Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer.
Mammalian MutY homologue (MUTYH) is an adenine DNA glycosylase that excises adenine inserted opposite 8-oxoguanine (8-oxoG). The inherited variations in human MUTYH gene are known to cause MUTYH-associated polyposis (MAP), which is associated with colorectal cancer. MUTYH is involved in base excision repair (BER) with proliferating cell nuclear antigen (PCNA) in DNA replication, which is unique and critical for effective mutation-avoidance. It is also reported that MUTYH has a Zn-binding motif in a unique interdomain connector (IDC) region, which interacts with Rad9-Rad1-Hus1 complex (9-1-1) in DNA damage response, and with apurinic/apyrimidinic endonuclease 1 (APE1) in BER. However, the structural basis for the BER pathway by MUTYH and its interacting proteins is unclear. Here, we determined the crystal structures of complexes between mouse MUTYH and DNA, and between the C-terminal domain of mouse MUTYH and human PCNA. The structures elucidated the repair mechanism for the A:8-oxoG mispair including DNA replication-coupled repair process involving MUTYH and PCNA. The Zn-binding motif was revealed to comprise one histidine and three cysteine residues. The IDC, including the Zn-binding motif, is exposed on the MUTYH surface, suggesting its interaction modes with 9-1-1 and APE1, respectively. The structure of MUTYH explains how MAP mutations perturb MUTYH function.


Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery.
Lipid-based nanoparticles (LNPs) for the delivery of mRNA have jumped to the forefront of non-viral gene delivery. Despite this exciting development, poor endosomal escape after LNP cell entry remains an unsolved, rate-limiting bottleneck. Here we report the use of a galectin 8-GFP (Gal8-GFP) cell reporter system to visualize the endosomal escape capabilities of LNP-encapsulated mRNA. LNPs substituted with phytosterols in place of cholesterol exhibited various levels of Gal8 recruitment in the Gal8-GFP reporter system. In live-cell imaging, LNPs containing β-sitosterol (LNP-Sito) showed a 10-fold increase in detectable endosomal perturbation events when compared to the standard cholesterol LNPs (LNP-Chol), suggesting the superior capability of LNP-Sito to escape from endosomal entrapment. Trafficking studies of these LNPs showed strong localization with late endosomes. This highly sensitive and robust Gal8-GFP reporter system can be a valuable tool to elucidate intricacies of LNP trafficking and ephemeral endosomal escape events, enabling advancements in gene delivery.


Functional connectivity patterns of trait empathy are associated with age.
Empathy is the capacity to feel and understand others' mental states. In some individuals, there is an imbalance between the affective and cognitive components of empathy, which can lead to deficits. This study investigated the functional connectivity of the anterior insula (AI) and dorsomedial prefrontal cortex (dmPFC), which play key roles in empathy, in covariation with the affective and cognitive subscales of the Interpersonal Reactivity Index (IRI), as a function of age and sex, as an exploratory analysis. Seed-based functional connectivity analyses were performed on 33 healthy participants that were subdivided according to their age (16 adults and 17 adolescents) and sex (16 women and 17 men). Adolescents reported lower cognitive empathy than adults and men less affective empathy than women. The connectivity of the dmPFC and AI, in covariation with the cognitive and affective subscales of empathy, respectively, differed between adolescents and adults, but was similar in men and women. Adolescents had patterns of negative covariations between the regions of interest and many brain regions associated with the default-mode and salience networks. These findings support that lower self-report levels of empathy in certain individuals could be reflected in the functional connectivity patterns of the dmPFC and AI.


Conventional and Nonconventional Sources of Exosomes-Isolation Methods and Influence on Their Downstream Biomedical Application.
Despite extensive study of extracellular vesicles (EVs), specifically exosomes (EXs) as biomarkers, important modulators of physiological or pathological processes, or therapeutic agents, relatively little is known about nonconventional sources of EXs, such as invertebrate or plant EXs, and their uses. Likewise, there is no clear information on the overview of storage conditions and currently used isolation methods, including new ones, such as microfluidics, which fundamentally affect the characterization of EXs and their other biomedical applications. The purpose of this review is to briefly summarize conventional and nonconventional sources of EXs, storage conditions and typical isolation methods, widely used kits and new "smart" technologies with emphasis on the influence of isolation techniques on EX content, protein detection, RNA, mRNA and others. At the same time, attention is paid to a brief overview of the direction of biomedical application of EXs, especially in diagnostics, therapy, senescence and aging and, with regard to the current situation, in issues related to Covid-19.


[DNA content in nuclei of buccal epithelial cells in practically healthy people].
The results obtained have permitted establishing that changes of DNA content in epitheliocyte nuclei in practically healthy people can be induced by hormonal background in the organism, on the one hand, and by the level of cell differentiation in this globe of mucous membrane of the oral cavity, on the other hand.


Tolerance and Persistence of Ebola Virus in Primary Cells from Mops condylurus, a Potential Ebola Virus Reservoir.
Although there have been documented Ebola virus disease outbreaks for more than 40 years, the natural reservoir host has not been identified. Recent studies provide evidence that the Angolan free-tailed bat (Mops condylurus), an insectivorous microbat, is a possible ebolavirus reservoir. To investigate the potential role of this bat species in the ecology of ebolaviruses, replication, tolerance, and persistence of Ebola virus (EBOV) were investigated in 10 different primary bat cell isolates from M. condylurus. Varying EBOV replication kinetics corresponded to the expression levels of the integral membrane protein NPC1. All primary cells were highly tolerant to EBOV infection without cytopathic effects. The observed persistent EBOV infection for 150 days in lung primary cells, without resultant selective pressure leading to virus mutation, indicate the intrinsic ability of EBOV to persist in this bat species. These results provide further evidence for this bat species to be a likely reservoir of ebolaviruses.


Mechanical coupling of cytoskeletal elasticity and force generation is crucial for understanding the migrating nature of keloid fibroblasts.
One of the key features of keloid is its fibroblasts migrating beyond the original wound border. During migration, cells not only undergo molecular changes but also mechanical modulation. This process is led by actin filaments serving as the backbone of intra-cellular force and transduces external mechanical signal via focal adhesion complex into the cell. Here, we focus on determining the mechanical changes of actin filaments and the spatial distribution of forces in response to changing chemical stimulations and during cell migration. Atomic force microscopy and micropost array detector are used to determine and compare the magnitude and distribution of filament elasticity and force generation in fibroblasts and keloid fibroblasts. We found both filament elasticity and force generation show spatial distribution in a polarized and migrating cell. Such spatial distribution is disrupted when mechano-signalling is perturbed by focal adhesion kinase inhibitor and in keloid fibroblasts. The demonstration of keloid pathology at the nanoscale highlights the coupling of cytoskeletal function with physical characters at the subcellular level and provides new research directions for migration-related disease such as keloid.


Individual- and community-level determinants of maternal health service utilization in southern Ethiopia: A multilevel analysis.
Maternal health service utilization decreases maternal morbidity and mortality. However, the existing evidence is inadequate to design effective intervention strategies in Ethiopia. This study aimed to examine the utilization of maternal health service and identify its determinants among women of reproductive age in southern Ethiopia. A community-based cross-sectional study was conducted from October 21 to November 11, 2022 on a sample of 1140 women selected randomly from the Northern Zone of the Sidama region. Data were collected using the Open Data Kit mobile application and exported to Stata version 15 for analysis. We used a multilevel mixed-effects modified Poisson regression with robust standard error to identify determinants of maternal health service utilization. Utilization of antenatal care, health facility delivery, and postnatal care was 52.0% (95% confidence interval: 49.0%, 55.0%), 48.5% (95% confidence interval: 45.6%, 51.4%), and 26.0% (95% confidence interval: 23.0%, 29.0%), respectively. Antenatal care use was associated with receiving model family training (adjusted prevalence ratio: 1.19; 95% confidence interval: 1.06, 1.35), knowledge of antenatal care (adjusted prevalence ratio: 1.54; 95% confidence interval: 1.31, 1.81), perceived quality of antenatal care (adjusted prevalence ratio: 1.02; 95% confidence interval: 1.01, 1.03), and having birth preparedness plan (adjusted prevalence ratio: 1.13; 95% confidence interval: 1.02, 1.25). The identified determinants of health facility delivery use were middle wealth rank (adjusted prevalence ratio: 1.35; 95% confidence interval: 1.03, 1.77), perceived quality of health facility delivery (adjusted prevalence ratio: 1.02; 95% confidence interval: 1.01, 1.03), antenatal care (adjusted prevalence ratio: 1.76; 95% confidence interval: 1.36, 2.26), and high community-level women literacy (adjusted prevalence ratio: 1.55; 95% confidence interval: 1.10, 2.19). Postnatal care use was associated with facing health problems during postpartum period (adjusted prevalence ratio: 1.79; 95% confidence interval: 1.18, 2.72), urban residence (adjusted prevalence ratio: 3.52; 95% confidence interval: 2.15, 5.78), knowledge of postnatal care (adjusted prevalence ratio: 1.11; 95% confidence interval: 1.04, 1.19), and low community-level poverty (adjusted prevalence ratio: 0.43; 95% confidence interval: 0.25, 0.73). Maternal health service use was low in the study area and was influenced by individual- and community-level determinants. Any intervention strategies must consider multi-sectorial collaboration to address determinants at different levels. The programs should focus on the provision of model family training, the needs of women who have a poor perception, and knowledge of maternal health service at the individual level.


High frequency of coinfecting enteropathogens in Aeromonas-associated diarrhea of hospitalized Peruvian infants.
Rectal swabs from 391 infants less than 18 months of age who were hospitalized with acute diarrhea and from 138 similarly aged healthy infants were examined for the etiologic agents of diarrhea. Aeromonas spp. were recovered from 205 of 391 (52.4%) diarrheic patients, whereas they were recovered from 12 of 138 (8.7%) controls (P less than 10(-11). Among the 205 Aeromonas-positive diarrheic patients, 118 (57.6%) were found to be coinfected with other common enteropathogens. Of the 164 Aeromonas-positive initial diarrheic specimens, 82 (50.0%) had one or more other enteropathogens present; 30 patients were coinfected with rotavirus, 20 with enterotoxigenic Escherichia coli, 16 with Campylobacter spp., 14 with Shigella spp., 13 with enteropathogenic E. coli, 4 with Vibrio spp., 1 with Salmonella spp., and 1 with Plesiomonas spp. of Aeromonas strains from cases compared with that from controls supports an etiologic role for this organism. However, frequent concomitant infections with other well-recognized enteropathogens and a lack of disease correlation with common Aeromonas phenotypes suggest that only a subset of Aeromonas strains may be diarrhea causing and that such strains may be common to several of the existing species.


Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex1.
Loss-of-function mutations in Calsequestrin 2 (CASQ2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT patients also exhibit bradycardia and atrial arrhythmias for which the underlying mechanism remains unknown. We aimed to study the sinoatrial node (SAN) dysfunction due to loss of CASQ2. In vivo electrocardiogram (ECG) monitoring, in vitro high-resolution optical mapping, confocal imaging of intracellular Ca(2+) cycling, and 3D atrial immunohistology were performed in wild-type (WT) and Casq2 null (Casq2(-/-)) mice. Casq2(-/-) mice exhibited bradycardia, SAN conduction abnormalities, and beat-to-beat heart rate variability due to enhanced atrial ectopic activity both at baseline and with autonomic stimulation. Loss of CASQ2 increased fibrosis within the pacemaker complex, depressed primary SAN activity, and conduction, but enhanced atrial ectopic activity and atrial fibrillation (AF) associated with macro- and micro-reentry during autonomic stimulation. In SAN myocytes, CASQ2 deficiency induced perturbations in intracellular Ca(2+) cycling, including abnormal Ca(2+) release, periods of significantly elevated diastolic Ca(2+) levels leading to pauses and unstable pacemaker rate. Importantly, Ca(2+) cycling dysfunction occurred not only at the SAN cellular level but was also globally manifested as an increased delay between action potential (AP) and Ca(2+) transient upstrokes throughout the atrial pacemaker complex. Loss of CASQ2 causes abnormal sarcoplasmic reticulum Ca(2+) release and selective interstitial fibrosis in the atrial pacemaker complex, which disrupt SAN pacemaking but enhance latent pacemaker activity, create conduction abnormalities and increase susceptibility to AF. These functional and extensive structural alterations could contribute to SAN dysfunction as well as AF in CPVT patients.


Mechanisms of specific immunological unresponsiveness to bacterial lipopolysaccharides.
Low-dose priming of mice with Escherichia coli O113 lipopolysaccharide (LPS) results in the development of immunological memory, whereas low-dose priming with E. coli O55 LPS or Serratia marcescens LPS induces significant antigen-specific unresponsiveness. All three preparations of LPS induced proliferation of mouse splenocytes with similar time course and [3H]thymidine uptake. There was no correlation between the small amounts of serum antibody detected by enzyme-linked immunosorbent assay after low-dose priming and the subsequent generation of either memory or unresponsiveness. Further, the passive transfer of small amounts of LPS-specific antibody had no significant effect on the magnitude of the plaque-forming cell (PFC) response elicited after subsequent immunization. Reduction of the PFC response to E. coli O55 LPS occurred after low-dose priming of nu/nu (as well as nu/+) mice; however, unresponsiveness could not be generated in nu/nu mice by low-dose priming with S. marcescens LPS. Thus, although the development of low-dose unresponsiveness to S. marcescens LPS appears to involve T cells, the response of E. coli O55 LPS does not. Enhancement of the primary PFC response to S. marcescens LPS could be transferred with low-dose primed spleen cells depleted of Lyt-2+ T cells; this suggests that the magnitude of the PFC response to this preparation of LPS is negatively influenced by Lyt-2+ T cells and positively influenced by Lyt-2- spleen cells (i.e., L3T4+ T cells). These findings indicate that T cells appear to be involved in regulating the magnitude of the antibody response to some types of bacterial LPS.


[Effects of the local stimulation of the insular cortex on respiration in rats].
Two distinct patterns of respiratory responses to electrical microstimulation were elicited from the rat insular cortex: a decrease in respiratory airflow and tidal volume with no alteration of the respiratory rate (the inhibition response) and an increase in respiratory rate and inspiratory airflow (the excitation response). Gastric motility changes could also be elicited from the anterior insular cortex simultaneously with the inhibition response. The data suggests overlapping of the inhibition response area in the anterior insular cortex with a gastrointestinal representation there, and of the excitation response area in the posterior insular cortex with a cardiovascular representation.


Induced DNA demethylation can reshape chromatin topology at the IGF2-H19 locus.
Choriocarcinomas are embryonal tumours with loss of imprinting and hypermethylation at the insulin-like growth factor 2 (IGF2)-H19 locus. The DNA methyltransferase inhibitor, 5-Aza-2'deoxycytidine (5-AzaCdR) is an approved epigenetic cancer therapy. However, it is not known to what extent 5-AzaCdR influences other epigenetic marks. In this study, we set out to determine whether 5-AzaCdR treatment can reprogram the epigenomic organization of the IGF2-H19 locus in a choriocarcinoma cancer cell line (JEG3). We found that localized DNA demethylation at the H19 imprinting control region (ICR) induced by 5-AzaCdR, reduced IGF2, increased H19 expression, increased CTCF and cohesin recruitment and changed histone modifications. Furthermore chromatin accessibility was increased locus-wide and chromatin looping topography was altered such that a CTCF site downstream of the H19 enhancers switched its association with the CTCF site upstream of the IGF2 promoters to associate with the ICR. We identified a stable chromatin looping domain, which forms independently of DNA methylation. This domain contains the IGF2 gene and is marked by a histone H3 lysine 27 trimethylation block between CTCF site upstream of the IGF2 promoters and the Centrally Conserved Domain upstream of the ICR. Together, these data provide new insights into the responsiveness of chromatin topography to DNA methylation changes.


Seat belt and child seat use in Lipetskaya Oblast, Russia: frequencies, attitudes, and perceptions.
Despite the importance of understanding seat belt use patterns among drivers and passengers for the purpose of direct interventions or monitoring improvements, no study has described wearing rates for all seat positions in Russia. This study describes observed seat belt use and knowledge, attitudes, and perceptions of seat belt use in Lipetskaya Oblast, Russia. An observational study on the use of seat belts and child restraints in the Lipetskaya region conducted during October 2010 collected data in 6 districts and on 3 different road types. A roadside survey gathered information on knowledge, attitudes, and perceptions toward the use of seat belts from randomly selected drivers. Frequencies of seat belt use by seat position, gender, and road type were calculated. A multivariable logit model disclosed the associations between seat belt use and sociodemographic factors. The study design permitted comparison of observed seat belt use to self-reported seat belt use. A total of 25,795 vehicles and 39,833 drivers and passengers contributed observations. Overall, 55 percent of drivers were observed to be using seat belts. More than half (58%) of front seat passengers wore seat belts and only 9 percent of back seat passengers were observed to be wearing seat belts; 11 percent of cars with children had any type of child safety measure. Drivers on urban roads were less likely to wear seat belts compared to those on main highways and rural roads. Nearly 60 percent of survey respondents mentioned "seat belts save lives," and more than half mentioned law requirements and fines. Although the observed seat belt use in Lipetskaya Oblast is much higher than previous estimates in Russia, overall wearing rates remain far from universal. Rear seat passengers and children are particularly at risk. Because combined education and enforcement has proven to be effective elsewhere, such interventions are needed to improve seat belt use.


A reaction energy profile and fragment attributed molecular system energy change (FAMSEC)-based protocol designed to uncover reaction mechanisms: a case study of the proline-catalysed aldol reaction.
A REP-FAMSEC (reaction energy profile-fragment attributed molecular system energy change) protocol designed to explain each consecutive energy change along the reaction pathway is reported. It mainly explores interactions between meaningful polyatomic fragments of a molecular system and, by quantifying energetic contributions, pin-points fragments (atoms) leading to or opposing a chemical change. Its usefulness is tested, as a case study, on the proline-catalysed aldol reaction for which a number of mechanisms have been debated for over four decades. The relative stability of S-proline conformers, their catalytic (in)activity and the superior affinity of the higher energy conformer to acetone is fully explained at atomic and molecular fragment levels, but still appealing to general chemist knowledge. We found that (i) contrary to the generally accepted view, CN-bond formation cannot be explained by the Nδ-, Cδ+ atom pair, but rather by the O-atom of acetone and its strongest inter-molecular attractive interactions with the N-atom as well as the C-atom of the COO group of proline (at this initial stage the lower energy conformer of proline is eliminated) and (ii) the following 'first' H-transfer from N to O atoms of the proline moiety is nearly energy-free even though initially the H-atom interacts three times stronger with the N- than O-atom; a full explanation of this phenomenon is provided.


Temporally Altered miRNA Expression in a Piglet Model of Hypoxic Ischemic Brain Injury.
Hypoxic ischemic encephalopathy (HIE) is the most frequent cause of acquired infant brain injury. Early, clinically relevant biomarkers are required to allow timely application of therapeutic interventions. We previously reported early alterations in several microRNAs (miRNA) in umbilical cord blood at birth in infants with HIE. However, the exact timing of these alterations is unknown. Here, we report serial changes in six circulating, cross-species/bridging biomarkers in a clinically relevant porcine model of neonatal HIE with functional analysis. Six miRNAs-miR-374a, miR-181b, miR-181a, miR-151a, miR-148a and miR-128-were significantly and rapidly upregulated 1-h post-HI. Changes in miR-374a, miR-181b and miR-181a appeared specific to moderate-severe HI. Histopathological injury and five miRNAs displayed positive correlations and were predictive of MRS Lac/Cr ratios. Bioinformatic analysis identified that components of the bone morphogenic protein (BMP) family may be targets of miR-181a. Inhibition of miR-181a increased neurite length in both SH-SY5Y cells at 1 DIV (days in vitro) and in primary cultures of rat neuronal midbrain at 3 DIV. In agreement, inhibition of miR-181a increased expression of BMPR2 in differentiating SH-SY5Y cells. These miRNAs may therefore act as early biomarkers of HIE, thereby allowing for rapid diagnosis and timely therapeutic intervention and may regulate expression of signalling pathways vital to neuronal survival.


A Framework of Combining Short-Term Spatial/Frequency Feature Extraction and Long-Term IndRNN for Activity Recognition.
Smartphone-sensors-based human activity recognition is attracting increasing interest due to the popularization of smartphones. It is a difficult long-range temporal recognition problem, especially with large intraclass distances such as carrying smartphones at different locations and small interclass distances such as taking a train or subway. To address this problem, we propose a new framework of combining short-term spatial/frequency feature extraction and a long-term independently recurrent neural network (IndRNN) for activity recognition. Considering the periodic characteristics of the sensor data, short-term temporal features are first extracted in the spatial and frequency domains. Then, the IndRNN, which can capture long-term patterns, is used to further obtain the long-term features for classification. Given the large differences when the smartphone is carried at different locations, a group-based location recognition is first developed to pinpoint the location of the smartphone. The Sussex-Huawei Locomotion (SHL) dataset from the SHL Challenge is used for evaluation. An earlier version of the proposed method won the second place award in the SHL Challenge 2020 (first place if not considering the multiple models fusion approach). The proposed method is further improved in this paper and achieves 80.72% accuracy, better than the existing methods using a single model.


The evolution of selective autophagy as a mechanism of oxidative stress response: The evolutionarily acquired ability of selective autophagy receptors to respond to oxidative stress is beneficial for human longevity.
Ageing is associated with a decline in autophagy and elevated reactive oxygen species (ROS), which can breach the capacity of antioxidant systems. Resulting oxidative stress can cause further cellular damage, including DNA breaks and protein misfolding. This poses a challenge for longevous organisms, including humans. In this review, we hypothesise that in the course of human evolution selective autophagy receptors (SARs) acquired the ability to sense and respond to localised oxidative stress. We posit that in the vicinity of protein aggregates and dysfunctional mitochondria oxidation of key cysteine residues in SARs induces their oligomerisation which initiates autophagy. The degradation of damaged cellular components thus could reduce ROS production and restore redox homeostasis. This evolutionarily acquired function of SARs may represent one of the biological adaptations that contributed to longer lifespan. Inversely, loss of this mechanism can lead to age-related diseases associated with impaired autophagy and oxidative stress.


Association of central nervous system sarcoma with familial polyposis coli.
Familial polyposis of the colon is associated with an increased incidence in other parts of the body of benign and malignant, soft and hard connective tissue tumours. Clinical details and autopsy findings are reported in a 35-year-old man with familial polyposis who died from reticulum cell sarcoma (microglioma) involving his brain stem and upper spinal cord. While other central nervous system malignancy has been reported in association with familial polyposis, a sarcomatous tumour has not been previously described. In the clinical assessment of patients with familial polyposis the possibility should be considered of associated tumours in extracolonic sites, including the central nervous system.


Achieving long-term continuance of menopausal ERT/HRT: consensus opinion of the North American Menopause Society.
Estrogen replacement therapy (ERT, defined as estrogen alone) or hormone replacement therapy (HRT, defined as estrogen plus some form of progestogen) may be beneficial for many women as they approach menopause and beyond. If hormones are indicated for some women, optimal continuance is a clinical goal. The North American Menopause Society (NAMS) has developed a consensus opinion on how best to achieve this goal. NAMS held a closed conference of experts in the field to determine why women who begin ERT/HRT stop taking the medication, to review what has been learned from continuance research in other therapeutic areas, to make recommendations about how to help women achieve long-term continuance of therapy, and to suggest areas for research. The proceedings of the conference were used to assist the NAMS Board of Trustees in developing this consensus opinion of the Society. On the basis of current knowledge, the experts and NAMS established the following recommendations for helping women achieve long-term continuance of ERT/HRT: (1) involve the woman in the decision-making process, (2) explain benefits and risk with clarity and personalize them, (3) clarify and discuss the woman's preferences beginning early in decision making and use these preferences to modify a regimen to improve continuance, (4) provide educational information that the woman can understand, (5) help the woman systematize medication taking, and (6) follow up with the woman. Areas of needed research were identified. As with all long-term prescription therapies, ERT/HRT for menopause-related effects is associated with suboptimal continuance. Many techniques can be used to help improve continuance. However, more research is needed to help women achieve optimal success.


Development of a zebrafish spleen cell line, ZSSJ, and its growth arrest by gamma irradiation and capacity to act as feeder cells.
A zebrafish spleen cell line, ZSSJ, was developed and its growth arrest by gamma radiation determined and its capacity to stimulate the proliferation of the zebrafish blastula cell line, ZEB2J, measured. ZSSJ was initiated by explant outgrowth, grew adherent with mainly an epithelial-like morphology, and stained strongly for alkaline phosphatase. ZSSJ was not only grown in L-15 with 15% fetal bovine serum at 26 degrees C to 28 degrees degrees C but also grew at room temperature. Cultures of ZSSJ have undergone approximately 40 population doublings, had few cells staining for b-galactosidase activity, which is commonly present in senescent cultures, and many cells with an aneuploid karyotype, which is frequently associated with immortalization. ZSSJ growth was arrested by 30 to 50 Gy of g-irradiation, whereas after 20 Gy, some slight growth was observed. By contrast, growth of the rainbow trout spleen stromal cell line, RTS34st, which has been used as a feeder for zebrafish ES cell cultures, was arrested completely by 20 Gy. In cocultures, nongrowth-arrested ZSSJ stimulated ZEB2J proliferation better than growth-arrested ZSSJ and better than RTS34st. ZSSJ should be useful as a feeder cell line for zebrafish ES cell cultures.


[Socioeconomic mortality inequality in Korea: mortality follow-up of the 1998 National Health and Nutrition Examination Survey (NHANES) data].
This study was conducted to examine the relationships of the several socioeconomic position indicators with the mortality risk in a representative longitudinal study of South Korea. The 1998 National Health and Nutrition Examination Survey was conducted on a cross-sectional probability sample of South Korean households, and it contained unique 13-digit personal identification numbers that were linked to the data on mortality from the National Statistical Office of Korea. Of 5,607 males and females, 264 died between 1999 and 2003. Cox's regression was used to estimate the relative risks (RR) and their 95% confidence intervals (CI) of mortality. Socioeconomic differences in mortality were observed after adjustments were made for gender and age. Compared with those people having college or higher education, those people without any formal education had a greater mortality risk (RR = 2.21, 95% CI = 1.12-4.40). The mortality risk among manual workers was significantly greater than that for the non-manual workers (RR = 2.73, 95% CI = 1.47-5.06). A non-standard employment status was also associated with an increase in mortality: temporary or daily workers had a greater mortality risk than did the full-time workers (RR = 3.01, 95% CI = 1.50-6.03). The mortality risk for the low occupational class was 3.06 times greater than that of the high and middle occupational classes (95% Cl = 1.75-5.36). In addition, graded mortality differences according to equivalized monthly household income were found. A reduction of monthly household income by 500 thousand Korean Won (about 400 US dollars) was related with a 20% excess risk of mortality. Self-reported poor living standards were also associated with an increased risk of mortality. Those without health insurance had a 3.63 times greater risk of mortality than the insured (95% CI = 1.61-8.19). This study showed the socioeconomic differentials in mortality in a national longitudinal study of South Korea. The existence of socioeconomic mortality inequalities requires increased social discussion on social policies in Korean society. Furthermore, the mechanisms for the socioeconomic inequalities of mortality need to be explored in future studies.


Impairment of multicycle influenza virus growth in Vero (WHO) cells by loss of trypsin activity.
We demonstrated that influenza virus replication in Vero (WHO) cells, a subline of African green monkey kidney cells, is impaired by rapid inactivation of trypsin in the culture fluids. Trypsin inactivation was caused by a factor secreted by Vero cells into the media. Repeated addition of trypsin to the culture medium of influenza virus-infected Vero cells restores the multicycle growth pattern of influenza A virus strains, allowing high yields to be obtained at a low multiplicity of infection. These findings may permit efficient use of Vero (WHO) cells in the production of influenza vaccines.


Guided-mode resonance filters with shallow grating.
A shallow grating triple-layer guided-mode resonance (GMR) filter and its properties are presented. For this type of GMR filter, the grating layer has the equal refractive index to the waveguide layer. It is shown that the GMR filter with shallow grating has good characteristics of narrow bandwidth, symmetrical line shape, and low-reflection sideband. The spectral FWHM of the GMR filter can be controlled by varying the grating thickness. The desired FWHM at the same resonance wavelength with symmetrical line shape and low-reflection sideband can be obtained by adjusting the grating thickness and the grating period with the total thickness of the grating and waveguide layers kept unchanged.


Bisphosphonate-related osteonecrosis of the jaws (Bronj).
Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is an extremely therapy resistant osteomyelitis-like disease exclusively involving the jaw bones of patients in treatment with bisphosphonates (BPs). The aim of this study was to evaluate the radiological and clinical findings and management of 51 patients with BRONJ diagnosed from 2004 to 2009 in our Reference Center. A prospective study was performed. The patients were examined every 2-6 months, depending on their clinical conditions. Positive outcome variables were the resolution of symptoms, persistence of bone exposure and /or fistula and the status of the lesional mucosa. The higher prevalence of the disease was noted in 2006 and 2007 and at the time of diagnosis 90% of patients had been treated with iv BPs. The main precipitating event leading to BRONJ was an invasive dental procedure in 61% of patients while no traumatic event could be identified in 16% of patients. The median time of follow-up was 19 months (range: 2-57), during which 31% of patients healed and 39% succumbed. In 78% of patients the therapy was medical, in 16% it consisted in surgical deep curettage and only in 6% it was necessary to perform an osteotomy to avoid a mandibular pathological fracture. All the patients in treatment with oral BPs healed from BRONJ with a median time of conservative treatment of 19 months. Prevention has lead to a progressive reduction in the prevalence of BRONJ. In our experience medical treatment is often sufficient to keep the disease under control and to lead to the healing of the lesions by spontaneous loss of the sequestrum. This approach seems to be very effective in patients who were in treatment with oral Bps preparations; BRONJ seems to have a more benign clinical behaviour in these patients.


Villus height and gut development in weaned piglets receiving diets containing either glucose, lactose or starch.
The present study was designed to evaluate the differential effects of dietary glucose, lactose and starch on small-intestinal morphology, organ weights. pH of chyme and haptoglobin levels in blood plasma of weaned piglets. It was hypothesised that lactose consumption would ameliorate the weaning-induced decrease in gut integrity. A total of forty-two barrows were used. Piglets were weaned at 27 (SD 0.8) d of age and weighed 8.0 (SD 0.51) kg. On the day before weaning (day -1) all pigs were blocked according to body weight and randomly assigned to seven groups (n 6 per group). The groups differed in diet and day of dissection. On the day of weaning, dissection was performed on one group of six piglets. The remaining groups were fed one of three experimental diets in which glucose, lactose or starch had been iso-energetically exchanged, supplying 24% dietary energy. The piglets received a liquid diet (air-dry meal:water of 1:2, w/w). The piglets were given access to a maximum of dietary energy in order to prevent confounding between feed intake and villus architecture. The piglets were dissected and sampled on days 0, 3, or 10 post-weaning. The results show that the carbohydrate source did not affect growth performance, organ weights, villus architecture, pH of chyme and plasma haptoglobin level. The weaning transition resulted in decreased villus height and increased haptoglobin levels. In the contents of the caecum and large intestine, the pH decreased after weaning. It is concluded that at least under conditions of similar feed intake and low infectious pressure, dietary lactose does not ameliorate the weaning-induced compromise of small-intestinal integrity when compared with either glucose or starch.


Spatial contrasts and temporal changes in fine-scale heat exposure and vulnerability in the Paris region.
Heat is identified as a key climate risk in Europe. Vulnerability to heat can be aggravated by enhanced exposure (e.g., urban heat island), individual susceptibility (e.g., age, income), and adaptive capacity (e.g., home ownership, presence of vegetation). We investigated the spatial and temporal patterns of the environmental and social drivers of vulnerability to heat in the Paris region, France, over the 2000-2020 period, and their association with mortality (restricted to 2000-2017). Daily temperatures were modeled for the 5265 IRIS of the Paris region for 2000-2020. Annual land use and socioeconomic data were collected for each IRIS. They were used to identify a priori five classes of heat-vulnerable areas based on a cluster analysis. The temperature-mortality relationship was investigated using a time-series approach stratified by clusters of vulnerability. The Paris region exhibited a strong urban heat island effect, with a marked shift in temperature distributions after 2015. The clustering suggested that the most heat-vulnerable IRIS in the Paris region have a high or very high exposure to temperature in a highly urbanized environment with little vegetation, but are not systematically associated with social deprivation. A similar J-shape temperature-mortality relationship was observed in the five clusters. Between 2000 and 2017, around 8000 deaths were attributable to heat, 5600 of which were observed in the most vulnerable clusters. Vulnerability assessments based on geographical indicators are key tools for urban planners and decision-makers. They complement the knowledge about individual risk factors but should be further evaluated through interdisciplinary collaborations.


Have Mischievous Responders Misidentified Sexual Minority Youth Disparities in the National Longitudinal Study of Adolescent to Adult Health?
The National Longitudinal Study of Adolescent to Adult Health (Add Health) has been instrumental in identifying sexual minority youth health disparities. Recent commentary suggested that some Wave 1 youth responders, especially males, intentionally mismarked same-sex attraction and, as a result, published reports of health disparities from these data may be suspect. We use two recently developed approaches to identify "jokesters" and mischievous responding and apply them to the Add Health data. First, we show that Wave 1 same-sex attracted youth, including those who later reported completely heterosexual identities in adulthood, were no more likely than different-sex attracted youth and consistently heterosexual participants to be "jokesters." Second, after accounting for mischievous responses, we replicated six previously established disparities: depressive symptoms, suicidal ideation and behaviors, alcohol use, cocaine use, parental satisfaction, and school connectedness. Accounting for mischievousness resulted in the elimination of one observed disparity between heterosexual and sexual minority youth: suicidal ideation for males who reported romantic attraction to both sexes. Results also showed that accounting for mischievous responding may underestimate disparities for sexual minority youth, particularly females. Overall, results presented here support previous studies that identified health disparities among sexual minority youth using these data.


Viral persistence and disease: cytopathology in the absence of cytolysis.
Realising that viruses could persist and thereby cause chronic disease has been one of the major accomplishments in virology. In this review we will discuss the principles by which viruses can persist and how such persistence can lead to disease. Our focus will be on the ability of certain viruses to interfere subtly with the cell's ability to produce specific differentiated products as hormones, neurotransmitters, cytokines and immunoglobulins, etc., in the absence of their ability to lyse the cell they infect. By this means viruses can replicate in histologically normal appearing cells and tissues. Despite viral replication the infected cell maintains its normal anatomic architecture and yet the virus disorders the differentiated or luxury function of the cell leading to disturbances in homeostasis and disease. Viruses by this means likely underline a wide variety of clinical illnesses, currently of unknown aetiology, that affect the endocrine, immune, nervous and other differentiated systems.


MYB - A regulatory factor in hematopoiesis.
MYB is a transcription factor which was identified in birds as a viral oncogene (v-MYB). Its cellular counterpart was subsequently isolated as c-MYB which has three functional domains - DNA binding domain, transactivation domain and negative regulatory domain. c-MYB is essential for survival, and deletion of both alleles of the gene results in embryonic death. It is highly expressed in hematopoietic cells, thymus and neural tissue, and required for T and B lymphocyte development and erythroid maturation. Additionally, aberrant MYB expression has been found in numerous solid cancer cells and human leukemia. Recent studies have also implicated c-MYB in the regulation of expression of fetal hemoglobin which is highly beneficial to the β-hemoglobinopathies (beta thalassemia and sickle cell disease). These findings suggest that MYB could be a potential therapeutic target in leukemia, and possibly also a target for therapeutic increase of fetal hemoglobin in the β-hemoglobinopathies.


The Feasibility of a School Nurse-Led Mindfulness Program.
The purpose of this study was to evaluate the feasibility of a school nurse-led mindfulness program in a public school. Elementary students in an urban public school system are exposed to many stressors including poverty, family disturbances, and mental health conflicts. Previous research suggests that mindfulness interventions given by teachers promote prosocial behavior and stress reduction; however, there are no studies that have determined whether the school nurse could lead the program. A pre- to posttest design was employed using school-aged children enrolled in the fourth grade who were administered a mindfulness program. The participants were assessed for emotional states before and after the intervention. A total of 12 students completed the intervention. Students found the mindfulness program to be helpful, and the school nurse may be able to successfully complete the intervention. With appropriate planning, school nurses may be able to successfully implement the mindfulness curriculum in an urban public school.


Submicroscopic deletions at 16p13.3 in Rubinstein-Taybi syndrome: frequency and clinical manifestations in a North American population.
Rubinstein-Taybi syndrome (RTS) is a well delineated multiple congenital anomaly syndrome characterised by mental retardation, broad thumbs and toes, short stature, and specific facial features. The recent localisation of the disorder to 16p13.3 and subsequent identification of a submicroscopic deletion of this region in RTS patients led us to screen a large cohort of affected subjects using the RT1 probe. Among 64 patients with clinical evidence of RTS, seven (11%) had a deletion. Another patient had a translocation of the region without evidence of a deletion. The features of coloboma, growth retardation, naevus flammeus, and hypotonia have a positive predictive value for the presence of an RT1 deletion. Because of the relatively low frequency of deletions in RTS, the RT1 probe is useful in diagnostic confirmation, but has limited use as a screening tool.


The Supports Intensity Scale Children's Version-Icelandic Translation: Examining Measurement Properties.
An innovation in developing the Supports Intensity Scale-Children's Version (SIS-C) was the adoption of latent variable modeling approaches to norm development. In regard to translated versions of the SIS-C, the latent modeling approaches provided opportunities to leverage the large standardization sample generated in the United States (n = 4,015) to generate translation-specific norms from data collected on smaller samples in other countries and enable future cross-cultural analyses. In this study, data were collected on children in Iceland who received special education services (as defined and delivered in Iceland), a more diverse group of children with disabilities than the U.S. sample. This provided a unique context to explore cross-cultural differences. Findings indicated the structure of the SIS-C (i.e., seven support need domains organized under an overall support needs construct), was supported in the Icelandic context. However, findings also suggested that supports planning teams in Iceland must consider specific age-related factors that differ from other cultural contexts.


Individual expectation: an overlooked, but pertinent, factor in the treatment of individuals experiencing musculoskeletal pain.
Physical therapists consider many factors in the treatment of patients with musculoskeletal pain. The current literature suggests expectation is an influential component of clinical outcomes related to musculoskeletal pain for which physical therapists frequently do not account. The purpose of this clinical perspective is to highlight the potential role of expectation in the clinical outcomes associated with the rehabilitation of individuals experiencing musculoskeletal pain. The discussion focuses on the definition and measurement of expectation, the relationship between expectation and outcomes related to musculoskeletal pain conditions, the mechanisms through which expectation may alter musculoskeletal pain conditions, and suggested ways in which clinicians may integrate the current literature regarding expectation into clinical practice.


Thermochemistry and aqueous solubilities of hydrotalcite-like solids.
Hydrotalcites are used in technology as catalysts and anion exchangers and are important sinks for environmental contaminants. Their compositional variability makes it important, but difficult, to estimate their aqueous solubility. We report calorimetric measurements of the heats of formation of cobalt-aluminum hydrotalcite phases. The heat and free energy of formation from the elements are equal to those of mechanical mixtures of binary compounds, namely hydroxides and carbonates. The interlayer anion is much more important than the cation in determining the solubility of the hydrotalcite phase and its ability to contain or release heavy metals to the environment. Because hydrotalcites do not have an unreactive polymer as a structural core, their aqueous stability will change dramatically with composition, particularly with anion content. This simple mechanical mixture model allows prediction of aqueous solubilities and trace metal retention in a variety of geochemical settings.


Predictors of HPV vaccination uptake: a longitudinal study among parents.
To assess among parents longitudinal predictors of human papillomavirus (HPV) vaccination uptake for their daughters, random samples of parents were identified via municipal services and sent baseline questionnaires in June 2009 and follow-up questionnaires in November 2011 after their uptake decision. Hierarchical logistic regression analysis was used to assess whether demographic characteristics, and affective and social cognitive factors, predicted uptake at follow-up. Response rates of the baseline and follow-up questionnaire were 29.8% (1762/5918) and 74.3% (793/1067), respectively. Uptake was predicted by a later (2011) versus earlier (2010) decision about uptake as HPV vaccination implementation [odds ratio (OR) 2.48; 95% confidence interval (CI) 1.11-5.52], anticipated regret about no uptake (OR 1.43; 95% CI 1.08-1.89) and intention (OR 2.61; 95% CI 1.47-4.61). There was an interaction between ambivalence and attitude (OR 1.68; 95% CI 1.14-2.47); parents with a positive attitude and a high ambivalence toward vaccination were more likely to have their daughter vaccinated than parents with a positive attitude and a low ambivalence. An informed choice about uptake (5/7 correct items) was made by 44%. In conclusion, uptake was predicted by intention, a later (2011) versus earlier (2010) decision and by anticipated regret about no uptake. Decisions regarding new vaccines are difficult to make, we recommend a well-balanced implementation process.


Membrane disruption, but not metabolic rewiring, is the key mechanism of anticancer-action of FASN-inhibitors: a multi-omics analysis in ovarian cancer.
Fatty-acid(FA)-synthase(FASN) is a druggable lipogenic oncoprotein whose blockade causes metabolic disruption. Whether drug-induced metabolic perturbation is essential for anticancer drug-action, or is just a secondary-maybe even a defence response-is still unclear. To address this, SKOV3 and OVCAR3 ovarian cancer(OC) cell lines with clear cell and serous histology, two main OC subtypes, were exposed to FASN-inhibitor G28UCM. Growth-inhibition was compared with treatment-induced cell-metabolomes, lipidomes, proteomes and kinomes. SKOV3 and OVCAR3 were equally sensitive to low-dose G28UCM, but SKOV3 was more resistant than OVCAR3 to higher concentrations. Metabolite levels generally decreased upon treatment, but individual acylcarnitines, glycerophospholipids, sphingolipids, amino-acids, biogenic amines, and monosaccharides reacted differently. Drug-induced effects on central-carbon-metabolism and oxidative-phosphorylation (OXPHOS) were essentially different in the two cell lines, since drug-naïve SKOV3 are known to prefer glycolysis, while OVCAR3 favour OXPHOS. Moreover, drug-dependent increase of desaturases and polyunsaturated-fatty-acids (PUFAs) were more pronounced in SKOV3 and appear to correlate with G28UCM-tolerance. In contrast, expression and phosphorylation of proteins that control apoptosis, FA synthesis and membrane-related processes (beta-oxidation, membrane-maintenance, transport, translation, signalling and stress-response) were concordantly affected. Overall, membrane-disruption and second-messenger-silencing were crucial for anticancer drug-action, while metabolic-rewiring was only secondary and may support high-dose-FASN-inhibitor-tolerance. These findings may guide future anti-metabolic cancer intervention.


Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19.
Background Type 2 diabetes (T2DM) and obesity are significant risks for mortality in Covid19. Metformin has been hypothesized as a treatment for COVID19. Metformin has sex specific immunomodulatory effects which may elucidate treatment mechanisms in COVID-19. In this study we sought to identify whether metformin reduced mortality from Covid19 and if sex specific interactions exist. Methods De-identified claims data from UnitedHealth were used to identify persons with at least 6 months continuous coverage who were hospitalized with Covid-19. Persons in the metformin group had at least 90 days of metformin claims in the 12 months before hospitalization. Unadjusted and multivariate models were conducted to assess risk of mortality based on metformin as a home medication in individuals with T2DM and obesity, controlling for pre-morbid conditions, medications, demographics, and state. Heterogeneity of effect was assessed by sex. Results 6,256 persons were included; 52.8% female; mean age 75 years. Metformin was associated with decreased mortality in women by logistic regression, OR 0.792 (0.640, 0.979); mixed effects OR 0.780 (0.631, 0.965); Cox proportional-hazards: HR 0.785 (0.650, 0.951); and propensity matching, OR of 0.759 (0.601, 0.960). TNF-alpha inhibitors were associated with decreased mortality in the 38 persons taking them, by propensity matching, OR 0.19 (0.0378, 0.983). Conclusions Metformin was significantly associated with reduced mortality in women with obesity or T2DM in observational analyses of claims data from individuals hospitalized with Covid-19. This sex-specific finding is consistent with metformin reducing TNF-alpha in females over males, and suggests that metformin conveys protection in Covid-19 through TNF-alpha effects. Prospective studies are needed to understand mechanism and causality.


Single-molecule dissection of stacking forces in DNA.
We directly measured at the single-molecule level the forces and lifetimes of DNA base-pair stacking interactions for all stack sequence combinations. Our experimental approach combined dual-beam optical tweezers with DNA origami components to allow positioning of blunt-end DNA helices so that the weak stacking force could be isolated. Base-pair stack arrays that lacked a covalent backbone connection spontaneously dissociated at average rates ranging from 0.02 to 500 per second, depending on the sequence combination and stack array size. Forces in the range from 2 to 8 piconewtons that act along the helical direction only mildly accelerated the stochastic unstacking process. The free-energy increments per stack that we estimate from the measured forward and backward kinetic rates ranged from -0.8 to -3.4 kilocalories per mole, depending on the sequence combination. Our data contributes to understanding the mechanics of DNA processing in biology, and it is helpful for designing the kinetics of DNA-based nanoscale devices according to user specifications.


Targeting the regulation of CFTR channels.
In this issue of the Biochemical Journal, Zhang et al. reveal a new strategy for modifying the regulated function of CFTR (cystic fibrosis transmembrane conductance regulator) on the apical surface of epithelial cells. Simply stated, these authors tested the idea that the cAMP-dependent channel activity of CFTR could be effectively enhanced by disruption of a protein-protein interaction which is normally inhibitory for the production of cAMP. This particular protein-protein interaction [between the PDZ motif of LPA2 (type 2 lysophosphatidic acid receptor) and the scaffold protein Nherf2 (Na+/H+ exchanger regulatory factor 2)] is localized in the CFTR interactome on the apical membrane of epithelial cells. Hence disruption of the LPA2-Nherf2 interaction should lead to a localized elevation in cAMP and, consequently, increased cAMP-dependent CFTR activity on the surface of epithelial cells. Zhang et al. confirmed these expectations for a small-molecule compound targeting the LPA2-Nherf2 interaction using relevant cultures and tissues thought to model the human respiratory epithelium. The success of this strategy depended on previous knowledge regarding the role for multiple PDZ-motif-mediated interactions in signalling (directly or indirectly) to CFTR. Given the number and diversity of such PDZ-mediated interactions, future structural and computational studies will be essential for guiding the design of specific pharmacological interventions.


Role of chemotherapy and GM-CSF on hemopoietic progenitor cell mobilization in multiple myeloma.
Circulating hemopoietic progenitors were evaluated in 19 multiple myeloma patients at diagnosis. Eleven patients received either high-dose cyclophosphamide (7 g/m2, 8 patients) or etoposide (2 g/m2, 3 patients) followed by GM-CSF administration; the remaining 8 patients received intermediate-dose cyclophosphamide (1.2 g/m2 on days 1 and 3), 4 of them with GM-CSF support. The highest levels of circulating progenitor cells were observed among patients in the high-dose chemotherapy group (median CFU-GM peak value of 6432 per ml), while in patients receiving intermediate-dose, with or without GM-CSF, median peak values were 2588 and 462 per ml, respectively. In all groups a remarkable heterogeneity in the yield of circulating progenitors was observed; this was particularly pronounced in the high-dose group, where CFU-GM peak values ranged between 200 and 38,070 per ml. At variance with the effect observed in previously untreated patients with lymphoma or breast cancer, the degree of mobilization in myeloma patients was rather unpredictable. The only pre-treatment characteristic correlating to some extent with a poor expansion of the circulating progenitor pool was heavy BM infiltration with plasma cells. The mobilizing effect was not restricted to the myeloid lineage, as demonstrated by the rise of BFU-E; CD34+ cells were increased as well. Indeed, a simultaneous evaluation of CFU-GM and CD34+ cells was carried out and a highly significant correlation (r = 0.9) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)


A unifying framework for improving health care.
The quality health care around world is suboptimal. To improve the quality of contemporary health care delivery, advocates have proposed a number of scientific and technical initiatives. All these initiatives, however, have arisen and continue to operate in siloes, resulting in confusion and incommensurability among those concerned with health care improvement. Participants in the quality improvement (QI) space typically stress their own, often narrow, perspective, failing to place QI in context or to acknowledge other approaches. In order to improve delivery of health care, the following is required: Provide a unifying framework for improving health care. We argue this is best done under a Health System Science (HSS) framework but with full understanding that the fundamental principles of HSS are rooted in evidence-based medicine (EBM) and decision sciences. Understand that QI initiatives are fundamentally local activities. Hence, incentivizing bottom-up, local QI initiatives would improve health care delivery to a far greater extent than the current top-down initiatives undertaken in a response to various regulatory mandates. Akin to the "Choosing Wisely" initiative, which challenged professional societies, each institution should identify (a) the extent to which its practices are evidence-based and (b) the top 5 health care practices or interventions that, at a given institution, represent overuse, underuse, or misuse/error or undermine clinicians' efforts to deliver kind and empathic care. Providing a framework that can unify the current patchwork of the initiatives would help create a common basis to help align all the existing QI efforts. In addition, thinking small (at local level) may lead to health care quality improvements that national initiatives (thinking big), focused on regulation, competition, or legal requirements, have failed to achieve.


Mesencephalic dopamine neurons interfacing the shell of nucleus accumbens and the dorsolateral striatum in the rat.
Parallel corticostriatonigral circuits have been proposed that separately process motor, cognitive, and emotional-motivational information. Functional integration requires that interactions exist between neurons participating in these circuits. This makes it imperative to study the complex anatomical substrate underlying corticostriatonigral circuits. It has previously been proposed that dopaminergic neurons in the ventral mesencephalon may play a role in this circuit interaction. Therefore, we studied in rats convergence of basal ganglia circuits by depositing an anterograde neuroanatomical tracer into the ventral striatum together with a retrograde fluorescent tracer ipsilaterally in the dorsolateral striatum. In the mesencephalon, using confocal microscopy, we looked for possible appositions of anterogradely labeled fibers and retrogradely labeled neurons, "enhancing" the latter via intracellular injection of Lucifer Yellow. Tyrosine hydroxylase (TH) immunofluorescence served to identify dopaminergic neurons. In neurophysiological experiments, we combined orthodromic stimulation in the medial ventral striatum with recording from ventral mesencephalic neurons characterized by antidromic stimulation from the dorsal striatum. We observed terminal fields of anterogradely labeled fibers that overlap populations of retrogradely labeled nigrostriatal cell bodies in the substantia nigra pars compacta and lateral ventral tegmental area (VTA), with numerous close appositions between boutons of anterogradely labeled fibers and nigrostriatal, TH-immunopositive neurons. Neurophysiological stimulation in the medial ventral striatum caused inhibition of dopaminergic nigrostriatal neurons projecting to the ventrolateral striatal territory. Responding nigrostriatal neurons were located in the medial substantia nigra and adjacent VTA. Our results strongly suggest a functional link between ventromedial, emotional-motivational striatum, and the sensorimotor dorsal striatum via dopaminergic nigrostriatal neurons.


Vascular cell lines expressing SSAO/VAP-1: a new experimental tool to study its involvement in vascular diseases.
PrAO (primary amine oxidase), also known as SSAO (semicarbazide-sensitive amine oxidase)/VAP-1 (vascular adhesion protein-1), is an enzyme (EC 22.214.171.124) that is highly expressed in blood vessels and participates in many cell processes, including glucose handling or inflammatory leucocyte recruitment. High activity levels of this enzyme are associated with diabetes, atherosclerosis, AD (Alzheimer's disease) or stroke, among others, thus meaning that studies concerning SSAO as a therapeutic target are becoming more frequent. However, the study of this enzyme is difficult, owing to its loss of expression in cell cultures. We have developed an endothelial cell line that stably expresses the human SSAO/VAP-1 to be used as endothelial cell model for the study of this enzyme. The transfected protein is mainly expressed as a dimer in the membrane of these cells, and we demonstrate its specific localization in the lipid rafts of endothelial cells. The protein shows levels of enzymatic activity and kinetic parameters comparable with those observed in vivo by the same cell type. The transfected SSAO/VAP-1 is also able to mediate the adhesion of leucocytes to the endothelium, a known function of this protein under inflammatory conditions. This distinctive function is not exerted by the SSAO/VAP-1 transfected protein in a smooth muscle cell line that expresses 3-fold higher protein levels. These differences have been widely reported to exist in vivo. Furthermore, using this endothelial cell model, we describe for the first time the involvement of the leucocyte-adhesion activity of SSAO/VAP-1 in the Aβ (amyloid β-peptide)-mediated pro-inflammatory effect. The characterization of this new cell line shows the correct behaviour of the transfected protein and endorses the use of these cellular models for the in-depth study of the currently poorly understood functions of SSAO/VAP-1 and its involvement in the above-mentioned pathologies. This cellular model will be also useful for the evaluation of potential compounds that could modulate its activity for therapeutic purposes.


Flextensional ultrasonic piezoelectric micro-motor.
This paper presents the experimental design, construction, and operational characteristics of a new type of standing wave piezoelectric ultrasonic micro-motor. The motor uses a composite stator, consisting of a metallic flex-tensional mode converter, or "cymbal", bonded to a 2-mm-square piezoelectric plate. The cymbal converts contour-mode vibrations of the plate into oscillations in the cymbal, perpendicular to the stator plane. These are further converted into rotational movement in a rotor pressed against the cymbal by means of an elastic-fin friction drive to produce the required rotary actuation. The motor operates on a single-phase electrical supply, and direct control of the output speed and torque can be achieved by adjusting the amplitude and frequency of the supply voltage. Noncontact optical techniques were used to assess the performance of the developed micro-motor. The operational characteristics were developed from the acceleration and deceleration characteristics. No-load output speed (11 rev s(-1)) and stall torque (27 nNm) were derived using high-speed imaging and image analysis. Maximum efficiency was 0.6%.


Physicochemical and binder properties of starch obtained from Cyperus esculentus.
The purpose of this study was to isolate starch from the tubers of Cyperus esculentus L. and evaluate its physicochemical and binder properties. Extraction of starch using sodium metabisulfite yielded 37 g of starch per 100 g of the tubers. Scanning electron microscopy indicated that Cyperus starch consists of oval to elliptical particles with a smooth surface. Cyperus starch demonstrates a narrow particle size distribution with a mean of 8.25 μm. Cyperus starch conforms well to United States Pharmacopeia standards established for widely used starches like maize and potato. The X-ray powder diffraction pattern and moisture sorption profile of Cyperus starch were comparable to that of maize starch. Cyperus starch had lower swelling power than maize and potato starch, indicative of stronger associative forces within the granules. Carr's index and Hausner ratio indicate that Cyperus starch should have comparable flow properties with respect to maize and potato starch. Cyperus starch was employed as binder for the formulation of metronidazole tablets. Formulations containing 5%, 7.5%, and 10% Cyperus starch were compared with those containing 10% potato starch. At 10% binder concentration, the tablets containing Cyperus starch exhibited better hardness and negligible friability as compared with those with potato starch. Although the binder concentration had a significant effect on the disintegration time of the tablets, it did not seem to affect the dissolution profile. These results indicate that Cyperus starch provides excellent binding properties without compromising drug release characteristics and should be explored in pharmaceutical formulations.


Update on the "Dutch hypothesis" for chronic respiratory disease.
Many patients with chronic obstructive lung disease show increased airways responsiveness to histamine. We investigated the hypothesis that increased airways responsiveness predicts the development and remission of chronic respiratory symptoms. We used data from 24-year follow-up (1965-90) of 2684 participants in a cohort study in Vlagtwedde and Vlaardingen, Netherlands. Increased airways responsiveness was defined as a PC10 value (concentration of histamine for which challenge led to a 10% fall in forced expiratory volume in 1 s) of less than 8 mg/ml. Information on respiratory symptoms was collected by means of a standard questionnaire every 3 years. Logistic regression was used to control for age, area of residence, cigarette smoking status, and sex. Participants with increased airways responsiveness (1281 observations) were more likely than those without increased airways responsiveness (5801 observations) to develop the following symptoms during any 3-year follow-up interval: chronic cough (odds ratio 1.9 [95% CI 1.2-2.9]), chronic phlegm (2.0 [1.3-3.0]), dyspnoea (2.3[1.5-3.5]), asthmatic attacks (3.7[2.2-6.1]), and persistent wheeze (2.7[1.7-4.4]). The estimate of the odds ratio for the development of any of the six symptoms was 1.7 (1.2-2.3). Participants with increased airways responsiveness were less likely than those without this characteristic to show remission of these respiratory symptoms. The estimate of the odds ratio for the remission of any of the six symptoms was 0.42 (0.28-0.61). These prospective analyses show that increased airways responsiveness is positively associated with the development of chronic respiratory symptoms and negatively associated with the remission of these symptoms in adults.


Genealogical Diversity of Endogenous Retrovirus in the Jawless Fish Genome.
Retroviral integration into ancient vertebrate genomes left traces that can shed light on the early history of viruses. In this study, we explored the early evolution of retroviruses by isolating nine Spuma endogenous retroviruses (ERVs) and one Epsilon ERV from the genomes of Agnatha and Chondrichthyes. Phylogenetic analysis of protein sequences revealed a striking pattern of co-evolution between jawless fish ERV and their host, while shark ERV underwent ancient cross-class viral transmission with jawless fish, ray-finned fish, and amphibians. Nucleotide sequence analysis showed that jawless fish ERV emerged in the Palaeozoic period, relatively later than ray-finned fish ERV. Moreover, codon analysis suggested that the jawless fish ERV employed an infection strategy that mimics the host codon. The genealogical diversity of ERVs in the jawless fish genome highlights the importance of studying different viral species. Overall, our findings provide valuable insights into the evolution of retroviruses and their interactions with their hosts.


[Short-term energy and protein support in mechanically ventilated patients with acute exacerbation of cor pulmonale].
Twenty-one mechanically ventilated patients with acute exacerbation of cor pulmonale had received home made "Nutritient" via nasal gastric tube as energy and protein support for four weeks (energy supplement 37-45 kcal.kg-1.d-1, protein 1.40-1.67 g.kg-1.d-1). Anthropometry, serum albumin, serum prealbumin were measured on the 1st day and at the end of the 1st, 2nd, 4th week of ventilation. The results were compared with those in 15 age-matched ventilated patients who received routine hospital nasal gastric feeding (energy 24-29 kcal.kg-1.d-1, protein: 0.92-1.09 g.kg-1.d-1). All patients were in protein deficient type malnutrition. At the end of the 1st week of ventilation, serum albumin dropped significantly in both groups, resulting in a status of mixed type malnutrition. At the end of the 2nd week, however, serum prealbumin in the experimental group (24.31 +/- 4.80 mg/dl) returned nearly to normal level, being significantly higher than that in the control group (15.10 +/- 3.10 mg/dl, P < 0.01). At the end of the 4th week, both serum albumin (3.90 +/- 0.31 g/dl) and prealbumin (27.33 +/- 3.30 mg/dl) in experimental group returned to normal, being also significantly higher than those in the control group (3.00 +/- 0.23 g/dl, P < 0.05; 17.11 +/- 3.22 mg/dl, P < 0.01). Anthropometry showed no significant change between the two groups during ventilation. It is shown that nasal tube administration of "Nutritient" provides much higher energy and protein as compared with routine nasal feeding, and enables the patient to overcome protein deficiency and to reach positive nitrogen balance earlier.


Plasma testosterone is associated with Framingham risk score.
The Framingham risk score predicts a patient's 10-year risk of developing cardiovascular disease. Many risk factors included in its calculation influence or are influenced by circulating testosterone. To investigate the possible association between testosterone and cardiovascular risk, as defined by the Framingham score, a Veterans Affairs (VA) database was analyzed. A retrospective chart review was performed. Inclusion criteria were male sex and age ≥ 20 years. Exclusion criteria included pre-existing cardiovascular disease, stroke, and diabetes. Data were collected on veterans who had total plasma testosterone checked in the year 2008. The study included 1,479 patients (mean age 61 years). Framingham score was negatively associated with both total testosterone (p < 0.0001) and free testosterone (p = 0.0003). There was a positive association between total testosterone and high-density lipoprotein and negative associations between total testosterone and body mass index (BMI), total cholesterol, triglycerides, and blood pressure medication use. Free testosterone was positively associated with total cholesterol, low-density lipoprotein, and current smoking status and negatively associated with age, BMI, and blood pressure medication use. The BMI was not associated with Framingham score. Lower plasma testosterone may suggest the presence of cardiovascular risk factors and potentially increased risk for heart disease.


[Neurobiology of schizophrenia].
Summarizing the most interesting data obtained in schizophrenia by the genetic, morphological and psychopharmacological studies, the authors try to take stock of the two main physiopathological process involved in this disorder, as to say, modifications in the limbic structures anatomy and chemical disturbances in different neurotransmitter system.


Neuropsychological functions and visual contrast sensitivity in schizophrenia: the potential impact of comorbid posttraumatic stress disorder (PTSD).
Previous studies have revealed a high prevalence of posttraumatic stress disorder (PTSD) in patients with other severe mental disorders, including schizophrenia. However, the neuropsychological and psychophysical correlates of comorbid PTSD are less exactly defined. The purpose of the present study was to assess immediate and delayed memory, attention, visuospatial skills, language, and basic visual information processing in patients with schizophrenia with or without PTSD. We recruited 125 patients with schizophrenia and 70 healthy controls matched for visual acuity, age, gender, education, and socioeconomic status. Twenty-one of patients with schizophrenia exhibited comorbid PTSD. We administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and visual contrast sensitivity tasks for low spatial/high temporal frequency (0.3 cycle/degree and 18 Hz) and high spatial/low temporal frequency (10 cycles/degree and 1Hz) sinusoidal gratings. All patients were clinically stable and received antipsychotic medications. Results revealed that relative to healthy controls, patients with schizophrenia exhibited significant and generalized neuropsychological dysfunctions and reduced visual contrast sensitivity, which was more pronounced at low spatial/high temporal frequency. When we compared schizophrenia patients with and without PTSD, we found that patients with comorbid PTSD displayed lower scores for RBANS attention, immediate and delayed memory, and visuospatial scores. Schizophrenia patients with or without PTSD displayed similar visual contrast sensitivity. In conclusion, comorbid PTSD in schizophrenia may be associated with worse neuropsychological functions, whereas it does not affect basic visual information processing.


Cholesterol ester accumulation in cultured aortic smooth muscle cells. Induction of cholesterol ester retention by chloroquine and low density lipoprotein and its reversion by mixtures of high density apolipoprotein and sphingomyelin.
Accretion of cholesterol ester was studied in rat aortic smooth muscle cells in culture. Confluent multilayers of smooth muscle cells were exposed to human low density lipoprotein (LDL) and chloroquine and this treatment resulted in a very marked increase in cellular cholesterol ester. The degree of enrichment in cholesterol ester was related inversely to the cell density in the petri dish and was maximal in 48 h. The morphological changes after 48 h incubation with chloroquine and LDL consisted of accumulation of numerous membrane-bound inclusions containing electron-dense and electron-lucent material, some of which resembled secondary lysosomes. These changes resembled some of the changes observed in human and experimental atheromatosis. Similar inclusions were seen also in cultured human skin fibroblasts which accumulated large amounts of cholesterol ester during 48 h incubation with LDL and chloroquine. Removal of the accumulated cellular cholesterol ester was studied in the two cell types and it was markedly enhanced in the presence of lipoprotein-deficient serum and high density apolipoprotein-sphingomyelin mixture. The morphological findings after 24 h of post incubation revealed the presence of empty vacuoles, membrane whorls and cytoplasmic lipid droplets. The present results indicate that aortic smooth muscle cells in culture can serve as a good model to study the role of the lysosomal system in atherogenesis.


[Perinatal results in patients with chronic hypertension at the National Institute of Perinatology].
There are many causes of Chronic Hypertension, and all can be present in pregnant women. The literature reports an incidence between 1-3%. The prognosis usually is favorable, if we have an excellent control of blood pressure along pregnancy. But the risks like abruptio placentae, fetal demise or fetal growth restriction have a greater incidence than in the health population, furthermore the superimposed preeclampsia increase notably the perinatal morbidity. The objective of this study is to determine the perinatal outcomes in women with chronic hypertension in the Instituto Nacional de Perinatología. In the study we included 66 patients with chronic hypertension with age between 21-45 years old, and 54.4% had an age between 30-40 years. The evolution time of hypertensive disease was 5 years or less principally (71.2% of the patients).


African primary care research: choosing a topic and developing a proposal.
This is the first in a series of articles on primary care research in the African context. The aim of the series is to help build capacity for primary care research amongst the emerging departments of family medicine and primary care on the continent. Many of the departments are developing Masters of Medicine programmes in Family Medicine and their students will all be required to complete research studies as part of their degree. This series is being written with this audience in particular in mind--both the students who must conceptualise and implement a research project as well as their supervisors who must assist them.This article gives an overview of the African primary care context, followed by a typology of primary care research. The article then goes on to assist the reader with choosing a topic and defining their research question. Finally the article addresses the structure and contents of a research proposal and the ethical issues that should be considered.


New innovations: therapeutic opportunities for intellectual disabilities.
Intellectual disability is common and is associated with significant morbidity. Until the latter half of the 20th century, there were no efficacious treatments. Following initial breakthroughs associated with newborn screening and metabolic corrections, little progress was made until recently. With improved understanding of genetic and cellular mechanisms, novel treatment options are beginning to appear for a number of specific conditions. Fragile X and tuberous sclerosis offer paradigms for the development of targeted therapeutics, but advances in understanding of other disorders such as Down syndrome and Rett syndrome, for example, are also resulting in promising treatment directions. In addition, better understanding of the underlying neurobiology is leading to novel developments in enzyme replacement for storage disorders and adjunctive therapies for metabolic disorders, as well as potentially more generalizable approaches that target dysfunctional cell regulation via RNA and chromatin. Physiologic therapies, including deep brain stimulation and transcranial magnetic stimulation, offer yet another direction to enhance cognitive functioning. Current options and evolving opportunities for the intellectually disabled are reviewed and exemplified.


Improved walking ability with wearable robot-assisted training in patients suffering chronic stroke.
Wearable robotic devices provide safe and intensive rehabilitation, enabling repeated motions for motor function recovery in stroke patients. The aim of this small case series was to demonstrate the training effects of a three-week robotic leg orthosis, and to investigate possible mechanisms of the sensory-motor alterations and improvements by using gait analysis and EMG. Three survivors of chronic strokes participated in robot-assisted gait therapy for three weeks. EMG signals from the rectus femoris (RF), tibialis anterior (TA), biceps femoris (BF), and medial gastrocnemius (MG), as well as kinetics and kinematics data of the lower limb, were recorded before and after the training. The normalized root mean squared (RMS) values of the muscles, the joint moments, joint angles, and the results of two clinical scales (Berg Balance scale, BBS, and the lower extremity subscale of Fugl-Meyer assessment, LE-FMA) were used for analysis. All participants experienced improved balance and functional performances and increased BBS and LE-FMA scores. The EMG results showed there was an increase of the normalized RMS values of the MG and BF on the affected side. Additionally, EMG activities of the agonist and antagonist pair (i.e. RF and BF) appeared to return to similar levels after training. The peak moment of hip flexor, knee extensor, and plantar flexor, which all contributed to push-off power, were found to have increased after training. In summary, the three-week training period using the wearable RLO improved the three participants' gait performance by regaining push-off power and improved muscle activation and walking speed.


A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation.
Reactivation of silenced tumor suppressor genes by 5-azacytidine (Vidaza) and its congener 5-aza-2'-deoxycytidine (decitabine) has provided an alternate approach to cancer therapy. We have shown previously that these drugs selectively and rapidly induce degradation of the maintenance DNA methyltransferase (DNMT) 1 by a proteasomal pathway. Because the toxicity of these compounds is largely due to their incorporation into DNA, it is critical to explore novel, nonnucleoside compounds that can effectively reactivate the silenced genes. Here, we report that a quinoline-based compound, designated SGI-1027, inhibits the activity of DNMT1, DNMT3A, and DNMT3B as well M. SssI with comparable IC(50) (6-13 micromol/L) by competing with S-adenosylmethionine in the methylation reaction. Treatment of different cancer cell lines with SGI-1027 resulted in selective degradation of DNMT1 with minimal or no effects on DNMT3A and DNMT3B. At a concentration of 2.5 to 5 micromol/L (similar to that of decitabine), complete degradation of DNMT1 protein was achieved within 24 h without significantly affecting its mRNA level. MG132 blocked SGI-1027-induced depletion of DNMT1, indicating the involvement of proteasomal pathway. Prolonged treatment of RKO cells with SGI-1027 led to demethylation and reexpression of the silenced tumor suppressor genes P16, MLH1, and TIMP3. Further, this compound did not exhibit significant toxicity in a rat hepatoma (H4IIE) cell line. This study provides a novel class of DNA hypomethylating agents that have the potential for use in epigenetic cancer therapy.


Potential Prognostic Value of Preoperative Leukocyte Count, Lactate Dehydrogenase and C-Reactive Protein in Thymic Epithelial Tumors.
Thymic epithelial tumors are the most common mediastinal tumors. Surgery is the mainstay of treatment and complete resection provides the best survival rate. However, advanced tumors often require multimodality treatment and thus we analyzed the prognostic potential of routine circulating biomarkers that might help to risk-stratify patients beyond tumor stage and histology. Preoperative values for white blood cell count (WBC), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were analyzed in 220 thymic epithelial tumor patients operated between 1999 and 2018. Increased CRP levels (>1 mg/dl) were significantly more often measured in thymic carcinoma and neuroendocrine tumors when compared to thymoma. LDH serum activity was higher in thymic neuroendocrine tumors when compared to thymoma or thymic carcinoma. The median disease specific survival was significantly longer in thymoma cases than in thymic carcinoma and neuroendocrine tumors. Increased preoperative LDH level (>240 U/L) associated with shorter survival in thymus carcinoma (HR 4.76, p = 0.0299). In summary, higher CRP associated with carcinoma and neuroendocrine tumors, while LDH increased primarily in neuroendocrine tumors suggesting that biomarker analysis should be performed in a histology specific manner. Importantly, preoperative serum LDH might be a prognosticator in thymic carcinoma and may help to risk stratify surgically treated patients in multimodal treatment regimens.


Glucose concentration and streptomycin alter in vitro muscle function and metabolism.
Cell culture conditions can vary between laboratories and have been optimised for 2D cell culture. In this study, engineered muscle was cultured in 5.5 mM low glucose (LG) or 25 mM high glucose (HG) and in the absence or presence (+S) of streptomycin and the effect on C2C12 tissue-engineered muscle function and metabolism was determined. Following 2 weeks differentiation, streptomycin (3-fold) and LG (0.5-fold) significantly decreased force generation. LG and/or streptomycin resulted in upward and leftward shifts in the force-frequency curve and slowed time-to-peak tension and half-relaxation time. Despite changes in contractile dynamics, no change in myosin isoform was detected. Instead, changes in troponin isoform, calcium sequestering proteins (CSQ and parvalbumin) and the calcium uptake protein SERCA predicted the changes in contractile dynamics. Culturing in LG and/or streptomycin resulted in increased fatigue resistance despite no change in the mitochondrial enzymes SDH, ATPsynthase and cytochrome C. However, LG resulted in increases in the β-oxidation enzymes LCAD and VLCAD and the fatty acid transporter CPT-1, indicative of a greater capacity for fat oxidation. In contrast, HG resulted in increased GLUT4 content and the glycolytic enzyme PFK, indicative of a more glycolytic phenotype. These data suggest that streptomycin has negative effects on force generation and that glucose can be used to shift engineered muscle phenotype via changes in calcium-handling and metabolic proteins.


The role of chemokines in oral tolerance. Abrogation of nonresponsiveness by treatment with antimonocyte chemotactic protein-1.
Peripheral antigen-specific tolerance can be induced by feeding protein antigens. The mechanism has been described as either clonal anergy/deletion or induction of antigen-specific regulatory cells that produce transforming growth factor (TGF)-beta, depending on the dose of antigen fed. Experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, can be prevented by feeding myelin basic protein (MBP) or proteolipid protein (PLP). We decided to address the role of chemokines in the induction of oral tolerance. We have used a model antigen system of feeding a high dose of human gamma globulin (HGG) to mice that have been subsequently immunized with HGG emulsified in CFA. The result was decreased recall proliferative, delayed-type hypersensitivity (DTH) and Th1 cytokine responses. By contrast, Th2 cytokine responses were enhanced. Interestingly, macrophage inflammatory protein (MIP)-1alpha production was decreased, whereas monocyte chemotactic protein (MCP)-1 production was enhanced. Induction of oral tolerance was prevented by the administration of anti-MCP-1 to mice fed HGG. These results show that chemokines play an important role in the induction of oral tolerance.


Pathophysiology and modern management of Paget's disease.
Paget's disease of bone is a slowly progressive and frequently disabling disorder of unknown cause. Recent evidence suggests that it may be associated with a viral infection. Until the late 1960s, no effective treatments were available. Now there are three that are suppressive and useful for symptomatic relief. Recent studies suggest that it may be possible to produce permanent remissions of the disease and thus prevent complications.


The influence of multiple indices of socioeconomic disadvantage across the adult life course on the metabolic syndrome: the Vietnam Experience Study.
Few studies have explored the relationship between individual and combined multiple indicators of socioeconomic status across the life course and the metabolic syndrome, or attempted to understand the mechanisms underlying any associations. The present study examined the associations between 4 indicators of socioeconomic status, individually and in combination, and metabolic syndrome risk in a study of male US veterans and examined the influence of health behaviors, intelligence, and psychologic distress on these associations. Participants (N = 4253) were drawn from the Vietnam Experience Study. From military service files, telephone interviews, and a medical examination, occupational, sociodemographic, health behavior, intelligence, psychologic, and health data were collected. The 4 indices of socioeconomic status were as follows: education achieved, early adulthood income, household income in midlife, and occupational prestige in midlife. Metabolic syndrome was diagnosed from the following: body mass index, fasting blood glucose or a diagnosis of diabetes, blood pressure-a diagnosis of hypertension or taking antihypertensives, high-density lipoprotein cholesterol, and triglyceride levels. In models that adjusted for age, men in the lower 2 groups on the combined measure of socioeconomic status experienced a higher risk of metabolic syndrome. This association was accounted for mainly by education achieved, household income in midlife, and occupational prestige in midlife. Intelligence appeared to explain much of this association. Combined socioeconomic status measures across the life course were related to metabolic syndrome but in a threshold rather than dose-response manner. Intelligence appeared to mediate this relationship.


Synaptic influences on rat ganglion-cell photoreceptors.
The intrinsically photosensitive retinal ganglion cells (ipRGCs) provide a conduit through which rods and cones can access brain circuits mediating circadian entrainment, pupillary constriction and other non-image-forming visual functions. We characterized synaptic inputs to ipRGCs in rats using whole-cell and multielectrode array recording techniques. In constant darkness all ipRGCs received spontaneous excitatory and inhibitory synaptic inputs. Light stimulation evoked in all ipRGCs both synaptically driven ('extrinsic') and autonomous melanopsin-based ('intrinsic') responses. The extrinsic light responses were depolarizing, about 5 log units more sensitive than the intrinsic light response, and transient near threshold but sustained to brighter light. Pharmacological data showed that ON bipolar cells and amacrine cells make the most prominent direct contributions to these extrinsic light responses, whereas OFF bipolar cells make a very weak contribution. The spatial extent of the synaptically driven light responses was comparable to that of the intrinsic photoresponse, suggesting that synaptic contacts are made onto the entire dendritic field of the ipRGCs. These synaptic influences increase the sensitivity of ipRGCs to light, and also extend their temporal bandpass to higher frequencies. These extrinsic ipRGC light responses can explain some of the previously reported properties of circadian photoentrainment and other non-image-forming visual behaviours.


Picturing Participation: Catalyzing Conversations About Community Engagement in HIV Community-Based Organizations.
Community engagement is considered a cornerstone of health promotion practice. Yet engagement is a fuzzy term signifying a range of practices. Health scholarship has focused primarily on individual effects of engagement. To understand the complexities of engagement, organizations must also consider relational, structural, and/or organizational factors that inform stakeholders' subjective understandings and experiences. Community engagement processes are not neutral; they can reproduce and/or dismantle power structures, often in contradictory or unexpected ways. This article discusses diverse stakeholders' subjective experiences and understandings of engagement within the HIV sector in Toronto, Canada. In our study, a team of community members, service providers, and academics partnered with three HIV community-based organizations to do this work. We used photovoice, a participatory and action-oriented photography method, to identify, document, and analyze participants' understandings at respective sites. Through collaborative analysis, we identified seven themes that may catalyze conversations about engagement within organizations: reflecting on journey; honoring relationships; accessibility and support mechanisms; advocacy, peer leadership, and social justice; diversity and difference; navigating grief and loss; and nonparticipation. Having frank and transparent discussions that are grounded in stakeholders' subjective experiences, and the sociopolitical and structural conditions of involvement, can help organizations take a more intersectional and nuanced approach to community engagement. Together, our findings can be used as a framework to support organizations in thinking more deeply and complexly about how to meaningfully, ethically, and sustainably engage communities (both individually and collectively) in HIV programming, and organizational policy change. The article concludes with questions for practice.


The Effect of Sleeve Gastrectomy on the Hormonal Profile of Patients with Polycystic Ovary Syndrome.
To prospectively evaluate the hormonal profile and weight loss of women with obesity and PCOS submitted to sleeve gastrectomy (SG). A Prospective study carried out at the Hospital das Clínicas, Federal University of Pernambuco, Recife, Brazil, in 2018, where 18 patients with PCOS, whose age varied from 18 to 40 years, with an indication for bariatric surgery were evaluated. Plasma estradiol (E2), fasting insulin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured prior to bariatric surgery and 3 months after surgery. The LH/FSH ratio and BMI of the study participants were also calculated. Postoperative E2 levels were higher (preoperative mean of 63.4 pg/dL versus postoperative mean of 91.0 pg/dL), with no statistical significance then (p = 0.139). It was observed, at the postoperative period, statistically significant decreases in mean fasting insulin levels (24.4 mIU/mL vs. 9.0 mIU/mL; p < 0.001), LH levels (7.2 vs. 4.5; p = 0.047), and an inverted LH/FSH ratio (1.5 vs. 0.9; p = 0.008); relevant weight loss occurred (mean BMI, 40.5 kg/m2 vs. 33.4 kg/m2; p < 0.001). Relevant changes in the hormone profile and significant alterations in the gonadotropic and insulin patterns were seen. In addition to satisfactory weight loss, the observed endocrine alterations revealed an internal environment that was more homeostatic and conducive to reproduction, indicating that SG was able to produce attractive physiological outcomes for women with PCOS.


Deletion 4q21/4q22 syndrome: two patients with de novo 4q21.3q23 and 4q13.2q23 deletions.
We report on 2 patients with de novo proximal interstitial deletions of the long arm of chromosomes 4: in one the deletion resulted in monosomy (4)(q21.3q23), in the other it produced monosomy (4)(q13.2q23). Review of 9 cases of deletions involving the 4q21/4q22 region reported previously detected a characteristic phenotype in 8 patients. This phenotype was present in our patients. We conclude that the deletion in the 4q21/4q22 region results in a specific clinical syndrome associated with central nervous system overgrowth that may be a result of anomalous imprinting in the 4q21/4q22 region.


Continuous quality improvement. Concepts and applications for physician care.
There has been a growing interest by health care leaders in the continuous quality improvement method of quality management. This method uses measurements of quality "indicators" to initiate and drive organizational changes in a never-ending cycle of continuous improvement. Many discussions of the continuous quality improvement method have emphasized the organizational and attitudinal changes necessary to fully implement the model while deemphasizing the uses of measures of quality to guide improvement. In this article, we emphasize the concepts behind the measurement of quality that underline the continuous quality improvement model and give examples of how these concepts can be immediately applied to guide improvement in the quality of physician care.


Cardiac surgery in nonagenarians: Rethinking operative strategies in the era of TAVR and TMVR.
As growth of the elderly population continues to increase alongside improvements in percutaneous and minimally invasive interventions, cardiac surgeons question the role of high-risk surgery in treating these patients. TAVR has transformed the management of symptomatic severe aortic stenosis in elderly patients and has become standard therapy for patients greater than 80 years of age. With improvements in procedural risks and technical complications for both transcatheter valves and percutaneous interventions, should we rethink the operative strategies for octogenarians and nonagenarians, particularly as they apply to concurrent high-risk operations?