Au nanoparticle-decorated silicon pyramids for plasmon-enhanced hot electron near-infrared photodetection.
The heterojunction between metal and silicon (Si) is an attractive route to extend the response of Si-based photodiodes into the near-infrared (NIR) region, so-called Schottky barrier diodes. Photons absorbed into a metallic nanostructure excite the surface plasmon resonances (SPRs), which can be damped non-radiatively through the creation of hot electrons. Unfortunately, the quantum efficiency of hot electron detectors remains low due to low optical absorption and poor electron injection efficiency. In this study, we propose an efficient and low-cost plasmonic hot electron NIR photodetector based on a Au nanoparticle (Au NP)-decorated Si pyramid Schottky junction. The large-area and lithography-free photodetector is realized by using an anisotropic chemical wet etching and rapid thermal annealing (RTA) of a thin Au film. We experimentally demonstrate that these hot electron detectors have broad photoresponsivity spectra in the NIR region of 1200-1475 nm, with a low dark current on the order of 10-5 A cm-2. The observed responsivities enable these devices to be competitive with other reported Si-based NIR hot electron photodetectors using perfectly periodic nanostructures. The improved performance is attributed to the pyramid surface which can enhance light trapping and the localized electric field, and the nano-sized Au NPs which are beneficial for the tunneling of hot electrons. The simple and large-area preparation processes make them suitable for large-scale thermophotovoltaic cell and low-cost NIR detection applications.


Senescence of mesenchymal stem cells (Review).
Mesenchymal stem cells (MSCs) have been used in cell-based therapy for various diseases, due to their immunomodulatory and inflammatory effects. However, the function of MSCs is known to decline with age, a process that is called senescence. To date, the process of MSC senescence remains unknown as in-depth understanding of the mechanisms involved in cellular senescence is lacking. First, senescent MSCs are so heterogeneous that not all of them express the same phenotypic markers. In addition, the genes and signaling pathways which regulate this process in MSCs are still unknown. Thus, an understanding of the molecular processes controlling MSC senescence is crucial to determining the drivers and effectors of age-associated MSC dysfunction. Moreover, the proper use of MSCs for clinical application requires a general understanding of the MSC aging process. Furthermore, such knowledge is essential for the development of therapeutic interventions that can slow or reverse age-related degenerative changes to enhance repair processes and maintain healthy function in aging tissues. To further clarify the properties of senescent cells, as well as to present significant findings from studies on the mechanisms of cellular aging, we summarize these biological features in the senescence of MSCs in this scenario. This review summarizes recent advances in our understanding of the markers and differentiation potential indicating MSC senescence, as well as factors affecting MSC senescence with particular emphasis on the roles of oxidative stress, intrinsic changes in telomere shortening, histone deacetylase and DNA methyltransferase, genes and signaling pathways and immunological properties.


Geographic Distance From Transplant Center Does Not Impact Pediatric Heart Transplant Outcomes.
Many pediatric heart transplant recipients live a significant distance from their transplant center. This results in families either traveling long distances or relying on outside physicians to assume aspects of their care. Distance has been implicated to play a role in congenital heart disease outcomes, but its impact on heart transplantation has not been reported. The aim of this study was to assess the impact of distance on pediatric heart transplant outcomes. The Scientific Registry of Transplant Recipients database was queried for all pediatric heart transplant recipients from large US children's hospitals (1987-2014). Patients were stratified into 4 groups (<20, 20-50, 50-100, and >100 miles) based on distance. Survival curves were generated and compared using the log-rank test. Cox proportional hazards regression was performed to adjust for differences between groups. A total of 4768 patients were included in the analysis, of which 1435 (30.1%) were <20 miles, 940 (19.7%) were 20 to 50 miles, 806 (16.9%) were 50 to 100 miles, and 1587 (33.3%) were >100 miles from their transplant center. There was no difference in posttransplant survival based on distance after adjusting for patient age, gender, ethnicity, blood type, diagnosis, listing status, and the need for pretransplant ventricular assist device, extracorporeal membrane oxygenation, or ventilator support. There is no significant difference in graft survival after pediatric heart transplantation based on patient distance from their transplant center. Our data suggest the current strategy of transitioning some aspects of transplant care to local physicians or management from a distance does not increase posttransplant mortality risk.


Comparative Gene Expression and Physiological Analyses Reveal Molecular Mechanisms in Wound-Induced Spore Formation in the Edible Seaweed Nori.
Genetic reprogramming of differentiated cells is studied broadly in multicellular Viridiplantae as an adaptation to herbivory or damage; however, mechanisms underlying cell development and redifferentiation are largely unknown in red algae, their nearest multicellular relatives. Here we investgate cell reprogramming in the widely cultivated, edible seaweed Neopyropia yezoesis ("nori"), where vegetative cells in wounded blades differentiate and release as large numbers of asexual spores. Based upon physiological changes and transcriptomic dynamics after wound stress in N. yezoensis and its congener Neoporphyra haitanensis, another cultivar that does not differentiate spores after wounding, we propose a three-phase model of wound-induced spore development in N. yezoensis. In Phase I, propagation of ROS by RBOH and SOD elicites systematic transduction of the wound signal, while Ca2+ dependent signaling induces cell reprogramming. In Phase II, a TOR signaling pathway and regulation of cyclin and CDK genes result in cell divisions that spread inward from the wound edge. Once sporangia form, Phase III involves expression of proteins required for spore maturation and cell wall softening. Our analyses not only provide the first model for core molecular processes controlling cellular reprogramming in rhodophytes, but also have practical implications for achieving greater control over seeding in commercial nori farming.


Stereoselective synthesis of an anti-HIV drug candidate.
The asymmetric synthesis of a Merck anti-HIV drug candidate is described. The target molecule contains four stereogenic centers, three of which are located in a highly functionalized cyclopentane unit. The convergent synthesis involves the preparation of two key advanced intermediates: the cyclopentane unit and a substituted pyrazole unit. The cyclopentane unit was prepared via two different procedures; a highly diastereoselective Diels-Alder reaction with a chiral oxazolidinone auxiliary and a sequence that incorporated a molybdenum-catalyzed asymmetric allylic alkylation reaction to set the stereocenters. The other key step was a highly diastereoselective hydroxyl-directed reductive amination. The overall yield for the 16-step synthesis was 10%.


Occupational exposure to antineoplastic drugs: what about hospital sanitation personnel?
Occupational exposure to antineoplastic drugs (ANPs) occurs mainly through dermal contact. Our study was set up to assess the potential exposure of hospital sanitation (HS) personnel, for whom almost no data are available, through contamination of surfaces they regularly touch. In the oncology departments of two hospitals around Montreal, surface wipe samples of 120-2000 cm2 were taken at 10 sites cleaned by the HS personnel and five other sites frequently touched by nursing and pharmacy personnel. A few hand wipe samples were collected to explore skin contamination. Wipes were analyzed by ultra-performance liquid chromatography tandem-mass spectrometry for 10 ANPs. Overall, 60.9% of 212 surface samples presented at least one ANP above the limits of detection (LOD). Cyclophosphamide and gemcitabine were most often detected (52% and 31% of samples respectively), followed by 5-fluorouracil and irinotecan (15% each). Highest concentrations of five ANPs were found in outpatient clinics on toilet floors (5-fluorouracil, 49 ng/cm2; irinotecan, 3.6 ng/cm2), a perfusion pump (cyclophosphamide, 19.6 ng/cm2) and on a cytotoxic waste bin cover (gemcitabine, 4.97 ng/cm2). Floors in patient rooms had highest levels of cytarabine (0.12 ng/cm2) and methotrexate (6.38 ng/cm2). Hand wipes were positive for two of 12 samples taken on HS personnel, seven of 18 samples on nurses, and two of 14 samples on pharmacy personnel. A notable proportion of surfaces showed measurable levels of ANPs, with highest concentrations found on surfaces cleaned by HS personnel, who would benefit from appropriate preventive training. As potential sources of worker exposure, several hospital surfaces need to be regularly monitored to evaluate environmental contamination and efficacy of cleaning.


Heavy Water Additive in Formamidinium: A Novel Approach to Enhance Perovskite Solar Cell Efficiency.
Heavy water or deuterium oxide (D2 O) comprises deuterium, a hydrogen isotope twice the mass of hydrogen. Contrary to the disadvantages of deuterated perovskites, such as shorter recombination lifetimes and lower/invariant efficiencies, the serendipitous effect of D2 O as a beneficial solvent additive for enhancing the power conversion efficiency (PCE) of triple-A cation (cesium (Cs)/methylammonium (MA)/formaminidium (FA)) perovskite solar cells from ≈19.2% (reference) to 20.8% (using 1 vol% D2 O) with higher stability is reported. Ultrafast optical spectroscopy confirms passivation of trap states, increased carrier recombination lifetimes, and enhanced charge carrier diffusion lengths in the deuterated samples. Fourier transform infrared spectroscopy and solid-state NMR spectroscopy validate the N-H2 group as the preferential isotope exchange site. Furthermore, the NMR results reveal the induced alteration of the FA to MA ratio due to deuteration causes a widespread alteration to several dynamic processes that influence the photophysical properties. First-principles density functional theory calculations reveal a decrease in PbI6 phonon frequencies in the deuterated perovskite lattice. This stabilizes the PbI6 structures and weakens the electron-LO phonon (Fröhlich) coupling, yielding higher electron mobility. Importantly, these findings demonstrate that selective isotope exchange potentially opens new opportunities for tuning perovskite optoelectronic properties.


Indirect and mitigated effects of pulsed resources on the population dynamics of a northern rodent.
Pulsed resources have significant effects on population and community dynamics in terrestrial ecosystems. Mast seeding is an important resource pulse in deciduous forests; these boom and bust cycles of seed production generate strong lagged population responses by post-dispersal seed predators such as rodents, which then cascade through multiple trophic levels and regulate population dynamics of their predators and prey. However, similar interactions in another major pulsed system, coniferous forests, are inconsistent, and the effects of interannual variation in conifer seed production on many consumer populations are largely unknown. We used large-scale manipulation and intensive monitoring to examine the population dynamics of deer mice (Peromyscus maniculatus) in relation to fall seed production by two northern conifers, white spruce (Picea glauca) and subalpine fir (Abies lasiocarpa). Previous studies have shown that spruce seeds are a preferred food source of mice, while fir seeds are generally avoided if other foods are available. Therefore, we expected that there would be a positive relationship between mouse demography and previous spruce seed production, but no effect of fir mast seeding. Supplementation of a mouse population using spruce seeds indicated that increased fall spruce seed availability can enhance overwinter survival and population densities in the following spring, summer, and fall. However, long-term population monitoring indicated that mouse demography was not positively affected by spruce mast seeding, likely due to strong interspecific competition with the North American red squirrel (Tamiasciurus hudoniscus), a dominant pre-dispersal spruce seed predator. Conversely, we observed an unexpected delayed effect of fir mast seeding, where increased fall fir seed production did not influence overwinter or spring mouse demography, but instead enhanced summer survival, body masses and pregnancy rates of overwintered adults. This led to increased summer population densities and may have been mediated by population responses of invertebrate post-dispersal seed predators to increased fir seed availability. Our results indicate that rodent responses to resource pulses in coniferous forests are more complex than in deciduous environments and reveal previously unobserved direct and indirect consumer-resource dynamics that require further examination. This system is ideal for the large-scale, integrative ecosystem studies that ecologists are encouraged to pursue.


Correlation between tumor invasion and somatostatin receptor subtypes in acromegaly.
The low expression of somatostatin receptor (SSTR) subtypes in somatotropinoma is associated with a poor response to somatostatin analogs (SSAs). However, the correlation between SSTRs and tumor invasion has not yet been clarified. Therefore, the authors aimed to investigate the relationship between SSTRs and tumor invasion, as well as the correlation between tumor invasiveness and pharmacological response to SSAs. A total of 102 patients with acromegaly who underwent surgery between December 2016 and December 2021 at the largest pituitary tumor surgery center in southern China were included in this retrospective study. Patients were divided into the noninvasive tumor group (Knosp grades 0-2 and Hardy-Wilson grade I or II) and invasive group (either Knosp grade 3 or 4 or Hardy-Wilson grade III or IV). The positive response to SSAs was defined by the following criteria after at least 3 months of SSA treatment: 1) ≥ 50% reduction or age- and sex-adjusted normal range of insulin-like growth factor-1 (IGF-1) level; 2) ≥ 80% reduction in or normal range of growth hormone (GH) level; or 3) > 20% reduction in tumor volume. The reference for the normal range of age- and sex-adjusted serum IGF-1 levels was derived from a survey of 2791 healthy adults (1339 males and 1452 females) in China. Demographics and clinical characteristics including tumor size, biochemical assessment, expression levels of SSTRs, and response to preoperative SSAs were compared between the invasive group and noninvasive group. Receiver operating characteristic (ROC) curve analysis was performed to assess the association between SSTR2 and tumor invasion. Compared with the noninvasive group, the invasive group presented with a larger tumor size (9.99 ± 10.41 cm3 vs 3.50 ± 4.02 cm3, p < 0.001), relatively lower SSTR2 expression (p < 0.001), and poorer response to SSAs (36.4% vs 91.7%, p < 0.001). In addition, there was a significant negative correlation between SSTR2 mRNA level and tumor size (r = -0.214, p = 0.031). However, there were no statistically significant differences in the expression of SSTR1, SSTR3, and SSTR5 between the groups. ROC analysis revealed that the low SSTR2 mRNA level was closely associated with tumor invasion (area under the curve 0.805, p < 0.0001). Tumor invasion is negatively correlated with SSTR2 level but is not associated with other SSTR subtypes. Patients with invasive tumors have a poorer response to SSA therapy, which may be due to the low level of SSTR2 expression. Therefore, SSTR2 could be considered as a routine investigative marker for aiding management of postoperative residual tumors.


'Better medicines for children' within the Integrated Management of Childhood Illness framework: a qualitative inquiry in Uganda.
The Integrated Management of Childhood Illnesses is the main approach for treating children in more than 100 low income countries worldwide. In 2007, the World Health Assembly urged countries to integrate 'better medicines for children' into their essential medicines lists and treatment guidelines. WHO regularly provides generic algorithms for IMCI and publishes the Model Essential Medicines List with child-friendly medicines based on new evidence for member countries to adopt. However, the status of 'better medicines for children' within the Integrated Management of Childhood Illnesses approach in Uganda has not been studied. Qualitative interviews were conducted with: two officials from the ministry of health; two district health officials and, 22 health workers from public health facilities. Interview transcripts were manually analyzed for manifest and latent content. Child-appropriate dosage formulations were not included in the package for the Integrated Management of Childhood Illnesses and ministry officials attributed this to resource constraints and lack of initial guidance from the World Health Organization. Underfunding reportedly undercut efforts to: orient health workers; do support supervision and update treatment guidelines to reflect 'better medicines for children'. Health workers reported difficulties in administering tablets and capsules to under-five children and that's why they preferred liquid oral dosage formulations, suppositories and injections. The IMCI strategy in Uganda was not revised to reflect child-appropriate dosage formulations - a missed opportunity for improving the quality of management of childhood illnesses. Funding was an obstacle to the integration of child-appropriate dosage formulations. Ministry of health should prioritize funding for the Integrated Management of Childhood Illnesses and revising the Essential Medicines and Health Supplies List of Uganda, the Uganda Clinical Guidelines and, the Treatment Charts for the Integrated Management of Childhood Illnesses to reflect child-appropriate dosage formulations.


Deletion of IGF-1 Receptors in Cardiomyocytes Attenuates Cardiac Aging in Male Mice.
IGF-1 receptor (IGF-1R) signaling is implicated in cardiac hypertrophy and longevity. However, the role of IGF-1R in age-related cardiac remodeling is only partially understood. We therefore sought to determine whether the deletion of the IGF-1R in cardiomyocytes might delay the development of aging-associated myocardial pathologies by examining 2-year-old male cardiomyocyte-specific IGF-1R knockout (CIGF1RKO) mice. Aging was associated with the induction of IGF-1R expression in hearts. Cardiomyocytes hypertrophied with age in wild-type (WT) mice. In contrast, the cardiac hypertrophic response associated with aging was blunted in CIGF1RKO mice. Concomitantly, fibrosis was reduced in aged CIGF1RKO compared with aged WT hearts. Expression of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, and receptor activator of nuclear factor-κB ligand was increased in aged WT hearts, but this increase was attenuated in aged CIGF1RKO hearts. Phosphorylation of Akt was increased in aged WT, but not in aged CIGF1RKO, hearts. In cultured cardiomyocytes, IGF-1 induced senescence as demonstrated by increased senescence-associated β-galactosidase staining, and a phosphoinositide 3-kinase inhibitor inhibited this effect. Furthermore, inhibition of phosphoinositide 3-kinase significantly prevented the increase in IL-1α, IL-1β, receptor activator of nuclear factor-κB ligand, and p21 protein expression by IGF-1. These data reveal an essential role for the IGF-1-IGF-1R-Akt pathway in mediating cardiomyocyte senescence.


How Religion, Social Class, and Race Intersect in the Shaping of Young Women's Understandings of Sex, Reproduction, and Contraception.
Using a complex religion framework, this study examines how and why three dimensions of religiosity-biblical literalism, personal religiosity, and religious service attendance-are related to young women's reproductive and contraceptive knowledge differently by social class and race. We triangulate the analysis of survey data from the Relationship Dynamics and Social Life study (RDSL) and semi-structured interview data from the National Study of Youth and Religion (NSYR) to identify and explain patterns. From the quantitative data, we find that all three dimensions of religiosity link to young women's understandings of sex, reproduction, and contraception in unique ways according to parental education and racial identity. There is a lack of knowledge about female reproductive biology for young women of higher SES with conservative Christian beliefs (regardless of race), but personal religiosity and religious service attendance are related to increased contraceptive knowledge for young black women and decreased knowledge for young white women. From the qualitative data, we find that class and race differences in the meaning of religion and how it informs sexual behavior help explain results from the quantitative data. Our results demonstrate the importance of taking a complex religion approach to studying religion and sex-related outcomes.


Energy metabolism and intracellular pH in boar spermatozoa.
The effect of energy metabolism on intracellular pH was studied in boar spermatozoa using nuclear magnetic resonance (NMR) spectroscopy and confocal microscopy with the pH-sensitive dye seminaphthorhodafluor (SNARF-1). Freshly ejaculated spermatozoa had a high adenylate energy charge (AEC=0.8), which decreased to 0.6 under aerobic conditions and to 0.2 under anaerobic conditions. Correspondingly, no ATP resonances but high AMP resonance were visible in (31)P-NMR-spectra of the spermatozoa. When an artificial oxygen buffer (Fluosol) and a purpose-built air supply system were used during (31)P-NMR data acquisition, ATP resonances reappeared whereas the AMP resonance disappeared. Boar spermatozoa kept under aerobic conditions have intracellular compartments that differ markedly in pH, as demonstrated by both (31)P-NMR spectroscopy and confocal microscopy. Using confocal microscopy, the midpiece of the flagellum in which all mitochondria are located was identified as an acidic compartment (pH(i-mp) 6.7). The intracellular pH of both the head (pH(i-h)) and the long principal piece of the flagellum (pH(i-pp)) were 7.2 and, thus, only slightly below the extracellular pH (pH(e) 7.3). Storage of spermatozoa in a glucose-free medium at 15 degrees C when they are immotile slowly shifted the pH(i-mp) from 6.7 to 6.9 within 20 h, whereas pH(i-h) and pH(i-pp) remained unchanged (pH 7.1-7.2). When glucose was present in the medium, all visible compartments of the spermatozoa as well as the medium were acidified to pH 6.2 within 20 h. Under these conditions a resonance at 4.8 mg kg(-1) appeared representing glycerol 3-phosphate.


Extrahepatic portal hypertension: long-term results of surgical treatment.
Long-term results of surgical treatment were analysed in 42 patients with extrahepatic portal hypertension treated in the Department of Surgery, Institute of Haematology in Warsaw in the period 1971-1987. In all, 71 operations were carried out, and 20 patients were treated by endoscopic sclerotherapy of oesophageal varices. Recurrence of haemorrhage was found in 6 out of 11 patients 54% after venous shunting, in 13 out of 17 patients (76%) after treatment by ligation of oesophageal varices and in 32 out of 35 patients (91%) after splenectomy. Following repeated sclerotherapy of oesophageal varices, recurrence of haemorrhage occurred in 3 out of 20 patients (15%). During 17 years four deaths occurred (10%) none of which was due to haemorrhage from oesophageal varices. The authors conclude that the method of repeated sclerotherapy is presently the most effective way of preventing haemorrhage from oesophageal varices and consider this form of management as the treatment of choice in patients with extrahepatic portal hypertension.


Regenerative capacity of skeletal muscle.
The aim of this review is to highlight advances in the field of skeletal muscle regeneration that have been made in the last year. Studies have increased our understanding of the activation of satellite cells within their niche on the muscle fibre, the contribution of satellite cell-derived muscle precursor cells to skeletal muscle regeneration and the reduction of satellite cell function in old muscle. Although other stem cells, either bone marrow derived or present within skeletal muscle or other tissues, do contribute to muscle regeneration, recent studies have highlighted that this is at best minimal compared with the ability of satellite cells to regenerate skeletal muscle. The effect of the host muscle environment has been shown to have a profound effect on skeletal muscle regeneration. Age and denervation have a detrimental effect and certain types of muscle injury a positive effect. Work continues on the effect of growth factors on muscle cell lines in vitro and muscle regeneration in vivo. Recent work has focused on the contribution of satellite-cell derived muscle precursor cells and other stem cells to skeletal muscle regeneration. The muscle environment has a profound effect on the regenerative capacity of resident and implanted cells. Muscle regeneration may be optimized by using the best stem cell population and by modifying the host muscle environment.


Mucinous carcinoma occurring in the male breast.
Male breast carcinoma is an uncommon neoplasm, accounting for 0.6% of all breast carcinomas. Invasive ductal carcinoma of no special type is the most common type of male breast carcinoma, and mucinous carcinoma occurring in the male breast is extremely rare. In the present study, we report a case of mucinous carcinoma of the male breast and discuss the clinicopathological features of this type of tumor. A 63-year-old Japanese male presented with a gradually enlarged nodule in the right breast. The resected breast specimen revealed pure mucinous carcinoma and immunohistochemical analyses demonstrated that tumor cells were positive for estrogen receptor (ER), but negative for progesterone receptor (PgR). In addition, HER2 expression was not amplified. Pure mucinous carcinoma is generally associated with a low incidence of lymph node or distant metastases, and excellent disease-free survival in females. However, certain cases of this type of tumor with axillary lymph node metastasis in the male breast have been reported. In addition, the immunoprofiles of mucinous carcinoma in males are fundamentally the same as those in females. More than 90% of cases show positive immunoreactivity for ER and/or PgR, and HER2 expression is not amplified. However, it has been reported that breast cancer in males is more frequently positive for ER than in females, and has less HER2 overexpression. The high rate of hormone receptor-positive breast cancer in males is considered to be due to similar conditions as those in breast cancer in postmenopausal women. The pathogenesis of male breast carcinoma, including mucinous carcinoma, remains unclear; therefore, additional clinicopathological studies are required.


Role of serum CXCL9 and CXCL13 in predicting infection after kidney transplant: A STROBE study.
Chemokines are majorly involved in inflammatory and immune responses. The interferon-γ-inducible chemokines C-X-C motif chemokines 9 and 10 (CXCL9 and CXCL10) are considerably associated with Th1 cells and monocytes, and their expression levels rapidly increase during the early episodes of renal allograft rejection and various infectious diseases. CXCL13 is one of the most potent B-cell and T follicular helper-cell chemoattractants. The expression of CXCL13 in the presence of infection indicates an important chemotactic activity in multiple infectious diseases. C-C motif chemokine ligand 2 (CCL2) can attract monocytes and macrophages during inflammatory responses. However, there are no studies on the role of these chemokines in posttransplant infection in kidney transplant recipients.In this study, CXCL9, CXCL10, CXCL13, and CCL2 were analyzed using the Bio-Plex suspension array system before transplant and 30 days after transplant.The serum levels of CXCL9 and CXCL13 30 days after kidney transplant were associated with infection within 1 year after transplant (P = .021 and P = .002, respectively). The serum levels of CXCL9 and CXCL13 before surgery and those of CCL2 and CXCL10 before and after surgery were not associated with infection within 1 year after transplant (P > .05). The combination of postoperative day (POD) 30 CXCL9 and postoperative day 30 CXCL13 provided the best results with an area under the curve of 0.721 (95% confidence interval, 0.591-0.852), with a sensitivity of 71.4% and specificity of 68.5% at the optimal cutoff value of 52.72 pg/mL.As important chemokines, CXCL9 and CXCL13 could be used to predict the occurrence of infection after kidney transplant.


Inosiplex: a novel treatment in rheumatoid arthritis?
In an open study inosiplex, a new synthetic immunomodulatory drug, was given to 15 patients with rheumatoid arthritis (RA) 3 g daily until clinical improvement occurred and then tapered. Nine of 15 patients experienced clinical benefit evidenced by a reduction of morning stiffness, fewer tender joints, decreased proximal interphalangeal joint circumference, and decreased sedimentation rate and fibrinogen level. Three patients responded rapidly to inosiplex (in two weeks) and a clear cut improvement was noticed within 1 month by all the responders. Two patients showed an exacerbation of the disease. No toxic drug effect was noticed. Although the mode of action of inosiplex in RA appears unclear, its rapidly of action and high rate of response should encourage further study of its use in the treatment of RA.


Quantitative prediction of ionization effect on human skin permeability.
Although skin permeability of an active ingredient can be severely affected by its ionization in a dose solution, most of the existing prediction models cannot predict such impacts. To provide reliable predictors, we curated a novel large dataset of in vitro human skin permeability coefficients for 322 entries comprising chemically diverse permeants whose ionization fractions can be calculated. Subsequently, we generated thousands of computational descriptors, including LogD (octanol-water distribution coefficient at a specific pH), and analyzed the dataset using nonlinear support vector regression (SVR) and Gaussian process regression (GPR) combined with greedy descriptor selection. The SVR model was slightly superior to the GPR model, with externally validated squared correlation coefficient, root mean square error, and mean absolute error values of 0.94, 0.29, and 0.21, respectively. These models indicate that Log D is effective for a comprehensive prediction of ionization effects on skin permeability. In addition, the proposed models satisfied the statistical criteria endorsed in recent model validation studies. These models can evaluate virtually generated compounds at any pH; therefore, they can be used for high-throughput evaluations of numerous active ingredients and optimization of their skin permeability with respect to permeant ionization.


Prisons. Vancouver Conference Review.
Interesting and innovative programmes to tackle the problems associated with HIV/AIDS in prison have been and are being tried throughout the world. However, a number of political, legal and cultural barriers exist hindering the development of effective prevention and care and treatment approaches.


FIO2 and acute respiratory distress syndrome definition during lung protective ventilation.
PaO2/FIO2 ratio (P/F) is the marker of hypoxemia used in the American-European Consensus Conference on lung injury. A high FIO2 level has been reported to variably alter PaO2/FIO2. We investigated the effect of high FIO2 levels on the course of P/F in lung protective mechanically ventilated patients with acute respiratory distress syndrome. Prospective, controlled, interventional study. University teaching French medical intensive care unit. Twenty-four patients with acute respiratory distress syndrome having P/F between 100 and 200 mm Hg at FIO2 0.5 received low-volume controlled ventilation (V(T) = 6 mL/kg predicted body weight) with a positive end-expiratory pressure at 2 cm H2O above the lower inflection point if present, or 10 cm H2O. The following FIO2 levels were applied randomly for 20 mins: 0.5, 0.6, 0.7, 0.8, 0.9, and 1. Increasing FIO2 above 0.7 was associated with a significant increase in P/F (p < 0.001). The mean P/F change between FIO2 0.5 and 1 (Delta P/F) was 47% +/- 35%. Sixteen patients (67%) had a P/F >200 at FIO2 1 whereas P/F was <200 at FIO2 0.5. Venous admixture (Q(VA)/Q(T)) decreased linearly for each FIO2 step (p < 0.001). The Q(VA)/Q(T) change between FIO2 0.5 and 1 was strongly correlated with Delta P/F (r = 0.84). Delta P/F was higher in patients with true shunt <30% (64% [54-93]) than in those with shunt >30% (20% [10-36]; p = 0.003). The P/F ratio increased significantly with a FIO2 >0.7. P/F variation, induced by a switch from FIO2 0.5 to 1, was responsible for two thirds of patients changing from the acute respiratory distress syndrome to the acute lung injury stage of the American-European Consensus Conference definition. FIO2 should be carefully defined for the screening of lung-injured patients.


Screening and diagnosis of prediabetes: where are we headed?
It is currently estimated that more than 300 million people have impaired glucose tolerance (IGT), putting them at increased risk for type 2 diabetes mellitus (T2DM) and its adverse consequences. In addition, many others are at risk on the basis of a family history of T2DM, obesity, dyslipidaemia and hypertension. Screening for risk should include both blood glucose testing in high-risk populations and prescreening (e.g. by questionnaire, waist circumference measurement) to identify high-risk individuals in overall low-risk populations; these individuals should then undergo glucose testing. Fasting plasma glucose measurement cannot diagnose IGT; the preferred definite test for diagnosis is oral glucose tolerance testing.


[Analysis of needlestick injuries and depression among the female medical staff in a city district in 2018].
Objective: To investigate needlestick injuries and depression among the female medical staff in a city district. Methods: Using cross-sectional survey methods, female medical staff from selected sixteen hospitals voluntarily participated in questionnaire survey on APP of mobile phone. They Data were uploaded assessment platform, saved by Excel, and analysed by SPSS 22.0 statistical software. Results: The lasted year, Incidence of needlestick injuries was 11.28%. Incidence of needlestick injuries was respectively 5.2%, 9.1% and 16.3% in Class-I hospital, Second-class Hospital and three levels of hospitals(χ(2)=28.900, P<0.01). And 6.3% Resting no more than 10 days of Incidence of needlestick injuries was 12.5%, others was 6.3%.Night shift no more than 5 days of Incidence of needlestick injuries was 8.5%, others was 15.1%. The rate of not less than 14 of BDI was respectively 18.6%, 29.1% and 32.7% in Class-I hospital, Second-class Hospital and three levels of hospitals (χ(2)=23.843, P<0.01). In recent one year, the rate of medical staff who have taken annual leave less than 10 days and higher than 10 days scoring over 14 in the Beck(Beck depression inventory, BDI) survey are respectively 29.1% and 17.8% (χ(2)=10.710, P<0.01). In recent one year, the rate of medical staff who worked in night shift less than 5 days and higher than 5 days each month scoring over 14 in the Beck survey are respectively 23.5% and 31.7%(χ(2)=8.886, P<0.01). In recent one year, the rate of medical staff who had needle injury and non-needle injury scoring over 14 in the Beck survey are respectively 35% and 25%(χ(2)=4.782, P<0.05). Conclusion: The needle injury rate, high score rate in Beck survey among the medical staff increased when the level of the hospital they worked for increased. Medical staff should improve their method of rest.


Moderate-intensity treadmill running promotes expansion of the satellite cell pool in young and old mice.
Satellite cells, the myogenic progenitors located at the myofibre surface, are essential for the repair of adult skeletal muscle. There is ample evidence for an age-linked decline in the number of satellite cells and performance in limb muscles. Hence, an effective means of activating and expanding the satellite cell pool may enhance muscle maintenance and reduce the impact of age-associated muscle deterioration (sarcopaenia). Accordingly, in the present study, we explored the beneficial effects of endurance exercise on satellite cells in young and old mice. Animals were subjected to an 8-week moderate-intensity treadmill-running approach that does not inflict apparent muscle damage (0° inclination, 11.5 m·min(-1) for 30 min·day(-1) , 6 days·week(-1) ). Myofibres of extensor digitorum longus muscles were then isolated from exercised and sedentary mice and used for monitoring the number of satellite cells, as well as for harvesting individual satellite cells for clonal growth assays. We specifically focused on satellite cell pools of single myofibres, with the view that daily wear of muscles probably affects individual myofibres rather than causing overall muscle damage. We found an expansion of the satellite cell pool in the exercised groups compared to the sedentary groups, with the same increase (~ 1.6-fold) in both ages. The results of the present study are in agreement with our findings obtained using rat gastrocnemius, indicating the consistent effect of exercise on satellite cell expansion in limb muscles. The experimental paradigm established in the present study is useful for investigating satellite cell dynamics at the myofibre niche, as well as for broader investigations of the impact of physiologically and pathologically relevant factors on adult myogenesis.


Modified Esthetic Splint Design for Management of Multiple Traumatic Injuries in Children: A Case Report.
Traumatic injuries to the dento-alveolar structures are emergencies that compromise the quality of life of the patients. In addition to symptomatic management, definitive functional restoration and suitable rehabilitation becomes a major treatment objective in such cases. The dynamics of the traumatic forces may cause multiple injuries of different grades to the oral and para-oral structures, which makes comprehensive management a greater challenge to the dentist. The present case report elaborates a modified esthetic splint designed to treat multiple dental injuries in children, which can promote healing, restore optimal functionality along with esthetic rehabilitation to psychologically benefit the child during the time of recovery.


Zoledronic Acid after Treatment with Denosumab is Associated with Bone Loss within 1 Year.
Bone mineral density (BMD) declines when zoledronic acid (ZA) is administered. This case series describes the patterns of change in BMD when 1 or 2 doses of ZA are administered after denosumab. Twelve patients who received at least 2 doses of denosumab followed by at least 1 dose of ZA and who had a dual energy X-ray absorptiometry (DXA) scan at the end of denosumab and 1 year after the first dose of ZA were included. We excluded patients with bone cancer or conditions affecting bone metabolism, including hyperparathyroidism, rickets, osteogenesis imperfecta, rheumatologic disorders, fibrous dysplasia, Paget's disease of bone, untreated hyperthyroidism, chronic kidney disease, liver cirrhosis, malabsorption, ongoing corticosteroid therapy, and aromatase inhibitor use. There was a significant decline in BMD at the femoral neck within 1 year of the first ZA dose and a non-significant downward trend in the hip and lumbar spine. This trend was more severe in patients with osteoporosis at the time of drug transition. No increase in clinical vertebral fractures was observed. BMD seemed to stabilize in a smaller number of patients who received a second dose of ZA and had a DXA scan 1 year later. A single dose of ZA administered approximately 6 months after denosumab leads to some BMD loss, mostly within 1 year of ZA administration, particularly in patients with osteoporosis at the time of denosumab discontinuation.


Changes in the abundance of androgen receptor isotypes: effects of ligand treatment, glutamine-stretch variation, and mutation of putative phosphorylation sites.
The SDS-polyacrylamide gel electrophoresis (SDS-PAGE) migration pattern of wild-type and mutated human androgen receptors (ARs) expressed in COS-1 cells was analyzed. In the absence of hormone, the wild-type AR migrated as a closely spaced 110-112 kDa doublet. Alkaline phosphatase treatment resulted in a single 110 kDa band showing that the 112 kDa upshift reflects receptors phosphorylation. Deletion of the N-terminal amino acids 46-101 or 100-142 resulted in mutant ARs migrating as single protein bands. Three consensus phosphorylation sites in this region were substituted, and the resulting mutated proteins were analyzed. Two Ser-Pro-directed kinase consensus sites at positions Ser-80 and Ser-93 were both necessary for the AR 112 kDa upshift. Substitution of the putative casein kinase II Ser-118 site had no effect on the AR migration pattern. Surprisingly, deletion of the glutamine repeat, located directly N-terminal of the Ser-Pro sites, resulted also in an AR single form. Lengthening of the glutamine repeat caused an increase in the spacing between the two isotypes of the doublet, showing that the number of glutamine residues determines the extent of the upshift. Hormone treatment induced an extra isotype with an apparent molecular mass of 114 kDa, resulting in a 110-112-114 kDa AR triplet. The hormone-induced upshift was dependent on the Ser-80 consensus phosphorylation site. Mutations in the DNA binding domain caused a different distribution of receptor protein over the three AR isotypes.(ABSTRACT TRUNCATED AT 250 WORDS)


Deciphering the phosphorylation "code" of the glucocorticoid receptor in vivo.
The glucocorticoid receptor (GR) is phosphorylated at multiple serine residues in a hormone-dependent manner, yet progress on elucidating the function of GR phosphorylation has been hindered by the lack of a simple assay to detect receptor phosphorylation in vivo. We have produced antibodies that specifically recognize phosphorylation sites within human GR at Ser(203) and Ser(211). In the absence of hormone, the level of GR phosphorylation at Ser(211) was low compared with phosphorylation at Ser(203). Phosphorylation of both residues increased upon treatment with the GR agonist dexamethasone. Using a battery of agonists and antagonists, we found that the transcriptional activity of GR correlated with the amount of phosphorylation at Ser(211), suggesting that Ser(211) phosphorylation is a biomarker for activated GR in vivo. Mechanistically, the kinetics of Ser(203) and Ser(211) phosphorylation in response to hormone differed, with Ser(211) displaying a more robust and sustained phosphorylation relative to Ser(203). Analysis of GR immunoprecipitates with phospho-GR-specific antibodies indicated that the receptor was phosphorylated heterogeneously at Ser(203) in the absence of hormone, whereas in the presence of hormone, a subpopulation of receptors was phosphorylated at both Ser(203) and Ser(211). Interestingly, biochemical fractionation studies following hormone treatment indicated that the Ser(203)-phosphorylated form of the receptor was predominantly cytoplasmic, whereas Ser(211)-phosphorylated GR was found in the nucleus. Likewise, by immunofluorescence, Ser(203)-phosphorylated GR was located in the cytoplasm and perinuclear regions of the cell, but not in the nucleoplasm, whereas strong phospho-Ser(211) staining was evident in the nucleoplasm of hormone-treated cells. Our results suggest that differentially phosphorylated receptor species are located in unique subcellular compartments, likely modulating distinct aspects of receptor function.


Traumatic intracerebral haematoma: complication of skull caliper traction. Case report.
Recently, a unique case of traumatic intracerebral haematoma complicating the insertion of skull calipers, has been observed. It is assumed it was due to: 1. the accidental penetration of the burr into the skull, while making the insertion hole for the caliper; 1. the failure to grip the skull with the special metal sleeve, the Blackburn skull caliper is provided with, so that the end plates were free to move in and out of the skull in this restless patient. The correct diagnosis was made only after severe uncal herniation had developed. The reasons for missing the correct diagnosis within useful time for proper treatment are considered to be: 1. carotid angiography performed too early in the process of haematoma formation: 2. the vascular displacements were only slight and not fully diagnostic; 3. a recognized complication, extradural haematoma, had already been excluded.


Genetic determinants of Vitamin D deficiency in the Middle Eastern Qatari population: a genome-wide association study.
Epidemiological studies have consistently revealed that Vitamin D deficiency is most prevalent in Middle Eastern countries. However, research on the impact of genetic loci and polygenic models related to Vitamin D has primarily focused on European populations. We conducted the first genome-wide association study to identify genetic determinants of Vitamin D levels in Middle Easterners using a whole genome sequencing approach in 6,047 subjects from the Qatar Biobank (QBB) project. We performed a GWAS meta-analysis, combining the QBB cohort with recent European GWAS data from the UK Biobank (involving 345,923 individuals). Additionally, we evaluated the performance of European-derived polygenic risk scores using UK Biobank data in the QBB cohort. Our study identified an association between a variant in a known locus for the group-specific component gene (GC), specifically rs2298850 (p-value = 1.71 × 10-08, Beta = -0.1285), and Vitamin D levels. Furthermore, our GWAS meta-analysis identified two novel variants at a known locus on chromosome 11, rs67609747 and rs1945603, that reached the GWAS significance threshold. Notably, we observed a moderately high heritability of Vitamin D, estimated at 18%, compared to Europeans. Despite the lower predictive performance of Vitamin D levels in Qataris compared to Europeans, the European-derived polygenic risk scores exhibited significant links to Vitamin D deficiency risk within the QBB cohort. This novel study reveals the genetic architecture contributing to Vitamin D deficiency in the Qatari population, emphasizing the genetic heterogeneity across different populations.


Quantitative optimization of reverse transfection conditions for 384-well siRNA library screening.
A necessary step in all small interfering RNA (siRNA) library screens is introduction of the siRNA into cells. We describe the use of a commercially available glyceraldehyde 3-phosphate dehydrogenase enzymatic assay that is capable of simultaneously assessing the efficiency of siRNA delivery into cells and the lipid toxicity. This assay has been modified to work in 384-well plates using reverse transfection. The assay is fast, inexpensive, and quantitative. Conditions identified as optimal using this technique have been employed successfully in library screens.


Patterns of pediatric supracondylar humerus fractures.
The Wilkins-modified Gartland classification of pediatric supracondylar humerus fractures does not consider coronal or sagittal obliquity. The purposes of our study were (1) to identify and describe fracture characteristics with unique properties and (2) to propose a fracture classification system that can be reproduced reliably. We retrospectively studied 203 consecutive displaced pediatric extension-type supracondylar humerus fractures treated operatively from January 1998 to January 2003. Fracture characteristics (eg, coronal and sagittal obliquity, postoperative alignment), type of surgical treatment, outcome, and complications were assessed and analyzed statistically with Student t test and a receiver operating characteristic curve. Significance was defined as P < 0.05. We incorporated significant cutoff values for fracture obliquity into our classification scheme and tested the classification's interobserver and intraobserver reliability. We identified 4 coronal (typical transverse, medial oblique, lateral oblique, and high fractures) and 2 sagittal (low sagittal and high sagittal) subtypes with significantly different characteristics and outcome. Compared with fractures with coronal obliquity of less than 10 degrees, fractures with coronal obliquity of 10 degrees or greater were associated with significantly more comminution and rotational malunion. Compared with fractures with sagittal obliquity of less than 20 degrees, fractures with sagittal obliquity of 20 degrees or greater were associated with a significantly higher incidence of additional injuries and were more likely to result in extension malunion. Analysis of the interobserver and intraobserver reliability for our system identified correlation coefficients ranging from 0.772 to 0.907 and 0.860 to 0.899, respectively. Because pediatric extension-type supracondylar humerus fractures vary significantly in terms of characteristics, identification of sagittal oblique and coronal oblique angles may have an important role in surgical decision making and may impact outcomes.


Polypeptide composition and organization of the sea urchin extraembryonic hyaline layer.
The protein composition and organization of the sea urchin extraembryonic hyaline layer was examined. Hyalin and a polypeptide of 45 kilodaltons (kDa) were present in hyaline layers isolated from 1-h-old embryos through to the pluteus larva stage. In contrast, several polypeptide species ranging in size from 175 to 32 kDa either decreased in amount or disappeared from the layer as embryonic development proceeded. Concomitant with the changes in composition, hyaline layers became progressively more refractory to dissolution by washing in Ca2+, Mg2(+)-free seawater. Incubation of intact layers, isolated from 1-h-old embryos, with proteinase K resulted in the selective digestion of hyalin and was accompanied by release of the 45-kDa polypeptide from the layers. Washing intact layers in 20 mM Tris (pH 8.0) also resulted in the selective removal of hyalin and the 45-kDa polypeptide. The Ca2(+)-precipitable protein hyalin, alone among the hyaline layer polypeptides, bound the Ca2(+)-antagonist ruthenium red. These results suggest a structural organization within the hyaline layer that is both heterogenous and dynamic throughout embryonic development.


Changing patterns of causation and the use of transplantation in the United kingdom.
Acute liver failure (ALF) is a rare condition in the United Kingdom. Comprehensive supportive intensive care of extra-hepatic organ failure and the early recognition of and use of transplantation for those who will not survive form the cornerstone of its management. Over the last 30 years there has been a reduction in the proportion of cases resulting from viral and seronegative hepatitis, and a progressive rise in those resulting from severe acetaminophen-induced hepatotoxicity. The latter cases mostly result from deliberate self-poisoning and formed the major cause of ALF hospital admissions and indication for emergency liver transplantation. The increasing misuse of acetaminophen has paralleled a rise in sales and greater availability of the drug. Introduction of legislation to restrict sales of acetaminophen has been followed by a fall in hospital admissions resulting from self-poisoning, a 20% reduction in deaths, and a 50% fall in the number of patients undergoing emergency liver transplantation. The reduction in acetaminophen-related ALF has been paralleled by an increase in the number of transplants performed in ALF of nonacetaminophen etiologies.


[Anxiety in neurological practice].
Anxiety and related disorders are the most common type of mental disorders in both the general population and the neurological clinic. A current typology of anxiety disorders includes panic disorder, agoraphobia, simple (specific) phobias, social anxiety disorder, and generalized anxiety disorder. Anxiety disorders often accompany diseases of the nervous system, worsen their course and impede treatment, and the degree of anxiety usually corresponds to the severity of neurological symptoms. Anxiety may precede brain diseases, but the answer to the question of whether it contributes to these diseases or predicts them or can be an early manifestation of these diseases requires further studies. Modern approaches to the treatment of anxiety involve the use of benzodiazepines, antidepressants, some mood stabilizers, antipsychotics, as well as psychological interventions.


Naloxone and epinephrine are equally effective for cardiopulmonary resuscitation in a rat asphyxia model.
It is not known whether naloxone is as efficacious as epinephrine during cardiopulmonary resuscitation (CPR). The aim of the study was to compare the effects of naloxone and epinephrine on the outcomes of CPR following asphyxial cardiac arrest in rats. Cardiac arrest was induced with asphyxia by clamping the tracheal tubes. Twenty-four Sprague-Dawley rats were randomized prospectively into a saline group (treated with normal saline, 1 ml intravenously, n = 8), an epinephrine group (treated with epinephrine, 0.04 mg/kg intravenously, n = 8) or a naloxone group (treated with naloxone, 1 mg/kg intravenously, n = 8) in a blind fashion during resuscitation after asphyxial cardiac arrest. After 5 min of untreated cardiac arrest, conventional manual CPR was started and each drug was administered at the same time. The rates of restoration of spontaneous circulation (ROSC) were one of eight (12.5%), seven of eight (87.5%) and seven of eight (87.5%) in the saline, epinephrine and naloxone groups, respectively. The rates of ROSC in the epinephrine and naloxone groups were equal and significantly greater than that in the saline group (P = 0.01 and P = 0.01, respectively). The administration of naloxone or epinephrine alone may increase the resuscitation rate, and both drugs are equally effective for CPR in a rat asphyxia model. However, the mechanism by which naloxone produces its efficacy during CPR remains unclear and further experimentation will be necessary.


Differential effects of static and dynamic compression on meniscal cell gene expression.
Cells of the meniscus are exposed to a wide range of time-varying mechanical stimuli that may regulate their metabolic activity in vivo. In this study, the biological response of the meniscus to compressive stimuli was evaluated in vitro, using a well-controlled explant culture system. Gene expression for relevant extracellular matrix proteins was quantified using real-time RT-PCR following a 24 h period of applied static (0.1 MPa compressive stress) or dynamic compression (0.08-0.16 MPa). Static and dynamic compression were found to differentially regulate mRNA levels for specific proteins of the extracellular matrix. Decreased mRNA levels were observed for decorin ( approximately 2.1 fold-difference) and type II collagen ( approximately 4.0 fold-difference) following 24 h of dynamic compression. Decorin mRNA levels also decreased following static compression ( approximately 4.5 fold-difference), as did mRNA levels for both types I ( approximately 3.3 fold-difference) and II collagen ( approximately 4.0 fold-difference). Following either static or dynamic compression, mRNA levels for aggrecan, biglycan and cytoskeletal proteins were unchanged. It is noteworthy that static compression was associated with a 2.6 fold-increase in mRNA levels for collagenase, or MMP-1, suggesting that the homeostatic balance between collagen biosynthesis and catabolism was altered by the mechanical stimuli. These findings demonstrate that the biosynthetic response of the meniscus to compression is regulated, in part, at the transcriptional level and that transcription of types I and II collagen as well as decorin may be regulated by common mechanical stimuli.


Response of cultured mammalian cells to diphtheria toxin. 3. Inhibition of protein synthesis studied at the subcellular level.
Diphtheria toxin inhibited protein synthesis in intact KB cells. The action of the toxin upon the cell did not result in disaggregation of polyribosomes, or in impairment of their ability to function in protein synthesis. A reduction in single ribosomes and a concomitant increase in polyribosomes did result from the action of toxin. Nascent peptides were not cleaved from polyribosomes by the action of toxin, but treatment of fully intoxicated cells with puromycin resulted in cleavage of these peptides, and caused accelerated polyribosome breakdown. Our data indicated that the toxin must enter the cell to exert its effect. The component or components sensitive to toxin were localized in the 100,000 x g supernatant fraction of cytoplasmic extracts. When extracts from intoxicated cells were treated with nicotinamide, a significant proportion of their capacity to synthesize protein was restored. The specificity of this reaction suggested that nicotinamide adenine dinucleotide is involved in the action of toxin in the intact cell, and that one component inactivated by toxin is soluble transferase II.


In vivo activity of cationic immune stimulating complexes (PLUSCOMs).
A particulate vaccine delivery system consisting of cationic ISCOM derivatives (PLUSCOMs) was compared to classic anionic ISCOMs with regard to antigen attachment and ability to elicit in vivo T cell responses against a model protein antigen (ovalbumin [OVA]). ISCOMs did not incorporate hydrophilic OVA whilst OVA readily adsorbed onto PLUSCOMs with increasing adsorption at higher protein concentrations. The zeta-potential of PLUSCOMs significantly decreased with increasing protein load, suggesting neutralization of the cationic charge upon absorption of the anionic OVA. Antigen-specific CD8 T cell responses were demonstrated in mice vaccinated with either PLUSCOMs or ISCOMs. Ex vivo restimulation of harvested T cells demonstrated that cells isolated from PLUSCOM and ISCOM vaccinated mice responded to the secondary OVA challenge more efficiently than mice vaccinated with OVA in solution. Restimulated cells from the mice vaccinated with particulate vaccines produced significantly more INF-gamma. Therefore PLUSCOMs are as effective as classic ISCOMs in inducing antigen-specific CD8 T cell responses and have advantages with regard to the incorporation of purified anionic antigens.


Key factors of therapeutic effects for surgery in patients with cirrhotic portal hypertension.
In the clinical management of cirrhotic portal hypertension, surgery is often necessary; however, the operative mortality rate is high. Data from 161 patients, who underwent surgery for cirrhotic portal hypertension, were analyzed, and 24 potential predictors of surgical outcome were assessed. A Kruskal-Wallis rank sum test was used for single-factor comparisons, and multivariate logistic regression for multifactor comparisons to identify key factors for poor surgical outcomes and calculate their scores. Six predictors of poor surgical outcomes were identified: postoperative bleeding within 30 h of > 2 L, with a score of 3; severe liver atrophy (an anteroposterior diameter of the left lobe of ≤ 55 mm and an oblique diameter of the right lobe ≤ 110 mm), with a score of 3; a base excess of <-3 mmol/L, with a score of 3; a platelet count of <3 T/L, with a score of 2; an amount of intraoperative bleeding of > 2 L, with a score of 2; and a red blood cell count of < 3 G/L, with a score of 1. For patients with good outcome (n = 147), all patients had a score of ≤ 3, except one patient who had a score of 4. With respect to patients who died (n = 14), all had a score of ≥ 5, except one patient who had a score of 4. A significant difference was observed between the two groups (p < 0.05). The mortality was 100% in patients with a score of ≥ 7. Six key factors for poor surgical outcomes were identified in this study. Operative mortality appears to be significantly increased in patients with a score of 5-6. Surgery should be contraindicated in patients with a score of ≥ 7. To reduce mortality, close attention should be paid to preoperative and intraoperative treatment and prevention to achieve a score of < 4.


Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary heart disease 2 trial (CE-MARC 2): a prospective, multicenter, randomized trial of diagnostic strategies in suspected coronary heart disease.
A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large-scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance. CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance-guided care, single-photon emission computed tomography-guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines-based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed. The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation.


A method for reconstructing patterns of somatosensory cerebral cortical activity.
An interactive graphics package was developed in order to acquire, display, and manipulate images of cerebral cortical autoradiographic data. The primary purpose for development of the system was to reconstruct accurate 2-dimensional maps of the functional activity within the somatosensory cerebral cortex. A Datacube Q-bus graphics module (QVG/QAF-123) was interfaced with the Micro PDP-11/23 to accept a standard RS170 video input signal, and autoradiographs of serial sections (each 20 microns thick) of a cerebral cortex were digitized individually to 768 X 512 X 8 bit resolution. Input look-up tables were used to standardize the autoradiographic data. Boundaries of the somatosensory cortex were entered (with a Summagraphics MM 1201 digitizer), and the image data was stored on disk file (a method of data compression was devised). A method for segmenting the image data for many (sequential) sections was developed that provided arrays from which the maps were generated. Thresholding, histogram equalization, edge detection and edge enhancement, and filters in both the spatial and frequency domains were employed to process the images of the maps. Plots of optical density values along any axis of the maps and gray level histograms of any map region could also be generated. Maps made by the described method are much higher in resolution than those produced by traditional (manual) methods, and permit analysis of the reconstructions in both the frequency and spatial domains.


Dietary Acid Load Is Not Associated with Serum Testosterone in Men: Insights from the NHANES.
The dietary acid load (DAL) is a novel marker of overall diet quality, which has been associated with overweight, type 2 diabetes and altered glucocorticoid secretion. A potential association with sex hormones is thus not inconceivable. We investigated whether DAL was associated with serum total testosterone concentrations of men in the National Health and Nutrition Examination Survey. The DAL scores, including the potential renal acid load (PRAL) and net endogenous acid production (NEAP), were estimated and compared between participants with low and normal testosterone levels. The investigated sample encompassed n = 377 males with a mean age of 49.50 years. Approximately 73% of the sample were of Non-Hispanic White origin. None of the examined DAL scores showed significant associations with serum testosterone levels. We observed no significant differences in the crude DAL scores between individuals with low testosterone levels and individuals with normal testosterone levels. Multivariate regression models adjusting for covariates confirmed the lack of associations between the PRAL and serum testosterone. Our results are of particular importance for those individuals who wish to lower their DAL in light of the presumable health effects of a more alkaline diet. Our data suggest that diet modifications toward a lower intake of animal protein and refined grains (which consecutively translates into a lower DAL) may not negatively affect men's testosterone levels.


High-temperature and pressure-induced ferroelectricity in hydrogen-bonded supramolecular crystals of anilic acids and 2,3-di(2-pyridinyl)pyrazine.
Cocrystallization of anilic acids (H2xa) and 2,3-di(2-pyridinyl)pyrazine (dppz) affords a variety of molecular geometries, including hydrogen-bonding and supramolecular structures. Proton-transferred 1:1 salts of [H-dppz][Hca] and [H-dppz][Hba] (H2ca = chloranilic acid, H2ba = bromanilic acid) were found to host room-temperature ferroelectricity with a spontaneous polarization of 3-4 μC/cm(2) along the hydrogen-bonded chains. Compared with the Curie points of other supramolecular ferroelectrics, those of the salts are relatively high (402 K and >420 K, respectively) because of the elongated hydrogen bonds, which stabilize the proton-ordered state against thermal agitation. In addition to the ferroelectric black (α) form, dppz and H2ba gave two different crystal forms with a 2:3 ratio: the brown β form of [H(1.5)-dppz]2[Hba]3 and the brownish-red γ form of [H-dppz]2[Hba]2[H2ba]. Mixed solutions of dppz with the less acidic fluoranilic acid (H2fa) exhibit valence instability; the H2fa molecules remain mostly neutral in absolute ethanol, whereas methanol (MeOH) solution apparently increases the deprotonated Hfa(-) content. Crystallizations of these solutions gave a neutral [dppz][H2fa] cocrystal and ionic [H-dppz(+)][Hfa(-)]·MeOH salt, respectively. The ferroelectricity induced by a modest hydrostatic pressure corroborates the conclusion that the ionic state with a dipolar [H-dppz(+)][Hfa(-)] chain is energetically close to the nonpolar neutral ground state of the [dppz][H2fa] crystal.


Screening, brief intervention, and referral for alcohol use in adolescents: a systematic review.
Alcohol use by adolescents is widespread and is connected to a number of negative health and social outcomes. Adolescents receiving emergent care for injuries are often linked with risky use of alcohol. The trauma system has widely adopted the use of screening, brief intervention, and referral to treatment (SBIRT) for preventing alcohol-related injury recidivism and other negative outcomes. The purpose of this article is to review the evidence around SBIRT with adolescent patients in acute care settings. This article reviews 7 randomized controlled trials evaluating risky drinking interventions among adolescent patients in acute care settings. All studies took place in the emergency departments of level I trauma centers. Four of the 7 studies reviewed demonstrated a significant intervention effect; however, no one intervention reduced both alcohol consumption and alcohol-related consequences. Two of these 4 studies only included patients ages 18 and older. Subgroup analyses with adolescents engaged in risky alcohol-related behaviors, conducted in 2 of the studies, showed significant intervention effects. Five studies showed positive consumption and/or consequences for all study participants regardless of condition, suggesting that an emergent injury and/or the screening process may have a protective effect. Based on existing evidence, it is not clear whether SBIRT is an effective approach to risky alcohol use among adolescent patients in acute care. Additional research is needed around interventions and implementation.


A Multicenter Clinical Study of Expected and Unexpected Side Reactions During and After Skin Cancer Treatment by Photodynamic Therapy.
Photodynamic therapy (PDT) has been widely used for oncologic indications, especially nonmelanoma skin cancer such as superficial and nodular basal cell carcinoma (BCC). We present a multicenter clinical study conducted between 2012 and 2014 analyzing the adverse reactions during and after PDT with a standardized protocol in 866 lesions. A total of 728 patients with positive clinical and histopathological diagnosis for BCC with up to 2 cm diameter were treated. The procedure consisted of curettage and topical application of cream containing 20% methyl 5-aminolevulinate. The illumination (630 nm and 150 J/cm2) was performed 3 hours after the cream application. The expected and unexpected effects observed were pain, healing, and inflammatory reactions. The pain intensity was correlated with the anatomical localization of the lesion. The patients reported a higher intensity of pain in lesions located on the head and neck rather than on the trunk and limbs. The number of sessions also influenced the pain response. A total of 83% of patients showed perfect healing and the other 17% presented abnormal healing. PDT plays an important role in BCC because of its low cost, ease of use, and low rate of side effects.


Mental state and its psychophysical conditions in patients with acute leukaemia treated with bone marrow transplantation.
Acute leukaemia and bone marrow transplantation (BMT) as a method of its treatment are great psychological stressors, which are responsible for anxiety and depression in the group of patients. The aim of the study was to assess the patients' mental state and its psychophysical predictors before and after BMT. The study was of a longitudinal and self-descriptive character. The questionnaires: LOT-R, AIS, Mini-Mac, CECS, RSCL and HADS were filled by 60 patients with acute leukaemia before and after BMT. There were no essential statistical differences between the severity of anxiety and depression before and after BMT but the pattern and the power of various mental state predictors changed in the course of the hospitalization. Anxiety before transplantation was greater when the psychological stress and the strategy of "anxious preoccupation" were stronger and the strategy of "fighting spirit" and the level of generalized optimism were weaker. The factors explained 51% variations of anxiety before transplantation. After BMT 77% variations of anxiety were explained, which were associated with a high level of distress at the end of the hospitalization, higher level of anxiety before transplantation, weaker strategy of "fighting spirit" before transplantation and stronger strategy of "anxious preoccupation" after BMT. Before transplantation 36% variations of depression were explained and estimated as weaker "fighting spirit" and worse "global life quality". The essential predictors of depressive symptoms after transplantation, explained by 81% variations of depression, were weaker "fighting spirit" before transplantation, stronger "anxious preoccupation" after transplantation, worse "global life quality" after transplantation and higher level of anxious and depressive symptoms on admission to hospital. The psychological and pharmacological interventions, which reduce anxiety, depression and "anxious preoccupation" as well as enhance "fighting spirit", should be introduced before BMT to improve the patients' mental state.


Secretory otitis media and hearing loss.
Hearing losses at 15 years of age were investigated in a material of 11,780 children born in Northern Finland in 1966 and followed-up since pregnancy. Two samples of the whole material, one representing a sample of 413 children with reported impaired hearing, and the other of 959 children with reported normal hearing were calculated to represent a total material of 11,748 cases. The correlation between the reported hearing and the audiometry results was very good. In the calculated material, 1,708 (14.6%) of the children exhibited a hearing loss exceeding 20 dB in at least one frequency in their school audiograms. The incidence of secretory otitis media as a risk diagnosis among those with impaired hearing was significantly higher than among those with normal hearing. Most of the hearing losses were found in the high frequencies.


Patellofemoral pain in general practice: the incidence and management.
Patellofemoral pain (PFP) is a nontraumatic knee problem primarily observed in physically active adolescents. The objective of this study was to determine the incidence and management of PFP in children and adolescents in general practice. A retrospective cohort study was conducted using a regional primary care database containing full electronic health records of over 300,000 patients. Patients with a new PFP diagnosis between the years 2013 and 2019 were extracted using a search algorithm based on International Classification of Primary Health Care coding and search terms in free text. Data on the management of PFP were manually checked and analysed. In addition, a sub-analysis for chronic and nonchronic PFP patients was performed. The mean incidence of PFP over the study period was 3.4 (95% CI 3.2-3.6) per 1,000 person years in the age group of 7-24 years. Girls had a higher incidence rate (4.6 [95% CI 4.3-5.0]) compared to boys (2.3 [95% CI 2.1-2.5]). Peak incidence was at age 13 years for both sexes. The most commonly applied management strategy was advice (55.1%), followed by referral to physiotherapy (28.2%), analgesics prescription (10.4%), and referral to the orthopaedic surgeon (8.9%). No differences were found in age, sex, and treatment between chronic and nonchronic PFP patients. The average Dutch general practitioner sees approximately 1.4 new child or adolescent with PFP per year. Overall management strategies were in concordance with current Dutch general practice guideline on nontraumatic knee problems. More insight should be gained in the population with chronic complaints.


Breaking down the barriers: siRNA delivery and endosome escape.
RNA interference (RNAi)-based technologies offer an attractive strategy for the sequence-specific silencing of disease-causing genes. The application of small interfering (si)RNAs as potential therapeutic agents requires safe and effective methods for their delivery to the cytoplasm of the target cells and tissues. Recent studies have shown significant progress in the development of targeting reagents that facilitate the recognition of and siRNA delivery to specific cell types. However, most of these delivery approaches are not optimized to enable the intracellular trafficking of the siRNAs into the cytoplasm where they must associate with the RNA-induced silencing complex (RISC) to direct the cleavage of mRNAs bearing complementary binding sites. In particular, the trafficking of siRNAs from endosomes into the cytoplasm represents a major rate-limiting step for many delivery approaches. This Commentary focuses on novel strategies designed to enhance endosomal escape and thereby increase the efficacy of siRNA-mediated gene silencing.


The importance of proper shoe gear and safety stirrups in the prevention of equestrian foot injuries.
The aim of this study was to compile specific foot injuries occurring in pediatric patients that result from equestrian sports and to highlight the importance of wearing adequate riding boots to protect the feet. During a 12-year period, 258 children were admitted to Children's Hospital of Geneva for injuries resulting from horseback riding. Amongst these children, 8 sustained foot lesions that required hospital admission. Four children had compression-type fractures of the cuboid (nutcracker fracture of the cuboid) associated with other complex midfoot fractures, 2 had Lisfranc fracture dislocations, 1 had a fracture of the talus with associated intern malleolar fracture, and the last had a fracture of the 5 metatarsals with lateral displacement. All the noted lesions complied with the same traumatic mechanisms. The horse fell on the patient, and the child's foot, entrapped in the stirrup, was caught in between the animal and the ground. The forefoot was bent by indirect violence in abduction by the stirrup, which acted as a fulcrum. Serious foot injuries may occur in children during equestrian activities. These lesions may be very disabling. Therefore, it is important for doctors, instructors, and parents to promote the use of appropriate safety equipment, including strengthened riding boots and safety stirrups.


New mechanisms of multidrug resistance: an introduction to the Cancer Drug Resistance special collection.
Cancer Drug Resistance publishes contributions to understanding the biology and consequences of mechanisms that interfere with successful treatment of cancer. Since virtually all patients who die of metastatic cancer have multidrug-resistant tumors, improved treatment will require an understanding of the mechanisms of resistance to design therapies that circumvent these mechanisms, exploit these mechanisms, or inactivate these multidrug resistance mechanisms. One example of a resistance mechanism is the expression of ATP-binding cassette efflux pumps, but unfortunately, inhibition of these transporters has not proved to be the solution to overcome multidrug resistance in cancer. Other mechanisms that confer multidrug resistance, and the confluence of multiple different mechanisms (multifactorial multidrug resistance) have been identified, and it is the goal of this Special Collection to expand this catalog of potential multidrug resistance mechanisms, to explore novel ways to overcome resistance, and to present thoughtful reviews on the problem of multidrug resistance in cancer.


Cup versus bottle feeding for hospitalized late preterm infants in Egypt: a quasi-experimental study.
Although previous studies have demonstrated beneficial breastfeeding outcomes when cup feeding rather than bottle feeding was used for feeding preterm infants, cup feeding has not been implemented in Egypt. The aim of the current study was to examine the effect of using cup feeding as an exclusive method of feeding preterm infants during hospitalization on breastfeeding outcomes after discharge. A quasi-experimental design, with the control group studied first, was used to examine the effect of cup feeding for preterm infants on breastfeeding outcomes after discharge. Sixty preterm infants (mean gestational age was 35.13 weeks and mean birth weight was 2150 grams) were recruited during Neonatal Intensive Care Unit (NICU) stay. Control group infants (n = 30) received only bottle feedings during hospitalization and the experimental group (n = 30) received only cup feedings during hospitalization. Both groups were followed up after discharge for six weeks to evaluate infant's breastfeeding behavior and mother's breastfeeding practices. Data were analyzed using descriptive statistics and repeated measures ANOVA for testing the differences between the cup feeding and bottle feeding groups over six weeks after discharge. Cup fed infants demonstrated significantly more mature breastfeeding behaviors when compared to bottle fed infants (p < 0.01) over six weeks, and had a significantly higher proportion of breast feedings one week after discharge (p = 0.03). Cup fed infants were more exclusively breast fed one week after discharge, supporting the Baby Friendly Hospital Initiative recommendations for using cup feeding and avoiding bottle feeding when providing supplementation for preterm infants. The current study provides initial evidence for the implementation of cup feeding as a method of supplementation for late preterm infants during hospitalization. Clinical Trial NCT00756587.


The N-Acetylmuramic Acid 6-Phosphate Phosphatase MupP Completes the Pseudomonas Peptidoglycan Recycling Pathway Leading to Intrinsic Fosfomycin Resistance.
Bacterial cells are encased in and stabilized by a netlike peptidoglycan (PGN) cell wall that undergoes turnover during bacterial growth. PGN turnover fragments are frequently salvaged by the cells via a pathway referred to as PGN recycling. Two different routes for the recycling of the cell wall sugar N-acetylmuramic acid (MurNAc) have been recognized in bacteria. In Escherichia coli and related enterobacteria, as well as in most Gram-positive bacteria, MurNAc is recovered via a catabolic route requiring a MurNAc 6-phosphate etherase (MurQ in E. coli) enzyme. However, many Gram-negative bacteria, including Pseudomonas species, lack a MurQ ortholog and use an alternative, anabolic recycling route that bypasses the de novo biosynthesis of uridyldiphosphate (UDP)-MurNAc, the first committed precursor of PGN. Bacteria featuring the latter pathway become intrinsically resistant to the antibiotic fosfomycin, which targets the de novo biosynthesis of UDP-MurNAc. We report here the identification and characterization of a phosphatase enzyme, named MupP, that had been predicted to complete the anabolic recycling pathway of Pseudomonas species but has remained unknown so far. It belongs to the large haloacid dehalogenase family of phosphatases and specifically converts MurNAc 6-phosphate to MurNAc. A ΔmupP mutant of Pseudomonas putida was highly susceptible to fosfomycin, accumulated large amounts of MurNAc 6-phosphate, and showed lower levels of UDP-MurNAc than wild-type cells, altogether consistent with a role for MupP in the anabolic PGN recycling route and as a determinant of intrinsic resistance to fosfomycin.IMPORTANCE Many Gram-negative bacteria, but not E. coli, make use of a cell wall salvage pathway that contributes to the pool of UDP-MurNAc, the first committed precursor of cell wall synthesis in bacteria. This salvage pathway is of particular interest because it confers intrinsic resistance to the antibiotic fosfomycin, which blocks de novo UDP-MurNAc biosynthesis. Here we identified and characterized a previously missing enzyme within the salvage pathway, the MurNAc 6-phosphate phosphatase MupP of P. putida MupP, together with the other enzymes of the anabolic recycling pathway, AnmK, AmgK, and MurU, yields UDP-MurNAc, renders bacteria intrinsically resistant to fosfomycin, and thus may serve as a novel drug target for antimicrobial therapy.


N-heterocyclic carbene copper(I) catalysed N-methylation of amines using CO2.
The N-methylation of amines using CO2 and PhSiH3 as source of CH3 was efficiently performed using a N-heterocyclic carbene copper(i) complex. The methodology was found compatible with aromatic and aliphatic primary and secondary amines. Synthetic and computational studies have been carried out to support the proposed reaction mechanism for this transformation.


Perspectives on Understanding Aberrant Brain Networks in Epilepsy.
Epilepsy is a neurological disorder affecting approximately 70 million people worldwide. It is characterized by seizures that are complex aberrant dynamical events typically treated with drugs and surgery. Unfortunately, not all patients become seizure-free, and there is an opportunity for novel approaches to treat epilepsy using a network view of the brain. The traditional seizure focus theory presumed that seizures originated within a discrete cortical area with subsequent recruitment of adjacent cortices with seizure progression. However, a more recent view challenges this concept, suggesting that epilepsy is a network disease, and both focal and generalized seizures arise from aberrant activity in a distributed network. Changes in the anatomical configuration or widespread neural activities spanning lobes and hemispheres could make the brain more susceptible to seizures. In this perspective paper, we summarize the current state of knowledge, address several important challenges that could further improve our understanding of the human brain in epilepsy, and invite novel studies addressing these challenges.


The effect of cross-cultural dialogue on child welfare parenting classes: anecdotal evidence in black and white.
The child welfare system indicates that evidence of successful completion of parenting classes is instrumental in determining whether parents are actively engaged in the process of permanency planning. Such classes vary in length and intensity with topics ranging from "How to Raise Healthy Families" to "How to Discipline Your Child." Two social workers (one white and one black), who initially disagreed about the format of a parenting class, chronicle their efforts to collaborate and create a class format that recognizes the psychosocial and, more specifically, the cultural influences inherent in facilitating these classes. The juxtaposition of the clinical concepts of projection and projective identification are evaluated against the backdrop of the social concepts of empowerment and diversity.


Percutaneous transluminal coronary angioplasty. Its success rate and affecting factors.
From December 1987 to October 1983, percutaneous transluminal coronary angioplasty (PTCA) was performed in 302 patients with 392 diseased vessels and 440 lesions. The success rate was 93.71% in 302 patients, 94.90% in 392 diseased vessels and 95.00% in 440 lesions. The success rate was 98.92% in Type A lesion, 95.71% in Type B lesion, and 86.57% in Type C lesion (A vs B P = NS, A vs C P < 0.01). There were 55 lesions with total or subtotal occlusion, the success rate was 89.09% (93.10% in Type B lesion and 84.62% in Type C lesion). As to the diseased vessels, the success rate was 95.65% in LAD, 94.38% in LCX and 93.75% in RCA. The results showed no significant difference. In this series, acute ischemic complications were found in 6.59% (29/440). Of these 29 lesions, 23 were treated successfully, 5 developed Q wave myocardial infarction and 1 died.


Headache during pregnancy and in the postpartum: a prospective study.
The association between sex hormones and chronic headache has been the subject of a good deal of speculation. Headache is predicted to improve during pregnancy, when estrogen levels rise steadily until delivery. Retrospective studies have suggested that women with a history of migraines do tend to report decreases in headache activity with pregnancy. The purpose of this naturalistic study was to examine changes in headache that may occur during pregnancy and postpartum in women complaining of migraine, tension-type, or combined migraine and tension-type headaches in a prospective design. Thirty women recorded their headaches daily throughout pregnancy and up to 12 weeks postpartum. Results based on these ratings demonstrated a nonsignificant trend for headache to decrease throughout pregnancy and to increase during the birth week. Headache patterns varied slightly depending on headache diagnosis and parity. Contrary to previous retrospective study reports, migraine sufferers demonstrated an increase in headache in the third trimester. In addition, there was a tendency in multiparous women for headaches to increase in the third trimester, whereas primiparous women reported less headache activity throughout pregnancy and the postpartum.


Animals, anoxic environments, and reasons to go deep.
One of the classic questions in the early evolution of eukaryotic life concerns the role of oxygen. Many unicellular eukaryotes are strict anaerobes and many animals have long anoxic phases in their life cycle. But are there also animals that can complete their life cycle without oxygen? In an ongoing debate in BMC Biology, Danovaro and colleagues say "yes" while Bernhard and colleagues say "no". The debate concerns reports of anoxic metazoans in deep sea anaerobic habitats.


Inhibition of human natural killer cell activity by Pseudomonas aeruginosa alkaline protease and elastase.
The present study was designed to examine the effect of Pseudomonas aeruginosa alkaline protease (AP) and elastase (Ela) on human natural killer (NK) cell activity in vitro. AP and Ela were found to inhibit NK cell function. Addition of alpha interferon and interleukin-2 did not abolish this inhibition of NK cell activity. Adhesion of effector to target cells was studied in a single-cell agarose assay of monocyte-depleted NK-cell-enriched cell populations. AP and Ela were shown to inhibit effector/target cell conjugate formation. Furthermore, AP and Ela inhibited the binding of the monoclonal antibody Leu-11, which reacts with the Fc receptor of NK cells. The inhibition of NK cell binding to the target cell by P. aeruginosa proteases is most likely due to proteolytic cleavage of the surface receptors involved in the binding of the effector cell to the target cell.


Vestibular decruitment: an indicator of central pathology?
Torok studied the ratio obtained between the responses to two different heat stimulation intensities of the same temperature. A decrease in response to the strong stimulus (i.e., a diminished ratio) was called "vestibular decruitment," and was regarded as a topodiagnostic indicator of central vestibular lesion, reflecting "adaptation" or "fatigue." The authors studied the reliability of vestibular decruitment obtained by Torok's technique in the indication of central vestibular pathology. Twenty-eight normal individuals and 30 patients previously diagnosed by other methods with diffuse pathology of the central nervous system were evaluated. The results obtained show that the two stimuli used are both supraliminal and of different intensity regarding the labyrinth. In no case was vestibular recruitment obtained. In view of the high percentage of normal individuals (57.14%) who presented vestibular decruitment, we consider the latter to lack topodiagnostic value as an indicator of either central or vestibular pathology; the smaller response to the mass stimulus might be explained by the vestibular habituation phenomenon that occurs on applying Torok's technique in both normal individuals and in patients with central vestibular pathology.


Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene.
To report the spectrum of ophthalmic findings in patients with Stargardt dystrophy or fundus flavimaculatus who have a specific sequence variation in the ABCR gene. Twenty-nine patients with Stargardt dystrophy or fundus flavimaculatus from different pedigrees were identified with possible disease-causing sequence variations in the ABCR gene from a group of 66 patients who were screened for sequence variations in this gene. Patients underwent a routine ocular examination, including slitlamp biomicroscopy and a dilated fundus examination. Fluorescein angiography was performed on 22 patients, and electroretinographic measurements were obtained on 24 of 29 patients. Kinetic visual fields were measured with a Goldmann perimeter in 26 patients. Single-strand conformation polymorphism analysis and DNA sequencing were used to identify variations in coding sequences of the ABCR gene. Three clinical phenotypes were observed among these 29 patients. In phenotype I, 9 of 12 patients had a sequence change in exon 42 of the ABCR gene in which the amino acid glutamic acid was substituted for glycine (Gly1961Glu). In only 4 of these 9 patients was a second possible disease-causing mutation found on the other ABCR allele. In addition to an atrophic-appearing macular lesion, phenotype I was characterized by localized perifoveal yellowish white flecks, the absence of a dark choroid, and normal electroretinographic amplitudes. Phenotype II consisted of 10 patients who showed a dark choroid and more diffuse yellowish white flecks in the fundus. None exhibited the Gly1961Glu change. Phenotype III consisted of 7 patients who showed extensive atrophic-appearing changes of the retinal pigment epithelium. Electroretinographic cone and rod amplitudes were reduced. One patient showed the Gly1961Glu change. A wide variation in clinical phenotype can occur in patients with sequence changes in the ABCR gene. In individual patients, a certain phenotype seems to be associated with the presence of a Gly1961Glu change in exon 42 of the ABCR gene. The identification of correlations between specific mutations in the ABCR gene and clinical phenotypes will better facilitate the counseling of patients on their visual prognosis. This information will also likely be important for future therapeutic trials in patients with Stargardt dystrophy.


Metrics, baseline scores, and a tool to improve sponsor performance on clinical trial diversity: retrospective cross sectional study.
To develop a measure for fair inclusion in pivotal trials by assessing transparency and representation of enrolled women, older adults (aged 65 years and older), and racially and ethnically minoritized patients. Retrospective cross sectional study. Sponsors of novel oncology therapeutics that were approved by the US Food and Drug Administration over 1 January 2012 to 31 December 2017. Trial data from Drugs@FDA, ClinicalTrials.gov, and corresponding publications; cancer incidence demographics from US Cancer Statistics and the American Cancer Society. Transparency measures assess whether trials publicly report participant sex, age, and racial and ethnic identity. Representation measures assess whether trial participant demographics represent more than 80% of the US patient population for studied conditions, calculated by dividing the percentage of study participants in each demographic subgroup by the percentage of the US cancer population with the studied condition per group. Composite fair inclusion measures assess average transparency and representation scores, overall and for each demographic group. Results are reported at the trial, product, and sponsor levels. Between 1 January 2012 and 31 December 2017, the FDA approved 59 novel cancer therapeutics, submitted by 25 sponsors (all industry companies) on the basis of 64 pivotal trials. All 25 sponsors (100%) reported participant sex, 10 (40%) reported age, and six (24%) reported race and ethnicity. Although 14 (56%) sponsors had adequate representation of women in trials, only six (24%) adequately represented older adults, and four (16%) adequately represented racially and ethnically minoritized patients (black, Asian, Hispanic or Latinx). On overall fair inclusion, one sponsor scored 100% and the median sponsor score was 81% (interquartile range 75-87%). More than half of sponsors (13 (56%) of 25) fairly included women, 20% (n=5) fairly included older adults, and 4% (n=1) fairly included racially and ethnically minoritized patients in trials. 80% of product had pivotal trials that fairly included women, 24% fairly included older adults, and 5% fairly included racially and ethnically minoritized patients. This novel approach evaluates trials, products, and sponsors on their fair inclusion of demographic groups in research. For oncology trials, substantial room was noted for improved inclusion of older adults and patients who identify as black or Latinx and transparency around the number of participants identifying as Native Hawaiian, Pacific Islander, American Indian, and Alaska Native. These measures can be used by sponsors, ethics committees, among others, to set and evaluate trial diversity goals to help spur progress toward greater research equity in the US.


Structural insights into the specificity and catalytic mechanism of mycobacterial nucleotide pool sanitizing enzyme MutT2.
Mis-incorporation of modified nucleotides, such as 5-methyl-dCTP or 8-oxo-dGTP, in DNA can be detrimental to genomic integrity. MutT proteins are sanitization enzymes which function by hydrolyzing such nucleotides and regulating the pool of free nucleotides in the cytoplasm. Mycobacterial genomes have a set of four MutT homologs, namely, MutT1, MutT2, MutT3 and MutT4. Mycobacterial MutT2 hydrolyzes 5 m-dCTP and 8-oxo-dGTP to their respective monophosphate products. Additionally, it can hydrolyze canonical nucleotides dCTP and CTP, with a suggested role in sustaining their optimal levels in the nucleotide pool. The structures of M. smegmatis MutT2 and its complexes with cytosine derivatives have been determined at resolutions ranging from 1.10 Å to 1.73 Å. The apo enzyme and its complexes with products (dCMP, CMP and 5 m-dCMP) crystallize in space group P21212, while those involving substrates (dCTP, CTP and 5 m-dCTP) crystallize in space group P21. The molecule takes an α/β/α sandwich fold arrangement, as observed in other MutT homologs. The nucleoside moiety of the ligands is similarly located in all the complexes, while the location of the remaining tail exhibits variability. This is the first report of a MutT2-type protein in complex with ligands. A critical interaction involving Asp116 confers the specificity of the enzyme towards cytosine moieties. A conserved set of enzyme-ligand interactions along with concerted movements of important water molecules provide insights into the mechanism of action.