Anterior Segment Ischemia After Peripheral Annular Lamellar Sclerokeratoplasty for Advanced Terrien Marginal Degeneration.
A man with 360° bilateral peripheral thinning, peripheral vascularization, and lipid deposition diagnosed with Terrien marginal degeneration, underwent a 360° peripheral annular lamellar sclerokeratoplasty (PALK) (tuck-in) in the right eye for 90% peripheral thinning and high astigmatism. One-week postoperatively, a sudden drop in vision to counting fingers 1 m from 20/50 with circumciliary congestion, diffuse corneal edema, intense anterior chamber inflammation, keratic precipitates with fixed dilated pupil, and hypotony led to a diagnosis of suspected anterior segment ischemia. Anterior segment fluorescein angiography was suggestive of ischemia. After intensive topical and systemic steroids tapered over 6 months, his symptoms and signs improved. At the last follow-up 4 years later, his best contact lens-corrected visual acuity was 20/30. Anterior segment ischemia has not been reported after a PALK for advanced corneal ectatic disorders. Prompt diagnosis and commencement of intensive steroids was helpful in reversing this condition.


Influence of the age at diagnosis in the disease expression of primary Sjögren syndrome. Analysis of 12,753 patients from the Sjögren Big Data Consortium.
To analyse how the main components of the disease phenotype (sicca symptoms, diagnostic tests, immunological markers and systemic disease) can be driven by the age at diagnosis of primary Sjögren's syndrome (pSS). By January 2021, the participant centres had included 12,753 patients from 25 countries that fulfilled the 2002/2016 classification criteria for pSS. The age at diagnosis was defined as the time when the attending physician confirmed fulfilment of the criteria. Patients were clustered according to age at diagnosis. 50 clusters with more than 100 observations (from 27 to 76 years) were used to study the influence of the age at diagnosis in the disease expression. There was a consistent increase in the frequency of oral dryness according to the age at diagnosis, with a frequency of <90% in patients diagnosed at the youngest ages and >95% in those diagnosed at the oldest ages. The smooth curves that best fitted a linear model were the frequency of dry mouth (adjusted R2 0.87) and the frequency of abnormal oral tests (adjusted R2 0.72). Therefore, for each 1-year increase in the age at diagnosis, the frequency of dry mouth increased by 0.13%, and the frequency of abnormal oral diagnostic tests by 0.11%. There was a consistent year-by-year decrease in the frequency of all autoantibodies and immunological markers except for cryoglobulins. According to the linear models, for each 1-year increase in the age at diagnosis, the frequency of a positive result decreased by 0.57% (for anti-Ro antibodies), 0.47% (for RF) and 0.42% (for anti-La antibodies). The ESSDAI domains which showed a more consistent decrease were glandular and lymph node involvement (for each 1-year increase in the age at diagnosis, the frequency of activity decreased by 0.18%), and constitutional, cutaneous, and haematological involvements (the frequency decreased by 0.09% for each 1-year increase). In contrast, other domains showed an ascending pattern, especially pulmonary involvement (for each 1-year increase in the age at diagnosis, the frequency of activity increased by 0.22%), and peripheral nerve involvement (the frequency increased by 0.09% for each 1-year increase). The influence of the age at diagnosis on the key phenotypic features of pSS is strong, and should be considered critical not only for designing a personalised diagnostic approach, but also to be carefully considered when analysing the results of diagnostic tests and immunological parameters, and when internal organ involvement is suspected at diagnosis.


Increasing Research Capacity in a Safety Net Setting Through an Academic Clinical Partnership.
Safety net settings care for a disproportionate share of low-resource patients often have fewer resources to invest in nursing research. To address this dilemma, an academic-clinical partnership was formed in an effort to increase nursing research capacity at a safety net setting. Penn Presbyterian Medical Center and the Center for Health Outcomes and Policy Research located at the University of Pennsylvania partnered researchers and baccalaureate-prepared nurses in an 18-month research skill development program. This article describes the programmatic design, conceptual framework, resource requirements, and effect on the institutional partners and participants.


Left bronchial isomerism, normal atrial arrangement and bronchomalacia mimicking asthma: a new syndrome?
Three children who presented with steroid-resistant airflow obstruction are described. They all had bronchomalacia in the setting of a rare visceral arrangement, namely left bronchial isomerism with normal atrial arrangement. Imaging and, in two cases, a normal residual volume in the face of severe airflow obstruction were diagnostic pointers to a nonasthmatic cause of wheeze. Although the association of these abnormalities may be coincidental, together they may constitute a new clinical syndrome.


Plasma leptin determination in ruminants: effect of nutritional status and body fatness on plasma leptin concentration assessed by a specific RIA in sheep.
A specific leptin RIA was developed to assess concentrations of leptin in ovine plasma, and was shown to be efficient with bovine and caprine plasma. A specific, high-affinity antibody was generated against recombinant ovine leptin which, when used in a competitive leptin RIA, provided valid estimates of linearity (r=+0.989-0.998), recovery (102%), repeatability (13%) and limit of sensitivity (0.83 ng/ml for 100 microl sample size). Serial dilutions of five ovine, bovine or caprine plasma samples showed good linearity and parallelism with the recombinant ovine leptin standard curve. A comparison of this RIA was made with a commercial 'multi-species' RIA kit using 56 ovine plasma samples. Major differences were found in assay sensitivity. Non-lactating, non-pregnant, ovariectomized ewes were fed a ration for 65 days which provided 90+/-9% (control; n=12) or 39+/-2% of maintenance energy requirements (underfed; n=16) in order to analyse the respective effects of body fatness (estimated by either an in vivo dilution technique or body condition scoring) and of nutritional status on plasma leptin concentration. There was a significant positive correlation between body fatness or body condition score and plasma leptin levels (r=+0.68, P<0.001 or r=+0.72, P<0.001 respectively). When concentrations of leptin were assessed over time, underfed ewes exhibited a dramatic reduction in plasma leptin values (-56%, P<0.001). These data provide strong evidence that, in sheep, the variations in plasma concentrations of leptin are related to variations in body fatness (35%) and, to a lesser extent, in nutritional status (17%).


Isotope cerebral perfusion studies before and after extracranial/intracranial bypass.
A quick, inexpensive, and reliable method of estimating cerebral perfusion is described that uses simple gamma camera and computer facilities readily available in almost all neuroradiology departments. Eighty-eight patients with unilateral cerebral ischemia were studied who satisfied the criteria for inclusion in the international cooperative study for extracranial/intracranial arterial anastomosis. The results of their isotope cerebral perfusion studies were compared with their computed tomographic scans and cerebral angiograms. The aims of the study were: (1) to ascertain whether the isotope study could predict the presence of a stenosis or occlusion; (2) to determine whether it could forecast the presence of a collateral blood flow and allow an assessment of the contribution of the collaterals to the overall cerebral perfusion; and (3) to assess the patency of the extracranial/intracranial bypass and monitor the effects of that procedure on hemisphere perfusion. The results show that this examination does predict the angiographic findings in nearly all patients and provides useful information about the natural collateral blood flow so that appropriate surgical treatment can be planned for the patient. The changes in cerebral perfusion after bypass were correlated with postoperative angiograms and offer a possible means of assessing and monitoring the effects of revascularization surgery and its contribution to the perfusion of that hemisphere.


Effects of Hange-koboku-to (Banxia-houpo-tang) on neuropeptide levels in human plasma and saliva.
Hange-koboku-to (Banxia-houpo-tang), a Chinese herbal (Kampo) medicine, has been used for improvement of hoarse voice, something foreign body sensation in the throat and/or esophagus, and swallowing reflex, among other conditions. One of the mechanisms of the empirical effects is assumed to be due to local changes in neuropeptide levels locally. We investigated the effects of Hange-koboku-to on neuropeptides, calcitonin gene-related peptide (CGRP), substance P, somatostatin, and vasoactive intestinal peptide (VIP) in plasma and saliva, as well as on salivary secretion in healthy subjects. A single oral administration of Hange-koboku-to caused significant increases in substance P-immunoreactive substance (IS) (40 min) in plasma, and slightly increased in CGRP-IS and somatostatin-IS in plasma compared with placebo. In saliva neuropeptides, Hange-koboku-to caused significant increases in substance P-IS (20 min) and somatostatin-IS (40, 60 min), and a slight increase in VIP-IS. However, a single Hange-koboku-to stimulation did not have a significant effect of sialosis volume. These results seem to suggest that Hange-koboku-to improves hoarse voice, something foreign body sensation in the throat and esophagus, and swallowing reflex disorder, by stimulation of neuropeptidergic nerves locally.


Cancer incidence in Germany attributable to human papillomavirus in 2013.
It is estimated that a total of 120,000 new cancer cases in men and in women in more developed countries could be avoided if exposure to HPV was prevented. We used the nationwide pool of German population-based cancer registry data to estimate the burden of HPV-attributable cancer in this population for the year 2013. Incident cases of cervical cancer, squamous cell carcinoma of the anus, oropharynx (OP), as well as of the vulva, vagina and penis were classified as potentially HPV-associated and identified from the nationwide cancer registry data-pool. We calculated the incidence and proportions of cancer with potentially HPV-associated morphologies. Estimation of the HPV-attributable incidence was based on prevalence-estimates of viral DNA in tumor cells in the respective sites, as provided from the international literature. From the overall 15,936 incident cases of anogenital and OP cancers in 2013, 6239 female and 1358 male cancer cases were estimated to be attributable to HPV. The majority of HPV-attributable cases were contributed by cervical cancer (70.9% of female cancers) and oropharyngeal cancer (46.9% of male cancers). Even if most HPV-attributable cases were contributed by cervical cancer, anogenital cancer at sites other than the cervix, and oropharyngeal cancer substantially contribute to the burden of HPV-associated cancer. Our nationwide cancer registry data-analyses provide the baseline for long-term population-based monitoring of vaccination-effects on cancer incidence in Germany.


Pharmacologic Impact (aka "Breaking Bad") of Medications on Wound Healing and Wound Development: A Literature-based Overview.
Patients with wounds often are provided pharmacologic interventions for their wounds as well as for their acute or chronic illnesses. Drugs can promote wound healing or substantively hinder it; some medications cause wound or skin reactions. A comprehensive review of extant literature was conducted to examine the impact of drug therapy on wound healing and skin health. MEDLINE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched for English-language articles published between 2000 and 2016 using the terms drugs, medications, drug skin eruptions, adverse skin reactions, wound healing, delayed wound healing, nonhealing wound, herbals, and herbal supplements. The search yielded 140 articles (CINAHL) and 240 articles (MEDLINE) for medications and wound healing. For medications and adverse skin effects, the search identified 256 articles (CINAHL) and 259 articles (MEDLINE). The articles included mostly narrative reviews, some clinical trials, and animal studies. Notable findings were synthesized in a table per pharmacological class and/or agent focusing on wound healing impact and drug-induced adverse skin reactions. The medications most likely to impair wound healing and damage skin integrity include antibiotics, anticonvulsants, angiogenesis inhibitors, steroids, and nonsteroidal anti-inflammatory drugs. Conversely, drugs such as ferrous sulfate, insulin, thyroid hormones, and vitamins may facilitate wound healing. Selected clinical practices, including obtaining a detailed medication history that encompasses herbal supplements use; assessing nutrition status especially protein blood levels affecting drug protein binding; and scrutinizing patient history and physical characteristics for risk factors (eg, atopy history) can help diminish and/or eliminate adverse integumentary outcomes. "Deprescribing" (discontinuing unnecessary medications) should be utilized when possible. Contemporary wound care clinicians must be cognizant of these mitigating clinical approaches.


Neurosurgery in Papua New Guinea.
An audit of neurosurgery in Papua New Guinea (PNG) based on the experience of a visiting neurosurgeon is presented. The objectives of the study were to determine the type and frequency of neurosurgical conditions in PNG, whether major neurosurgery can be performed successfully in PNG, and to develop a strategy for the development of neurosurgical services in PNG. The audit was carried out over two periods of 2 weeks duration in 1992 and 1993 in Port Moresby and Goroka. Instrumentation and equipment were limited and no additional equipment was used. Myelography and angiography were available in Port Moresby. There were 82 patients in total, 55 (67.1%) were consultations, 23 (28%) had elective surgery, four (4.8%) had emergency surgery and 16 (19.5%) await surgery. Cases were subdivided into nine major groupings: neurotrauma 18 (seven severe); spine 18; congenital 13; hydrancephaly four; scalp, skull and orbit six; vascular three; peripheral nerve three; and neurology five. Seventy-two (87.8%) patients required CT/MRI which were unavailable. Four ventriculograms were performed in lieu of CT/MRI. Fifteen (18.3%) cases could not be treated in PNG. Neurosurgical problems in PNG can often be adequately managed with limited resources. Complex procedures were performed with gratifying results and acceptable morbidity. There is sufficient pathology in a country of four million people to justify training a small number of neurosurgeons by the end of the decade. CT scanning will be a necessary adjunct.


Alpha-linoleate and photosynthetic activity in Chlorella protothecoides.
Green cells of Chlorella protothecoides grown in nitrogen-rich low glucose media may be reversibly transformed to entirely chlorophyll-less cells in low nitrogen high glucose media. Photosynthetic rates and fatty ester compositions were determined during light and dark bleaching and during greening. Linolenic acid content remained unchanged during greening or bleaching. During light greening chlorophyll content and photosynthetic activity increased while oleic acid content decreased dramatically. As a result, the percent composition of linolenate appeared to parallel photosynthetic capability. Implication of alpha-linolenate in oxygen production, therefore, can not be based upon fatty acid percentage composition data alone.


Computer-aided diagnosis of keratoconus through VAE-augmented images using deep learning.
Detecting clinical keratoconus (KCN) poses a challenging and time-consuming task. During the diagnostic process, ophthalmologists are required to review demographic and clinical ophthalmic examinations in order to make an accurate diagnosis. This study aims to develop and evaluate the accuracy of deep convolutional neural network (CNN) models for the detection of keratoconus (KCN) using corneal topographic maps. We retrospectively collected 1758 corneal images (978 normal and 780 keratoconus) from 1010 subjects of the KCN group with clinically evident keratoconus and the normal group with regular astigmatism. To expand the dataset, we developed a model using Variational Auto Encoder (VAE) to generate and augment images, resulting in a dataset of 4000 samples. Four deep learning models were used to extract and identify deep corneal features of original and synthesized images. We demonstrated that the utilization of synthesized images during training process increased classification performance. The overall average accuracy of the deep learning models ranged from 99% for VGG16 to 95% for EfficientNet-B0. All CNN models exhibited sensitivity and specificity above 0.94, with the VGG16 model achieving an AUC of 0.99. The customized CNN model achieved satisfactory results with an accuracy and AUC of 0.97 at a much faster processing speed compared to other models. In conclusion, the DL models showed high accuracy in screening for keratoconus based on corneal topography images. This is a development toward the potential clinical implementation of a more enhanced computer-aided diagnosis (CAD) system for KCN detection, which would aid ophthalmologists in validating the clinical decision and carrying out prompt and precise KCN treatment.


Evaluation of a web-based teaching module on examination of the hand.
To evaluate the effectiveness of an online module in the development of medical students' clinical hand examination skills. We developed a Web-based module to teach examination of the hand to first-year medical students (n = 99) to address the core skills expected in undergraduate medical training in Canada. The module was compared to the standard recommended text and tutor-led teaching using a validated objective structured clinical examination (OSCE) and a written knowledge test. A total of 17 students completed the OSCE from the book-based learning group, 18 from the tutor-led group, and 26 from the online module group. The average total OSCE score was significantly higher for students in the online module group compared to the textbook group (73.2% and 60.5%, respectively; p = 0.003). There was no significant difference between students in the online module and tutor-led groups (73.2% and 69.0%, respectively; p = 0.31). The online module group had a significantly higher mean total knowledge score than the textbook group (8.4 and 5.7, respectively; p < 0.001; maximum score 10) and the tutor-led group (8.4 and 7.4, respectively; p = 0.04). Our study provides evidence that a well designed Web-based module, supported by sound educational theory, is an effective tool in the teaching of musculoskeletal examination skills, and provides some advantages over tutor-led teaching in terms of knowledge retention.


High prevalence of overuse injury among iron-distance triathletes.
Triathlon is an increasingly popular sport at both the elite and the recreational level. However, there have been few high-quality studies of injuries and illnesses among triathletes. To register overuse problems and acute injuries among iron-distance triathletes throughout a training season leading up to a major event. A 26-week prospective cohort study was conducted including 174 participants of the 2011 Norseman Xtreme Triathlon. Data on overuse injuries located in the shoulder, lower back, thigh, knee and lower leg were collected every second week using the Oslo Sports Trauma Research Center Overuse Injury Questionnaire. Illnesses, acute injuries and overuse problems affecting other anatomical areas were also recorded using standard injury surveillance methods. The average prevalence of overuse problems was 56% (95% CI 51 to 61) (490 cases). The average prevalence of substantial overuse problems was 20% (95% CI 18 to 21) (165 cases). The most prevalent sites of overuse problems were the knee (25%), lower leg (23%) and lower back (23%). The acute injury incidence was 0.97 injuries per 1000 h of training (36 cases) and 1.02 injuries per 1000 h of competition (5 cases). A majority of moderate and severe acute injuries were located at the knee, shoulder/clavicle and sternum/ribs. The predominant types of acute injuries were contusions, fractures and sprains. The incidence of illness was 5.3/1000 athlete-days (156 cases). Overuse problems constitute the majority of injury cases among iron-distance triathletes, and are far more common than acute injuries and illnesses. The most prevalent sites of injury in the present study were the knee, lower leg, lower back and shoulder. Future injury prevention studies in iron-distance triathletes should focus on these areas.


Autonomic response specificity during motor imagery.
It has been reported that activation of autonomic effectors during mental simulation of voluntary motor actions (motor imagery: MI) may be explained by two different factors, i.e., functions of preparation or anticipation of actual exercise (motor anticipation) and the central motor programming/planning which acts during actual motor action (motor programming). This study was designed to clarify how these factors participate during MI, utilizing two mental tasks with high mental stress, i.e., MI and mental arithmetic (MA). Several autonomic effectors' responses were compared between MI of a 500 m speed skating sprint and MA. Subjects were eight 18 to 25 year old young male speed skate athletes, all of them could easily and vividly imagine a 500 m speed skating sprint. Duration of the MI ranged from 35 to 38 sec and these were very close to each subject's actual best record (means of absolute differences were less than 0.6 sec, i.e., less than 1.7% relatively). A significant decrease of skin resistance (SR), increases of heart rate (HR) and respiration rate were observed in both MI and MA when compared to each control resting level (excluding one subject for respiration rate during MI). SR decreased during MI (mean and SD of 8 subjects: 45.9 +/- 17.7%) and MA (39.7 +/- 16.8%), with no significant differences between MI and MA (t = 1.29, by paired t-test). HR increased significantly above control values in MA (10.3 +/- 4.3%) and MI (44.3 +/- 18.8%). However, the increase during MA was significantly smaller (t = 4.99, p < 0.001) than in MI. Respiratory rate increased significantly in both MI (46.5 +/- 30.9%) and MA (27.7 +/- 14.6%), with no significant difference between MI and MA (t = 1.82) due to the large individual variation in MI. The frequency of respiration was fairly regular during MA, but quite irregular during MI (similar to those during actual motor actions). The central nervous system which acts in MI may possess the function of activation of target effectors which play an important role in actual exercise, on the basis of incremental vigilance level induced by the function of motor anticipation.


Trends and Outcomes of Type 2 Myocardial Infarction During the COVID-19 Pandemic in the United States.
There is limited data on the impact of type 2 myocardial infarction (T2MI) during the coronavirus disease 2019 (COVID-19) pandemic. The National Inpatient Sample (NIS) database from January 2019 to December 2020 was queried to identify T2MI hospitalizations based on the appropriate International Classification of Disease, Tenth Revision-Clinical Modification codes. Monthly trends of COVID-19 and T2MI hospitalizations were evaluated using Joinpoint regression analysis. In addition, the multivariate logistic and linear regression analysis was used to compare in-hospital mortality, coronary angiography use, and resource utilization between 2019 and 2020. A total of 743,535 patients hospitalized with a diagnosis of T2MI were identified in the years 2019 (n=331,180) and 2020 (n=412,355). There was an increasing trend in T2MI hospitalizations throughout the study period corresponding to the increase in COVID-19 hospitalizations in 2020. The adjusted odds of in-hospital mortality associated with T2MI hospitalizations were significantly higher in 2020 compared with 2019 (11.1% vs. 8.1%: adjusted odds ratio, 1.19 [1.13-1.26]; p<0.01). In addition, T2MI hospitalizations were associated with lower odds of coronary angiography and higher total hospitalization charges, with no difference in the length of stay in 2020 compared with 2019. We found a significant increase in T2MI hospitalizations with higher in-hospital mortality, total hospitalization costs, and lower coronary angiography use during the early COVID-19 pandemic corresponding to the trends in the rise of COVID-19 hospitalizations. Further research into the factors associated with increased mortality can increase our preparedness for future pandemics.


Post-lesion transcommissural growth of olivary climbing fibres creates functional synaptic microzones.
In the adult mammalian central nervous system, reinnervation and recovery from trauma is limited. During development, however, postlesion plasticity may generate alternate paths, providing models to investigate reinnervating axon-target interactions. After unilateral transection of the neonatal rat olivocerebellar path, axons from the ipsilateral inferior olive grow into the denervated hemicerebellum and develop climbing fibre (CF)-like arbors on Purkinje cells (PCs). However, the synaptic function and extent of PC reinnervation remain unknown. In adult rats pedunculotomized on postnatal day 3 the morphological and electrophysiological properties of reinnervating olivocerebellar axons were studied, using axonal reconstruction and patch-clamp PC recording of CF-induced synaptic currents. Reinnervated PCs displayed normal CF currents, and the frequency of PC reinnervation decreased with increasing laterality. Reinnervating CF arbors were predominantly normal but 6% branched within the molecular layer forming smaller secondary arbors. CFs arose from transcommissural olivary axons, which branched extensively near their target PCs to produce on average 36 CFs, which is six times more than normal. Axons terminating in the hemisphere developed more CFs than those terminating in the vermis. However, the precise parasagittal microzone organization was preserved. Transcommissural axons also branched, although to a lesser extent, to the deep cerebellar nuclei and terminated in a distribution indicative of the olivo-cortico-nuclear circuit. These results show that reinnervating olivocerebellar axons are highly plastic in the cerebellum, compensating anatomically and functionally for early postnatal denervation, and that this reparation obeys precise topographic constraints although axonal plasticity is modified by target (PC or deep nuclear neurons) interactions.


Informed Consent Documents Used in Critical Care Trials Often Do Not Implement Recommendations.
Informed consent documents are often poorly understood by research participants. In critical care, issues such as time pressure, patient capacity, and surrogate decision making complicate the consent process further. Recommendations exist for addressing critical care-specific consent issues; we examined how well existing practice implements these recommendations. We conducted a systematic search of the literature for recommendations specific to critical care informed consent and rated existing informed consent documents on their implementation of 1) 18 of these critical care recommendations and 2) 36 previously developed general informed consent recommendations. Four hundred twelve registered critical care trials were identified and a request sent to the principal investigators for an example of the informed consent document associated with the trial. Each consent document was rated on both set of recommendations. We evaluated informed consent documents for trials conducted in English or French registered with clinicaltrials.gov. Not applicable. Not applicable. Independent coders rated implementation of each recommendation on a four-point scale. Of 412 requests, 137 informed consent documents were returned, for a response rate of 34.1%. Of these, 86 met inclusion criteria and were assessed. Overall agreement between raters was 90.6% (weighted κ = 0.79; 0.77-0.81). Implementation of the 18 critical care recommendations was highly variable, ranging between 2% and 96.5%. Critical care studies often do not provide the information recommended for those providing consent for research. These clear recommendations provide testable hypotheses about how to improve the consent process for patients and family members considering trial participation in the critical care setting.


Epidemiology and survival of the five stages of chronic kidney disease in a systolic heart failure population.
The epidemiology of the five stages of chronic kidney disease (CKD) in systolic heart failure (HF) patients has predominantly been described in hospitalized White patients, with little known about the prevalence in outpatient Blacks and Hispanics. The purpose of this study was to compare the prevalence of the five stages of CKD by race, ethnicity (Whites, Blacks, and Hispanics), and gender in an outpatient systolic HF population and also to evaluate the impact of CKD on mortality. We conducted a prospective study of 1301 patients recruited from two hospital facilities in Louisiana and Florida, USA. All patients were enrolled in a systolic HF disease management programme (HFDMP), which enrolled patients with an ejection fraction of < or =40% by echocardiography. The estimated glomerular filtration rate was calculated using the abbreviated Modification of Diet in Renal Disease Study equation. Patients were classified into five stages of CKD according to the National Kidney Foundation classification system. A total of 338 patients (26%) were found to have CKD. Patients with CKD were older, more likely to be Hispanics, to have less education, New York Heart Association class III, elevated systolic blood pressure, and diabetes. There was no statistical difference in prevalence by gender. Survival was reduced in patients with CKD. The prevalence of CKD in an outpatient systolic HFDMP is high, with over one in four patients affected. CKD patients had significantly lower survival rates compared with patients without CKD.


Multi-locus analysis of genomic time series data from experimental evolution.
Genomic time series data generated by evolve-and-resequence (E&R) experiments offer a powerful window into the mechanisms that drive evolution. However, standard population genetic inference procedures do not account for sampling serially over time, and new methods are needed to make full use of modern experimental evolution data. To address this problem, we develop a Gaussian process approximation to the multi-locus Wright-Fisher process with selection over a time course of tens of generations. The mean and covariance structure of the Gaussian process are obtained by computing the corresponding moments in discrete-time Wright-Fisher models conditioned on the presence of a linked selected site. This enables our method to account for the effects of linkage and selection, both along the genome and across sampled time points, in an approximate but principled manner. We first use simulated data to demonstrate the power of our method to correctly detect, locate and estimate the fitness of a selected allele from among several linked sites. We study how this power changes for different values of selection strength, initial haplotypic diversity, population size, sampling frequency, experimental duration, number of replicates, and sequencing coverage depth. In addition to providing quantitative estimates of selection parameters from experimental evolution data, our model can be used by practitioners to design E&R experiments with requisite power. We also explore how our likelihood-based approach can be used to infer other model parameters, including effective population size and recombination rate. Then, we apply our method to analyze genome-wide data from a real E&R experiment designed to study the adaptation of D. melanogaster to a new laboratory environment with alternating cold and hot temperatures.


Acute-phase high-density lipoprotein in the rat does not contain serum amyloid A protein.
Serum amyloid A protein (SAA) is an acute-phase apolipoprotein of high-density lipoprotein (HDL). Its N-terminal sequence is identical with that of amyloid A protein (AA), the subunit of AA amyloid fibrils. However, rats do not develop AA amyloidosis, and we report here that neither normal nor acute-phase rat HDL contains a protein corresponding to SAA of other species. mRNA coding for a sequence homologous with the C-terminal but not with the N-terminal part of human SAA is synthesized in greatly increased amounts in acute-phase rat liver. These observations indicate that the failure of rats to develop AA amyloid results from the absence of most of the AA-like part of their SAA-like protein, and that the N-terminal portion of SAA probably contains the lipid-binding sequences.


Increased serum thioredoxin levels are not correlated with executive functions in children with attention deficit hyperactivity disorder.
The first step of this study aims to determine whether thioredoxin (Trx) has a potential role in attention deficit hyperactivity disorder (ADHD) by measuring serum Trx levels in children with ADHD. In the second step, this study aims to reveal whether there is any relationship between Trx and executive functions. This is the first study investigating the serum levels of Trx in children with ADHD. This study sample included 45 patients diagnosed with ADHD and 30 healthy controls. Conners Teacher Rating Scale (CTRS) and Behavior Rating Inventory of Executive Function (BRIEF) are used to evaluate ADHD presentation, severity and executive functions, respectively. Trx levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit. Significantly higher Trx levels were found in children with ADHD. No significant correlations were found between serum Trx levels and executive functions for controls or ADHD group; although hyperactive/impulsive ADHD presentation showed positive correlations with some subdomains of executive function. Serum Trx levels and disease severity, measured by CTRS, showed non-significant correlations. This study may be the first step in the study of the role played by Trx and oxidative stress in ADHD, further research is needed to support these preliminary findings.


Migration of Mn cations in delithiated lithium manganese oxides.
Li2MnO3 is an integrated component in lithium-manganese-rich nickel manganese cobalt oxides, and the conversion of Li2MnO3 to a spinel-like structure after electrochemical activation has been associated with the continuous potential decay of the material. Delithiated Li2MnO3 and delithiated LiMn2O4 were used as model materials to investigate the mechanism of forming the spinel-like structure. An in situ high-energy X-ray diffraction technique was used to trace the structural change of materials at elevated temperatures, a procedure to mimic the structural transformation during the normal cycling of batteries. It was also found that the migration of Mn atoms from the octahedral sites to tetrahedral sites is the key step for phase transformation from a monoclinic structure to a spinel structure.


Faced with a double-edged risk: Ugandan university students' perception of the emergency contraceptive pill in Uganda.
Whereas in high-income countries potential users of Emergency Contraception (EC) have information and access to emergency contraceptive pills (ECPs), it has remained secretive in low-income countries like Uganda. Although several studies have been conducted in relation to EC, few have addressed users' perceptions. The objective of our study was to explore perceptions of EC by university students in Kampala, Uganda. Seven focus group discussions and four key informant interviews were conducted at Makerere University, Kampala. The transcribed data was analyzed for content and recurrent themes. Participants expressed ambivalence about ECPs. The method was generally recommended but only to the "right people", in this context being those aged eighteen years and more. There were reservations surrounding provision of ECPs like similarity with abortion and fear of side effects. Users' and potential-users' perceptions are crucial in the accessibility and utilization of ECPs.


Use of video to facilitate end-of-life discussions with patients with cancer: a randomized controlled trial.
To determine whether the use of a goals-of-care video to supplement a verbal description can improve end-of-life decision making for patients with cancer. Fifty participants with malignant glioma were randomly assigned to either a verbal narrative of goals-of-care options at the end of life (control), or a video after the same verbal narrative (intervention) in this randomized controlled trial. The video depicts three levels of medical care: life-prolonging care (cardiopulmonary resuscitation [CPR], ventilation), basic care (hospitalization, no CPR), and comfort care (symptom relief). The primary study outcome was participants' preferences for end-of-life care. The secondary outcome was participants' uncertainty regarding decision making (score range, 3 to 15; higher score indicating less uncertainty). Participants' comfort level with the video was also measured. Fifty participants were randomly assigned to either the verbal narrative (n = 27) or video (n = 23). After the verbal description, 25.9% of participants preferred life-prolonging care, 51.9% basic care, and 22.2% comfort care. In the video arm, no participants preferred life-prolonging care, 4.4% preferred basic care, 91.3% preferred comfort care, and 4.4% were uncertain (P < .0001). The mean uncertainty score was higher in the video group than in the verbal group (13.7 v 11.5, respectively; P < .002). In the intervention arm, 82.6% of participants reported being very comfortable watching the video. Compared with participants who only heard a verbal description, participants who viewed a goals-of-care video were more likely to prefer comfort care and avoid CPR, and were more certain of their end-of-life decision making. Participants reported feeling comfortable watching the video.


Information dissemination evolution under group feedback.
In this paper, based on the feedback mechanism from the perspective of network groups, the evolutionary characteristics and laws of group networks under information dissemination are studied. First, the network is divided into groups of different sizes, and each group is given a dynamically changing group activity and a positive degree of response to different categories of information. Second, a feedback-based model of information dissemination in group networks is developed, which takes into account the differences between same-group and cross-group dissemination of information. Next, the model is applied to a scale-free network and a small-world network for simulation experiments. The experimental results show that, under the feedback mechanism, the main factor affecting the final evolutionary results of each group size in the small-world network is group positivity, which has little relationship with the initial size; similarly, the main factor affecting the average degree of each group in the scale-free network is also group positivity, which has nothing to do with the initial average degree. Finally, the method is applied to a real network to verify the rationality and effectiveness of the proposed model.


Insight into the role of reduced graphene oxide in enhancing photocatalytic hydrogen evolution in disordered carbon nitride.
Compared to crystalline carbon nitride, the performance of disordered carbon nitride (d-CN) as a hydrogen production photocatalyst is extremely poor. Owing to its disordered atomic orientation, it is prone to numerous defect states. These energy states are potential sites for trapping and recombination of photogenerated charge carriers. As a result, rapid recombination of photogenerated charge carriers places a fundamental photophysical challenge in charge separation and transport, which inhibits its photocatalytic activity. In the presence of reduced graphene oxide (rGO), d-CN shows enhanced photocatalytic production of hydrogen. However, photophysical insight into the tacit role of rGO is not well understood which limits the rational design of d-CN as a photocatalyst. Particularly, understanding of the early time-scale (in fs to ps) recombination mechanism and the charge transport kinetics has not yet been achieved. With the help of ultrafast transient absorption spectroscopy, femtosecond time-resolved photoluminescence spectroscopy and transient photocurrent measurements, this article deciphers the ultrafast dynamics of the separation and transport of photogenerated charge carriers in d-CN facilitated by rGO. It is found that rGO substantially suppresses the bimolecular and trap-assisted recombination and enables a faster separation of charge carriers. As a result, it increases the lifetime of the charge carriers to be transported to the surface catalytic sites, and therefore, augments the rate of hydrogen production almost by an order of magnitude. Our findings therefore offer a proof-of-concept for overcoming the trap-mediated recombination problems in disordered carbon nitride.


Case report: seizures in a child caused by a large venous angioma.
Cerebral venous angioma is a congenital anomaly of the medullary vein, the vessel that drains into the transparenchymal venous stem. This lesion is also referred to as a developmental venous anomaly. A few reports in the literature have documented developmental venous anomaly-related epilepsy, neurologic deficits, and intracranial hemorrhage. A 3-year-old boy was referred to our hospital after he sustained an afebrile, tonic-clonic, focal seizure of 15 minutes' duration that affected his right arm, leg, and eyebrow. Cerebral digital subtraction angiography showed a bilateral, large periventricular developmental venous anomaly. This report describes the clinical and radiologic findings for this large venous angioma that caused seizures in a child.


The effects of ouabain and phenytoin on myocardial noradrenaline.
In guinea pigs, 160 mug kg-1 of ouabain decreased noradrenaline content of the right atrium and left ventricle by 44% and 68%, respectively, 2 hr after intraperitoneal injection. In rats, 20 mg kg-1 decreased noradrenaline content of the right atrium and left ventricle by 35% and 55%, respectively, at 1 hr. In mice, 10 mg kg-1 decreased myocardial noradrenaline by 33% and 20 mg kg-1 by 45% at 15 min. Phenytoin, 10 mg kg-1 in the guinea pig, 80 mg-1 in the rat, and 40 mg kg-1, in the mouse suppressed the effect of ouabain. Hexamethonium did not suppress the effect. In isolated, perfused guinea pig and rat hearts, 5.5 + 10-8 M and 6.8 + 10-6 M, respectively, caused an increase in noradrenaline output, which was usually followed by oscillatory fluxes; the initial increase in output was obtunded and the oscillations were entirely prevented by premedication with phenytoin but not by the addition of the drug to the perfusion medium.


[Body weight regulation through the central nervous system. The development of a pathogenetically based adiposity therapy].
The last decade witnessed a dramatic increase in knowledge concerning regulation of body weight and obesity. According to recent concepts constancy of body weight is a side product of regulatory events which ensure constant glucose fluxes to the brain. Within these control systems glucocorticoids and melanocortins play a fundamental role at several sites. The melanocortin neurons in the arcuate nucleus of the hypothalamus are important mediators of the feedback effects of leptin and insulin. Glucocorticoid and mineralocorticoid receptors in hippocampal neurons are crucial, as they define the balance between glucose allocation processes and food intake. Thereby, the hippocampal structures determine the setpoint for body weight regulation. A modulation of these brain structures by intranasal administration of melanocortin and inhisulin has been shown to reduce body weight and body fat mass in humans. So the manipulation of weight-regulating centers in the brain opens a novel approach to a pathogenetically based treatment of obesity.


A versatile bottom-up interface self-assembly strategy to hairy nanoparticle-based 2D monolayered composite and functional nanosheets.
Herein, we present a universal bottom-up interface self-assembly of hairy nanoparticle strategy for 2D monolayered composite and functional nanosheets, including polymeric composite nanosheets and functional porous polymer and carbon nanosheets. By using diverse hairy nanoparticles as building blocks, a series of 2D monolayered polymeric composite nanosheets was prepared, demonstrating the universality of our strategy. Furthermore, the 2D polymeric composites could be easily transformed into 2D monolayered functional porous polymer and carbon nanosheets. We hope that this strategy will open a new door for the design and fabrication of advanced 2D composite and functional nanosheets and thus provide new opportunities for different fields including the environment, energy, catalysis and medicine.


Gastroesophageal reflux in infants with a history of near-miss sudden infant death.
From January 1984 through August 1986, 130 infants were referred to our department with a history of apnea, hypotonia, and cyanosis or pallor, suggesting near-miss sudden infant death syndrome. Protocol consisted of medical history, clinical examination, overnight polygraphic recording, and cardiologic, gastrointestinal, metabolic, neurologic, and toxicologic workups. In 49 of these infants who needed vigorous stimulation or mouth to mouth resuscitation, the event occurred shortly after feeding. Combined, continuous esophageal pH monitoring and polygraphic recording in these 49 infants showed pathologic gastroesophageal reflux (GER) in 34 patients. An abnormal overnight polygraphic recording was observed in 8 of 34 infants with pathologic GER. Other investigations led to etiologic diagnoses in 42 of the remaining infants. Severe GER was frequently found in children with apnea after feeding but clearly is not the only mechanism involved. Infants with a history of apnea after a feeding should be investigated for GER and appropriately treated.


Biomechanical comparison of Cross-pin and Endobutton-CL femoral fixation of a flexor tendon graft for anterior cruciate ligament reconstruction--a porcine femur-graft-tibia complex study.
A stable fixation of the graft is imperative for early aggressive rehabilitation after anterior cruciate ligament (ACL) reconstruction. The suspension devices such as Endobutton-CL and Cross-pin system are common techniques of femoral fixation for the hamstring tendon graft and provide superior initial biomechanical properties than the screws system. It remains unclear how such implants perform under cyclic loading and initial pull-out strength. Cross-pin and Endobutton-CL femoral fixation devices were tested for initial fixation strength in porcine knee joints by cyclic loads following a load-to-failure test. The Cross-pin and Endobutton-CL were used for femoral fixation of a porcine profundus flexor digitorum tendon autograft in 20 porcine knees. Ten specimens of femoral-graft-tibia complex in each group were loaded cyclically to between 0 and 150 N at 1 Hz for 1000 cycles following a load-to-failure test at a rate of 150 mm/min. The amount of total femur-graft-tibia complex graft displacement was significantly lower in the Cross-pin fixation group (5.37 +/- 0.28 mm) than in Endobutton-CL fixation group (6.08 +/- 0.61 mm: P < 0.05). There were no significant differences in the maximal failure load, yield load, and stiffness between the Cross-pin and Endobutton-CL fixation groups. This biomechanical study reveals that the Endobutton-CL and Cross-pin femoral fixation devices have an equally strong and safe fixation for ACL reconstruction. However, the Cross-pin fixation has significantly less displacement of femur-graft-tibia complex than that of Endobutton-CL fixation in response to the cyclic loading test. It indicates that the Cross-pin fixation is more suitable for early aggressive rehabilitation following ACL reconstruction.


Carcinoma of the anal canal. A clinical and pathologic study of 188 cases.
Among 188 patients presenting with carcinoma of the anal canal the predominant cell types were squamous cell (56%) and nonkeratinizing basaloid (35%). Thirteen patients who had predominantly small (less than or equal to 2 cm) and only superficially invasive squamous cell lesions were treated with local excision, and although one required later abdominal perineal (AP) resection for local recurrence, all were apparently cured. Local excision should be preferred as initial treatment for such lesions. One hundred eighteen patients with squamous cell and nonkeratinizing basaloid carcinomas were primarily treated with AP resection. The operative mortality rate was 2.5%. Among 114 patients who survived surgery and had adequate follow-up, 40% developed recurrent disease, and 71% have survived 5 or more years. Pathologic staging based on depth of tumor invasion and regional nodal involvement was strongly predictive of survival as was tumor histology with progressively poorer survival rates from low-grade squamous cell to high-grade squamous cell to nonkeratinizing basaloid types. Tumor size was inversely related to prognosis and was strongly associated with stage. Squamous cell anal carcinoma was dominantly a local disease with approximately 70% of patients presenting with tumor apparently limited to the bowel wall, only 20% with regional node involvement and only 2% with distant metastasis. Even among those patients who recurred after AP resection approximately 80% had all known disease still limited to the pelvic area. Corresponding figures for nonkeratinizing basaloid tumors were 50 percent presenting limited to the bowel wall, 30% with regional nodes, 20% with distant metastasis, and 60% with initial recurrence limited to the pelvis. Among the 13 patients studied with small cell anal carcinoma, the authors found the disease to be very virulent either initially presenting with or rapidly evolving into diffuse dissemination. Only one of the seven patients who could be treated surgically survived 5 years. As is true for small cell carcinomas primary to other sites, this neoplasm should be regarded as a systemic disease. With these findings as a foundation, possible future strategies for management of anal carcinoma are discussed.


A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma.
Seventy-four previously untreated patients with metastatic colorectal adenocarcinoma were prospectively randomized into one of three treatment regimens: (1) 5-fluorouracil (5-FU) 450 mg/m2 as an intravenous (IV) bolus daily for five days or toxicity, then 200 mg/m2 IV bolus every other day for six doses; (2) methotrexate (MTX) 50 mg/m2 in normal saline by IV infusion over four hours followed by an IV bolus of 5-FU 600 mg/m2. This was administered weekly for 4 weeks and then every 2 weeks. (3) Leucovorin 500 mg/m2 in a two-hour IV infusion of normal saline with 5-FU 600 mg/m2 as an IV bolus one hour after the Leucovorin began every week for 6 weeks. The combined complete and partial response rates in the three regimens were 11%, 5%, and 48%, respectively (P = .0009). The median duration of response in the 5-FU and Leucovorin regimen was 10 months. There was no statistically significant difference between the treatment regimens with respect to survival time (P = .6). Toxicity in the 5-FU and Leucovorin regimen was predominantly diarrhea (13 of 30 patients, 40%). In this regimen, eight of 13 patients (52%) who developed diarrhea not only required a dose reduction of 5-FU, but also hospitalization for IV hydration. The predominant toxicity in the 5-FU alone regimen and the 5-FU and MTX regimen was leukopenia. One drug-related death occurred in each regimen.


Towards mixed sequence recognition by triple helix formation.
The formation of intermolecular DNA triple helices offers the possibility of designing compounds with extensive sequence recognition properties which may be useful as antigene agents or tools in molecular biology. One major limitation of this approach is that these structures are generally restricted to homo-purine. homopyrimidine target sites. This review describes the strategies that have been employed to overcome this drawback and outlines the potential for triplex formation at mixed sequence DNA targets.


Periconceptional vitamin useand leukemia risk in children with Down syndrome: a Children's Oncology Group study.
Periconceptional vitamin supplementation reduces the risk of neural tube defects, and possibly may reduce the risk of certain childhood malignancies, including acute lymphoblastic leukemia (ALL). Because children with Down syndrome (DS) experience a 20-fold higher risk of leukemia than the general population, the authors evaluated whether periconceptional vitamin supplementation reduced the risk of leukemia in children with DS. From 1997 to 2002, 158 children ages birth-18 years with DS and acute leukemia (n = 61 children with acute myeloid leukemia [AML] and n = 97 children with ALL) were enrolled through the Children's Oncology Group in North America. Children with DS alone (n = 173) were identified through the cases' pediatric clinics and frequency matched to cases on age. Mothers of cases and controls completed a telephone interview that included questions regarding vitamin supplement use in the periconceptional period and after knowledge of pregnancy. A decreased risk of leukemia was observed with vitamin supplementation in the periconceptional period (odds ratio [OR] = 0.63; 95% confidence interval [95% CI], 0.39-1.00). When stratified by leukemia type, the reduced risk was observed for ALL (OR = 0.51; 95% CI, 0.30-0.89), but not for AML (OR = 0.92; 95% CI, 0.48-1.76). Compared with vitamin use in the periconceptional period, use only after knowledge of pregnancy was associated with an increased risk of leukemia (OR = 1.61; 95% CI, 1.00-2.58). This was observed for both ALL and AML. These data added to a growing body of evidence that suggests that periconceptional vitamin use may be protective in the development of certain childhood cancers.


Eocene "Chusquea" fossil from Patagonia is a conifer, not a bamboo.
Chusquea oxyphylla Freng. & Parodi, 1941, a fossilized leafy branch from the early Eocene (52 Ma), late-Gondwanan Laguna del Hunco biota of southern Argentina, is still cited as the oldest potential bamboo fossil and as evidence for a Gondwanan origin of bamboos. On recent examination, the holotype specimen was found to lack any typical bamboo characters such as nodes, sheaths, ligules, pseudopetioles, or parallel leaf venation. Instead, it has decurrent, clasping, univeined, heterofacially twisted leaves with thickened, central-longitudinal bands of presumed transfusion tissue. These and other features allow confident placement in the living Neotropical and West Pacific disjunct genus Retrophyllum (Podocarpaceae), which was recently described from the same fossil site based on abundant, well-preserved material. However, the 1941 fossil holds nomenclatural priority, requiring the new combination Retrophyllum oxyphyllum (Freng. & Parodi) Wilf, comb. nov. No reliable bamboo fossils remain from Gondwana, and the oldest South American bamboo fossils are Pliocene. Chusquea joins a growing list of living New World genera that are no longer included in Paleogene Patagonian floras, whose extant relatives are primarily concentrated in Australasia and Malesia via the ancient Gondwanan route through Antarctica.


Enhanced tetrahedral ordering of water molecules in minor grooves of DNA: relative role of DNA rigidity, nanoconfinement, and surface specific interactions.
Confinement and surface specific interactions can induce structures otherwise unstable at that temperature and pressure. Here we study the groove specific water dynamics in the nucleic acid sequences, poly-AT and poly-GC, in long B-DNA duplex chains by large scale atomistic molecular dynamics simulations, accompanied by thermodynamic analysis. While water dynamics in the major groove remains insensitive to the sequence differences, exactly the opposite is true for the minor groove water. Much slower water dynamics observed in the minor grooves (especially in the AT minor) can be attributed to an enhanced tetrahedral ordering (<t(h)>) of water. The largest value of <t(h)> in the AT minor groove is related to the spine of hydration found in X-ray structure. The calculated configurational entropy (S(C)) of the water molecules is found to be correlated with the self-diffusion coefficient of water in different region via Adam-Gibbs relation D = A exp(-B/TS(C)), and also with <t(h)>.


Automated semantic labeling of pediatric musculoskeletal radiographs using deep learning.
An automated method for identifying the anatomical region of an image independent of metadata labels could improve radiologist workflow (e.g., automated hanging protocols) and help facilitate the automated curation of large medical imaging data sets for machine learning purposes. Deep learning is a potential tool for this purpose. To develop and test the performance of deep convolutional neural networks (DCNN) for the automated classification of pediatric musculoskeletal radiographs by anatomical area. We utilized a database of 250 pediatric bone radiographs (50 each of the shoulder, elbow, hand, pelvis and knee) to train 5 DCNNs, one to detect each anatomical region amongst the others, based on ResNet-18 pretrained on ImageNet (transfer learning). For each DCNN, the radiographs were randomly split into training (64%), validation (12%) and test (24%) data sets. The training and validation data sets were augmented 30 times using standard preprocessing methods. We also tested our DCNNs on a separate test set of 100 radiographs from a single institution. Receiver operating characteristics (ROC) with area under the curve (AUC) were used to evaluate DCNN performances. All five DCNN trained for classification of the radiographs into anatomical region achieved ROC AUC of 1, respectively, for both test sets. Classification of the test radiographs occurred at a rate of 33 radiographs per s. DCNNs trained on a small set of images with 30 times augmentation through standard processing techniques are able to automatically classify pediatric musculoskeletal radiographs into anatomical region with near-perfect to perfect accuracy at superhuman speeds. This concept may apply to other body parts and radiographic views with the potential to create an all-encompassing semantic-labeling DCNN.


Pergolide presynaptically inhibits calcium-stimulated release of gamma-aminobutyric acid.
The release of gamma-aminobutyric acid (GABA) in rat dorsolateral striatum was studied using in vivo microdialysis. Dialysis was conducted 2 days after probe implantation in awake, freely moving rats using a modified Ringer solution. Calcium induced a reversible increase in GABA release that was abolished by tetrodotoxin but was only slightly attenuated by a maximally effective dose of pergolide, a D2 receptor agonist. It was thus concluded that pergolide inhibits calcium-stimulated release of GABA presynaptically by a mechanism distinct from that of tetrodotoxin.


[The principles of the dissemination of information on sexually transmitted infections and on the drugs used in delivering medical care].
An analysis is submitted of the problem of dissemination of information about infections caught by sexual intercourse or genital contact and about medication used in the treatment of this kind of pathology. The main principles are worked out of dissemination of medical information among different subjects who are interested in dissemination and securing information highlighting different aspects of the above problem. The presented approaches toward formation of information related to the problem of sexually transmitted infections permit harmonizing the interests of different subjects of the drug market and of the market of medical care to be delivered to patients presenting with the above kind of pathology.


Design of selective, ATP-competitive inhibitors of Akt.
This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.


Immune system changes in cytapheresis donors.
In vitro measurements of several variables of the immune system were made in 21 healthy donors who had been subjected to frequent cytapheresis an a group of whole blood donor controls matched for age and sex. Significant changes noted in the apheresis donors compared to controls included a 23 percent lower mean absolute lymphocyte count (p less than .01), a 25 percent lower mean T cell count (p less than .01), and a 46 percent lower mean B cell count (p less than .001). Serum protein changes included a 27 percent lower mean gamma globulin level (p less than .01), and 14 percent lower mean IgG level (p less than .05) in the apheresis donors when compared to the control group. The possible implications of these findings are discussed, and we suggest that donors undergoing multiple cytapheresis procedures be closely monitored to determine the safe donation frequency.


Investigation of occupational and environmental causes of respiratory cancers (ICARE): a multicenter, population-based case-control study in France.
Occupational causes of respiratory cancers need to be further investigated: the role of occupational exposures in the aetiology of head and neck cancers remains largely unknown, and there are still substantial uncertainties for a number of suspected lung carcinogens. The main objective of the study is to examine occupational risk factors for lung and head and neck cancers. ICARE is a multi-center, population-based case-control study, which included a group of 2926 lung cancer cases, a group of 2415 head and neck cancer cases, and a common control group of 3555 subjects. Incident cases were identified in collaboration with cancer registries, in 10 geographical areas. The control group was a random sample of the population of these areas, with a distribution by sex and age comparable to that of the cases, and a distribution by socioeconomic status comparable to that of the population. Subjects were interviewed face to face, using a standardized questionnaire collecting particularly information on tobacco and alcohol consumption, residential history and a detailed description of occupational history. Biological samples were also collected from study subjects. The main occupational exposures of interest are asbestos, man-made mineral fibers, formaldehyde, polycyclic aromatic hydrocarbons, chromium and nickel compounds, arsenic, wood dust, textile dust, solvents, strong acids, cutting fluids, silica, diesel fumes, welding fumes. The complete list of exposures of interest includes more than 60 substances. Occupational exposure assessment will use several complementary methods: case-by-case evaluation of exposure by experts; development and use of algorithms to assess exposure from the questionnaires; application of job-exposure matrices. The large number of subjects should allow to uncover exposures associated with moderate increase in risks, and to evaluate risks associated with infrequent or widely dispersed exposures. It will be possible to study joint effects of exposure to different occupational risk factors, to examine the interactions between occupational exposures, tobacco smoking, alcohol drinking, and genetic risk factors, and to estimate the proportion of respiratory cancers attributable to occupational exposures in France. In addition, information on many non-occupational risk factors is available, and the study will provide an excellent framework for numerous studies in various fields.


Semantic and Physical Properties of Peripheral Vision Are Used for Scene Categorization in Central Vision.
Theories of visual recognition postulate that our ability to understand our visual environment at a glance is based on the extraction of the gist of the visual scene, a first global and rudimentary visual representation. Gist perception would be based on the rapid analysis of low spatial frequencies in the visual signal and would allow a coarse categorization of the scene. We aimed to study whether the low spatial resolution information available in peripheral vision could modulate the processing of visual information presented in central vision. We combined behavioral measures (Experiments 1 and 2) and fMRI measures (Experiment 2). Participants categorized a scene presented in central vision (artificial vs. natural categories) while ignoring another scene, either semantically congruent or incongruent, presented in peripheral vision. The two scenes could either share the same physical properties (similar amplitude spectrum and spatial configuration) or not. Categorization of the central scene was impaired by a semantically incongruent peripheral scene, in particular when the two scenes were physically similar. This semantic interference effect was associated with increased activation of the inferior frontal gyrus. When the two scenes were semantically congruent, the dissimilarity of their physical properties impaired the categorization of the central scene. This effect was associated with increased activation in occipito-temporal areas. In line with the hypothesis of predictive mechanisms involved in visual recognition, results suggest that semantic and physical properties of the information coming from peripheral vision would be automatically used to generate predictions that guide the processing of signal in central vision.


Radiological Assessment of Accelerated versus Traditional Approaches to Postoperative Rehabilitation following Matrix-Induced Autologous Chondrocyte Implantation.
To assess the safety and efficacy of accelerated compared with traditional postoperative weightbearing (WB) rehabilitation following matrix-induced autologous chondrocyte implantation (MACI) of the knee, using MRI. A randomized controlled study design was used to assess MRI-based outcomes of MACI grafts in 70 patients (45 men, 25 women) who underwent MACI to the medial or lateral femoral condyle, in combination with either traditional or accelerated approaches to postoperative WB rehabilitation. High-resolution MRI was undertaken and assessed 8 previously defined pertinent parameters of graft repair, as well as a combined MRI composite score at 3, 12, and 24 months postsurgery. The association between clinical and MRI-based outcomes, patient demographics, chondral defect parameters, and injury/surgery history was investigated. Both groups significantly improved (P < 0.05) in the MRI composite score and pertinent descriptors of graft repair throughout the postoperative period until 24 months postsurgery. There were no differences (P > 0.05) observed between the 2 groups. Patient age, body mass index, chondral defect size, and duration of preoperative symptoms were significantly correlated (P < 0.05) with several MRI-based outcomes at 24 months, whereas there were no significant pertinent correlations (P > 0.05) observed between clinical and MRI-based outcomes. The accelerated WB approach was not detrimental to graft development at any stage throughout the postoperative assessment timeline from baseline to 24 months postsurgery and may potentially accelerate patient return to normal function, while reducing postoperative muscle loss, intra-articular adhesions, and associated gait abnormalities.


[Learning relationships between anemia women the Rebublic Uzbekistan and indicators of serum of protein among women].
Relationships between anemia and indicators of serum of protein was learned among 551 women who are at the age of 15-49 years, in three regions of the Republic of Uzbekistan. The results showed that among all examined women hypoproteinemia was 18.9%, hyperproteinemia was 5.8%, with the rest of the women indicators corresponded to the limit of the rate. Accordingly, hypo- and hyperproteinemia appeared most frequently among women who has anemia with indefinite etiology is 27.6% and 8.6%. Among women who has iron deficiency anemia these indicators formed 18.4 and 5.4%, in healthy women it was 18.3 and 4.8%.


Understanding heterogeneity of fetal hemoglobin induction through comparative analysis of F and A erythroblasts.
Reversing the developmental switch from fetal hemoglobin (HbF, α2γ2) to adult hemoglobin (HbA, α2β2) is an important therapeutic approach in sickle cell disease (SCD) and β-thalassemia. In healthy individuals, SCD patients, and patients treated with pharmacologic HbF inducers, HbF is present only in a subset of red blood cells known as F cells. Despite more than 50 years of observations, the cause for this heterocellular HbF expression pattern, even among genetically identical cells, remains unknown. Adult F cells might represent a reversion of a given cell to a fetal-like epigenetic and transcriptional state. Alternatively, isolated transcriptional or posttranscriptional events at the γ-globin genes might underlie heterocellularity. Here, we set out to understand the heterogeneity of HbF activation by developing techniques to purify and profile differentiation stage-matched late erythroblast F cells and non-F cells (A cells) from the human HUDEP2 erythroid cell line and primary human erythroid cultures. Transcriptional and proteomic profiling of these cells demonstrated very few differences between F and A cells at the RNA level either under baseline conditions or after treatment with HbF inducers hydroxyurea or pomalidomide. Surprisingly, we did not find differences in expression of any known HbF regulators, including BCL11A or LRF, that would account for HbF activation. Our analysis shows that F erythroblasts are not significantly different from non-HbF-expressing cells and that the primary differences likely occur at the transcriptional level at the β-globin locus.


Short communication: A decrease in diameter of milk fat globules accompanies milk fat depression induced by conjugated linoleic acid supplementation in lactating dairy cows.
Milk fat is secreted from the mammary gland in the form of milk fat globules (MFG). Although milk fat depression has been studied since the beginning of the last century, the extent to which this phenomenon alters MFG synthesis is not fully understood. The aim of this study was to evaluate the effect of conjugated linoleic acid (CLA) on the size and distribution of MFG during milk fat depression in dairy cows. Twelve Holstein cows in mid lactation (145 ± 31 d in milk, 583 ± 34.6 kg of body weight, and 27.2 ± 2.4 kg of milk/d) were randomly assigned to a control diet or control plus Ca-protected CLA at 15 g/kg of dry matter for a 6-d period. The average diameter and particle size distribution of MFG were measured using a Mastersizer 3000 laser particle size analyzer (Malvern Instruments Ltd., Malvern, UK). Feeding CLA did not affect dry matter intake (16.2 ± 0.4 kg/d), milk production (28.4 ± 0.4 kg/d), milk protein, or lactose, but it decreased milk fat content (3.46 vs. 2.52%). In addition, surface area-related mean diameter of fat globules in cows fed CLA was lower compared with controls (3.02 vs. 3.45 μm). The percentage of large fat globules decreased and that of small fat globules increased in response to CLA. Overall, the data suggest that the milk fat depression induced by CLA is accompanied by a decrease in average diameter of MFG.


Preparation and characterization of EGCase I, applicable to the comprehensive analysis of GSLs, using a rhodococcal expression system.
Endoglycoceramidase (EGCase) is a glycosidase capable of hydrolyzing the β -glycosidic linkage between the oligosaccharides and ceramides of glycosphingolipids (GSLs). Three molecular species of EGCase differing in specificity were found in the culture fluid of Rhodococcus equi (formerly Rhodococcus sp. M-750) and designated EGCase I, II, and III. This study describes the molecular cloning of EGCase I and characterization of the recombinant enzyme, which was highly expressed in a rhodococcal expression system using Rhodococcus erythropolis. Kinetic analysis revealed the turnover number (k(cat)) (k(cat)) of the recombinant EGCase I to be 22- and 1,200-fold higher than that of EGCase II toward GM1a and Gb3Cer, respectively, although the K(m) of both enzymes was almost the same for these substrates. Comparison of the three-dimensional structure of EGCase I (model) and EGCase II (crystal) indicated that a flexible loop hangs over the catalytic cleft of EGCase II but not EGCase I. Deletion of the loop from EGCase II increased the k(cat) of the mutant enzyme, suggesting that the loop is a critical factor affecting the turnover of substrates and products in the catalytic region. Recombinant EGCase I exhibited broad specificity and good reaction efficiency compared with EGCase II, making EGCase I well-suited to a comprehensive analysis of GSLs.


Supersaturating drug delivery system of fixed drug combination: sulfamethoxazole and trimethoprim.
Background: The drug supersaturation in the intestinal lumen for few hours could result in high bioavailability. The goal of this study was the development of a supersaturating drug delivery system containing sulfamethoxazole and trimethoprim at fixed dose combination (sulfamethoxazole:trimethoprim 5:1 w/w). Methods: The amorphous solid dispersions were formed at three different proportions containing 30, 50 and 70% of Eudragit EPO in the formulation. Results: The supersaturation state is formed by the amorphous drugs produced by spray drying technique, and the maintenance of this state is due to the chemical interactions between the drugs and the polymer selected, which was observed in the fluorescence interaction studies realized between the drugs and the polymer. The Formulation containing 70% of the polymer was able to produce and maintain the supersaturated state of both drugs for 24 h. Solid state characterization demonstrated the amorphization of the drugs in the solid dispersion and indicated the hydrogen bond formation responsible for the improvement in the apparent solubility. This formulation presented an improved antibacterial activity when compared to the combination of the drugs. Conclusion: For the first time, a supersaturating drug delivery system was developed to the complementary antibacterial drugs. This ternary formulation is a powerful alternative to improve oral absorption of recognized safety drugs, reducing the dose and consequently the antibiotic resistance emergence.


Nitric oxide is an essential mediator of the protective effects of remote ischaemic preconditioning in a mouse model of liver ischaemia/reperfusion injury.
NO (nitric oxide) may protect the liver from IR (ischaemia/reperfusion) injury. RIPC (remote ischaemic preconditioning) also protects against liver IR injury; however, the molecular mediator(s) of RIPC are currently unknown. The aim of the present study was to assess the role of NO in hindlimb RIPC-induced protection against liver IR injury. Mice were allocated to the following groups: sham group; RIPC group (six cycles of 4×4 min IR of hindlimb); IR group [40 min lobar (70%) hepatic ischaemia and 2-h reperfusion]; RIPC+IR group (RIPC followed by IR group procedures); and C-PTIO [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt]+RIPC+IR group [C-PTIO (a direct NO scavenger) was administered, followed by the RIPC+IR group procedure]. Hepatic MBF (microcirculatory blood flow) was measured throughout the experiment. Circulating NOx (nitrite and nitrate) levels, plasma liver transaminases, hepatic histopathological and TEM (transmission electron microscopy) studies were performed at the end of the experiment. NOx concentrations were significantly elevated (P<0.05) in the RIPC and RIPC+IR groups. Compared with liver IR alone, RIPC+IR preserved hepatic MBF during liver reperfusion (P<0.05). In contrast, C-PTIO+RIPC+IR reduced MBF compared with RIPC+IR (P<0.05). RIPC+IR reduced plasma transaminases (P<0.05), and histopathological and ultrastructural features of injury compared with IR alone. The protective effects of RIPC+IR in reducing liver IR injury were abrogated in the group that received antecedent C-PTIO (C-PTIO+RIPC+IR). In conclusion, NO is an essential mediator of the protection afforded by hindlimb RIPC against liver IR injury. The mechanisms underlying this protection involve preservation of the sinusoidal structure and maintenance of blood flow through the hepatic microcirculation.


More prominent muscle involvement in patients with dermatomyositis with anti-Mi2 autoantibodies.
To define the clinical phenotype of dermatomyositis (DM) with anti-Mi2 autoantibodies. In this longitudinal cohort study, the prevalence and severity of clinical features at disease onset and during follow-up in patients with anti-Mi2-positive DM were compared to patients with anti-Mi2-negative DM, antisynthetase syndrome (AS), and immune-mediated necrotizing myopathy (IMNM). Longitudinal anti-Mi2 autoantibody titers were assessed. A total of 58 patients with anti-Mi2-positive DM, 143 patients with anti-Mi2-negative DM, 162 patients with AS, and 170 patients with IMNM were included. Among patients with anti-Mi2-positive DM, muscle weakness was present in 60% at disease onset and occurred in 98% during longitudinal follow-up; fewer patients with anti-Mi2-negative DM developed weakness (85%; p = 0.008). Patients with anti-Mi2-positive DM were weaker and had higher creatine kinase (CK) levels than patients with anti-Mi2-negative DM or patients with AS. Muscle biopsies from patients with anti-Mi2-positive DM had prominent necrosis. Anti-Mi2 autoantibody levels correlated with CK levels and strength (p < 0.001). With treatment, most patients with anti-Mi2-positive DM had improved strength and CK levels; among 10 with multiple serum samples collected over 4 or more years, anti-Mi2 autoantibody titers declined in all and normalized in 3, 2 of whom stopped immunosuppressant treatment and never relapsed. Patients with anti-Mi2-positive DM had less calcinosis (9% vs 28%; p = 0.003), interstitial lung disease (5% vs 16%; p = 0.04), and fever (7% vs 21%; p = 0.02) than did patients with anti-Mi2-negative DM. Patients with anti-Mi2-positive DM have more severe muscle disease than patients with anti-Mi2-negative DM or patients with AS. Anti-Mi2 autoantibody levels correlate with disease severity and may normalize in patients who enter remission.


Population Outcomes of Three Approaches to Detection of Congenital Hearing Loss.
Universal newborn hearing screening was implemented worldwide largely on modeled, not measured, long-term benefits. Comparative quantification of population benefits would justify its high cost. Natural experiment comparing 3 population approaches to detecting bilateral congenital hearing loss (>25 dB, better ear) in Australian states with similar demographics and services: (1) universal newborn hearing screening, New South Wales 2003-2005, n = 69; (2) Risk factor screening (neonatal intensive care screening + universal risk factor referral), Victoria 2003-2005, n = 65; and (3) largely opportunistic detection, Victoria 1991-1993, n = 86. Children in (1) and (2) were followed at age 5 to 6 years and in (3) at 7 to 8 years. Outcomes were compared between states using adjusted linear regression. Children were diagnosed younger with universal than risk factor screening (adjusted mean difference -8.0 months, 95% confidence interval -12.3 to -3.7). For children without intellectual disability, moving from opportunistic to risk factor to universal screening incrementally improved age of diagnosis (22.5 vs 16.2 vs 8.1 months, P < .001), receptive (81.8 vs 83.0 vs 88.9, P = .05) and expressive (74.9 vs 80.7 vs 89.3, P < .001) language and receptive vocabulary (79.4 vs 83.8 vs 91.5, P < .001); these nonetheless remained well short of cognition (mean 103.4, SD 15.2). Behavior and health-related quality of life were unaffected. With new randomized trials unlikely, this may represent the most definitive population-based evidence supporting universal newborn hearing screening. Although outperforming risk factor screening, school entry language still lagged cognitive abilities by nearly a SD. Prompt intervention and efficacy research are needed for children to reach their potential.


Comparison of procalcitonin, C-reactive protein, white blood cell count and clinical status in diagnosing pneumonia in patients hospitalized with acute exacerbations of COPD: A prospective observational study.
Lower respiratory tract infection is the most common cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The aim of the present study was to compare the accuracy of procalcitonin (PCT), C-reactive protein (CRP) and white blood cell count (WBC) as single diagnostic tests and in combination with clinical signs and symptoms to diagnose pneumonia in patients hospitalized with AECOPD. This was a prospective, single centre observational study. Patients with spirometry-confirmed COPD who were hospitalized due to AECOPD were consecutively recruited at the hospital's Emergency Unit. Pneumonia was defined as a new pulmonary infiltrate on chest X-ray. The values of PCT, CRP and WBC were determined at admission. Receiver operating characteristic (ROC) curve analysis was used to study the accuracy of various diagnostic tests. Of the 113 included patients, 35 (31%) had pneumonia at admission. Area under the ROC curve (AUC) for PCT, CRP and WBC as a single test to distinguish between patients with and without pneumonia was 0.67 (95% CI 0.55-0.79), 0.73 (95% CI 0.63-0.84) and 0.67 (95% CI 0.55-0.79), respectively ( p = 0.42 for the test of difference). The AUC for a model of clinical signs and symptoms was 0.84 (95% CI 0.76-0.92). When biomarkers were added to the clinical model, the AUCs of the combined models were not significantly different from that of the clinical model alone ( p = 0.54). PCT had about the same accuracy as CRP and WBC in predicting pneumonia in patients hospitalized with AECOPD both as a single test and in combination with clinical signs and symptoms.


Cetacean strandings in Costa Rica (1966-1999).
Cetacean strandings in Costa Rica are reported for a period of 33 years, with a total of 35 strandings, 13 species and 247 individuals involved. The vast majority of documented strandings occurred on the Pacific coast and correspond to single individuals (32 and 28 strandings respectively). The highest stranding number was in the period from 1990 to 1999 (n = 24). Physeter catodon (cachalot or sperm whale) is the species with the highest frequency of strandings (n = 8) and the family Delphinidae has the majority of species (n = 8) and strandings (n = 22). No other general tendencies were determined with the existing data.


Association of Daily Physical Activity and Sedentary Behaviour with Protein Intake Patterns in Older Adults: A Multi-Study Analysis across Five Countries.
Physical activity and protein intake are associated with ageing-related outcomes, including loss of muscle strength and functional decline, so may contribute to strategies to improve healthy ageing. We investigated the cross-sectional associations between physical activity or sedentary behaviour and protein intake patterns in community-dwelling older adults across five countries. Self-reported physical activity and dietary intake data were obtained from two cohort studies (Newcastle 85+ Study, UK; LiLACS, New Zealand Māori and Non-Māori) and three national food consumption surveys (DNFCS, The Netherlands; FINDIET, Finland; INRAN-SCAI, Italy). Associations between physical activity and total protein intake, number of eating occasions providing protein, number of meals with specified protein thresholds, and protein intake distribution over the day (calculated as a coefficient of variance) were assessed by regression and repeated measures ANOVA models adjusting for covariates. Greater physical activity was associated with higher total protein intake and more eating occasions containing protein, although associations were mostly explained by higher energy intake. Comparable associations were observed for sedentary behaviour in older adults in Italy. Evidence for older people with higher physical activity or less sedentary behaviour achieving more meals with specified protein levels was mixed across the five countries. A skewed protein distribution was observed, with most protein consumed at midday and evening meals without significant differences between physical activity or sedentary behaviour levels. Findings from this multi-study analysis indicate there is little evidence that total protein and protein intake patterns, irrespective of energy intake, differ by physical activity or sedentary behaviour levels in older adults.


Presence of 2-hydroxyethyl methacrylate (HEMA) and other (meth)acrylates in nail cosmetics, and compliance with EU legislation: An online market survey.
During the last 15-20 years, allergic contact dermatitis from acrylates-containing nail cosmetics (acrylic nails, gel nails, gel nail polish) has been increasingly reported. 2-Hydroxyethyl methacrylate (HEMA) is considered to be the major allergenic culprit; few data on its presence in nail cosmetics are available. To investigate (1) the frequency in which HEMA and di-HEMA trimethylhexyl dicarbamate are present in nail cosmetics; (2) whether nail cosmetics comply with EU regulations; (3) which other (meth)acrylates are present in nail cosmetics and how often. One-line market survey. HEMA was present in nearly 60% of 394 cosmetic nail products and di-HEMA trimethylhexyl dicarbamate in 34%. Mandatory warnings on the packages of products containing HEMA were absent in 35% ('For professional use only') resp. 55% ('Can cause an allergic reaction'). Forty-five other (meth)acrylates were identified, of which the most frequent were hydroxypropyl methacrylate (25%), isobornyl methacrylate (16%) and trimethylolpropane triacrylate (12%). Some ingredient lists mentioned non-INCI names or non-specific names. HEMA was by far the most common ingredient of nail cosmetics, being present in nearly 60% of the products. Violations of EU legislation occurred in >30% (mandatory warnings missing) resp. 10% (mislabelling) of nail cosmetics.


Risk Stratification of Severe Aortic Stenosis With Preserved Left Ventricular Ejection Fraction Using Peak Aortic Jet Velocity: An Outcome Study.
Current guidelines consider aortic valve replacement reasonable in asymptomatic patients with very severe aortic stenosis (AS); however, the definition of very severe AS based on peak aortic jet velocity (Vmax) remains unclear with a 5-m/s cutoff in US guidelines and 5.5 m/s in European guidelines. Because ≈20% of patients with severe AS and preserved left ventricular ejection fraction have Vmax in this range, we aimed to assess the relationship between Vmax and mortality and determine the best threshold to define very severe AS. A total of 1140 patients with severe AS (aortic valve area ≤1 cm2, Vmax ≥4 m/s) and preserved left ventricular ejection fraction were included. The population was divided into 4 groups according to Vmax (4-4.49, 4.5-4.99, 5-5.49, and ≥5.5 m/s). After adjustment for covariates (including surgery), there was no difference in all-cause mortality between Vmax 4 to 4.49 m/s and Vmax 4.5 to 4.99 m/s (P=0.64). Both Vmax 5 to 5.49 m/s and Vmax ≥5.5 m/s exhibited significant excess mortality compared with Vmax 4 to 4.49 m/s (adjusted hazard ratio=1.34 [1.18-1.52]; P<0.001, and 1.28 [1.16-1.41]; P<0.001, respectively). Mortality risk was similar for Vmax 5 to 5.49 m/s and Vmax ≥5.5 m/s (P=0.93). Compared with Vmax <5 m/s, patients with Vmax ≥5 m/s had greater mortality risk (adjusted hazard ratio=1.86 [1.55-2.54]; P<0.001), even in the subgroup of asymptomatic even in the subgroup of asymptomatic patients (adjusted hazard ratio=2.08 [1.25-3.46]; P=0.005). Our results demonstrate the strong relationship between Vmax and mortality in patients with severe AS and preserved left ventricular ejection fraction irrespective of symptoms. Vmax ≥5 m/s at the time of AS diagnosis identifies patients with very severe AS at high risk of death.


Simvastatin versus pravastatin: efficacy and tolerability in patients with primary hypercholesterolemia.
One hundred patients with primary hypercholesterolemia (total plasma cholesterol greater than or equal to 6.2 mmol/L [240 mg/dl]) were enrolled in an open, randomized, parallel comparative study of simvastatin and pravastatin. All patients started or continued a standard lipid-lowering diet for at least six weeks prior to entry into the four-week placebo baseline period. Fifty patients received simvastatin and 50 patients received pravastatin, both at the recommended starting dose of 10 mg/day, for a treatment period of six weeks. Total cholesterol levels were reduced by 24% (from 7.59 mmol/L to 5.80 mmol/L) with simvastatin, and by 15% (from 7.48 mmol/L to 6.35 mmol/L) with pravastatin. Low-density-lipoprotein cholesterol levels were reduced by 33% and 22% and high-density-lipoprotein cholesterol levels were increased by 10% and 7% with simvastatin and pravastatin, respectively. Plasma total triglyceride levels were reduced by 12% with simvastatin and by 6% with pravastatin. Adverse experiences were similar between treatment groups and both drugs were well tolerated. No patients were withdrawn from the study due to clinical adverse experiences; one patient in the pravastatin group required a reduction in dose to 5 mg/day due to insomnia. At the recommended starting dose, simvastatin had a significantly greater lipid-lowering effect than pravastatin. These results may have implications for the appropriate lipid-reduction therapy for patients at risk of coronary heart disease.


Advances in self-assembled injectable hydrogels for cancer therapy.
Non-specific toxicity of chemotherapeutics and evolution of malignant tumors against them are major challenges for existing cancer chemotherapeutic regimens. Engineering of nanomaterials has attempted to minimize the toxicity of anticancer drugs, but systemic delivery of these nanomaterials still imposes many hurdles in their clinical use like burst release of chemotherapeutics and toxicity and immunogenicity associated with excipients of nanomaterials. However, there has been a surge in the development of natural and synthetic nanomaterials to deliver anticancer agents to the diseased (tumor) site as it can minimize the systemic circulation of anticancer drugs and reduce the toxicity-related challenges. Therefore, localized drug delivery is considered as the most effective way to deliver therapeutics but is further challenged by poor biodegradability, high immunogenicity, poor drug entrapment efficacy and inability to maintain sustained release of anticancer agents at the tumor site. This review maps out recent advancements in engineering of low molecular weight hydrogels derived from amino acid, fatty acyl, steroidal lipid and drug conjugated amphiphilic scaffolds. We have summarized the efforts for the development of molecular hydrogels in terms of biocompatibility, therapeutic potential and challenges associated with existing molecular hydrogels for cancer therapy.


Ultrahigh Energy Storage in Tungsten Bronze Dielectric Ceramics Through a Weakly Coupled Relaxor Design.
Dielectric energy-storage capacitors, known for their ultra-fast discharge time and high-power density, find widespread applications in high-power pulse devices. However, ceramics featuring a tetragonal tungsten bronze structure (TTBs) have received limited attention due to their lower energy-storage capacity compared to perovskite counterparts. Herein, we report a TTBs relaxor ferroelectric ceramic based on the Gd0.03 Ba0.47 Sr0.485-1.5 x Smx Nb2 O6 composition, exhibiting an ultrahigh recoverable energy density of 9 J/cm3 and an efficiency of 84% under an electric field of 660 kV/cm. Notably, the energy storage performance of this ceramic shows remarkable stability against frequency, temperature, and cycling electric field. The introduction of Sm3+ doping was found to create weakly coupled polar nanoregions (PNRs) in the Gd0.03 Ba0.47 Sr0.485 Nb2 O6 ceramic. Structural characterizations reveal that the incommensurability parameter increases with higher Sm3+ content, indicative of a highly disordered A-site structure. Simultaneously, the breakdown strength is also enhanced by raising the conduction activation energy, widening the band gap, and reducing the electric field-induced strain. This work presents a significant improvement on the energy storage capabilities of TTBs-based capacitors, expanding the material choice for high-power pulse device applications. This article is protected by copyright. All rights reserved.


T4 RNA ligase as a nucleic acid synthesis and modification reagent.
Oligodeoxyribonucleotides corresponding to portions of the recognition sequence and analogues thereof of the Eco RI restriction endonuclease have been synthesized using T4 RNA ligase. The successive addition of deoxyribonucleoside-3',5'-bisphosphates to preformed deoxyoligomers allowed stepwise oligodeoxyribonucleotide synthesis. Single strand deoxyoligomers were also joined to one another by the enzyme. In addition, biotin, and fluorophore tetramethylrhodamine, and hexylamine have been added to RNA via an ATP-independent RNA ligase reaction using their ADP adducts as substrates. When the beta-substituent on ADP is a good leaving group, e.g. p-nitrophenol or 4-methylumbelliferol, the RNA product is the 2'-(3')-cyclicphosphate derivative.


Mild oxidative damage in the diabetic rat heart is attenuated by glyoxalase-1 overexpression.
Diabetes significantly increases the risk of heart failure. The increase in advanced glycation endproducts (AGEs) and oxidative stress have been associated with diabetic cardiomyopathy. We recently demonstrated that there is a direct link between AGEs and oxidative stress. Therefore, the aim of the current study was to investigate if a reduction of AGEs by overexpression of the glycation precursor detoxifying enzyme glyoxalase-I (GLO-I) can prevent diabetes-induced oxidative damage, inflammation and fibrosis in the heart. Diabetes was induced in wild-type and GLO-I transgenic rats by streptozotocin. After 24-weeks of diabetes, cardiac function was monitored with ultrasound under isoflurane anesthesia. Blood was drawn and heart tissue was collected for further analysis. Analysis with UPLC-MSMS showed that the AGE Nε-(1-carboxymethyl)lysine and its precursor 3-deoxyglucosone were significantly elevated in the diabetic hearts. Markers of oxidative damage, inflammation, and fibrosis were mildly up-regulated in the heart of the diabetic rats and were attenuated by GLO-I overexpression. In this model of diabetes, these processes were not accompanied by significant changes in systolic heart function, i.e., stroke volume, fractional shortening and ejection fraction. This study shows that 24-weeks of diabetes in rats induce early signs of mild cardiac alterations as indicated by an increase of oxidative stress, inflammation and fibrosis which are mediated, at least partially, by glycation.


"Tender Care": Iranian Women's Needs to Cope with Hysterectomy and Oophorectomy- A Qualitative Content Analysis Study.
Gynecological surgeries associated with loss of feminine organs evoke more personal, interpersonal and psychological distress that may diminish women's quality of life. Women need and seek support to cope with various distresses which may change over the course of diagnosis to treatment. This study aimed to explore Iranian women's needs to cope with hysterectomy and oophorectomy. This qualitative study was conducted in Kerman and Tehran, Iran from 2015 to 2017. Thirty interviews were conducted with 28 eligible participants including 24 main participants including one gynecologist, one midwife and one nursing faculty member, one gynecologist and one midwife and 2 husbands. They were recruited through purposeful sampling. Data were collected through semi-structured and in-depth interviews and analyzed with Graneheim and Lundman's method of conventional content analysis. The trial version of the MAX QDA 10 Software was used to manage the coding process. "Tender care" emerged as the main theme. It was comprised of three categories: "to be well-informed, "to be treated with compassion in healthcare setting", and "to be welcomed in the society". Women after hysterectomy/oophorectomy were preoccupied with many physical and emotional concerns. They need a whole package of care which consists of proper information to know what to do, a well-prepared/trained healthcare setting to meet their needs, and visibility in the society as a whole person. A multidisciplinary approach must be activated to meet their coping requirements and it is necessary to address these needs in each level of healthcare services.