Arachidonate has a positive effect on the electrogenic sodium-potassium pump in the mouse diaphragm

Sodium arachidonate 5 X 10(-5) mol X l-1 shortened the time course of hyperpolarization caused by the electrogenic Na+-K+ pump in intact muscle fibres in the mouse diaphragm preincubated in a K+-free physiological solution. Contrary to experiments on membrane fragments, no inhibition of the ouabain-sensitive Na+-K+ ATPase was observed. It is unlikely that the arachidonate may be identical with the endogenous "ouabain-like" substance (Bidard et al. 1984).     

La protein has a positive effect on the translation of TOP mRNAs in vivo

In vertebrates, the mRNAs encoding ribosomal proteins, as well as other proteins implicated in translation, are characterized by a 5'-untranslated region (5'-UTR), including a stretch of pyrimidines at the 5'-end. The 5'-terminal oligopyrimidine (5'-TOP) sequence, which is involved in the growth-dependent translational regulation characteristic of this class of genes (so-called TOP genes), has been shown to specifically bind the La protein in vitro, suggesting that La might be implicated in translational regulation in vivo. In order to substantiate this hypothesis, we have examined the effect of La on TOP mRNA translational control in both stable and transient transfection experiments. In particular we have constructed and analyzed three stably transfected Xenopus cell lines inducible for overexpression of wild-type La or of putative dominant negative mutated forms. Moreover, La-expressing plasmids have been transiently co-transfected together with a plasmid expressing a reporter TOP mRNA in a human cell line. Our results suggest that in vivo La protein plays a positive role in the translation of TOP mRNA. They also suggest that the function of La is to counteract translational repression exerted by a negative factor, possibly cellular nucleic acid binding protein (CNBP), which has been previously shown to bind the 5'-UTR downstream from the 5'-TOP sequence.     

Hypoxia has a greater effect than exercise on the redistribution of pulmonary blood flow in swine.

Strenuous exercise combined with hypoxia is implicated in the development of high-altitude pulmonary edema (HAPE), which is believed to result from rupture of pulmonary capillaries secondary to high vascular pressures. The relative importance of hypoxia and exercise in altering the distribution of pulmonary blood flow (PBF) is unknown. Six chronically catheterized specific pathogen-free Yorkshire hybrid pigs (25.5 +/- 0.7 kg, means +/- SD) underwent incremental treadmill exercise tests in normoxia (Fi(O(2)) = 0.21) and hypoxia (Fi(O(2)) = 0.125, balanced order), consisting of 5 min at 30, 60, and 90% of the previously determined Vo(2max). At steady state (~4 min), metabolic and cardiac output data were collected and fluorescent microspheres were injected over approximately 30 s. Later the fluorescent intensity of each color in each 2-cm(3) lung piece was determined and regional perfusion was calculated from the weight-normalized fluorescence. Both hypoxia and exercise shifted PBF away from the ventral cranial lung regions toward the dorsal caudal regions of the lung, but hypoxia caused a greater dorsal caudal shift in PBF at rest than did near-maximal exercise in normoxia. The variance in PBF due to hypoxia, exercise, and vascular structure was 16 +/- 4.2, 4.0 +/- 4.4, and 59.4 +/- 11.4%, respectively, and the interaction between hypoxia and exercise represented 12 +/- 6.5%. This observation implies that there is already a maximal shift with in PBF with hypoxia in the dorsal-caudal regions in pigs that cannot be exceeded with the addition of exercise. However, exercise greatly increases the pulmonary arterial pressures and therefore the risk of capillary rupture in high flow regions.     

Simulation of individual risk based on the results of exercise tests and analysis of risk factors

The materials of a cross-sectional and prospective Russian-US population study (the Russian Lipid Research Clinics Prevalence Study) have been used to develop models intended for estimating the probability of death from coronary heart disease, all cardiovascular disease, and all causes over 10 and 20 years. The prediction was performed by constructing artificial neural networks. Testing on an independent sample has shown an accuracy of 66–73%.     

Active recovery has a positive and acute effect on recovery from fatigue induced by repeated maximal voluntary contractions of the plantar flexors

This study investigated the acute effect of active recovery (AR) following fatigue induced by 80 three-second maximal voluntary isometric plantar flexion contractions (MVICs) in 12 young men. AR consisted of a total of 180 voluntary isometric ramp contractions of the plantar flexors (0.75-s contraction/relaxation) targeting 10% of MVIC torque. MVIC torque, voluntary activation and root mean square values of electromyographic signals for the triceps surae normalized by each peak-to-peak amplitude of compound motor action potential were determined before, and immediately, 10, 20 and 30 min after the fatiguing task. Evoked torques were similarly assessed except for immediately after it. The AR and passive recovery were randomly performed on two days by each participant between 5 min and 10 min after the fatiguing task. For all the parameters other than MVIC torque, there was no significant difference between the conditions at any time point. MVIC torque decreased significantly immediately after the fatiguing task regardless of condition (P < 0.05), and the corresponding decrease in MVIC torque recovered 30 min after the fatiguing task only in AR (P < 0.05). These results suggest an acute positive effect of AR on recovery of neuromuscular function and/or contractile properties after fatigue.     

Radish introduction affects soil biota and has a positive impact on the growth of a native plant

Introduced plants may out-compete natives by belowground allelopathic effects on soil communities including the symbionts of native plants. We tested for an allelopathic effect of an introduced crucifer, Raphanus sativus, on a common neighboring legume, Lupinus nanus, on the legume’s rhizobium affiliates, and on the broader soil community. In both field observations and a greenhouse experiment, we found that R. sativus decreased the density of nodules on L. nanus roots. However, in the greenhouse experiment, R. sativus soils only decreased the density of small, likely non-beneficial rhizobium nodules. In the same experiment, R. sativus soils decreased fungivorous nematode abundance, though there was no effect of R. sativus introduction on fungal density. In the greenhouse experiment, R. sativus soils had a net positive effect on L. nanus biomass. One explanation of this effect is that R. sativus introduction might alter the mutualistic/parasitic relationship between L. nanus and its rhizobial associates with a net benefit to L. nanus. Our results suggest that introduced brassicas can quickly alter belowground communities, but that the net effect of this on neighboring plants is not necessarily negative.     

Helicobacter pylori infection in childhood: risk factors and effect on growth.

OBJECTIVE--To investigate the current prevalence of Helicobacter pylori infection in childhood, the risk factors for infection, and the effect of infection on growth in preadolescent schoolchildren. DESIGN--Population based sample of 7 year old schoolchildren followed up at age 11; data on risk factors for infection collected at age 7; presence of infection at age 11 determined by measurement of salivary IgG against H pylori by a newly developed enzyme linked immunosorbent assay (ELISA). Height was measured at 7 and 11 years of age. SUBJECTS--554 schoolchildren from Edinburgh. RESULTS--62 (11%) children had H pylori infection. Independent risk factors for infection were single parent families (adjusted odds ratio = 2.5; 95% confidence interval 1.1 to 5.7), the 10% most crowded homes (3.1; 1.3 to 7.2), and schools serving predominantly rented housing estates (2.5; 1.0 to 6.5). School catchment area was more important than parental social class or housing tenure. Growth in height between 7 and 11 was diminished in infected children by a mean of 1.1 cm (0.3 to 2.0 cm) over four years. This growth reduction was largely confined to girls (1.6 cm over four years), among whom it correlated with salivary IgG (P = 0.015). CONCLUSION--Data from salivary assay to investigate the epidemiology of H pylori suggest that factors relating to the type of community in which the child lives may now be as important for acquisition of this infection as features of the family home. The greater reduction of growth among infected girls raises the possibility that H pylori infection may delay or diminish the pubertal growth spurt.     

Cyclosporine has a direct effect on the differentiation of a mucin-secreting cell line

Cyclosporine is a potent immunosuppressant used in the treatment of ulcerative colitis and keratoconjunctivitis sicca. Neither the etiologies of these diseases nor the mechanism by which cyclosporine exerts its therapeutic effect is well understood. Since both diseases are linked by a common decrease in mucin-filled goblet cells, this study tests a hypothesis that cyclosporine acts directly on goblet cells to promote their differentiation and production of secretory mucins. The HT29-18N2 human colon adenocarcinoma cell line, which is capable of forming monolayers of well-differentiated goblet cells, was used as a model system. Cyclosporine induced a dose-dependent increase in intracellular mucin stores. A 2-week exposure to 1 microM cyclosporine resulted in an average increase in mucin volume of 94%. This increase resulted from both a higher percentage of cells with mucin stores and an increased volume of mucin per cell. PSC-833, a nonimmunosuppressive analog of cyclosporine, also increased mucin production. The intracellular accumulation of mucin was not a result of reduced secretion, since the time required for the release of pulse-radiolabeled glycoproteins was similar for both control and cyclosporine-treated monolayers. The effect of cyclosporine was not mediated by the drug's previously documented abilities to decrease cellular proliferation rates, inhibit calmodulin, antagonize prolactin receptor binding, or modulate prostaglandin production.     

The effect on cardiovascular risk factors of migration from rural to urban areas in Peru: PERU MIGRANT Study

Background

Mass-migration observed in Peru from the 1970s occurred because of the need to escape from politically motivated violence and work related reasons. The majority of the migrant population, mostly Andean peasants from the mountainous areas, tends to settle in clusters in certain parts of the capital and their rural environment could not be more different than the urban one. Because the key driver for migration was not the usual economic and work-related reasons, the selection effects whereby migrants differ from non-migrants are likely to be less prominent in Peru. Thus the Peruvian context offers a unique opportunity to test the effects of migration.

Methods/Design

The PERU MIGRANT (PEru's Rural to Urban MIGRANTs) study was designed to investigate the magnitude of differences between rural-to-urban migrant and non-migrant groups in specific CVD risk factors. For this, three groups were selected: Rural, people who have always have lived in a rural environment; Rural-urban, people who migrated from rural to urban areas; and, Urban, people who have always lived in a urban environment.

Discussion

Overall response rate at enrolment was 73.2% and overall response rate at completion of the study was 61.6%. A rejection form was obtained in 282/323 people who refused to take part in the study (87.3%). Refusals did not differ by sex in rural and migrant groups, but 70% of refusals in the urban group were males. In terms of age, most refusals were observed in the oldest age-group (>60 years old) in all study groups. The final total sample size achieved was 98.9% of the target sample size (989/1000). Of these, 52.8% (522/989) were females. Final size of the rural, migrant and urban study groups were 201, 589 and 199 urban people, respectively. Migrant's average age at first migration and years lived in an urban environment were 14.4 years (IQR 10–17) and 32 years (IQR 25–39), respectively. This paper describes the PERU MIGRANT study design together with a critical analysis of the potential for bias and confounding in migrant studies, and strategies for reducing these problems. A discussion of the potential advantages provided by the case of migration in Peru to the field of migration and health is also presented.     

Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial

Coronary heart disease (CHD) risk factors and the risk of CHD increase with increased adiposity. Fat loss induced by negative energy balance improves all metabolic CHD risk factors. To determine whether fat loss induced by long-term calorie restriction (CR) or increased energy expenditure induced by exercise (EX) has different effects on CHD risk factors in nonobese subjects, we conducted a 1-yr controlled trial involving 48 nonobese subjects who were randomly assigned to one of three groups: CR, 20% CR diet (n = 18); EX, 20% increase in energy expenditure through daily exercise with no increase in energy intake (n = 18); or HL, healthy lifestyle guidelines (n = 10). Subjects were 29 women and 17 men aged 57 +/- 3 yr, with BMI 27.3 +/- 2.0 kg/m(2). Assessments included total body fat by DEXA, lipoproteins, blood pressure, HOMA-IR, C-reactive protein (CRP), and estimated 10-yr CHD risk score. Body fat decreased by 6.3 +/- 3.8 kg in CR, 5.6 +/- 4.4 kg in EX, and 0.4 +/- 1.7 kg in HL, which corresponded to reductions of 24.9, 22.3, and 1.2% of baseline body fat mass, respectively. These CR- and EX-induced energy deficits were accompanied by reductions in most of the major CHD risk factors, including plasma LDL-cholesterol, total cholesterol/HDL ratio, HOMA-IR index, and CRP concentrations that were similar in the two intervention groups. Data from the present study provide evidence that CR- and EX-induced negative energy balance result in substantial and similar improvements in the major risk factors for CHD in normal-weight and overweight middle-aged adults.     

Metformin modifies the exercise training effects on risk factors for cardiovascular disease in impaired glucose tolerant adults

Impaired glucose tolerant (IGT) adults are at elevated risk for cardiovascular disease (CVD). Exercise or metformin reduce CVD risk, but the efficacy of combining treatments is unclear.

Objective:

To determine the effects of exercise training plus metformin (EM), compared with each treatment alone, on CVD risk factors in IGT adults.

Design and Methods:

Subjects were assigned to placebo (P), metformin (M), exercise training plus placebo (EP), or EM (8/group). In a double‐blind design, P or 2,000 mg/d of M were administered for 12 weeks and half performed aerobic and resistance training 3 days/week for ～60 min/day at 70% pretraining heart rate peak. Outcomes included adiposity, blood pressure (BP), lipids, and high sensitivity C‐reactive protein (hs‐CRP). Z‐scores were calculated to determine metabolic syndrome severity.

Results:

M and EM, but not EP, decreased body weight compared with P (P < 0.05). M and EP lowered systolic blood pressure by 6% (P < 0.05), diastolic blood pressure by 6% (P < 0.05), and hs‐CRP by 20% (M: trend P = 0.06; EP: P < 0.05) compared with P. Treatments raised high‐density lipoprotein cholesterol (P < 0.05; EM: trend P = 0.06) compared with P and lowered triacyglycerol (P < 0.05) and metabolic syndrome Z‐score compared with baseline (EP; trend P = 0.07 and EM or M; P < 0.05).

Conclusions:

Although exercise and/or metformin improve some CVD risk factors, only training or metformin alone lowered hs‐CRP and BP. Thus, metformin may attenuate the effects of training on some CVD risk factors and metabolic syndrome severity in IGT adults.     

Effect of blood-flow restriction exercise on falls and fall related risk factors in older adults 60 years or above: a systematic review

This systematic review investigated the effect of low-load resistance training combined with blood-flow restriction (LL-BFR) on falls in older adults ≥60 years of age. The databases Embase, Medline, and Cochrane Library were searched from inception to October 1^st, 2019 and reference lists of retrieved publications. Main outcomes were fall rates or proportion of fallers. Additional outcomes were physical performance, lower extremity muscle strength or function, and balance. Mean difference ±SD on falls and fall related outcomes were reported and Cochrane Collaboration’s risk of bias tool was used to evaluate quality of evidence. Eight RCT-studies met the inclusion criteria. None reported falls data. Assessing physical performance tests (n=12), 8/12 of the LL-BFR groups showed a significant within-group improvement and 5/12 significant between-group effects comparing LL-BFR to respective controls. For muscle strength tests (n=16), 9/16 showed significant positive within-group improvement and 3/16 significant between-group effects. One study reported data on balance with conflicting results. In conclusion, LL-BFR might increase physical performance and muscle strength in older adults ≥60 years of age. None of the included studies investigated the effect on falls. Larger adequately powered studies are required before introducing LL-BFR as an alternative exercise modality to decrease fall risk.     

The narcotic antagonist naltrexone has a biphasic effect on the nicotinic acetylcholine receptor

It is known that narcotic antagonists interact with many cholinergic pathways but less in known about specific mechanisms. Using neonatal rat myoballs to study single channel behaviour of the acetylcholinegated nicotinic receptor, it was found that micromolar concentrations of naltrexone had no effect on channel conductance but caused open channel blockade by increasing the flickering from the open to the closed state in a concentration-dependent manner. At micromolar concentrations of naltrexone, the frequency of channel opening was decreased and bursts were grouped in clusters, whereas at nanomolar levels the frequency of opening was increased. The sequential model for ion-channel blockade cannot explain these effects, and an alternative allosteric mechanism of action is proposed.     

The effect of tuberculosis on mortality in HIV positive people: a meta-analysis

Background

Tuberculosis is a leading cause of death in people living with HIV (PLWH). We conducted a meta analysis to assess the effect of tuberculosis on mortality in people living with HIV.

Methods

Meta-analysis of cohort studies assessing the effect of tuberculosis on mortality in PLWH. To identify eligible studies we systematically searched electronic databases (until December 2008), performed manual searches of citations from relevant articles, and reviewed conference proceedings. Multivariate hazard ratios (HR) of mortality in PLWH with and without tuberculosis, estimated in individual cohort studies, were pooled using random effect weighting according to “Der Simonian Laird method” if the p-value of the heterogeneity test was <0.05.

Results

Fifteen cohort studies were systematically retrieved. Pooled overall analysis of these 15 studies estimating the effect of tuberculosis on mortality in PLWH showed a Hazard Ratio (HR) of 1.8 (95% confidence interval (CI): 1.4–2.3). Subanalysis of 8 studies in which the cohort was not exposed to highly active antiretroviral therapy (HAART) showed an HR of 2.6 (95% CI: 1.8–3.6). Subanalysis of 6 studies showed that tuberculosis did not show an effect on mortality in PLWH exposed to HAART: HR 1.1 (95% CI: 0.9–1.3).

Conclusion

These results provide an indication of the magnitude of benefit to an individual that could have been expected if tuberculosis had been prevented. It emphasizes the need for additional studies assessing the effect of preventing tuberculosis or early diagnosis and treatment of tuberculosis in PLWH on reducing mortality. Furthermore, the results of the subgroup analyses in cohorts largely exposed to HAART provide additional support to WHO''s revised guidelines, which include promoting the initiation of HAART for PLWH co-infected with tuberculosis. The causal effect of tuberculosis on mortality in PLWH exposed to HAART needs to be further evaluated once the results of more cohort studies become available.     

Prenylation has a compound specific effect on the estrogenicity of naringenin and genistein

A variety of plant derived substances, so-called phytoestrogens (PEs), although structurally not related to steroids, produce effects similar to the mammalian estradiol. However, little is known so far about the structural requirements which determine PE activities. Taking into consideration that prenylation reactions are relatively common in plant secondary metabolism, the activity of a set of three PE derivatives of genistein and naringenin, namely genistein, 8-prenylgenistein (8PG), 6-(1,1-dimethylallyl)genistein (6DMAG), naringenin, 8-prenylnaringenin (8PN) and 6-(1,1-dimethylallyl)naringenin (6DMAN) was compared regarding structure–estrogenicity relationships in three functionally different estrogen receptor assays.Strong estrogenic activities were recorded for 6DMAN and 8PN in all assays used, while the parent compound naringenin showed only very weak estrogenicity.In contrast, in the case of genistein derivatives, only genistein itself exhibited estrogenic activity in a yeast based assay. In MVLN breast cancer cells, a bioluminescent MCF-7-derived cell line, the estrogenic activity of all three genistein derivatives was similar. Studying alkaline phosphatase activity in Ishikawa endometrial cancer cells as an estrogenic response marker revealed a similar pattern of estrogenicity of the genistein derivatives compared to the yeast based assay although a slight estrogenic effect of 6DMAG and 8PG was apparent.In summary, this study demonstrates that prenylation often found in plant secondary metabolism differentially modifies estrogenic properties of PEs depending on the basic structure of the respective PE.     

Necrotic core thickness and positive arterial remodeling index: emergent biomechanical factors for evaluating the risk of plaque rupture

Fibrous cap thickness is often considered as diagnostic of the degree of plaque instability. Necrotic core area (Core(area)) and the arterial remodeling index (Remod(index)), on the other hand, are difficult to use as clinical morphological indexes: literature data show a wide dispersion of Core(area) thresholds above which plaque becomes unstable. Although histopathology shows a strong correlation between Core(area) and Remod(index), it remains unclear how these interact and affect peak cap stress (Cap(stress)), a known predictor of rupture. The aim of this study was to investigate the change in plaque vulnerability as a function of necrotic core size and plaque morphology. Cap(stress) value was calculated on 5,500 idealized atherosclerotic vessel models that had the original feature of mimicking the positive arterial remodeling process described by Glagov. Twenty-four nonruptured plaques acquired by intravascular ultrasound on patients were used to test the performance of the associated idealized morphological models. Taking advantage of the extensive simulations, we investigated the effects of anatomical plaque features on Cap(stress). It was found that: 1) at the early stages of positive remodeling, lesions were more prone to rupture, which could explain the progression and growth of clinically silent plaques and 2) in addition to cap thickness, necrotic core thickness, rather than area, was critical in determining plaque stability. This study demonstrates that plaque instability is to be viewed not as a consequence of fibrous cap thickness alone but rather as a combination of cap thickness, necrotic core thickness, and the arterial remodeling index.     

Protein shape change has a major effect on the gating energy of a mechanosensitive channel

Increasing experimental evidence has shown that membrane protein functionality depends on molecular composition of cell membranes. However, the origin of this dependence is not fully understood. It is reasonable to assume that specific lipid-protein interactions are important, yet more generic effects due to mechanical properties of lipid bilayers likely play a significant role too. Previously it has been demonstrated using models for elastic properties of membranes and lateral pressure profiles of lipid bilayers that the mechanical properties of a lipid bilayer can contribute as much as ∼10 k_BT to the free energy difference associated with a change in protein conformational state. Here, we extend those previous approaches to a more realistic model for a large mechanosensitive channel (MscL). We use molecular dynamics together with the MARTINI model to simulate the open and closed states of MscL embedded in a DOPC bilayer. We introduce a procedure to calculate the mechanical energy change in the channel gating using a three-dimensional pressure distribution inside a membrane, computed from the molecular dynamics simulations. We decompose the mechanical energy to terms associated with area dilation and shape contribution. Our results highlight that the lateral pressure profile of a lipid bilayer together with the shape change in gating can induce a contribution of ∼30 k_BT on the gating energy of MscL. This contribution arises largely from the interfacial tension between hydrophobic and hydrophilic regions in a lipid bilayer.