Microglial proliferation in cortical neural cultures exposed to feline immunodeficiency virus

Microglia are thought to play an important role in neurodegenerative changes due to infection with human or animal immunodeficiency viruses. Using feline immunodeficiency virus and cat neural cultures, we observed a dramatic increase in the accumulation of microglia from a basal rate of 5-7% day(-1) to 25-126% day(-1). Both live virus and heat-inactivated virus induced proliferation. Negligible proliferation was seen in purified microglial cultures. Conditioned medium from astrocytes or mixed neural cultures treated with feline immunodeficiency virus stimulated the proliferation of purified microglia. Disease progression may be facilitated by early non-infectious interactions of lentiviruses with neural tissue that promote the activation and proliferation of microglia.     

An indirect treatment comparison of the efficacy of patisiran and tafamidis for the treatment of hereditary transthyretin-mediated amyloidosis with polyneuropathy

Background: Hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a progressive, life-threatening disease. Until recently, tafamidis was the only approved pharmacotherapy. Patisiran significantly improved polyneuropathy and quality of life (QoL) in the phase III APOLLO trial. In the absence of direct comparisons, this analysis aimed to evaluate the comparative efficacy of tafamidis and patisiran in hATTR amyloidosis with polyneuropathy.

Research design and methods: Randomized controlled trial evidence for tafamidis was identified by systematic literature review. Indirect treatment comparisons were performed using the standard pairwise Bucher method for endpoints used in both APOLLO and the tafamidis Fx-005 trial: change from baseline in Neuropathy Impairment Score-lower limbs (NIS-LL), Norfolk QoL-Diabetic Neuropathy questionnaire (QoL-DN), NIS-LL response, and mBMI vs. placebo. Inter-trial population differences were assessed by sensitivity analysis.

Results: The base-case analysis (FAP Stage 1 APOLLO patients vs. intent-to-treat Fx-005 population) suggested patisiran had a greater treatment effect vs. tafamidis for all endpoints, with significant improvements in mean change in NIS-LL (–5.49) and QoL-DN (–13.10) from baseline to Month 18. Similar trends were observed in all sensitivity analyses.

Conclusions: In the absence of direct comparisons, this analysis suggests patisiran has a greater treatment effect than tafamidis in patients with hATTR amyloidosis with polyneuropathy.     

Supplementation with NAD+ and Its Precursors to Prevent Cognitive Decline across Disease Contexts

The preservation of cognitive ability by increasing nicotinamide adenine dinucleotide (NAD⁺) levels through supplementation with NAD⁺ precursors has been identified as a promising treatment strategy for a number of conditions; principally, age-related cognitive decline (including Alzheimer’s disease and vascular dementia), but also diabetes, stroke, and traumatic brain injury. Candidate factors have included NAD⁺ itself, its reduced form NADH, nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and niacin (or nicotinic acid). This review summarises the research findings for each source of cognitive impairment for which NAD⁺ precursor supplementation has been investigated as a therapy. The findings are mostly positive but have been made primarily in animal models, with some reports of null or adverse effects. Given the increasing popularity and availability of these factors as nutritional supplements, further properly controlled clinical research is needed to provide definitive answers regarding this strategy’s likely impact on human cognitive health when used to address different sources of impairment.     

HIV-1 infection alters the retinol-binding protein:transthyretin ratio even in the absence of the acute phase response

The ratio of retinol-binding protein (RBP) to transthyretin (TTR) has been proposed as an indirect method with which to assess vitamin A status in the context of inflammation. Few studies have been conducted among adults, and none examined the effect of HIV-1 infection. Our goal was to assess the RBP:TTR ratio among adults, including the effects of HIV-1 and the acute phase response. We used data from a cross-sectional study of 600 Kenyan women, of whom 400 had HIV-1. The effect of vitamin A supplementation among the HIV-1-infected participants was subsequently assessed in a randomized trial. Among HIV-1-uninfected women without an acute phase response, a RBP:TTR cut-off value of 0.25 had approximately 80% sensitivity and specificity to detect vitamin A deficiency (retinol <0.70 micromol/L). No RBP:TTR cut-off value demonstrated both high sensitivity and specificity among HIV-1 infected women without evidence of inflammation. HIV-1 infection and advanced HIV-1 disease were associated with higher RBP:TTR ratios. The effect of HIV-1 was independent of the acute phase response, which also increased the RBP:TTR ratio. Serum retinol increased with vitamin A supplementation among those with a low RBP:TTR ratio, although the effect was small and was not present among those with concurrent inflammation. Thus, the RBP:TTR ratio has modest ability to predict vitamin A deficiency among healthy adults, but HIV-1 infection alters the ratio, even in the absence of the acute phase response. Our results raise questions about the utility of this measurement given the high prevalence of HIV-1 infection in areas where vitamin A deficiency is common.     

Temporal Dynamics of the Intestinal Microbiome Following Short-Term Dietary Restriction

Short-term dietary restriction has been proposed as an intriguing pre-operative conditioning strategy designed to attenuate the surgical stress response and improve outcomes. However, it is unclear how this nutritional intervention influences the microbiome, which is known to modulate the systemic condition. Healthy individuals were recruited to participate in a four-day, 70% protein-restricted, 30% calorie-restricted diet, and stool samples were collected at baseline, after the restricted diet, and after resuming normal food intake. Taxonomy and functional pathway analysis was performed via shotgun metagenomic sequencing, prevalence filtering, and differential abundance analysis. High prevalence species were altered by the dietary intervention but quickly returned to baseline after restarting a regular diet. Composition and functional changes after the restricted diet included the decreased relative abundance of commensal bacteria and a catabolic phenotype. Notable species changes included Faecalibacterium prausnitzii and Roseburia intestinalis, which are major butyrate producers within the colon and are characteristically decreased in many disease states. The macronutrient components of the diet might have influenced these changes. We conclude that short-term dietary restriction modulates the ecology of the gut microbiome, with this modulation being characterized by a relative dysbiosis.     

The Role of Iron in Hepatitis C Infection

Iron overload of varying degrees is common among patients with chronic hepatitis C. The clinical significance of this iron overload is uncertain. Studies that have evaluated the effect of hepatic iron stores on the response to anti-viral treatment or on the natural history of chronic hepatitis C have found variable results depending on the technique used to measure hepatic iron stores and the degree of iron overload present among the study population. We have tried to comprehensively analyze the literature regarding the clinical interaction between iron overload and the natural history of chronic hepatitis C. The one clear relationship that emerges is that pre treatment serum ferritin inversely correlates with the odds of achieving sustained virological(SVR) response after combination interferon ribavirin treatment. We have also reviewed the limited literature that reports the effect of therapeutic phlebotomy to reverse iron overload among patients with chronic hepatitis C. A small meta-analysis of 6 prospective randomized trials and a subsequent seventh trial do suggest that phlebotomy to induce iron depletion enhances the likelihood of achieving (SVR) after anti-viral therapy. However, these studies are primarily in patients receiving interferon monotherapy, which is of course now obsolete. Finally, a few small studies suggest that therapeutic phlebotomy to induce iron depletion reduces liver transaminase levels and may improve histology, and perhaps even reduce the risk of hepato-cellular carcinoma. Prospective randomized controlled trials of phlebotomy among patients with advanced hepatitis C and iron overload are needed.     

Establishing biennial paramedic experience benchmarks

Objective. Since stroke symptoms are often vague, and acute therapies for stroke are more recently available, it has been hypothesized that stroke patients may not be treated with the same urgency as myocardial infarction (MI) patients by emergency medical services (EMS). To examine this hypothesis, EMS transport times were examined for both stroke and MI patients who used a paramedic-level, county-based EMS system for transportation to a single hospital during 1999. Methods. Patients were first identified by their hospital discharge diagnosis as stroke (ICD-9 430–436, n = 50) or MI (ICD-9 410, n = 55). Trip sheets with corresponding transport times were retrospectively obtained from the 911 center. A separate analysis was performed on patients identified by dispatchers with a chief complaint of stroke (n = 85) or MI (n = 372). Results. Comparing stroke and MI patients identified by ICD-9 codes, mean EMS transport times in minutes did not meaningfully differ with respect to dispatch to scene arrival time (8.3 vs 8.9, p = 0.61), scene time (19.5 vs 21.4, p = 0.23), and transport time (13.7 vs 16.2, p = 0.10). Mean total call times in minutes from dispatch to hospital arrival were similar between stroke and MI patients (41.5 vs 46.4, p = 0.22). Results were similar when comparing patients identified by dispatchers with a chief complaint indicative of stroke or MI. Conclusion. In this single county, EMS response times were not different between stroke and MI patients. Replication in other EMS settings is needed to confirm these findings.