Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Blood and plasma donations among a cohort of intravenous drug users

We evaluated the blood and plasma donation histories of a cohort of 2921 intravenous drug users in Baltimore, Md, and correlated these histories with their human immunodeficiency virus (HIV) serologic status, numbers of CD4 lymphocytes in the peripheral blood, and stigmata of intravenous drug use (scarred veins). Of the 793 intravenous drug users (27.1%) who had donated blood or plasma, 652 (82.2%) donated after they had started using intravenous drugs. Most subjects donated at commercial plasma centers, where they were paid $10 to $15 per donation. Although the HIV-1 seroprevalence of the entire cohort was 24.1%, the HIV-1 seroprevalence among those reporting plasma or blood donations declined progressively with time, from 17.1% in those who last donated in 1985 to 3.6% in those who last donated in 1988-1989. Many of the 437 intravenous drug users who had donated plasma or blood since 1985, when screening for HIV-1 was initiated, had not been notified and counseled about their HIV test results. Current programs to exclude individuals with a history of intravenous drug use from the plasma donor pool should be reevaluated and improved.     

Valve-related complications with the Hancock I porcine bioprosthesis. A twelve- to fourteen-year follow-up study

Valve-related morbidity and mortality after heart valve replacement with the Hancock I porcine bioprosthesis has been retrospectively analyzed. From June 1974 through December 1976, 253 Hancock I bioprostheses (150 mitral and 103 aortic) were inserted in 220 selected patients who survived the operation and had follow-up until June 1989 (mean follow-up 13.5 years, with an accumulative follow-up of 2956.4 patient-years). One hundred seventeen patients had mitral valve replacement, 70 had aortic valve replacement, and 33 had combined mitral and aortic valve replacement. There were 27 thromboembolic events. The probability of being free from thromboembolism at 14 years was 81.0% +/- 7.4% for the mitral valve replacement group, 85.4% +/- 6.7% for the aortic group, and 67.1% +/- 18.4% for the mitral-aortic group. Fifteen episodes of prosthetic valve endocarditis occurred. There were 10 instances of nonstructural dysfunction (paravalvular leaks) in seven mitral valves (4.6%) and in three aortic valves (2.9%). One hundred twenty-two bioprostheses in 106 patients resulted in structural deterioration. The probability of freedom from structural deterioration at 14 years was 37.2% +/- 3.9% for the mitral group, 43.9% +/- 7.1% for the aortic group, and 30.1% +/- 8.9% for the mitral-aortic group. The logistic regression analysis between age at the time of operation and bioprosthetic life (structural deterioration-free period) demonstrates a linear regression curve (r = 0.53). There were 56 late deaths (27 patients died at reoperation). The actuarial survival rate (including hospital mortality) at 14 years was 57.2% +/- 5.4% for the entire series, with no statistically significant difference between groups. The probability of remaining free from valve-related morbidity and mortality at 14 years was 16.7% +/- 4.8% for the mitral group, 20.8% +/- 6.2% for the aortic group, and 14.0% +/- 7.0% for the mitral-aortic group. The long-term results of this series show that the clinical performance of the Hancock I porcine valve appears satisfactory during the first 6 years. The behavior of this bioprosthesis at 14 years' follow-up changes drastically, because only a minor group of patients is free from valve-related complications, justifying the restriction of its use for selected patients.     

Steroid conversion and prostaglandin production by chorionic and decidual cells in relation to term and preterm labour

The production of progesterone from pregnenolone, of cortisol from cortisone and of prostaglandin E (PGE) under basal and arachidonic acid-stimulated conditions was measured in cells dispersed from chorion and decidua. The cells were obtained after delivery from four groups of women: following spontaneous labour at term (38-42 weeks gestation), at elective caesarean section at term before the onset of labour, after induced labour at term, and after uncomplicated preterm (27-36 weeks) labour. Chorionic cells had a high progesterone output with relatively low cortisol and PGE production, whereas decidual cells had a high cortisol and PGE production rate. Free arachidonic acid stimulated PGE production in both decidual and chorionic cells. There were no significant differences in either steroid or PGE production among the four groups studied. These data suggest that steroid dehydrogenase activity in choriodecidual cells is not related to the mode of onset of labour and that the increased prostaglandin production in intrauterine tissues associated with parturition is due to enhanced availability of arachidonic acid.     

Prophylactic resection of a tricuspid valve vegetation in infective endocarditis

A heroin addict who appeared to have recovered clinically from infective endocarditis of the tricuspid valve as judged by the usual criteria underwent prophylactic resection of a large vegetation on the tricuspid valve in order to prevent severe pulmonary embolism. Prophylactic surgery was justified by the size and as judged by cross-sectional echocardiography of the vegetation and its morphology.     

Actin-free Gc globulin: a rapidly assessed biomarker of organ dysfunction in acute liver failure and cirrhosis.

Reductions in serum levels of Gc globulin, a hepatically synthesized component of the extracellular actin scavenger system responsible for complexing circulating actin and attenuating intravascular microthrombus formation, are associated with poor outcome in acute liver failure. Clinically applicable assays of the important actin-free fraction (Af-Gc) have not been available until now. We measured actin-free Gc globulin levels with a novel, rapid assay in 61 cases of acute liver failure (ALF) and in 91 patients with cirrhosis (40 of whom were clinically unstable with extrahepatic organ dysfunction), and studied associations with liver dysfunction, extrahepatic organ dysfunction, indices of disseminated coagulation, and outcome. Reductions in Af-Gc levels mirrored hepatic dysfunction and organ dysfunction in both groups, and discriminated patients with poor prognosis from those with good prognosis in the ALF cohort. Levels were lowest in patients with ALF (10% of control values), but levels were also markedly reduced in both unstable (28%) and stable (44%) patients with cirrhosis. Associations with markers of disseminated intravascular coagulation were seen in both groups, most notably in the cirrhosis cohort, supporting a pathophysiological role for reduced Af-Gc in the evolution of organ dysfunction. In acetaminophen-induced ALF, Af-Gc identified patients with poor prognosis as well as did the Acute Physiology and Chronic Health Evaluation (APACHE II) score (area under the receiver operating characteristic curve, 0.7), and in cirrhosis, Af-Gc was an independent predictor of mortality by multifactorial analysis. In conclusion, the importance of Af-Gc reductions in the development of multiple organ dysfunction in ALF and cirrhosis is highlighted, probably resulting from reduced hepatic production and peripheral exhaustion of this arm of the extracellular actin scavenger system.