Performance of the SarQoL quality of life tool in a UK population of older people with probable sarcopenia and implications for use in clinical trials: findings from the SarcNet registry.
The Sarcopenia Quality of Life (SarQoL) questionnaire is a disease-specific sarcopenia quality of life tool. We aimed to independently assess SarQoL with a particular focus on its suitability as a clinical trial outcome measure. We analysed data from the UK Sarcopenia Network and Registry. Measures of physical performance and lean mass were collected at baseline. SarQoL and the Strength, Assistance, Rise, Climb - Falls (SARC-F) questionnaire (to assess functional ability) were collected at both baseline and six-month follow-up. Global changes in fitness and quality of life at 6 months were elicited on seven-point Likert scales. Internal consistency was assessed using Cronbach's alpha. Responsiveness (Cohen's d and Guyatt coefficients) and minimum clinically important differences were calculated for participants reporting slight improvement or worsening in their global scores. Concurrent validity was assessed by correlating baseline SarQoL scores with measures of physical performance and functional ability. We analysed data from 147 participants, 125 of whom underwent follow up assessment; mean age 78 years; 72 (49%) were women. Internal consistency was good; Cronbach's alpha was 0.944 at baseline and 0.732 at telephone follow-up. Correlation between baseline and follow-up SarQoL was weak (r = 0.27; p = 0.03). The minimum clinically important improvement ranged from 5 to 21 points giving trial sample size estimates of 25-100 participants. SarQoL scores were moderately correlated with handgrip (r = 0.37; p < 0.001), SARC-F (r = - 0.45; p < 0.001), short physical performance battery (r = 0.48; p < 0.001) and 4-m walk speed (r = 0.48; p < 0.001). SarQoL has acceptable performance in older UK participants with probable sarcopenia and is sufficiently responsive for use in clinical trials for sarcopenia.


Longevity and mitochondrial membrane potential.
In Saccharomyces cerevisiae yeast cells a decrease in the mitochondrial membrane potential caused by protonophores or by a loss of mitochondrial DNA leads to an increase in longevity (replicative life span). The loss of mitochondrial DNA also activates retrograde signaling that results in certain changes in transcription. Recently, Miceli and coauthors ((2011) Front. Genet., 2, 102) showed that retrograde response is triggered by a drop in the membrane potential. Independently, it has been shown that retrograde response activates autophagic mitochondrial degradation (mitophagy). Together, it suggests that activation of selective mitophagy increases lifespan by protecting cells from accumulation of damaged mitochondria in cells. Low concentrations of protonophores can be beneficial by increasing the accuracy of the mitophagosomal degradation of mitochondria with deleterious mutations in their DNA.


Gender confirming medical interventions and eating disorder symptoms among transgender individuals.
Studies indicate that transgender individuals may be at risk of developing eating disorder symptoms (EDS). Elevated risk may be attributed to body dissatisfaction and/or societal reactions to nonconforming gender expression, such as nonaffirmation of a person's gender identity (e.g., using incorrect pronouns). Limited research suggests that gender-confirming medical interventions (GCMIs) may prevent or reduce EDS among transgender people. Participants included 154 transfeminine spectrum (TFS) and 288 transmasculine spectrum (TMS) individuals who completed the Trans Health Survey. Serial multiple mediation analyses controlling for age, education, and income were used to examine whether body satisfaction and nonaffirmation mediate any found relationships between various GCMIs (genital surgery, chest surgery, hormone use, hysterectomy, and hair removal) and EDS. For TFS individuals, the nonaffirmation to body satisfaction path mediated relationships between all GCMIs and EDS, although body satisfaction alone accounted for more of the indirect effects than this path for chest surgery. For TMS individuals, relationships between all GCMIs and EDS were mediated by the nonaffirmation to body satisfaction path. Findings support the hypothesis that GCMIs reduce experiences of nonaffirmation, which increases body satisfaction and thus decreases EDS. Among TFS participants, the relationship between chest surgery and lower levels of EDS was mediated most strongly by body satisfaction alone, suggesting that satisfaction with one's body may result in lower EDS even if affirmation from the external world is unchanged. Implications of these findings for intervention, policy, and legal efforts are discussed, and future research recommendations are provided. (PsycINFO Database Record


Macrophage specific caspase-1/11 deficiency protects against cholesterol crystallization and hepatic inflammation in hyperlipidemic mice.
While non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis combined with inflammation, the mechanisms triggering hepatic inflammation are unknown. In Ldlr(-/-) mice, we have previously shown that lysosomal cholesterol accumulation in Kupffer cells (KCs) correlates with hepatic inflammation and cholesterol crystallization. Previously, cholesterol crystals have been shown to induce the activation of inflammasomes. Inflammasomes are protein complexes that induce the processing and release of pro-inflammatory cytokines IL-1b and IL-18 via caspase-1 activation. Whereas caspase-1 activation is independent of caspase-11 in the canonical pathway of inflammasome activation, caspase-11 was found to trigger caspase-1-dependent IL-1b and IL-18 in response to non-canonical inflammasome activators. So far, it has not been investigated whether inflammasome activation stimulates the formation of cholesterol crystals. We hypothesized that inflammasome activation in KCs stimulates cholesterol crystallization, thereby leading to hepatic inflammation. Ldlr (-/-) mice were transplanted (tp) with wild-type (Wt) or caspase-1/11(-/-) (dKO) bone marrow and fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 12 weeks. In vitro, bone marrow derived macrophages (BMDM) from wt or caspase-1/11(-/-) mice were incubated with oxLDL for 24h and autophagy was assessed. In line with our hypothesis, caspase-1/11(-/-)-tp mice had less severe hepatic inflammation than Wt-tp animals, as evident from liver histology and gene expression analysis in isolated KCs. Mechanistically, KCs from caspase-1/11(-/-)-tp mice showed less cholesterol crystals, enhanced cholesterol efflux and increased autophagy. In wt BMDM, oxLDL incubation led to disturbed autophagy activity whereas BMDM from caspase-1/11(-/-) mice had normal autophagy activity. Altogether, these data suggest a vicious cycle whereby disturbed autophagy and decreased cholesterol efflux leads to newly formed cholesterol crystals and thereby maintain hepatic inflammation during NASH by further activating the inflammasome.


HIV testing in the workplace.
Because the incidence of AIDS continues to grow, affecting a greater number of the working population, the disease is also rapidly becoming a major issue for employers. AIDS has implications for employer decisions in the areas of hiring, termination, training, promotions, benefits, collective bargaining, health and safety in the workplace. This article examines the advantages and disadvantages of HIV screening in the workplace. Technical issues regarding the validity of current HIV tests being used are outlined. Precedent-setting court decisions are reviewed, and the resulting legal and ethical implications and dilemmas of employers and health care providers are examined.


Novel pathway analysis of genomic polymorphism-cancer risk interaction in the Breast Cancer Prevention Trial.
Tamoxifen was approved for breast cancer risk reduction in high-risk women based on the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention Trial (P-1:BCPT), which showed 50% fewer breast cancers with tamoxifen versus placebo, supporting tamoxifen's efficacy in preventing breast cancer. Poor metabolizing CYP2D6 variants are currently the subject of intensive scrutiny regarding their impact on clinical outcomes in the adjuvant setting. Our study extends to variants in a wider spectrum of tamoxifen-metabolizing genes and applies to the prevention setting. Our case-only study, nested within P-1:BCPT, explored associations of polymorphisms in estrogen/tamoxifen-metabolizing genes with responsiveness to preventive tamoxifen. Thirty-nine candidate polymorphisms in 17 candidate genes were genotyped in 249 P-1:BCPT cases. CVP2D6_C1111T, individually and within a CYP2D6 haplotype, showed borderline significant association with treatment arm. Path analysis of the entire tamoxifen pathway gene network showed that the tamoxifen pathway model was consistent with the pattern of observed genotype variability within the placebo-arm dataset. However, correlation of variations in genes in the tamoxifen arm differed significantly from the predictions of the tamoxifen pathway model. Strong correlations between allelic variation in the tamoxifen pathway at CYP1A1-CYP3A4, CYP3A4-CYP2C9, and CYP2C9-SULT1A2, in addition to CYP2D6 and its adjacent genes, were seen in the placebo-arm but not the tamoxifen-arm. In conclusion, beyond reinforcing a role for CYP2D6 in tamoxifen response, our pathway analysis strongly suggests that specific combinations of allelic variants in other genes make major contributions to the tamoxifen-resistance phenotype.


Fluorescence-based sorting of Caenorhabditis elegans via acoustofluidics.
Effectively isolating and categorizing large quantities of Caenorhabditis elegans (C. elegans) based on different phenotypes is important for most worm research, especially genetics. Here we present an integrated acoustofluidic chip capable of identifying worms of interest based on expression of a fluorescent protein in a continuous flow and then separate them accordingly in a high-throughput manner. Utilizing planar fiber optics as the detection unit, our acoustofluidic device requires no temporary immobilization of worms for interrogation/detection, thereby improving the throughput. Implementing surface acoustic waves (SAW) as the sorting unit, our device provides a contact-free method to move worms of interest to the desired outlet, thus ensuring the biocompatibility for our chip. Our device can sort worms of different developmental stages (L3 and L4 stage worms) at high throughput and accuracy. For example, L3 worms can be processed at a throughput of around 70 worms per min with a sample purity over 99%, which remains over 90% when the throughput is increased to around 115 worms per min. In our acoustofluidic chip, the time period to complete the detection and sorting of one worm is only 50 ms, which outperforms nearly all existing microfluidics-based worm sorting devices and may be further reduced to achieve higher throughput.


Generalized molecular chaos hypothesis and the H theorem: problem of constraints and amendment of nonextensive statistical mechanics.
Quite unexpectedly, kinetic theory is found to specify the correct definition of average value to be employed in nonextensive statistical mechanics. It is shown that the normal average is consistent with the generalized Stosszahlansatz (i.e., molecular chaos hypothesis) and the associated H theorem, whereas the q average widely used in the relevant literature is not. In the course of the analysis, the distributions with finite cutoff factors are rigorously treated. Accordingly, the formulation of nonextensive statistical mechanics is amended based on the normal average. In addition, the Shore-Johnson theorem, which supports the use of the q average, is carefully re-examined and it is found that one of the axioms may not be appropriate for systems to be treated within the framework of nonextensive statistical mechanics.


Clinical Benefit of Intravascular Imaging Compared With Conventional Angiography in Left Main Coronary Artery Intervention.
The RENOVATE-COMPLEX-PCI (Randomized Controlled Trial of Intravascular Imaging Guidance Versus Angiography-Guidance on Clinical Outcomes After Complex Percutaneous Coronary Intervention) demonstrated that intravascular imaging-guided percutaneous coronary intervention (PCI) improved clinical outcome compared with angiography-guided PCI for patients with complex coronary artery lesions. This study aims to assess whether the prognostic benefit of intravascular imaging-guided procedural optimization persists in patients undergoing PCI for left main coronary artery disease. Of 1639 patients enrolled in the RENOVATE-COMPLEX-PCI, 192 patients with left main coronary artery disease were selected for the current prespecified substudy. Selected patients were randomly assigned to either the intravascular imaging-guided PCI group (n=138) or the angiography-guided PCI group (n=54). The primary end point was target vessel failure defined as a composite of cardiac death, target vessel-related myocardial infarction, or clinically driven target vessel revascularization. At a median follow-up of 2.1 years (interquartile range 1.1 to 3.0 years), intravascular imaging-guided PCI was associated with lower incidence of primary end point compared with angiography-guided PCI (6.8% versus 25.1%; hazard ratio, 0.31 [95% CI, 0.13-0.76]; P=0.010). This significant reduction in primary end point was mainly driven by a lower risk of cardiac death or spontaneous target vessel-related myocardial infarction (1.6% versus 12.7%; hazard ratio, 0.16 [95% CI, 0.03-0.82]; P=0.028). Intravascular imaging-guided PCI was independently associated with a lower risk of primary end point, even after adjusting for various clinical factors (hazard ratio, 0.29 [95% CI, 0.12-0.72]; P=0.007). Intravascular imaging-guided PCI showed clinical benefit over angiography-guided PCI for left main coronary artery disease in reducing the risk of cardiac death, target vessel-related myocardial infarction, or target vessel revascularization. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03381872.


Multimodal treatment of oligometastatic non-small cell lung cancer.
The management of patients with oligometastatic non-small cell lung cancer has undergone significant improvement in recent years. The combination of increase in sensitivity of diagnostic tests, development in systemic therapies, surgical techniques and radiotherapy allowing radical ablative treatment of metastases have significantly influenced the treatment of advanced lung cancer, mainly in the patients in which these treatment modalities converge.We report a rare case of a young patient with an oligometastatic lung adenocarcinoma with a single synchronous brain metastasis, who underwent aggressive locoregional and systemic therapies and is still in annual follow-up with excellent quality of life and progression-free survival of 164 months.


Decompressive Craniectomy for Malignant Middle Cerebral Artery Stroke.
Advancements in the treatment of ischemic stroke have led to a recent decline in overall stroke mortality, but patients with hemispheric infarcts remain at high risk for death. Recent advances in the approach to this devastating disease include early identification of patients at high risk for swelling and standardized approaches to medical therapy. However, surgical decompression continues to be the most effective treatment for malignant edema from large hemispheric strokes. Patient selection in the past had been strictly limited to younger ages and the nondominant hemisphere. More recent evidence demonstrates a mortality benefit in older patients with a limited impact on morbidity. Judicious patient selection and shared, informed decision making with families remain the optimal approach for this devastating disease.


The profiling of pre- and post-warming DNA in mouse embryos with microsatellite method.
This research aimed to identify the deoxyribonucleic acid (DNA) profile and changes of post-warming embryo after being frozen with vitrification method using microsatellite method. This research examined the mouse embryo blastocysts that were divided into four groups: Post-warming living blastocyst, post-warming living blastocyst with half fragmented cell, post-warming dead blastocyst, and pre-freezing living blastocyst. The isolation sample applied phenol-chloroform method. After obtaining polymerase chain reaction results, all the samples of pre-freezing fresh embryo, post-warming living embryo, dead embryo, and degenerated embryo were then examined by single-strand conformation polymorphism (SSCP). The amplification with D18mit14 primer was 100 bp and 150bp with D18mit87 primer, 150bp with D7mit22, and 300bp with D7mit25. The result of SSCP with D18mit14 primer showed that the blastocysts were fragmented and dead after warming process and formed into two DNA strand fragments, while the fresh embryos which passed freezing process did not form any fragment. D18mit87 primer SSCP indicated different fragments for each treatment. The result of SSCP using D7mit22 formed two different fragments for each treatment. While using D7mit25, the SSCP result formed some different fragments for each sample. Post-warming living embryo had similar ribbon to pre-freezing fresh embryo. D7mit222, D7mit25, and D18mit87 primers could be used as the aneuploidy marker on mouse embryos that were induced by post-warming process. The profile of living blastocyst, dead blastocyst, and post-warming fragmented blastocyst had different DNA tapes.


Bayesian spatial semi-parametric modeling of HIV variation in Kenya.
Spatial statistics has seen rapid application in many fields, especially epidemiology and public health. Many studies, nonetheless, make limited use of the geographical location information and also usually assume that the covariates, which are related to the response variable, have linear effects. We develop a Bayesian semi-parametric regression model for HIV prevalence data. Model estimation and inference is based on fully Bayesian approach via Markov Chain Monte Carlo (McMC). The model is applied to HIV prevalence data among men in Kenya, derived from the Kenya AIDS indicator survey, with n = 3,662. Past studies have concluded that HIV infection has a nonlinear association with age. In this study a smooth function based on penalized regression splines is used to estimate this nonlinear effect. Other covariates were assumed to have a linear effect. Spatial references to the counties were modeled as both structured and unstructured spatial effects. We observe that circumcision reduces the risk of HIV infection. The results also indicate that men in the urban areas were more likely to be infected by HIV as compared to their rural counterpart. Men with higher education had the lowest risk of HIV infection. A nonlinear relationship between HIV infection and age was established. Risk of HIV infection increases with age up to the age of 40 then declines with increase in age. Men who had STI in the last 12 months were more likely to be infected with HIV. Also men who had ever used a condom were found to have higher likelihood to be infected by HIV. A significant spatial variation of HIV infection in Kenya was also established. The study shows the practicality and flexibility of Bayesian semi-parametric regression model in analyzing epidemiological data.


Reproductive toxicity in birds predicted by physiologically-based kinetics and bioenergetics modelling.
Effects on the growth and reproduction of birds are important endpoints in the environmental risk assessment (ERA) of pesticides. Toxicokinetic-toxicodynamic models based on dynamic energy budget theory (DEB) are promising tools to predict these effects mechanistically and make extrapolations relevant to ERA. However, before DEB-TKTD models are accepted as part of ERA for birds, ecotoxicological case studies are required so that stakeholders can assess their capabilities. We present such a case-study, modelling the effects of the fluopyram metabolite benzamide on the northern bobwhite quail (Colinus virginianus). We parametrised a DEB-TKTD model for the embryo stage on the basis of an egg injection study, designed to provide data for model development. We found that information on various endpoints, such as survival, growth, and yolk utilisation were needed to clearly distinguish between the performance of model variants with different TKTD assumptions. The calibration data were best explained when it was assumed that chemical uptake occurs via the yolk and that benzamide places stress on energy assimilation and mobilisation. To be able to bridge from the in vitro tests to real-life exposure, we developed a physiologically-based toxicokinetic (PBK) model for the quail and used it to predict benzamide exposure inside the eggs based on dietary exposure in a standard reproductive toxicity study. We then combined the standard DEB model with the TKTD module calibrated to the egg injection studies and used it to predict effects on hatchling and 14-day chick weight based on the exposure predicted by the PBK model. Observed weight reductions, relative to controls, were accurately predicted. Thus, we demonstrate that DEB-TKTD models, in combination with suitable experimental data and, if necessary, with an exposure model, can be used in bird ERA to predict chemical effects on reproduction.


Internal-Illumination Photoacoustic Tomography Enhanced by a Graded-Scattering Fiber Diffuser.
The penetration depth of photoacoustic imaging in biological tissues has been fundamentally limited by the strong optical attenuation when light is delivered externally through the tissue surface. To address this issue, we previously reported internal-illumination photoacoustic imaging using a customized radial-emission optical fiber diffuser, which, however, has complex fabrication, high cost, and non-uniform light emission. To overcome these shortcomings, we have developed a new type of low-cost fiber diffusers based on a graded-scattering method in which the optical scattering of the fiber diffuser is gradually increased as the light travels. The graded scattering can compensate for the optical attenuation and provide relatively uniform light emission along the diffuser. We performed Monte Carlo numerical simulations to optimize several key design parameters, including the number of scattering segments, scattering anisotropy factor, divergence angle of the optical fiber, and reflective index of the surrounding medium. These optimized parameters collectively result in uniform light emission along the fiber diffuser and can be flexibly adjusted to accommodate different applications. We fabricated and characterized the prototype fiber diffuser made of agarose gel and intralipid. Equipped with the new fiber diffuser, we performed thorough proof-of-concept studies on ex vivo tissue phantoms and an in vivo swine model to demonstrate the deep-imaging capability (~10 cm achieved ex vivo) of photoacoustic tomography. We believe that the internal light delivery via the optimized fiber diffuser is an effective strategy to image deep targets (e.g., kidney) in large animals or humans.


[Viral hepatitis A and postpartum acute renal failure. Report of a case and review of the literature].
Hepatitis A virus infection (HAV) has been perceived as a self-limited disease. However, acute renal failure is an infrequent but well-described complication of HAV infection. Although the mechanisms responsible are uncertain, they may be related to the immune complex. In this report we describe a patient with HAV and acute renal failure in the postpartum period.


Polymorphisms in the vitamin D system and mortality - The Tromsø study.
Vitamin D deficiency is associated with diabetes, cancer, immunological and cardiovascular diseases as well as increased mortality. It has, however, been difficult to show a causal relation in randomized, controlled trials. Mendelian randomization studies provide another option for testing causality, and results indicate relations between the serum 25-hydroxyvitamin D (25(OH)D) level and some diseases, including mortality. We have from the Tromsø Study in 2012 published non-significant relations been vitamin D related single nucleotide polymorphisms (SNPs) and mortality, but have since then genotyped additional subjects, the observation time is longer and new SNPs have been included. For the present study genotyping was performed for SNPs in the NADSYN1, CYP2R1, GC and CYP24A1, VDR, CUBILIN and MEGALIN genes in 11 897 subjects who participated in the fourth survey of the Tromsø Study in 1994-1995. Serum 25(OH)D levels were measured in 6733 of these subjects. Genetic scores based on SNPs related to the serum 25(OH)D level (NADSYN1 and CYP2R1 SNPs (synthesis score) and GC and CYP24A1 SNPs (metabolism score)) and serum 25(OH)D percentile groups were created. Mortality data was updated till end of March 2017 and survival analysed with Cox regression adjusted for sex and age. During the observation period 5491 subjects died. The 25(OH)D synthesis (but not the metabolism) genetic score and the serum 25(OH)D percentile groups were (without Bonferroni correction) significantly related to mortality in favour of high serum 25(OH)D. None of the SNPs in the VDR or MEGALIN genes were related to mortality. However, for the rs12766939 in the CUBILIN gene with the major homozygote as reference, the hazard ratio for mortality for the minor homozygote genotype was 1.17 (1.06-1.29), P < 0.002. This should be viewed with caution, as rs12766939 was not in Hardy-Weinberg equilibrium. In conclusion, our study confirms a probable causal but weak relation between serum 25(OH)D level and mortality. The relation between rs12766939 and mortality needs confirmation in more homogenous cohorts.


Edge scattering of surface plasmons excited by scanning tunneling microscopy.
The scattering of electrically excited surface plasmon polaritons (SPPs) into photons at the edges of gold metal stripes is investigated. The SPPs are locally generated by the inelastic tunneling current of a scanning tunneling microscope (STM). The majority of the collected light arising from the scattering of SPPs at the stripe edges is emitted in the forward direction and is collected at large angle (close to the air-glass critical angle, θ(c)). A much weaker isotropic component of the scattered light gives rise to an interference pattern in the Fourier plane images, demonstrating that plasmons may be scattered coherently. An analysis of the interference pattern as a function of excitation position on the stripe is used to determine a value of 1.42 ± 0.18 for the relative plasmon wave vector (kSPP/k0) of the corresponding SPPs. From these results, we interpret the directional, large angle (θ~θ(c)) scattering to be mainly from plasmons on the air-gold interface, and the diffuse scattering forming interference fringes to be dominantly from plasmons on the gold-substrate interface.


Understanding public resistance to messages about health disparities.
Advocates and policymakers strategically communicate about health disparities in an effort to raise public awareness, often by emphasizing the social and economic factors that influence these disparities. Previous research suggests that predisposing political orientation and values related to self-reliance and personal responsibility may produce resistance to such messages. In this study, the authors culled 4 messages about the causes of disparities in life expectancy from public discourse and randomly presented them to a nationally representative sample of 732 Americans. Three indicators of message resistance were measured: belief that messages are weak, elicitation of anger, and production of counterarguments. Expected political differences in message resistance were identified, with Republicans perceiving messages to be weaker, arousing less anger, and eliciting more counterarguing than for Democrats. Among 3 messages that described the social determinants of health disparities, a message that identified the role of personal choices (explicitly acknowledging personal responsibility) produced the least anger and counterarguing among Republicans. Political differences in anger arousal and counterarguing can be explained, in part, by predisposing values toward personal responsibility. These findings have relevance for policy advocates seeking to bridge public divides surrounding health disparities and for scholars advancing theories of reactance to policy-relevant health messaging.


The Role of Cyclic Nucleotides in Compensatory Hepatocyte Proliferation.
The study of the mechanisms of liver regeneration is quite an intriguing field that has been extensively modeled. Through the process of compensatory proliferation of the hepatocytes, the liver mass is restored after loss of up to two-thirds of the entire mass. Cyclic nucleotides are intracellular second messengers which are involved in the transduction of a diverse array of stimuli, mediating metabolic and growth regulation. The relationship between cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling and liver regeneration has somehow been elusive to pioneer researchers in the field of liver regeneration. In this review, we will highlight the mechanistic approach involving cyclic nucleotide signaling and its regulation of cell cycle progression in proliferating hepatocytes, highlighting its usefulness to devising therapeutic tools for managing liver diseases. A structured search and review of relevant papers was conducted by the authors. Authors included forty-two peer-reviewed literature in the review which identified possible roles of cyclic nucleotides in hepatocyte proliferation. This review article confirms the biological importance of cyclic nucleotides and the mediatory growth signaling events that could bring about compensatory proliferation of the liver tissues.


Investigating community ownership of a text message programme to improve adherence to antiretroviral therapy and provider-client communication: a mixed methods research protocol.
Mobile phone ownership and use are growing fastest in sub-Saharan Africa, and there is evidence that mobile phone text messages can be used successfully to significantly improve adherence to antiretroviral therapy and reduce treatment interruptions. However, the effects of many mobile health interventions are often reduced by human resource shortages within health facilities. Also, research projects generating evidence for health interventions in developing countries are most often conducted using external funding sources, with limited sustainability and adoption by local governments following completion of the projects. Strong community participation driven by active outreach programmes and mobilisation of community resources are the key to successful adoption and long-term sustainability of effective interventions. Our aim was to develop a framework for community ownership of a text messaging programme to improve adherence to antiretroviral therapy; improve communication between patients and doctors and act as a reminder for appointments. We will use the exploratory sequential mixed methods approach. The first qualitative phase will entail focus group discussions with people living with HIV at the Yaoundé Central Hospital in Yaoundé, Cameroon (6-10 participants/group). The second quantitative phase will involve a cross-sectional survey (n=402). In this study, binary logistic regression techniques will be used to determine the factors associated with community readiness and acceptability of ownership. Data from both phases will be merged. This study has been approved by the Yaoundé Central Hospital Institutional Review Board. The results of this paper will be disseminated as peer-reviewed publications at conferences and as part of a doctoral thesis.


Neuroprotective effect of hyperbaric oxygen therapy in brain injury is mediated by preservation of mitochondrial membrane properties.
Recent experimental data have shown that hyperbaric oxygen therapy (HBOT) was associated increased Bcl-2 expression at the injury site that correlated with reduced apoptosis. We hypothesized that HBOT mediated enhancement of Bcl-2 expression and increased intracellular oxygen bio-availability may both contribute to preserve mitochondrial integrity and reduce the activation of the mitochondrial pathway of apoptosis. For this purpose, a cortical lesion was created in the parietal cortex of Sprague-Dawley rats by dynamic cortical deformation (DCD) and outcome measures in non-treated animals were compared with that of HBOT treated rats. Morphological analysis showed a profound reduction in neuronal counts in the perilesional area and a marked rarefaction of the density of the axonal-dendritic network. In treated animals, however, there was a significant attenuation of the impact of DCD over perilesional neurons, characterized by significantly higher cell counts and denser axonal network. In mitochondria isolated from injured brain tissue, there was a profound loss of mitochondrial transmembrane potential (Deltapsi(M)) that proved to be substantially reversed by HBOT. This finding correlated with a significant reduction of caspases 3 and 9 activation in HBOT treated animals but not of caspase 8, indicating a selective effect over the intrinsic pathway of apoptosis. All together, our results indicate that the neuroprotective effect of HBOT may represent the consequence of preserved mitochondrial integrity and subsequent inhibition of the mPTP and reduction of the mitochondrial pathway of apoptosis.


Relation between bone turnover, oestradiol, and energy balance in women distance runners.
To explore relations between biochemical markers of bone turnover, indices of nutritional status, and serum oestradiol concentration in women distance runners. Thirty three women distance runners of mean age (SD) 27.2 (1.8) years participated. Eighteen were defined as eumenorrhoeic, nine as amenorrhoeic, and six as oligomenorrhoeic. Mean (SD) running distance was 47.6 (22.4) km/week. Using bivariate correlation and regression analysis, serum levels of osteocalcin and bone alkaline phosphatase (BAP) and also urine deoxypyridinoline/creatinine (Dpyr/Cr) were correlated with mean daily energy balance, body mass index (BMI; kg/m2), and serum levels of total 3,5,3'-triiodothyronine and oestradiol within each group by menstrual status. All the amenorrhoeic women were in negative energy balance; they had a lower BMI, lower serum levels of oestradiol, triiodothyronine, osteocalcin and BAP and a lower urine Dpyr/Cr than any of the oligomenorrhoeic or eumenorrhoeic women. These variables were also lower in oligomenorrhoeic than in eumenorrhoeic women. Positive correlations were observed between serum levels of osteocalcin or BAP and both BMI and serum oestradiol concentration in amenorrhoeic, but not in oligomenorrhoeic or eumenorrhoeic women. Urine Dpyr/Cr did not correlate with any other variable within any group. Serum oestradiol concentration correlated positively with BMI in amenorrhoeic and oligomenorrhoeic, but not eumenorrhoeic women. Positive correlations between serum levels of bone formation markers, BMI and serum oestradiol concentration in our amenorrhoeic runners suggested that their reduced bone formation was linked to a low BMI and an oestrogen deficiency. Reduced bone turnover in amenorrhoeic distance runners has not previously been shown. These findings emphasise the importance of body mass and its possible link with a chronic energy deficit and hypothalamic dysfunction on bone remodelling balance in amenorrhoeic runners.


Alkaliphilus halophilus sp. nov., a strictly anaerobic and halophilic bacterium isolated from a saline lake, and emended description of the genus Alkaliphilus.
A novel strictly anaerobic, halophilic and fermentative strain, designated E2R(T), was isolated from sediments of Xiaokule salt lake in Xinjiang Province, China. Cells were straight to slightly curved, Gram-stain-positive rods that were motile by means of flagella and formed endospores. Strain E2R(T) was moderately halophilic and grew optimally in the presence of 7.5 % NaCl, at pH 8.0 and at 32°C. Substrates used include yeast extract, Casamino acids, tryptone, fructose, sucrose, xylose, ribose, lactate and tartrate. Thiosulfate could be used as an accessory electron acceptor and stimulated growth. The main fermentation products from fructose were formate and acetate. The predominant fatty acids were iso-C(15 : 0), iso-C(15 : 1) F and iso-C(13 : 0). 16S rRNA gene sequence analyses revealed that strain E2R(T) was related most closely to members of the genus Alkaliphilus (95.5-91.1 % similarity). The G+C content of strain E2R(T) was 28.5 mol%. Strain E2R(T) could be differentiated from its closest relatives based on its halophilic nature and its lower DNA G+C content. It could also be differentiated based on its substrate utilization pattern and relatively high levels of iso-C(15 : 0). On the basis of these data, strain E2R(T) is considered to represent a novel species of the genus Alkaliphilus, for which the name Alkaliphilus halophilus sp. nov. is proposed. The type strain is E2R(T) (=CGMCC 1.5124(T) =JCM 16124(T)). An emended description of the genus Alkaliphilus is also provided.


Can atmospheric pollution be considered a co-factor in extremely high level of SARS-CoV-2 lethality in Northern Italy?
This paper investigates the correlation between the high level of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) lethality and the atmospheric pollution in Northern Italy. Indeed, Lombardy and Emilia Romagna are Italian regions with both the highest level of virus lethality in the world and one of Europe's most polluted area. Based on this correlation, this paper analyzes the possible link between pollution and the development of acute respiratory distress syndrome and eventually death. We provide evidence that people living in an area with high levels of pollutant are more prone to develop chronic respiratory conditions and suitable to any infective agent. Moreover, a prolonged exposure to air pollution leads to a chronic inflammatory stimulus, even in young and healthy subjects. We conclude that the high level of pollution in Northern Italy should be considered an additional co-factor of the high level of lethality recorded in that area.


Expert Diagnosis of Plus Disease in Retinopathy of Prematurity From Computer-Based Image Analysis.
Published definitions of plus disease in retinopathy of prematurity (ROP) reference arterial tortuosity and venous dilation within the posterior pole based on a standard published photograph. One possible explanation for limited interexpert reliability for a diagnosis of plus disease is that experts deviate from the published definitions. To identify vascular features used by experts for diagnosis of plus disease through quantitative image analysis. A computer-based image analysis system (Imaging and Informatics in ROP [i-ROP]) was developed using a set of 77 digital fundus images, and the system was designed to classify images compared with a reference standard diagnosis (RSD). System performance was analyzed as a function of the field of view (circular crops with a radius of 1-6 disc diameters) and vessel subtype (arteries only, veins only, or all vessels). Routine ROP screening was conducted from June 29, 2011, to October 14, 2014, in neonatal intensive care units at 8 academic institutions, with a subset of 73 images independently classified by 11 ROP experts for validation. The RSD was compared with the majority diagnosis of experts. The primary outcome measure was the percentage of accuracy of the i-ROP system classification of plus disease, with the RSD as a function of the field of view and vessel type. Secondary outcome measures included the accuracy of the 11 experts compared with the RSD. Accuracy of plus disease diagnosis by the i-ROP computer-based system was highest (95%; 95% CI, 94%-95%) when it incorporated vascular tortuosity from both arteries and veins and with the widest field of view (6-disc diameter radius). Accuracy was 90% or less when using only arterial tortuosity and 85% or less using a 2- to 3-disc diameter view similar to the standard published photograph. Diagnostic accuracy of the i-ROP system (95%) was comparable to that of 11 expert physicians (mean 87%, range 79%-99%). Experts in ROP appear to consider findings from beyond the posterior retina when diagnosing plus disease and consider tortuosity of both arteries and veins, in contrast with published definitions. It is feasible for a computer-based image analysis system to perform comparably with ROP experts, using manually segmented images.


Improving needle tip identification during ultrasound-guided procedures in anaesthetic practice.
Ultrasound guidance is becoming standard practice for needle-based interventions in anaesthetic practice, such as vascular access and peripheral nerve blocks. However, difficulties in aligning the needle and the transducer can lead to incorrect identification of the needle tip, possibly damaging structures not visible on the ultrasound screen. Additional techniques specifically developed to aid alignment of needle and probe or identification of the needle tip are now available. In this scoping review, advantages and limitations of the following categories of those solutions are presented: needle guides; alterations to needle or needle tip; three- and four-dimensional ultrasound; magnetism, electromagnetic or GPS systems; optical tracking; augmented (virtual) reality; robotic assistance; and automated (computerised) needle detection. Most evidence originates from phantom studies, case reports and series, with few randomised clinical trials. Improved first-pass success and reduced performance time are the most frequently cited benefits, whereas the need for additional and often expensive hardware is the greatest limitation to widespread adoption. Novice ultrasound users seem to benefit most and great potential lies in education. Future research should focus on reporting relevant clinical parameters to learn which technique will benefit patients most in terms of success and safety.


E-cigarette and combustible cigarette cessation patterns, reasons, and methods among adolescents, young adults, and adults.
Research is limited regarding adolescents' and young adults' (AYA) patterns, methods of, and reasons for cigarette or e-cigarette cessation. Further, while adults may try to use e-cigarettes to quit combustible cigarettes, little is known about how adults then quit e-cigarettes. This study utilizes a national, cross-sectional online survey of 6131 diverse participants aged 13-40 years to examine reasons for quitting e-cigarettes or cigarettes, quit methods, and quit attempt outcomes among AYAs and adults. In our sample, 3137 (51.2%) had ever used an e-cigarette, of whom 2310 (37.7%) were aged 13-24 years and 827 (13.5%) were 25-40 years old; 2387 (38.9%) had ever used a combustible cigarette (1440 [23.5%] were 13-24 years old and 947 [15.4%] were 25-40 years old). Among e-cigarette ever-users, 39.4% of 13-24-year-olds intended to quit in the next 6 months, and 36.9% had a serious plan for quitting in the next 30 days; 25.2% wanted to decrease the amount they used while 34.8% wanted to quit completely. Similar rates were found among e-cigarette ever users aged 25-40 years, as well as past 30-day e-cigarette users, cigarette ever-users, and past 30-day cigarette users across all ages. "Cold turkey" (41.0%) followed by "tried to cut down slowly by vaping/smoking less often or fewer puffs" (25.5%) was the most common quit method among e-cigarette ever-users and cigarette ever-users of all ages. Further study of effective tobacco cessation methods to help both AYAs and adults successfully quit nicotine, whether from cigarettes or e-cigarettes, is urgently needed.


Acanthopanax versus 3-Methyladenine Ameliorates Sodium Taurocholate-Induced Severe Acute Pancreatitis by Inhibiting the Autophagic Pathway in Rats.
Objectives. To observe the therapeutic effects of Acanthopanax and 3-methyladenine against severe acute pancreatitis (SAP). Methods. Sodium taurocholate-induced SAP rats were equally randomized into a SAP group, an Acanthopanax group, and a 3-methyladenine group. Serum amylase levels were determined by ELISA; protein and mRNA expression levels of nucleus nuclear factor kappa B (NF-κB) p65, light chain 3II (LC3-II), and Beclin-1 and mRNA expression levels of Class III phosphatidylinositol 3-kinase (PI3K-III) in pancreas tissue were detected by Western blot and quantitative real-time PCR, respectively; mortality and pathological change of the pancreas were observed at 3, 12, and 24 h after operation. Results. There was no significant difference in mortality between SAP group and both treatment groups (P > 0.05). Serum amylase levels, protein, and mRNA expression levels of nucleus NF-κB p65, LC3-II, and Beclin-1 protein, mRNA expression levels of PI3K-III, and pathological score of the pancreas in both treatment groups were significantly lower than those in SAP group at 12 and 24 h after operation (P < 0.05 or 0.01). The number of autophagosomes and autophagolysosomes of pancreatic acinar cells in both treatment groups was smaller than that in SAP group at 12 and 24 h. Conclusions. Acanthopanax and 3-methyladenine had similar therapeutic effects against SAP in rats. The mechanism may be through inhibiting abnormal autophagy activation of pancreatic acinar cells.


Distinctive actions of connexin 46 and connexin 50 in anterior pituitary folliculostellate cells.
Folliculostellate cell gap junctions establish a network for the transmission of information within the anterior pituitary. Connexins make up gap junction channels. Changes in connexin (Cx) turnover modify gap junction-mediated intercellular communication. We have reported that cytokines and hormones influence Cx43 turnover and coupling in folliculostellate cells and in the folliculostellate cell line TtT/GF. In addition, the expression of different connexins alters intercellular communication and connexins may have functions besides cell coupling. Here we assessed the expression, turnover and subcellular localization of Cx46 and Cx50 in the anterior pituitary and TtT/GF cells. Then, we assessed the impact of various natural (lactation, annual reproductive cycle, bFGF) and pathological (autoimmune orchitis, diabetes/obesity) conditions associated with altered anterior pituitary hormone secretion on Cx46 and Cx50. Anterior pituitary Cx46 and Cx50 expression and subcellular distribution were cell-dependent. Cx46 was expressed by folliculostellate, TtT/GF and endocrine cells. In the cytoplasm, Cx46 was chiefly associated with lysosomes. Variously sized Cx46 molecules were recovered exclusively in the TtT/GF cell nuclear fraction. In the nucleus, Cx46 co-localized with Nopp-140, a nucleolar factor involved in rRNA processing. Neither cytoplasmic nor nuclear Cx46 and Cx43 co-localized. Cx50 localized to folliculostellate and TtT/GF cells, and to the walls of blood capillaries, not to endocrine cells. Cx50 was cytoplasmic and associated with the cell membrane, not nuclear. Cx50 did not co-localize with Cx46 but it co-localized in the cytoplasm and co-immunoprecipitated with Cx43. Cx46 and Cx50 responses to various physiological and pathological challenges were different, often opposite. Cx46 and Cx43 expression and phosphorylation profiles differed in the anterior pituitary, whereas Cx50 and Cx43 were similar. The data suggest that Cx46 participates to cellular growth and proliferation and that Cx50, together with Cx43, contributes to folliculostellate cell coupling.


A comparison of data-independent microwave beamforming algorithms for the early detection of breast cancer.
Ultrawideband (UWB) radar is one of the most promising alternatives to X-ray mammography as an imaging modality for the early detection of breast cancer. Several beamforming algorithms have been developed which exploit the dielectric contrast between normal and cancerous tissue at microwave frequencies in order to detect tumors. Dielectric heterogeneity within the breast greatly effects the ability of a beamformer to detect very small tumors, therefore the design of an effective beamformer for this application represents a significant challenge. This paper analyzes and compares 3 data-independent beamforming algorithms, testing each system on an anatomically correct, MRI derived breast model which incorporates recently-published data on dielectric properties.


Abnormal glucose tolerance and increased risk for cardiovascular disease in Japanese-Americans with normal fasting glucose.
To compare the American Diabetes Association (ADA) fasting glucose and the World Health Organization (WHO) oral glucose tolerance test (OGTT) criteria for diagnosing diabetes and detecting people at increased risk for cardiovascular disease (CVD). Study subjects were 596 Japanese-Americans. Fasting insulin, lipids, and C-peptide levels; systolic and diastolic blood pressures (BPs); BMI (kg/m2); and total and intra-abdominal body fat distribution by computed tomography (CT) were measured. Study subjects were categorized by ADA criteria as having normal fasting glucose (NFG), impaired fasting glucose (IFG), and diabetic fasting glucose and by WHO criteria for a 75-g OGTT as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetic glucose tolerance (DGT). Of 503 patients with NFG, 176 had IGT and 20 had DGT These patients had worse CVD risk factors than those with NGT . The mean values for NGT, IGT, and DGT, respectively, and analysis of covariance P values, adjusted for age and sex, are as follows; intra-abdominal fat area by CT 69.7, 95.0, and 101.1 cm2 (P < 0.0001); total CT fat area 437.7, 523.3, and 489.8 cm2 (P < 0.0001); fasting triglycerides 1.40, 1.77, and 1.74 mmol/l (P = 0.002); fasting HDL cholesterol 1.56, 1.50, and 1.49 mmol/l (P = 0.02); C-peptide 0.80, 0.90, 0.95 nmol/l (P = 0.002); systolic BP 124.9, 132.4, and 136.9 mmHg (P = 0.0035); diastolic BP 74.8, 77.7, and 78.2 mmHg (P = 0.01). NFG patients who had IGT or DGT had more intra-abdominal fat and total adiposity; higher insulin, C-peptide, and triglyceride levels; lower HDL cholesterol levels; and higher BPs than those with NGT. Classification by fasting glucose misses many Japanese-Americans with abnormal glucose tolerance and less favorable cardiovascular risk profiles.


Patient-reported barriers and facilitators to antiretroviral adherence in sub-Saharan Africa.
The aim of this study was to identify the range and frequency of patient-reported barriers and facilitators to antiretroviral treatment (ART) adherence in sub-Saharan Africa (SSA). Studies from 2005 to 2016 were identified by searching 10 electronic databases and through additional hand and web-searching. Inclusion criteria were HIV-positive adults taking ART based in any SSA country, qualitative study or quantitative survey and included at least one patient-reported barrier or facilitator to ART adherence. Exclusion criteria were only including data from treatment-naive patients initiating ART, only single-dose treatment, participants residing outside of SSA and reviews. After screening 11 283 records, 154 studies (161 papers) were included in this review. Forty-three barriers and 30 facilitators were reported across 24 SSA countries. The most frequently identified barriers across studies were forgetting (n = 76), lack of access to adequate food (n = 72), stigma and discrimination (n = 68), side effects (n = 67) and being outside the house or travelling (n = 60). The most frequently identified facilitators across studies were social support (n = 60), reminders (n = 55), feeling better or healthier after taking ART (n = 35), disclosing their HIV status (n = 26) and having a good relationship with a health provider (n = 22). This review addresses the gap in knowledge by collating all the patient-reported barriers and facilitators to ART adherence in SSA. Current barriers measures need to be adapted or new tools developed to include the wide variety of factors identified. The factors that have the greatest impact need to be isolated so interventions are developed that reduce the barriers and enhance the facilitators.


Multiple univariate analysis of radiologic and clinical features on 168 patients with lumbar spinal stenosis: what is the role of the erector spinae in the development of a patient's disability?
The weakening of paraspinal muscles in the paravertebral area may play a role in developing central lumbar spinal stenosis, resulting in lower back discomfort. The study thoroughly examined the correlation between the Oswestry Disability Index, Dural Sac cross-sectional area, Schizas grading Scale, Body Mass Index, and the cross-sectional areas of Erector Spinae, Multifidus, and Psoas muscles. The findings were also compared between patients with central Lumbar Spinal Stenosis and healthy individuals. Retrospective monocentric observational study. The study recruited 168 consecutive patients aged 60 or older diagnosed with central Lumbar Spinal Stenosis between January 2020 and July 2022. The patients' condition was evaluated by administering a preoperative Oswestry Disability Index questionnaire, measuring their Body Mass Index, and performing preoperative Magnetic Resonance Imaging. The analyzed parameters were the cross-sectional area of paraspinal muscles at the L4-L5 level, dural sac cross-sectional area, and Schizas grading Scale at the most stenotic level, using multiple linear univariate analyses. Two groups of healthy individuals were recruited: Group A (under 60 years old) and Group B (over 60 years old). The same data extrapolated from these groups were compared with those of patients with central lumbar stenosis using a two-tailed Mann-Whitney test. As the Erector Spinae degenerates, the Oswestry Disability Index tends to increase. Similarly, an increase in Body Mass Index is often accompanied by a decrease in the cross-sectional area of the Erector Spinae. Low dural sac cross-sectional area is statistically linked to a reduced Multifidus cross-sectional area. Interestingly, the Schizas grading scale does not appear to correlate with changes in the cross-sectional area of the paraspinal muscles. Additionally, there is no significant difference in the cross-sectional area of the Psoas muscle between individuals with central lumbar spinal stenosis and healthy individuals. Our study found that degeneration of the Erector Spinae plays a crucial role in the progression of perceived disability in Lumbar Spinal Stenosis. Prospective studies should investigate the long-term evolution of paraspinal muscles in decompressed patients.


Phalangeal Fractures and Fingertip Injuries.
A comprehensive analysis of the assessment, diagnosis, and management of phalangeal fractures and fingertip injuries should emphasize the importance of achieving the right balance between undertreatment and overtreatment. Phalangeal injuries are complex, requiring an in-depth understanding of hand anatomy, fracture patterns, and treatment options to optimize patient outcomes. A thorough examination of proximal and middle phalangeal fractures and fingertip injuries, including those to the nail bed and distal phalanx, is important. A systematic approach to addressing the most prevalent injuries in this category should be implemented while highlighting the need for patient-specific approaches to treatment and a multidisciplinary perspective to ensure the best possible outcomes for patients.


Histocompatibility profile in Chinese with ankylosing spondylitis.
Using the two-step microcytotoxicity test as recommended by NIH, U.S.A., 66 Chinese of definite ankylosing spondylitis (AS), 41 their first-degree relatives, and 43 normal Chinese received HLA analysis. The positive rates of HLA-B27 of these 3 groups were 95.5%, 56.1%, and 4.7% respectively. The results indicate: (i) The positive rate of HLA-B27 in patients with AS is significantly higher than their first-degree relatives, or the normal controls. (ii) The high positive rate of HLA-B27 in Chinese with AS is similar to those of other races.


Analysis of a cardiovascular disease genetic risk score in the Diabetes Heart Study.
It remains unclear whether the high cardiovascular disease (CVD) burden in people with type 2 diabetes (T2D) is associated with genetic variants that contribute to CVD in general populations. Recent studies have examined genetic risk scores of single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies for their cumulative contribution to CVD-related traits. Most analyses combined SNPs associated with a single phenotypic class, e.g., lipids. In the present analysis, we examined a more comprehensive risk score comprised of SNPs associated with a broad range of CVD risk phenotypes. The composite risk score was analyzed for potential associations with subclinical CVD, self-reported CVD events, and mortality in 983 T2D-affected individuals of European descent from 466 Diabetes Heart Study (DHS) families. Genetic association was examined using marginal models with generalized estimating equations for subclinical CVD and prior CVD events and Cox proportional hazards models with sandwich-based variance estimation for mortality; analyses were adjusted for age and sex. An increase in genetic risk score was significantly associated with higher levels of coronary artery calcified plaque (p = 1.23 × 10(-4)); however, no significant associations with self-reported myocardial infarction and CVD events and all-cause and CVD mortality were observed. These results suggest that a genetic risk score of SNPs associated with CVD events and risk factors does not significantly account for CVD risk in the DHS, highlighting the limitations of applying current genetic markers for CVD in individuals with diabetes.


Functions of BET proteins in erythroid gene expression.
Inhibitors of bromodomain and extraterminal motif proteins (BETs) are being evaluated for the treatment of cancer and other diseases, yet much remains to be learned about how BET proteins function during normal physiology. We used genomic and genetic approaches to examine BET function in a hematopoietic maturation system driven by GATA1, an acetylated transcription factor previously shown to interact with BETs. We found that BRD2, BRD3, and BRD4 were variably recruited to GATA1-regulated genes, with BRD3 binding the greatest number of GATA1-occupied sites. Pharmacologic BET inhibition impaired GATA1-mediated transcriptional activation, but not repression, genome-wide. Mechanistically, BETs promoted chromatin occupancy of GATA1 and subsequently supported transcriptional activation. Using a combination of CRISPR-Cas9-mediated genomic engineering and shRNA approaches, we observed that depletion of either BRD2 or BRD4 alone blunted erythroid gene activation. Surprisingly, depletion of BRD3 only affected erythroid transcription in the context of BRD2 deficiency. Consistent with functional overlap among BET proteins, forced BRD3 expression substantially rescued defects caused by BRD2 deficiency. These results suggest that pharmacologic BET inhibition should be interpreted in the context of distinct steps in transcriptional activation and overlapping functions among BET family members.


Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007.
To examine trends in the incidence and prevalence of rheumatoid arthritis (RA) from 1995 to 2007. To augment our preexisting inception cohort of patients with RA (1955-1994), we assembled a population-based incidence cohort of individuals >or=18 years of age who first fulfilled the American College of Rheumatology 1987 criteria for the classification of RA between January 1, 1995 and December 31, 2007 and a cohort of patients with prevalent RA on January 1, 2005. Incidence and prevalence rates were estimated and were age-and sex-adjusted to the white population in the US in 2000. Trends in incidence rates were examined using Poisson regression methods. The 1995-2007 incidence cohort comprised 466 patients (mean age 55.6 years), 69% of whom were female and 66% of whom were rheumatoid factor positive. The overall age- and sex-adjusted annual RA incidence was 40.9/100,000 population. The age-adjusted incidence in women was 53.1/100,000 population (versus 27.7/100,000 population in men). During the period of time from 1995 to 2007, the incidence of RA increased moderately in women (P = 0.02) but not in men (P = 0.74). The increase was similar among all age groups. The overall age- and sex-adjusted prevalence on January 1, 2005 was 0.72% (95% confidence interval [95% CI] 0.66, 0.77), which is an increase when compared with a prevalence of 0.62% (95% CI 0.55, 0.69) in 1995 (P < 0.001). Applying the prevalence on January 1, 2005 to the US population in 2005 showed that an estimated 1.5 million US adults were affected by RA. This is an increase from the previously reported 1.3 million adults with RA in the US. The incidence of RA in women appears to have increased during the period of time from 1995 to 2007. The reasons for this recent increase are unknown, but environmental factors may play a role. A corresponding increase in the prevalence of RA was also observed.


Tackling Food Insecurity in Cabo Verde Islands: The Nutritional, Agricultural and Environmental Values of the Legume Species.
Legume species are important food sources to reduce hunger and deal with malnutrition; they also play a crucial role in sustainable agriculture in the tropical dry islands of Cabo Verde. To improve the knowledge of the heritage of plant genetic resources in this Middle Income Country, this study had three main goals: (i) to provide a checklist of food legumes; (ii) to investigate which species are traded in local markets and, based on field surveys, to compare species for their chemical, phenolic, antioxidant, and nutritional composition; and (iii) to discuss the agronomic value and contribution to food security in this archipelago. Our results revealed that 15 species are used as food and 5 of them are locally traded (Cajanus cajan, Lablab purpureus, Phaseolus lunatus, Phaseolus vulgaris, and Vigna unguiculata). The role of these species as sources of important minerals, antioxidants, and nutritional components for food security is highlighted, and the native ones (Lablab purpureus and Vigna unguiculata) stand-out as particularly well-adapted to the climate of these islands, which are already experiencing the adverse effects of climate change. We conclude that the sustainable use of these genetic resources can contribute to the reduction of hunger and poverty, thus meeting some challenges of the Sustainable Development Goals.


Effects of 1 alpha, 25-dihydroxyvitamin D3-26,23-lactone and its intermediate metabolites on bone metabolism in vivo and in vitro.
Which intermediate metabolite of 23(S)25(R)-1 alpha,25-(OH)2D3-26,23-lactone causes the unique biological functions of 1 alpha,25-(OH)2D3-26,23-lactone different from that of 1 alpha,25-(OH)2D3 was examined comparatively. The three intermediate metabolites, 1 alpha,25(R)26-(OH)3D3, 1 alpha,23(S)25(R)26-(OH)4D3, and 23(S)25(R)-1 alpha,25-(OH)2D3-26,23-lactol stimulated bone resorption, as 1 alpha,25-(OH)2D3 did, in vitamin D-deficient rats. On the other hand, 1 alpha,25-(OH)2D3-26,23-lactone only inhibited bone resorption. 1 alpha,25-(OH)2D3, 1 alpha,25-(OH)2D3-26,23-lactone and the other three metabolites stimulated MNC formation from hematopoietic blast cells in a manner correlated with their binding affinities for the 1 alpha,25-(OH)2D3 receptor. However, CM obtained from 1 alpha,25-(OH)2D3-26,23-lactone-treated MC3T3-E1 cells inhibited MNC formation, probably by the action of some inhibitory factors elaborated by the cells treated with 1 alpha,25-(OH)2D3-26,23-lactone, whereas CM obtained from 1 alpha,25-(OH)2D3 or other metabolite-treated MC3T3-E1 cells stimulated MNC formation. These facts indicate that only 1 alpha,25-(OH)2D3-26,23-lactone has an inhibitory action of bone resorption and that the lactone ring plays a major part in its expression.


[Combination chemotherapy including cisplatin in lung cancer by bronchial artery infusion].
Chemotherapy with bronchial artery infusion (BAI) was given to 34 patients with primary lung cancer. Treatment regimens usually employed cis-diammine-dichloroplatinum (CDDP) plus peplomycin for squamous cell carcinoma, and CDDP plus vindesine for adenocarcinoma. The provisional therapeutic effects were evaluated roentgenographically with reference to histological type, T factor and degree of vascularization. Out of 10 cases of squamous cell carcinoma, 7 cases (70%) showed tumor regression greater than 50%, in contrast to 4 of 17 cases (23.5%) of adenocarcinoma. The effects in cases of squamous cell carcinoma were correlated with tumor vascularity. Twenty-two surgically treated cases were examined for the histological effects of BAI. Five of 6 cases (83.3%) of squamous cell carcinoma showed IIb effects by Shimosato's criteria. These results showed that the therapeutic effect of BAI was excellent in cases of squamous cell carcinoma in comparison with cases of adenocarcinoma. Serious side effects including esophago-bronchial fistula, massive hemoptysis and esophageal ulcer were observed in 4 cases.


Unsupervisedly Prompting AlphaFold2 for Accurate Few-Shot Protein Structure Prediction.
Data-driven predictive methods that can efficiently and accurately transform protein sequences into biologically active structures are highly valuable for scientific research and medical development. Determining an accurate folding landscape using coevolutionary information is fundamental to the success of modern protein structure prediction methods. As the state of the art, AlphaFold2 has dramatically raised the accuracy without performing explicit coevolutionary analysis. Nevertheless, its performance still shows strong dependence on available sequence homologues. Based on the interrogation on the cause of such dependence, we presented EvoGen, a meta generative model, to remedy the underperformance of AlphaFold2 for poor MSA targets. By prompting the model with calibrated or virtually generated homologue sequences, EvoGen helps AlphaFold2 fold accurately in the low-data regime and even achieve encouraging performance with single-sequence predictions. Being able to make accurate predictions with few-shot MSA not only generalizes AlphaFold2 better for orphan sequences but also democratizes its use for high-throughput applications. Besides, EvoGen combined with AlphaFold2 yields a probabilistic structure generation method that could explore alternative conformations of protein sequences, and the task-aware differentiable algorithm for sequence generation will benefit other related tasks including protein design.


Inositol hexakisphosphate increases the size of platelet aggregates.
The inositol phosphates, InsP5 and InsP6, have recently been identified as binding partners of fibrinogen, which is critically involved in hemostasis by crosslinking activated platelets at sites of vascular injury. Here, we investigated the putative physiological role of this interaction and found that platelets increase their InsP6 concentration upon stimulation with the PLC-activating agonists thrombin, collagen I and ADP and present a fraction of it at the outer plasma membrane. Cone and plate analysis in whole blood revealed that InsP6 specifically increases platelet aggregate size. This effect is fibrinogen-dependent, since it is inhibited by an antibody that blocks fibrinogen binding to platelets. Furthermore, InsP6 has only an effect on aggregate size of washed platelets when fibrinogen is present, while it has no influence in presence of von Willebrand factor or collagen. By employing blind docking studies we predicted the binding site for InsP6 at the bundle between the γ and β helical subunit of fibrinogen. Since InsP6 is unable to directly activate platelets and it did not exhibit an effect on thrombin formation or fibrin structure, our data indicate that InsP6 might be a hemostatic agent that is produced by platelets upon stimulation with PLC-activating agonists to promote platelet aggregation by supporting crosslinking of fibrinogen and activated platelets.


Validation of Nutritional Risk Screening-2002 in a Hospitalized Adult Population.
Malnutrition in hospitalized patients is a serious problem and is associated with a number of adverse outcomes. The Nutritional Risk Screening-2002 (NRS-2002) tool was designed to identify patients at nutrition risk. The validation of NRS-2002 compared with detailed clinical assessment of nutrition status was not studied before in hospitalized Turkish adults. The aim of this study is to determine validity, sensitivity, and specificity of the Turkish version of NRS-2002 in a hospitalized adult population. A total of 271 consecutive hospitalized patients aged >18 years admitted to surgical and medical wards of a university hospital in Turkey were included in this single-center non interventional validity study. Assessment by geriatricians was used as the reference method. Two geriatricians experienced in the field of malnutrition interpreted the patients' nutrition status after the evaluation of several parameters. Patients were divided into "at nutrition risk" and "not at nutrition risk" groups by geriatricians. Concordance between the 2 geriatricians' clinical assessments was analyzed by κ statistics. Excellent concordance was found; therefore, the first geriatrician's decisions were accepted as the gold standard. The correlation of nutrition status of the patients, determined with NRS-2002 and experienced geriatrician's decisions, was evaluated for the validity. NRS-2002 has a sensitivity of 88% and specificity of 92% when compared with professional assessment. The positive and negative predictive values were 87% and 92%, respectively. Testretest agreement was excellent as represented by a κ coefficient of 0.956. NRS-2002 is a valid tool to assess malnutrition risk in Turkish hospitalized patients.


Active immunization with tau epitope in a mouse model of tauopathy induced strong antibody response together with improvement in short memory and pSer396-tau pathology.
Abnormal tau hyperphosphorylation and its aggregation into neurofibrillary tangles are a hallmark of tauopathies, neurodegenerative disorders that include Alzheimer's disease (AD). Active and passive Tau-immunotherapy has been proposed as a therapeutic approach to AD with mixed results. One of the limitations of active immunotherapy may be associated with the mediocre immunogenicity of vaccines that are not inducing therapeutically potent titers of antibodies. The aim of this study was to test the efficacy of an anti-tau vaccine, AV-1980R/A composed of N terminal peptide of this molecule fused with an immunogenic MultiTEP platform and formulated in a strong adjuvant, AdvaxCpG in a Tg4510 mouse model of tauopathy. Experimental mice were immunized with AV-1980R/A and a control group of mice were injected with adjuvant only. Nontransgenic and tetracycline transactivator (tTA) transgenic littermates were included as baseline controls to contrast with the tau phenotype. Active immunization with AV-1980R/A induced very strong anti-tau humoral immune responses in both nontransgenic and transgenic mice with evidence of IgG in brains of AV-1980R/A vaccinated mice. These experimental animals displayed an improvement in short-term memory during a novel object recognition test. However, impairments in other behavioral tasks were not prevented by AV-1980R/A vaccinations. At the same time, high titers of anti-tau antibodies reduced hyperphosphorylated pSer396 tau but did not lower the level of other phosphorylated tau species in the brains of AV-1980R/A vaccinated mice. These data indicate that active immunotherapy with an N-terminal Tau epitope was only partially effective in improving cognition and reducing pathology in the stringent Tg4510 mouse model of tauopathy.


Ectopic expression of MyD118/Gadd45/CR6 (Gadd45beta/alpha/gamma) sensitizes neoplastic cells to genotoxic stress-induced apoptosis.
The MyD118/Gadd45/CR6 gene family (also termed Gadd45beta/alpha/gamma) has been identified as genes which are rapidly induced by genotoxic agents, during terminal differentiation, as well as by apoptotic cytokines. In recent years, evidence has emerged that the proteins encoded by these genes play pivotal roles in negative growth control, including growth suppression and apoptotic cell death. However, under what physiological condition these proteins mediate either cell cycle arrest or apoptosis, and the molecular nature of apoptotic pathways involved are currently unclear. Thus, to further explore the effects of these genes on cell growth and cell viability, either in the presence or absence of extrinsic stress, we have established M1 myeloblastic leukemia and H1299 lung carcinoma cell lines, where high level ectopic expression of MyD118, Gadd45, or CR6 can be induced by isopropyl beta-D-thiogalactopyranoside (IPTG). By taking advantage of these cell lines, it was observed that in the absence of genotoxic stress, inducible expression of MyD118, Gadd45 and/or CR6 resulted in retardation of cellular proliferation and accumulation of cells in the G1 phase of the cell cycle. Ectopic expression of these proteins also was found to sensitize the cells to apoptosis induced by genotoxic agents such as UV, MMS, gamma-irradiation and VP16. Finally, evidence has been obtained that in the absence of stress, ectopic expression of MyD118/Gadd45/CR6 is insufficient to activate the MTKl/JNK/p38 stress cascade, and that enhancement of genotoxic stress induced apoptosis by these proteins may involve apoptotic pathways other than the JNK/p38 pathways.


Relation of Alcohol Consumption to Risk of Heart Failure in Patients Aged 65 to 84 Years With Hypertension.
Although a high level of alcohol consumption is associated with cardiomyopathy, the benefit or risk of moderate alcohol consumption on incident heart failure (HF) is unknown. This study examined the association between alcohol consumption and risk for HF in older adults with hypertension. The study analyzed data from a cohort of 6,083 participants aged 65 to 84 years at baseline (1995 to 2001) followed for a median of 10.8 years during and after the Second Australian National Blood Pressure Study. Frequency and amount of alcohol consumption were self-reported at baseline and during the clinical trial. The percentages of current drinkers, former drinkers, and never-drinkers at baseline were 4,400 (72%), 394 (6%), and 1,289 (21%), respectively. Incident HF was diagnosed in 183 men and 136 women. After adjustment for multiple confounders, alcohol consumption was not significantly associated with HF. Compared with never-drinkers, the adjusted hazard ratios (95% confidence interval) for those who consume 1 to 7, 8 to 14, and >14 drinks/week at baseline were 0.87 (0.59 to 1.30), 0.96 (0.57 to 1.60), and 0.71 (0.25 to 2.02), respectively in women, and 0.81 (0.47 to 1.38), 0.77 (0.43 to 1.38), and 1.04 (0.59 to 1.84), respectively in men. The findings of lack of an association between alcohol consumption and risk of HF persisted in the analyses comparing the risk of HF across each level of drinking at baseline or at follow-up with never-drinkers. In the present study, there was no evidence for benefit or risk of alcohol consumption, reported at baseline or at follow-up, in relation to incident HF in both men and women.


Selective partial reduction of various heteroaromatic compounds with bridgehead nitrogen via Birch reduction protocol.
[reaction: see text] For the first time various heteroaromatic compounds with bridgehead nitrogen, including indolizines, bispyrrolopyrimidines, pyrroloquinolines, pyrroloisoquinolines, and bispyrrolopyrazines, were selectively partially reduced under Birch reduction conditions. It was found that the double bond in the fused heterocycles which possesses the highest LUMO density can be selectively reduced under these conditions. Indolizine 6, containing an ester group at C-6, was reductively alkylated to give dihydroindolizines 8 and 9 possessing a quaternary carbon center in good yield. It was found that ambident substrate 12, under Birch reduction conditions, underwent smooth partial reduction to give 4,5-dihydroquinoline 14 as a sole product with no evidence of reduction of the side chain olefin. It was also shown that electron-rich pyrroloisoquinoline 15, which cannot be reduced via catalytic hydrogenation conditions, was efficiently transformed into its dihydrocounterpart 16 by using the Birch reduction protocol. Finally, it was shown that various fused diazines were smoothly and stereoselectively reduced under Birch reduction conditions to give trans-4,5-disubstituted dihydropyrimidines 30 and 32 in virtually quantitative yields.


The relationship between adiponectin levels and epicardial adipose tissue thickness in non-obese children with asthma.
There is an association between adiponectin (APN) and asthma. However, the mechanisms underlying this association is unclear. APN is a predominantly anti-inflammatory protein with possible signalling activity in the lung that can be secreted by Epicardial Adipose Tissue (EAT). Our hypothesis is that serum APN levels may be directly and simply related to the amount of EAT accumulation, particularly when it is expressed as thickness in children with asthma. The aim of this study was to investigate whether serum adiponectin (APN) and epicardial adipose tissue thickness (EATT) have an effect in non-obese children with asthma and in healthy non-asthmatic children, and analyze their relationships with clinical outcomes. 68 children diagnosed with asthma (20 girls/48 boys) who had applied at the pediatric allergy and clinical immunology clinic of the hospital were included in this cross-sectional, observational study. The age-matched control group included 39 healthy children (18 girls/21 boys). EATT was measured by transthoracic echocardiography. The serum APN levels were also checked. Statistical analysis was performed by using independent sample t-test and Spearman correlation analyses. The mean age of the asthma group was 10.2 ± 2.7 years, and the average EATT was found to be 5.1 ± 0.1 mm. The mean age of the control group was 10.5 ± 2.8 years, and the average EATT was found to be 5.1 ± 0.7 mm. The EATT of the asthma group was found to be significantly higher (p < 0.001) in study group. In the asthma group the APN was 10.0 ± 5.3 mg/L, and in the control group the APN was 15.8 ± 10.5 mg/L (p < 0.001). We found that APN was significantly negatively correlated with EATT (r = -0.266, p = 0.006) in asthma and control groups. EATT is associated with non-obese asthmatic children. High EATT may be related with high release of pro-inflammatory cytokine and low release of APN. Low levels of APN may be related to low anti-inflammatory effects. Therefore, high EATT and low levels of APN may indicate pro-inflammantory profiles in non-obese asthmatic children.


Dental implant fractures - aetiology, treatment and case report.
This study aimed to investigate the etiology, clinical manifestations, and treatment options of dental implants fractures through a literature review and to relate a clinical report. A literature review was performed using the Medline database and this paper describes a case demonstrating the management of implant fracture. Twenty two articles were selected in the present literature review. Nowadays the use of dental implants to rehabilitate completely and partially edentulous patients became the best treatment option; however, this treatment is suitable to failure. The fracture of implant body is a possible complication. The fracture of implant body is a late complication and is related to the failure in implant design or material, non-passive fitting of the prosthetic crown and overloading. Clinically, prosthesis instability and spontaneous bleeding are observed. Three options of treatment have been indicated: complete removal of implant fragment, maintenance of implant fragment, and surface preparation of the fragment with insertion of a new abutment. The literature indicates the complete removal of the fragment as the best treatment option.


GmUFO1 Regulates Floral Organ Number and Shape in Soybean.
The UNUSUAL FLORAL ORGANS (UFO) gene is an essential regulatory factor of class B genes and plays a vital role in the process of inflorescence primordial and flower primordial development. The role of UFO genes in soybean was investigated to better understand the development of floral organs through gene cloning, expression analysis, and gene knockout. There are two copies of UFO genes in soybean and in situ hybridization, which have demonstrated similar expression patterns of the GmUFO1 and GmUFO2 genes in the flower primordium. The phenotypic observation of GmUFO1 knockout mutant lines (Gmufo1) showed an obvious alteration in the floral organ number and shape and mosaic organ formation. By contrast, GmUFO2 knockout mutant lines (Gmufo2) showed no obvious difference in the floral organs. However, the GmUFO1 and GmUFO2 double knockout lines (Gmufo1ufo2) showed more mosaic organs than the Gmufo1 lines, in addition to the alteration in the organ number and shape. Gene expression analysis also showed differences in the expression of major ABC function genes in the knockout lines. Based on the phenotypic and expression analysis, our results suggest the major role of GmUFO1 in the regulation of flower organ formation in soybeans and that GmUFO2 does not have any direct effect but might have an interaction role with GmUFO1 in the regulation of flower development. In conclusion, the present study identified UFO genes in soybean and improved our understanding of floral development, which could be useful for flower designs in hybrid soybean breeding.


DNA-Encoded Combinatorial Library of Macrocyclic Peptoids.
We report the design and synthesis of a DNA-encoded one-bead one-compound library of cyclic peptoids composed of more than 11 million molecules. We show that affinity-based screening of this large library can identify cyclic peptoid ligands for a target protein. In this work, we developed a simple method for amplifying the PCR product from DNA tags on a single bead, thereby enabling determination of the structures of hit cyclic peptoids with no need for high-throughput sequencing and complicated data analysis. We also developed a sublibrary screening strategy to minimize false positives caused by the interference of coding DNA tags before starting laborious and impractical hit confirmation. Given the simplicity and robustness of the synthesis and screening, along with the desirable features of macrocyclic peptoids including improved conformational rigidity, our method will be highly useful for discovering biologically active molecules modulating challenging targets such as protein-protein interactions that are not easily targeted by typical peptidomimetics and small-molecules.


Two-dimensional analysis of two-file flow of red cells along capillaries.
The effect of a tank-treading motion of the red cell membrane on a staggered "zipper"-type red cell flow in capillaries is examined, using a two-dimensional theoretical model. An approximately triangular cell with a thin flexible membrane enclosing a viscous fluid is adopted as a model of the red cell. The motion of model red cells arranged periodically along a two-dimensional channel in an idealized zipper-type arrangement is analyzed numerically by a finite element method applied to the Stokes equations for the flow both inside and outside the model cells. It is shown that, if the viscosity ratio of the internal fluid to the suspending fluid is lower than a critical value, there exists a stable zipper-type arrangement of cells. In that arrangement, the cells remain stationary relative to each other with the membrane tank-treading. In contrast, inhibiting tank-treading by increasing the viscosity ratio above the critical value induces a cyclic oscillatory motion of red cells. The critical viscosity ratio increases if the channel is narrowed or if the spacing between cells is reduced. The present results suggest that the membrane tank-treading tends to stabilize zipper-type arrangements of red cells in capillaries at high hematocrit.


CD63 associates with the alphaIIb beta3 integrin-CD9 complex on the surface of activated platelets.
The tetraspanins are integral membrane proteins expressed on cell surface and granular membranes of hematopoietic cells and have been identified in multi-molecular complexes with specific integrins. In resting platelets, CD63, a member of the tetraspanin superfamily, is present in dense granule and lysosomal membranes and, following platelet activation, translocates to the plasma membrane. In the present study, platelet activation by thrombin leads to incorporation of CD63 into the Triton-insoluble actin cytoskeletal fraction. This incorporation was inhibited by preincubation of platelets with RGDS or EGTA and did not occur in platelets from a patient with Glanzmann's thrombasthenia, suggesting that it was dependent upon alphaIIbbeta3. In activated platelets, the anti-CD63 MoAb, D545, co-immunoprecipitated CD63 with other surface-labeled proteins, including alphaIIbbeta3 and another tetraspanin, CD9. The association of CD63 with CD9 and alphaIIbbeta3, was not inhibited by preincubation of platelets with RGDS or EGTA. D545 did not inhibit the adhesion of activated platelets to purified extracellular matrix proteins, but significantly decreased adhesion of thrombin-activated platelets to neutrophils in a rosetting assay. D545 also caused disaggregation of platelets stimulated by ADP, but had no effect on aggregation induced by other agonists. These results are consistent with the proposal that CD63 becomes part of an alphaIIbbeta3-CD9-CD63 integrin-tetraspanin complex in activated platelets--an association that may modulate the function of alphaIIbbeta3-dependent interaction with other cells such as neutrophils.


Insecure attachment moderates women's adjustment to inflammatory bowel disease severity.
Insecure attachment was explored as a moderator of the relationship between disease severity and psychosocial variables in a study of adjustment in women with inflammatory bowel disease (IBD). Participants were 218 women recruited through notices placed in the community, in gastroenterologists' offices, and through online postings to support groups and message boards specifically for people with Crohn's disease, colitis, or IBD in general. Participants completed a mail-in or online survey assessing severity and frequency of symptoms, attachment style (separated into anxious and avoidant subscales), perceived social support, negative affect, and efficacy of coping with IBD. Anxious and avoidant attachment styles were correlated positively with disease severity and negative affect and negatively with perceived social support and coping efficacy. Hierarchical regressions indicated that disease severity was most strongly associated with negative affect for high avoidant attachment, as compared with moderate and low avoidant attachment. Disease activity was inversely related to perceived social support and coping efficacy for high and moderate, but not low, anxious attachment. Our study indicates that attachment moderates associations between disease severity in women with different kinds of IBD and psychological indicators of adjustment. Limitations and relationship to previous research on attachment and health are discussed.


LDL-cholesterol control in the primary prevention of cardiovascular diseases: An expert opinion for clinicians and health professionals.
Although adequate clinical management of patients with hypercholesterolemia without a history of known cardiovascular disease is essential for prevention, these subjects are often disregarded. Furthermore, the scientific literature on primary cardiovascular prevention is not as rich as that on secondary prevention; finally, physicians often lack adequate tools for the effective management of subjects in primary prevention and have to face some unsolved relevant issues. This document aims to discuss and review the evidence available on this topic and provide practical guidance. Available algorithms and risk charts represent the main tool for the assessment of cardiovascular risk in patients in primary prevention. The accuracy of such an estimate can be substantially improved considering the potential contribution of some additional risk factors (C-reactive protein, lipoprotein(a), family history of cardiovascular disease) and conditions (environmental pollution, sleep quality, socioeconomic status, educational level) whose impact on the cardiovascular risk has been better understood in recent years. The availability of non-invasive procedures to evaluate subclinical atherosclerosis may help to identify subjects needing an earlier intervention. Unveiling the presence of these conditions will improve cardiovascular risk estimation, granting a more appropriate intervention. The accurate assessment of cardiovascular risk in subjects in primary prevention with the use of algorithms and risk charts together with the evaluation of additional factors will allow physicians to approach each patient with personalized strategies, which should translate into an increased adherence to therapy and, as a consequence, a reduced cardiovascular risk.


Rho-kinase contributes to pressure-induced constriction of renal microvessels.
Renal afferent arterioles (AFF) regulate glomerular capillary pressure through two main mechanisms: the myogenic response (MYO) and tubuloglomerular feedback (TGF). Because Rho-kinase and nitric oxide synthase (NOS) are established factors that modulate vascular tone, we examined the role of these factors in pressure-induced AFF tone in Wistar-Kyoto rats and in spontaneously hypertensive rats (SHR) using an intravital CCD camera. Elevated renal perfusion pressure elicited marked AFF constriction that was partially inhibited by gadolinium, furosemide and fasudil, which inhibit MYO, TGF and Rho-kinase, respectively; however, this AFF constriction was completely blocked by combined treatment with fasudil+gadolinium or fasudil+furosemide. S-methyl-L-thiocitrulline (SMTC) partially reversed the fasudil-induced inhibition of TGF-mediated, but not that of MYO-mediated, AFF constriction. In SHR, the pressure-induced AFF response was enhanced, and MYO- and TGF-induced constriction were exaggerated. In the presence of gadolinium, SMTC partially mitigated the fasudil-induced inhibition of TGF-mediated AFF constriction. Immunoblot analyses demonstrated that both Rho-kinase activity and neuronal NOS were augmented in SHR kidneys. In conclusion, Rho-kinase contributes to MYO- and TGF-mediated AFF responses, and these responses are enhanced in SHR. Furthermore, neuronal NOS-induced nitric oxide modulates the TGF mechanism. This mechanism constitutes a target for Rho-kinase in TGF-mediated AFF constriction.


Inhibition of peroxisome proliferator-activated receptor γ: a potential link between chronic maternal hypoxia and impaired fetal growth.
Chronic exposure to hypoxia raises the risk of pregnancy disorders characterized by maternal vascular dysfunction and diminished fetal growth. In an effort to identify novel pathways for these hypoxia-related effects, we assessed gene expression profiles of peripheral blood mononuclear cells (PBMCs) obtained from 43 female, high-altitude or sea-level residents in the nonpregnant state or during pregnancy (20 or 36 wk). Hypoxia-related fetal growth restriction becomes apparent between 25 and 29 wk of gestation and continues until delivery. Our sampling strategy was designed to capture changes occurring before (20 wk) and during (36 wk) the time frame of slowed fetal growth. PBMC gene expression profiles were generated using human gene expression microarrays and compared between altitudes. Biological pathways were identified using pathway analysis. Modest transcriptional differences were observed between altitudes in the nonpregnant state. Of the genes that were differentially expressed at high altitude vs. sea level during pregnancy (20 wk: 59 probes mapped to 41 genes; 36 wk: 985 probes mapped to 700 genes), several are of pathological relevance for fetal growth restriction. In particular, transcriptional changes were consistent with the negative regulation of peroxisome proliferator-activated receptor γ (PPARγ) at high altitude; such effects were accompanied by reduced birth weight (P <0.05) and head circumference (P <0.01) at high altitude vs. sea level. Our findings indicate that chronic exposure to hypoxia during pregnancy alters maternal gene expression patterns in general and, in particular, expression of key genes involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of fetal growth restriction.


Neurologic prognosis and withdrawal of life support after resuscitation from cardiac arrest.
To study the impact of neurologic prognostication on the decision to withdraw life-sustaining therapies (LST) in comatose patients resuscitated after cardiac arrest. The authors prospectively studied a consecutive series of post-resuscitation comatose patients referred for neurologic prognostication at a single center for 4 years. For most patients, neurologic prognostication was not sought due to early death or rapid return to consciousness. Prognostication was based on Glasgow Coma Score (GCS) and Brainstem Reflex Score (BRS), with EEG and cortical evoked potentials (CEP), which were graded as benign, uncertain, and malignant. The outcomes were as follows: survivors (Group S), brain or cardiac death (Group D), and death from withdrawal of life sustaining therapy (Group W). In Group W, the time interval to withdrawal of LST was analyzed by EEG and CEP grades. Of 58 patients studied, 10 were in Group S, 8 in Group D, and 40 in Group W. Initial median GCS and BRS was similar for all groups with significant improvement noted in Group S, but not in Group D or Group W. In Group W, CEP grade correlated with the median duration of continued therapy before a decision to withdraw LST: 7 days for benign CEP, 2 days for uncertain CEP, and 1 day for malignant CEP, p = 0.0004. In patients with poor neurologic recovery early after resuscitation from cardiac arrest, physicians appear to use the cortical evoked potential grade to estimate prognosis. Cortical evoked potential grade correlated with the waiting time until life sustaining therapies were withdrawn after no improvement in neurologic examination was seen.


"What do You Mean I've Got to Wait for Six Weeks?!" Understanding the Sexual Behaviour of Men and Their Female Partners after Voluntary Medical Male Circumcision in the Western Cape.
Several studies have shown that voluntary male medical circumcision (VMMC) reduces the incidence of the Type-1 human immunodeficiency virus (HIV) in heterosexual men by up to 60%. However, there is an increased risk of transmission of STIs, including HIV, in the immediate post-operative period after receiving VMMC. This study is to understand sexual practices of couples in the post-operative period in a Coloured population in the Western Cape Province of South Africa. Coloured Males who had undergone VMMC in the previous six months in the Cape Town area and their partners participated in eight single-gender focus group discussions. The groups explored why the men decided to undergo VMMC, what kind of counselling they received, and how they experienced the 6-week post-operative period, including sexually. The primary motivation to VMMC uptake included religious injunction and hygiene reasons and protection against sexually transmitted infections not necessarily HIV. There was some exploration of alternative sexual practices. During the period immediately post operation the respondents spoke of pain and fear of any sexual arousal, but towards the end of the six week period, sexual desire returned. Both men and women felt that sex was important to maintain the relationship. Gaps were identified in the pre- and post-MC procedure counselling. There is a real risk that men in this population may begin sex before complete healing has occurred. VMMC counselling to encourage men to stay sexually safe in the wound-healing period, needs to take into account the real-life factors of the circumcised men. It is essential from a public health, and gender perspective that effective counselling strategies for the VMMC post-operative period, and the longer term, are developed and tested.


Hepatospheres: Three dimensional cell cultures resemble physiological conditions of the liver.
Studying physiological and pathophysiological mechanisms in the liver on a molecular basis is a challenging task. During two dimensional (2D) culture conditions hepatocytes dedifferentiate rapidly by losing metabolic functions and structural integrity. Hence, inappropriate 2D hepatocellular models hamper studies on the xenobiotic metabolism of the liver which strongly influences drug potency. Also, the lack of effective therapies against hepatocellular carcinoma shows the urgent need for robust models to investigate liver functions in a defined hepatic microenvironment. Here, we summarize and discuss three-dimensional cultures of hepatocytes, herein referred to as hepatospheres, which provide versatile tools to investigate hepatic metabolism, stemness and cancer development.