Coxsackievirus and adenovirus receptor is up-regulated in migratory germ cells during passage of the blood-testis barrier

The coxsackievirus and adenovirus receptor (CAR) is a cell adhesion molecule expressed in epithelial tight junctions and other cell-cell contacts. Using indirect immunofluorescence, quantitative RT-PCR, and Western blots, the expression and distribution of CAR in developing and adult testis are examined. CAR is highly expressed in both Sertoli and germ cells during perinatal and postnatal development, followed by a rapid down-regulation of both mRNA and protein levels. Interestingly, we find that CAR is a previously unknown downstream target for FSH because CAR mRNA levels were induced in primary cultures of FSH-stimulated Sertoli cells. In contrast to other epithelia, CAR is not a general component of tight junctions in the seminiferous epithelium, and Sertoli cells in the adult testis do not express CAR. Instead, CAR expression is stage dependent and specifically found in migratory germ cells. RT-PCR also demonstrated the presence of junctional adhesion molecule-like (JAML) in the testis. JAML was previously reported by others to form a functional complex with CAR regulating transepithelial migration of leukocytes. The expression of JAML in the testis suggests that a similar functional complex might be present during germ cell migration across the blood-testis barrier. Finally, an intermediate compartment occupied by CAR-positive, migrating germ cells and flanked by two occludin-containing junctions is identified. Together, these results implicate a function for CAR in testis morphogenesis and in migration of germ cells across the blood-testis barrier during spermatogenesis.     

The immunofluorescence antibody test (IFAT) for the diagnosis of schistosomiasis used in a non-endemic area

OBJECTIVE: To evaluate an immunofluorescence antibody test (IFAT) for diagnosis of schistosomiasis in nonimmune travellers and immigrants from endemic areas. METHODS: 65 patients (48 Danes and 17 immigrants) with schistosomiasis were included. The diagnosis of schistosomiasis was based on the presence of schistosome eggs in faeces, urine, sperm, rectal or bladder biopsies and/or the presence of specific antibodies determined by the serological immunofluorescence antibody test (IFAT). Egg excretion was detected using conventional methods and the IFAT performed on whole S. mansoni schistosomula worms, harvested after 8 weeks from mice. Two patterns of immunofluorescence were observed: Fluorescence in the gut of the schistosome called 'Gut Associated Antigen, GAA', and fluorescence of the surface of the schistosomula called 'Membrane Bound Antigen, MBA'. RESULTS: Eggs were found in 44% of the Danish patients and in 76% of immigrants. The diagnosis was based on a positive IFAT in 48% of the patients. In patients from nonendemic areas, the finding of antibodies against GAA was diagnostic while optimal sensitivity in the immigrants was reached by measuring antibodies against both GAA and MBA. CONCLUSION: In patients from nonendemic areas GAA is a sensitive marker of acute infection with schistosomiasis. In patients from endemic areas the demonstration of both GAA and MBA is necessary to properly identify long-lasting, nonacute infections. Egg-detection and/or measurement of CAA and CCA remain the methods of choice to monitor treatment as the immunofluorescence assay may remain positive for several years after treatment.     

Mild heat treatments induce long-term changes in metabolites associated with energy metabolism in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

Heat-induced hormesis, the beneficial effect of mild heat-induced stress, increases the average lifespan of many organisms. Yet little is known about the mechanisms underlying this effect. We used nuclear magnetic resonance spectroscopy to investigate the long-term effects of repeated mild heat treatments on the metabolome of male Drosophila melanogaster. 10 days after the heat treatment, metabolic aging appears to be slowed down, and a treatment response with 40 % higher levels of alanine and lactate and lower levels of aspartate and glutamate were measured. All treatment effects had disappeared 16 days later. Metabolic reprogramming has been associated with the life extending effects of dietary restriction. The metabolite changes induced by the hormetic treatment suggest that the positive effects might not be limited to the repair pathways induced, but that there also is a change in energy metabolism. A possible direct link between changes in energy metabolism and heat induced increase in Hsp70 expression is discussed.     

High adherence to all-oral directly acting antiviral HCV therapy among an inner-city patient population in a phase 2a study

Background

As treatment for chronic hepatitis C (HCV) virus has evolved to all-oral, interferon-free directly acting antiviral (DAA) therapy, the impact of these improvements on patient adherence has not been described.

Methods

Medication adherence was measured in 60 HCV, genotype-1, treatment-naïve participants enrolled in a phase 2a clinical trial at the National Institutes of Health and community clinics. Participants received either ledipasvir/sofosbuvir (LDV/SOF) (90 mg/400 mg) (one pill) daily for 12 weeks, LDV/SOF + GS-9451 (80 mg/day) (two pills) daily for 6 weeks, or LDV/SOF + GS-9669 (500 mg twice daily; three pills, two in the morning, one in the evening) for 6 weeks. Adherence was measured using medication event monitoring system (MEMS) caps, pill counts and patient report.

Results

Overall adherence to DAAs was high. Adherence declined over the course of the 12-week treatment (p = 0.04). While controlled psychiatric disease or symptoms of depression did not influence adherence, recent drug use was a risk factor for non-adherence to 12-week (p = 0.01), but not 6-week regimens. Adherence as measured by MEMS was lower than by patient report.

Conclusions

Adherence to short courses of DAA therapy with 1–3 pills a day was excellent in an urban population with multiple risk factors for non-adherence.

     

Sobrevida de Pacientes com Insuficiência Cardíaca Aguda e Fração de Ejeção Intermediária em um País em Desenvolvimento – Estudo de Coorte no Sul do Brasil

BackgroundHeart Failure with mid-range Ejection Fraction (HFmEF) was recently described by European and Brazilian guidelines on Heart Failure (HF). The ejection fraction (EF) is an important parameter to guide therapy and prognosis. Studies have shown conflicting results without representative data from developing countries.ObjectiveTo analyze and compare survival rate in patients with HFmEF, HF patients with reduced EF (HFrEF), and HF patients with preserved EF (HFpEF), and to evaluate the clinical characteristics of these patients.MethodsA cohort study that included adult patients with acute HF admitted through the emergency department to a tertiary hospital, reference in cardiology, in south Brazil from 2009 to 2011. The sample was divided into three groups according to EF: reduced, mid-range and preserved. A Kaplan-Meier curve was analyzed according to the EF, and a logistic regression analysis was done. Statistical significance was established as p < 0.05.ResultsA total of 380 patients were analyzed. Most patients had HFpEF (51%), followed by patients with HFrEF (32%) and HFmEF (17%). Patients with HFmEF showed intermediate characteristics related to age, blood pressure and ventricular diameters, and most patients were of ischemic etiology. Median follow-up time was 4.0 years. There was no statistical difference in overall survival or cardiovascular mortality (p=.0031) between the EF groups (reduced EF: 40.5% mortality; mid-range EF 39.7% and preserved EF 26%). Hospital mortality was 7.6%.ConclusionThere was no difference in overall survival rate between the EF groups. Patients with HFmEF showed higher mortality from cardiovascular diseases in comparison with HFpEF patients. (Arq Bras Cardiol. 2021; 116(1):14-23)     

Cingulo-opercular control network and disused motor circuits joined in standby mode

Whole-brain resting-state functional MRI (rs-fMRI) during 2 wk of upper-limb casting revealed that disused motor regions became more strongly connected to the cingulo-opercular network (CON), an executive control network that includes regions of the dorsal anterior cingulate cortex (dACC) and insula. Disuse-driven increases in functional connectivity (FC) were specific to the CON and somatomotor networks and did not involve any other networks, such as the salience, frontoparietal, or default mode networks. Censoring and modeling analyses showed that FC increases during casting were mediated by large, spontaneous activity pulses that appeared in the disused motor regions and CON control regions. During limb constraint, disused motor circuits appear to enter a standby mode characterized by spontaneous activity pulses and strengthened connectivity to CON executive control regions.

Disuse is a powerful paradigm for inducing plasticity that has uncovered key organizing principles of the human brain (1–4). Monocular deprivation—prolonged covering of one eye—revealed that multiple afferent inputs can compete for representational territory in the primary visual cortex (1). Similar competition between afferents also shapes the somatomotor system. Manipulations such as peripheral nerve deafferentation, whisker trimming, and limb constraint all drive plasticity in the primary somatosensory and motor cortex (2–4). Most plasticity studies to date have used focal techniques, such as microelectrode recordings, to study local changes in brain function. As a result, little is known about how behavior and experience shape the brain-wide functional networks that support complex cognitive operations (5).The brain is composed of networks of regions that cooperate to perform specific cognitive functions (5–8). These functional networks show synchronized spontaneous activity while the brain is at rest, a phenomenon known as resting-state functional connectivity (FC) (9–11). FC can be measured noninvasively in humans using resting-state functional MRI (rs-fMRI) and has been used to parse the brain into canonical functional networks (12, 13), including visual, auditory, and somatomotor networks (14, 15); ventral and dorsal attention networks (8, 16); a default mode network with roles in internally directed cognition and episodic memory (7, 11); a salience network thought to assess the homeostatic relevance of external stimuli (17); a frontoparietal control network supporting error processing and moment-to-moment adjustments in behavior (18–20); and a cingulo-opercular control network (CON), which maintains executive control during goal-directed behavior (18, 19, 21). Each functional network likely carries out a variety of additional functions.A more recent advance in human neuroscience has been the recognition of individual variability in network organization (22–25). Most early rs-fMRI studies examined central tendencies in network organization using group-averaged FC measurements (10, 12, 13). Recent work has demonstrated that functional networks can be identified in an individual-specific manner if sufficient rs-fMRI data are acquired, an approach termed precision functional mapping (PFM) (22, 23, 26–30). PFM respects the unique functional anatomy of each person and avoids averaging together functionally distinct brain regions across individuals.We recently demonstrated that PFM can be used to follow the time course of disuse-driven plasticity in the human brain (31). Three adult participants (Nico, Ashley, and Omar) were scanned at the same time of day for 42 to 64 consecutive days (30 min of rs-fMRI per day) before, during, and after 2 wk of dominant upper-extremity casting (Fig. 1 A and B). Casting caused persistent disuse of the dominant upper extremity during daily behaviors and led to a marked loss of strength and fine motor skill in all participants. During casting, the upper-extremity regions of the left primary somatomotor cortex (L-SM1_ue) and right cerebellum (R-Cblm_ue) functionally disconnected from the remainder of the somatomotor network. Disused motor circuits also exhibited large, spontaneous pulses of activity (Fig. 1C). Disuse pulses did not occur prior to casting, started to occur frequently within 1 to 2 d of casting, and quickly waned after cast removal.Open in a separate windowFig. 1.Experimental design and spontaneous activity pulses. (A) Three participants (Nico, Ashley, and Omar) wore casts covering the entire dominant upper extremity for 2 wk. (B) Participants were scanned every day for 42 to 64 consecutive days before, during, and after casting. All scans included 30 min of resting-state functional MRI. (C) During the Cast period, disused somatomotor circuits exhibited large pulses of spontaneous activity. (C, Left) Whole-brain ANOVA showing which brain regions contained disuse-driven pulses. (C, Right) Time courses of all pulses recorded from the disused primary somatomotor cortex.Somatomotor circuits do not function in isolation. Action selection and motor control are thought to be governed by complex interactions between the somatomotor network and control networks, including the CON (18). Prior studies of disuse-driven plasticity, including our own, have focused solely on somatomotor circuits. Here, we leveraged the whole-brain coverage of rs-fMRI and the statistical power of PFM to examine disuse-driven plasticity throughout the human brain.     

Diversity of gene expression in adenocarcinoma of the lung.

The global gene expression profiles for 67 human lung tumors representing 56 patients were examined by using 24,000-element cDNA microarrays. Subdivision of the tumors based on gene expression patterns faithfully recapitulated morphological classification of the tumors into squamous, large cell, small cell, and adenocarcinoma. The gene expression patterns made possible the subclassification of adenocarcinoma into subgroups that correlated with the degree of tumor differentiation as well as patient survival. Gene expression analysis thus promises to extend and refine standard pathologic analysis.     

Nutrition and Cardiovascular Disease—an Update

Purpose of Review

This review summarizes recent developments in nutrition and cardiovascular disease (CVD) prevention.

Recent Findings

Contemporary dietary guidance recommends healthy dietary patterns with emphasis on food-based recommendations because the totality of the diet (i.e., the combinations and quantities of foods and nutrients consumed) is an important determinant of health. In many guidelines, recommendations are still made for saturated fat, added sugar, sodium, and dietary cholesterol because these are over-consumed by many people and are related to chronic disease development. Epidemiological research illustrates the importance of considering the total diet and the interrelatedness of nutrients in a dietary pattern. Traditionally, epidemiological research focused on individual nutrients in isolation, which can result in erroneous conclusions. An example of this, which has led to substantial controversy, is the evidence from studies evaluating the association between saturated fat and CVD without considering the replacement nutrient. Another controversial topic is the relationship between dietary cholesterol and CVD, which is confounded by saturated fat intake. Finally, the totality of evidence shows that high sodium intake is associated with greater CVD risk; however, some epidemiological research has suggested that a low-sodium intake is detrimental, which has caused some controversy. Overall, this reductionist approach has led to a debate about recommendations for saturated fat, cholesterol, and sodium. However, if approaches that accounted for the interrelatedness of nutrients had been taken, it is likely that there would be less controversy about these nutrients. To encourage dietary pattern-based approaches and consideration of total intake, dietary guidelines should emphasize food-based recommendations that meet nutrient targets. Thus, nutrient targets should underpin food-based dietary guidelines, and recommended dietary patterns should comply with nutrient-based targets.

Summary

The evidence reviewed shows that it is imperative to consider total dietary patterns for CVD prevention. Dietary guidance should be aligned with nutrient targets and recommendations should be food and dietary pattern based.