure was the virological response in arm A versus B and in arm A versus C with respect to the percentage of patients whose plasma HIV-1 RNA levels fell below the level of quantification for the Amplicor assay (&lt;400 copies/ml) at weeks 24 and 48. Results At 48 weeks, the percentage of patients with plasma HIV-1 RNA levels &lt;400 copies/ml was 47.1% (arm A), 45.3% (arm B) and 42.7% (arm C) in the intention-to-treat analysis. The treatment difference between arm B–arm A was -1.8% (95% confidence intervals -10.1, 6.5) and for arm C–arm A was -4.5% (95% confidence intervals -12.7, 3.7) in the intention-to-treat analysis. These differences fell within the maximum allowable difference (±12%) for arm B compared with arm A. At week 24, the percentage of patients with HIV-1 RNA levels &lt;400 copies/ml was 59.6% (arm A), 57.6% (arm B) and 51.3% (arm C). Conclusions A twice-daily triple therapy regimen incorporating saquinavir SGC plus two NRTIs was of equivalent efficacy to the three-times daily regimen studied. All regimens were generally well tolerated.

The thesis A causal nexus of mutually interacting elements exists; normal cognition requires their balance whereas imbalance creates AD. Interacting elements include APP, presenilins (PS), mitochondria, mitophagy, unfolded protein response (UPR), Wnt/beta-catenin, cyclins, Notch, and calcium. In brief detail we describe, first, some effects of individual elements and, second, their mutual interactions. Literature review (citations will be provided). A. Effects of individual components: Presenilins: Correct protein function requires protein-folding. PS1 plus excessive unfolded proteins, initiate the UPR; ATP is required for chaperones to assist protein-folding. Insufficient ATP from dysfunctional mitochondria causes improper protein-folding, leading to amyloid. PS1wt maintains gamma-secretase as inactive. Mutated/dysfunctional PS1(PSImut) activates gamma-secretase, which cleaves APP to generate A-beta. PS1wt also cleaves Notch1, thus affecting neuronal plasticity and cerebral vascular density. APP and Notch1 are competitive substrates for gamma-secretase so Notch1 activation reduces A-beta generation. High Notch1 levels in AD neurons may exist to improve the known, poor cerebral capillary vascularity in AD. Wnt 5a and Wnt 7 signalling regulate adult neurogenesis in the SVZ, and also affect synapses; Wnt 3 affects differentiation of NSCs. Dysfunctional mitochondria in AD, major contributors to neuronal dysfunction, require elimination by mitophagy. Noteworthily, neuronal endocytosis initiates mitophagy before A-beta deposition. Mitophagy engulfs damaged mitochondria into autophagic vacuoles (AV); intermediate vacuoles develop, then fuse with lysosomes for digestion by cathepsins. AD brains showed 20-fold more AVs (they dispose impaired mitochondria, which stimulates biogenesis of normally functioning organelles). Calcium, whether high or low, stimulates autophagy. B. Interactions between elements of the causal nexus: Amyloid deposits in mitochondrial membranes create mitochondrial dysfunctions, decrease mitochondrial biogenesis, and impair neuronal function. A-beta causes low Wnt signaling, reducing neural β-catenin and neuronal viability. Interactions between PS1wt, cyclins and beta-catenin, disturb the neuronal cell cycle. PSImut produces many impairments: Whereas PS1wt cleaves Notch1, PSImut inhibits Notch1, thereby reducing capillary density; PSImut enhances release of calcium from ER, causing impaired neuronal function; either high or low calcium stimulates mitophagy; PSImut inactivates elements required to promote UPR. Notch1&3 direct astrocyte formation from NHCs. Normal cognition requires balance within a nexus of interacting elements; imbalance would promote AD.

1. A rich literature documents mitochondrial dysfunction in AD (fig 1), probably accounting for the dysfunctional neurons, astrocytes, and capillaries that underlie the dementia. 2. For correct function, proteins require folding, which needs ATP generated by mitochondria to provide energy for chaperones, e.g., HSP70, to assist that folding. 3. Stress causes accumulation of unfolded proteins, provoking the “Unfolded Protein Response” at the endoplasmic reticulum. Dysfunctional mitochondria producing insufficient ATP may result in improper protein folding leading to amyloid. 4. Dysfunctional mitochondria require elimination by mitophagy; also needed is biogenesis of new organelles having normal function. 5. Mitophagy, i.e., autophagocytic disposal of damaged mitochondria, commences by engulfing damaged mitochondria into an autophagocytic vacuole (AV), after which come intermediate vacuoles and ultimately fusion with a lysosome for enzymatic digestion of vacuoles’ contents. AD brains showed 20-fold more AVs than control brains (1); contents of those AVs would include impaired mitochondria. Review of relevant literature in AD regarding mitophagic elimination of dysfunctional mitochondria and biogenesis of new, functional, mitochondria. Mitophagic enhancement. Inositol inhibits mitophagy; lithium depletes inositol (by inhibiting IMP3) thus enhancing mitophagy (via an uncertain molecular mechanism (2)). Mitochondrial depletion stimulates mitochondrial biogenesis. Other drugs that enhance mitochondrial biogenesis include erythropoietin and pioglitazone. Erythropoietin activates eNOS, causing production of nitric oxide (NO), which then triggers transcription of genes involved in mitochondrial biogenesis (3). Thiazolidinediones, e.g., pioglitazone, induce mitochondrial biogenesis by increasing expression of PPAR-1α-coactivator, the principle regulator of mitochondrial biogenesis. (4). Treatment using concurrent combinations having different targets is more effective than sequentially using single agents. A clinical trial would test the hypothesis that a combination of lithium, erythropoietin, and pioglitazone, might impede the progression of MCI to AD, or of early to more advanced AD. Dysfunctional mitochondria underlie AD and may be disposed, by combining lithium, erythropoietin, and pioglitazone to enhance mitophagy, which then stimulates production of new organelles by enhancing mitochondrial biogenesis. 1. Nixon, J Cell Sci 2007;120:4081-4091. 2. Sarkar, J Cell Biol 2011;101:514-519. 3. Burger, Cardiovasc Res 2006;72:51-59. 4. Gosh, Mol Pharmacol 2007;71:1695-1702. A few of many references demonstrating abnormality of mitochondrial function or anatomy in AD brain.

A rich literature documents mitochondrial dysfunction in AD, probably accounting for the dysfunctional neurons, as well as astrocytes and capillaries, that underlie the dementia. For their correct functioning, proteins require folding, which needs ATP generated by mitochondria to provide energy for chaperones, e.g., HSP70, to assist that folding. Stress causes accumulation of unfolded proteins, provoking the “Unfolded Protein Response” at the endoplasmic reticulum. Dysfunctional mitochondria producing insufficient ATP may result in improper protein folding leading, crucially, to amyloid/oligomers. Dysfunctional mitochondria require elimination by mitophagy; also needed is biogenesis of new organelles having normal function. Mitophagy, i.e., autophagocytic disposal of damaged mitochondria, commences by engulfing damaged mitochondria into an autophagocytic vacuole (AV), after which comes a series of intermediate vacuoles and ultimately fusion with a lysosome for enzymatic digestion of contents. AD brains showed 20-fold more AVs than control brains (1); those AVs would include impaired mitochondria. Review of relevant literature in AD regarding mitophagic elimination of dysfunctional mitochondria and biogenesis of new, functional, mitochondria. (Full references will be provided). Mitophagic enhancement. Inositol inhibits mitophagy; lithium depletes inositol (by inhibiting IMP3) thus enhancing mitophagy [by an uncertain molecular mechanism (2)]. Mitochondrial depletion stimulates mitochondrial biogenesis. Other drugs that enhance mitochondrial biogenesis include erythropoietin and pioglitazone. Erythropoietin activates eNOS, causing production of nitric oxide (NO), which triggers transcription of genes involved in mitochondrial biogenesis (3). Thiazolidinediones, e.g., pioglitazone, induce mitochondrial biogenesis by increasing expression of PPAR-1α-coactivator, the principle regulator of mitochondrial biogenesis. (4). Treatment using concurrent combinations having different targets is more effective than sequentially using single agents. A clinical trial would test the hypothesis that a combination of lithium, erythropoietin, and pioglitazone, might impede the progression of MCI to AD, or of early to more advanced AD. Dysfunctional mitochondria underlie AD and may be cleared, by combining lithium, erythropoietin, and pioglitazone to enhance mitophagy, which then stimulates birth of new organelles by enhancing mitochondrial biogenesis. Nixon, J Cell Sci 2007;120:4081-4091. Sarkar, J Cell Biol 2011;101:514-519. Burger, Cardiovasc Res 2006;72:51-59. Gosh, Mol Pharmacol 2007;71:1695-1702.

For many years The Lancet has advocated on behalf of the Palestinians, sometimes justifiably, but often unjustifiably. On several occasions, I have protested against a distinguished medical journal advocating political issues—only tangentially medical. Now, the latest Lancet salvo is fired under the innocent title “Improving forensic investigation for polonium poisoning” (Oct 12, p 1308).1Froidevaux P Baechler S Bailat CJ et al.Improving forensic investigation for polonium poisoning.Lancet. 2013; 382: 1308Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar In this report (about Yasser Arafat's death), the authors state that “several samples containing body fluid stains (blood and urine) contained higher unexplained 210Po activities than the reference samples”.1Froidevaux P Baechler S Bailat CJ et al.Improving forensic investigation for polonium poisoning.Lancet. 2013; 382: 1308Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar No laboratory numerical data are provided; nor how many different samples showed increased activity or how urine stains were identified. It is shocking and reprehensible that The Lancet published such a report that could become a political bombshell without providing all the information needed for proper assessment of the validity of the data. If this report was subjected to peer review, then I can only assume that The Lancet selected those reviewers with great care! “Three scientific teams are currently analysing body, shrine, and earth samples”1Froidevaux P Baechler S Bailat CJ et al.Improving forensic investigation for polonium poisoning.Lancet. 2013; 382: 1308Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar…Was The Lancet so fearful those analyses would not show polonium poisoning that it deemed appropriate to publish this report in advance? Interestingly, the 17-page Russian forensic report on Arafat's death states that the working hypothesis regarding the subject's death being caused by penetration of 210Po into his body was recognised as unsubstantiated.2Al Jazeera Investigative UnitRussian forensic report on Arafat's death.http://www.aljazeera.com/investigations/killing-arafat/russian-forensic-report-arafat-death-20131189959812216.htmlGoogle Scholar I declare that I have no conflicts of interest. Improving forensic investigation for polonium poisoningAt the time of publication, the remains of Yasser Arafat have been exhumed and are being investigated for cause of death as a result of the findings of the case reported here. Full-Text PDF Offline: Celebrating progress in Palestinian health researchFor several years, Derek Summerfield, a psychiatrist and expert in torture and war-related violence, encouraged us to write about the predicaments of the Palestinian people. We said no. The occupied Palestinian territory seemed too difficult a subject to cover from a position of complete ignorance. Derek proposed a meeting with the public health scientist, Rita Giacaman. I can't easily put into words the impact this meeting had on me. Rita, who cofounded the Institute of Community and Public Health at Birzeit University, introduced The Lancet to Palestinian health, culture, and history. Full-Text PDF

Reversal of Alzheimer's dementia (AD) is the holy grail of AD research but has never been achieved, whereas prevention of AD is within reach. Two ways of preventing AD are presented here: use of thiamine and use of a triple mRNA vaccine. For its energy, the brain uses both glucose and ATP, both of whose formation involves thiamine-dependent processes such as pyruvate dehydrogenase complex (PDHC), α-ketoglutarate dehydrogenase complex (KGDHC), and transketolase (TK). For its activation, thiamine requires phosphorylation via thiamine phosphokinase (TPK), producing thiamine diphosphate (TDP) also known as thiamine pyrophosphate (TPP). Sang et al. reported that TPK levels in the frontal cortex from 129 AD patients were significantly reduced (p < .001), and that TPK gene knockout (ko) in mice caused low cerebral glucose, plus features of AD, namely, increased levels of Aβ40 and Aβ42, brain deposition of β-amyloid, tau hyperphosphorylation, neuroinflammation, and neuronal loss.1 Also, in a cross-species correlation analysis, Sang et al. found genome-wide correlations of gene expressions between those in cortex samples of the ko mice and cortex samples from AD patients, particularly pre-frontal and visual cortices. Thiamine deficiency, present in AD, has several pathogenic consequences, including oxidative stress, cerebral acidosis, impaired neurotransmission, and amyloid deposition.2 Comparing 43 AD patients and 338 controls, there was a 27.8% decreased blood level of TDP in AD (85.0 vs. 117.7 nmol/L. p < .001); for the diagnosis of AD, sensitivity was 81.5% and specificity was 77.2.3 Similar decrements in blood levels of TDP are reported by other authors. In the AD brain itself, Heroux et al. saw significant reductions: in the temporal cortex TDP was reduced by 29.3% and PDHC by 53.8; in the frontal cortex, KGDHC was reduced by 58.3% % and TK by 37.5%.4 KGDHC catalyzes conversion of α-ketoglutarate to succinyl-CoA, ultimately generating NADH and after that ATP; reduced levels of KGDHC have been consistently observed in post-mortem AD brains5; and thiamine deficiency reduced KGDHC levels in mouse brains by as much as 52%.6 It is also relevant that thiamine levels are low in mild cognitive impairment (MCI), demonstrating that thiamine deficiency is not just a late event in fully developed AD but occurs early in the pathogenic process.2 Among 75 patients with Parkinson's disease, 32 had MCI and were compared with the 43 whose cognition was normal: plasma thiamine was, respectively, 9.3 and 11.4 nmol/L (p = .028); MMSE scores were 28.2 and 29.1 (p = .006).7 Even in healthy persons, low thiamine levels correlate with lower results in neurocognitive tests. La Rue et al. reported data for 137 healthy persons with mean age 76.9 years, who had no overt cognitive loss, who completed cognitive testing in 1986 after its initial testing in 1980, and who had nutritional findings available from both 1980 and 1986.8 The Abstraction Scale from the Shipley-Hartford Intelligence test asks the subject to specify the missing items in several series (e.g., AB, BC, CD, D?) and is considered to be a very sensitive measure of abstraction ability. For thiamine, concurrent dietary intake was positively correlated with performance in the Abstract test, and the thiamine plasma level as measured by the erythrocyte transketolase activity coefficient (ETKAC) was negatively correlated with Abstract test results, indicating that a low erythrocyte thiamine concentration correlated with poorer ability for abstraction, because a higher ETKAC indicates a lower thiamine level. Also relevant with respect to a recommendation for supplementary thiamine as prophylaxis against cognitive loss, those persons taking supplementary thiamine had results that were 26.6% better (p < .01) in the Abstraction test than had those persons not taking supplementary thiamine, and were better by 5% in the Rey-Osterrieth copy test (p < .05) and 24% in the Rey-Osterrieth recall test (p < .05). Overall, therefore, data support that supplementary thiamine for persons at risk, that is, age >60 years, might be prophylactic against cognitive loss and eventual dementia. A daily dose of 100–150 mgs should be adequate, and it is available without prescription and costs little. The approach to prevention of AD by vaccination is based upon the finding that the brains of patients with established AD show deposition of amyloid beta (Aβ) oligomers and, also, excessive cyclophilin D. Aβ has two forms, one that is modified by pyroglutamate and one that is unmodified; together and via several mechanisms, those two separate forms of Aβ induce lower ATP levels, which causes synaptic hypometabolism and impaired neurotransmission. Cyclophilin D also participates: after translocating from the mitochondrial matrix to the inner mitochondrial membrane, it collaborates with ATP synthase subunit 9 to open the mitochondrial permeability transition pore that results in uncoupling of oxidative phosphorylation and reduced formation of ATP. In addition, cyclophilin D also mediates some forms of necrotic cell death. Further, in aged AD model mice, deficiency of cyclophilin D was beneficial by causing less calcium-induced mitochondrial swelling, increased mitochondrial calcium uptake capacity, preserved mitochondrial respiratory function, and improved spatial learning/memory. Detrimentally, Aβ upregulated the expression of cyclophilin D.9 Therefore, a self-replicating mRNA vaccine that reduces levels of all three elements, unmodified Aβ, pyroglutamate modified Aβ, and cyclophilin D, is potentially prophylactic, although its production would be a formidable undertaking. The details that support use of such a vaccine are described elsewhere.10 In summary, both supplementary thiamine and a triple mRNA vaccine have good a posteriori potential as prophylaxis against initiation of cognitive loss and the subsequent occurrence of AD. The chances of success would amplify if both approaches were used together. Of course, neither supplementary thiamine nor the described vaccine should be administered until their use is validated by clinical trial.

Mental disability is a serious and often disabling symptom of Long Covid, for which currently there is no recommendable pharmacotherapy for those patients whose response to psychotherapy is suboptimal. Treatment could be formulated by using drugs that address the brain cell-types that have been demonstrated as dominantly affected in Long Covid. Those cell-types are astrocytes, oligodendrocytes, endothelial cells/pericytes, and microglia. Lithium and fluoxetine each address all of those four cell-types. They should be administered in combination for both depth of benefit and reduction of dosages. Low dosage of each is likely to be well-tolerated and to cause neither adverse events (AE) nor serious adverse events (SAE).

In angina pecto&! . .Gke enough to do thejob 1som1Iz (ISOSORBIDE DINITRATE) 'Indlcationn: Based on a review of this I drug by the National Academy of Sciences-National Research Council and/or other information, FDA has classified the indications as follows: "Possibly" effective: When taken by the oral route, lsordil is indicated for the relief of angina pectoris (pain of coronary artery disease).It is not intended to abort the acute angina1 episode but is widely regarded as useful in the prophylactic treatment of angina pectoris.Final classification ofthe Iess-lhaneffective indications requires further investigation.Contralndicatton: Idiosyncrasy to this drug.Warnings: Data supporting the use of nitrites and nitrates during the early days of the acute phase of myocardial infarction (the period during which clinical and laboratory findings are unstable) are insufflcienl to establish safety Precautions: Tolerance to this drug and crosstolerance to other nitrites and nitrates may occur.In patients with functional or organic gastrointestinal hypermotility or malabsorption syndrome, it is suggested that Isordil Tembids capsules be the preferred therapy since a few patients have reported passing partially dissolved Isordil Tembids tablets in their stools; this phenomenon is believed to be on the basis of physiotogic variability and to reflect rapid gastrointestinal transit of the tablet.Adverse Reactions: Cutaneous vasodilation with flushing.Headache is common and may be severe and persistent.Transient episodes of dizziness and weakness as well as other signs of cerebral ischemia associated with postural hypotension may occasionally develop.This drug can act as a physiological antagonist to norepinephrine.acetylcholine, histamine, and many other agents.An occasional individual exhibits marked sensitivity to the hypotensive effects of nitrite, and severe responses (nausea.vomiting, weakness, restlessness, pallor, perspiration and collapse) can occur even with the usual therapeutic dose.AlcohoI may enhance this effect.Drug rash and/or exfoliative dermatitis may occasionally occur.Consult direction circular before prescribing.

Human cytomegalovirus (CMV) DNA copy number in white blood cells from both human immunodeficiency virus (HIV)-seronegative and HIV-seropositive patients was amplified from the immediate-early region of CMV DNA and quantified by colorimetric detection of the hybridization of the amplification product to a detector oligonucleotide probe in microtiter wells. By Mann-Whitney U test, significantly higher (P 100 CD4 cells/mm3. By prospective monitoring for increases in CMV DNA copy number, it may be possible to identify HIV-seropositive patients who are at imminent risk for development of symptomatic CMV retinitis.