Population vulnerability to heat: A case-crossover analysis of heat health alerts and hospital morbidity data in Victoria, Australia.
From 2010 to 2022, the Victorian Department of Health operated a heat health alert system. We explored whether changes to morbidity occurred during or directly after these alerts, and how this differed for certain population groups. We used a space-time-stratified case-crossover design and conditional logistic regression to examine the associations between heat health alerts and heat-related and all-cause emergency department (ED) presentations and hospital admissions at the state-wide level, with models created for the whole population and subgroups. Data were included for the warm season (November-March) from 2014 to 2021. Increases occurred in heat-related ED presentations (OR 1.73, 95% CI: 1.53-1.96) and heat-related hospital admissions (OR 1.23, 95% CI: 1.16-1.30) on days on or after heat health alerts. Effect sizes were largest for those 65 years and older, Aboriginal and Torres Strait Islander people, and those living in the most disadvantaged areas. We confirm that increases in morbidity occurred in Victoria during heat health alerts and describe which population groups are more likely to require healthcare in a hospital. These findings can inform responses before and during periods of extreme heat, data-driven adaptation strategies, and the development of heat health surveillance systems.


Intestinal permeability, gastric intramucosal pH, and systemic endotoxemia in patients undergoing cardiopulmonary bypass.
To examine the relationship between gastric intramucosal pH, intestinal permeability, endotoxemia, and oxygen delivery in patients undergoing cardiopulmonary bypass (CPB). Prospective, observational study. Tertiary care center. Fifty patients undergoing elective cardiac surgery and 10 patients awaiting elective cardiac surgery. Patients received chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) as a marker of intestinal permeability; insertion of a nasogastric tonometer to measure intramucosal pH (pHi); insertion of a pulmonary artery catheter to measure systemic oxygen delivery and consumption variables; arterial blood sampling for plasma endotoxin by the Limulus amebocyte lysate assay; and blood and urine sampling for measurement of 51Cr-EDTA. Systemic oxygen delivery, duration of gastric mucosal acidosis, absorption of 51Cr-EDTA, appearance of systemic endotoxemia, renal dysfunction, and duration of hospital stay. Median (range) 24-hour urinary recovery of 51Cr-EDTA in patients was 10.6% (2.1% to 40.2%) while that in controls was 1.2% (0.7% to 2.0%, P<.001). Intestinal permeability increased during CPB. The median (range) for the lowest pHi after bypass was 6.98 (6.74 to 7.17). The pHi did not decline until CPB was discontinued and the heart took over the load of the circulation. Endotoxin was detectable (>0.2 endotoxin unit per milliliter) in the plasma of 21 patients (42%) during the study, most of whom were endotoxemic by the end of CPB. There was no evident relationship between the degree of gut permeability, endotoxemia, gut ischemia, or systemic oxygen dynamics. Cardiopulmonary bypass is associated with increases in gut permeability, which precede gut mucosal ischemia. In cardiac surgical patients, a low pHi is not necessarily indicative of an adverse clinical outcome. Endotoxemia as measured by the Limulus amebocyte lysate assay is common. The increased intestinal absorption of 51Cr-EDTA and gastric mucosal acidosis occur as independent phenomena and are not related in severity or time of onset.


Hyaluronic acid, CD44 and RHAMM regulate myoblast behavior during embryogenesis.
Hyaluronic acid (HA) is an extracellular matrix (ECM) component that has been shown to play a significant role in regulating muscle cell behavior during repair and regeneration. For instance, ECM remodeling after muscle injury involves an upregulation in HA expression that is coupled with skeletal muscle precursor cell recruitment. However, little is known about the role of HA during skeletal muscle development. To gain insight into the way in which HA mediates embryonic myogenesis, we first determined the spatial distribution and gene expression of CD44, RHAMM and other HA related proteins in embryonic day (E)10.5 to E12.5 murine forelimbs. While HA and CD44 expression remained high, RHAMM decreased at both the protein (via immunohistochemistry) and RNA (via qPCR) levels. Next, we determined that 4-methylumbelliferone-mediated knockdown of HA synthesis inhibited the migration and proliferation of E11.5/E12.5 forelimb-derived cells. Then, the influence of CD44 and RHAMM on myoblast and connective tissue cell behavior was investigated using antibodies against these receptors. Anti-RHAMM, but not anti-CD44, significantly decreased the total distance myogenic progenitors migrated over 24 h, whereas both inhibited connective tissue cell migration. In contrast, anti-CD44 inhibited the proliferation of connective tissue cells and muscle progenitors, but anti-RHAMM had no effect. However, when myoblasts and connective tissue cells were depleted of CD44 and RHAMM by shRNA, motility and proliferation were significantly inhibited in both cells indicating that blocking cell surface-localized CD44 and RHAMM does not have as pronounced effect as global shRNA-mediated depletion of these receptors. These results show, for the first time, the distribution and activity of RHAMM in the context of skeletal muscle. Furthermore, our data indicate that HA, through interactions with CD44 and RHAMM, promotes myogenic progenitor migration and proliferation. Confirmation of the role of HA and its receptors in directing myogenesis will be useful for the design of regenerative therapies that aim to promote the restoration of damaged or diseased muscle.


Percutaneous pulmonary valve implantation: 5 years of follow-up: does age influence outcomes?
Percutaneous pulmonary valve implantation (PPVI) is a safe, less invasive alternative to surgical valve replacement for the congenital heart disease patient with right ventricular (RV) outflow tract dysfunction. The aim of this study was to determine whether reverse RV remodeling after PPVI was persistent in the longer term and whether timing of PPVI influenced outcomes. Consecutive patients from the pediatric and adult congenital heart disease programs were enrolled. Cardiac MRI, echocardiography, metabolic exercise testing, chest radiography, and hemodynamics before intervention were compared with repeated follow-up measurements to assess changes over time. Fifty-one patients (including 23 patients <16 years old) were followed for a mean 4.5±1.9 (0.9-6.9) years after implantation, 59% of patients having available comparative cardiac MRI data. Freedom from any reintervention was 87% and 68% at 3 and 5 years, and freedom from surgery was 90% at 5 years. For every decade younger at implantation, there was an increase of 3.9%±1.0% in cardiac MRI left ventricular ejection fraction (P<0.001) and 2.4±0.9 mL/kg/min in maxVO2 (P=0.005) and a decrease of 0.7±0.2 cm in RV end-diastolic dimension (P<0.001) after intervention. Younger patients displayed an additional decline in the RV/left ventricular end-diastolic volume ratio (P=0.05) and trended toward improved RV ejection fraction in late follow-up (50%±7% versus 41%±12%, P=0.07). This is the largest series to show that PPVI at a younger age yields incremental improvements in RV size and maximum oxygen consumption. Early valve implantation is associated with better RV function and should be considered in management planning for this population.


Emotional support for diabetes management: an international cross-cultural study.
The purpose of this study was to explore how emotional support emerged in interactions between peer supporters (PSs) and adults living with type 2 diabetes. Qualitative data were analyzed from 22 semistructured interviews with PSs in 3 settings: low-income Latinos in Chicago, middle-class Caucasians in the United Kingdom, and low-income African American women in North Carolina. Emotional support was defined as expressions of empathy, trust, and caring. Across all sites, emotional support gradually emerged over time, was often combined with informational support, and was conveyed both implicitly (through nonverbal actions connoting emotional acceptance; eg, a walk together without discussion of problems) and explicitly (eg, by reassurance or discussion of stressors). Cross-site differences did appear regarding the strategies to address barriers to diabetes management (eg, PSs in North Carolina and Chicago reported providing support for social stressors) and the role of PSs (eg, PSs in Chicago reported providing directive support). Across different settings and populations, emotional support for diabetes management evolved over time, was often integrated with informational support, and emerged through both implicit and explicit strategies that addressed varied context-specific stressors.


Lung ultrasound reduces the number of chest X-rays in newborns with pneumothorax.
Aim of the study: To determine the impact of lung ultrasonography as an imaging method used to diagnose and monitor newborns with symptomatic pneumothorax and to assess the risk factors for pneumothorax and the outcomes in newborns with symptomatic pneumothorax. Material and methods: A single-centre retrospective study enrolled patients born after 32 weeks of gestation, with a diagnosis of pneumothorax in the first week of life. The 118 patients who were included in the study were divided into two groups. Group A (51 infants) comprised those children who were treated between 2007 and 2010, while group B (n=67) those from the years 2013 to 2016. The children from group A were monitored with repeated chest X-rays. Those from group B received repeated lung ultrasonography supported by chest X-ray in those cases where there was diagnostic uncertainty. Comparison was made between the groups with respect to pneumothorax risk factors, treatment methods and the use of imaging during the period of treatment. The statistical analysis used χ2, Mann-Whitney and Student's t-tests. Results: There were no significant demographic or clinical differences between the two groups. Both the use of nCPAP (nasal continuous positive airway pressure) (p<0.001) and diagnosed perinatal asphyxia (p=0.036) were higher in group B. Congenital pneumonia occurred more often in group A (p=0.041). Earlier detection of pneumothorax (p=0.001) and shorter hospital stay (p=0.03) were observed in group B. However, the total number of imaging (lung ultrasound and chest X-ray combined) was higher (p<0.001) in group B. Conclusion: This study confirmed the usefulness of lung ultrasound in monitoring newborns with pneumothorax, moreover significantly limiting X-ray radiation.


Structural disorder in molecular framework materials.
It is increasingly apparent that many important classes of molecular framework material exhibit a variety of interesting and useful types of structural disorder. This tutorial review summarises a number of recent efforts to understand better both the complex microscopic nature of this disorder and also how it might be implicated in useful functionalities of these materials. We draw on a number of topical examples including topologically-disordered zeolitic imidazolate frameworks (ZIFs), porous aromatic frameworks (PAFs), the phenomena of temperature-, pressure- and desorption-induced amorphisation, partial interpenetration, ferroelectric transition-metal formates, negative thermal expansion in cyanide frameworks, and the mechanics and processing of layered frameworks. We outline the various uses of pair distribution function (PDF) analysis, dielectric spectroscopy, peak-shape analysis of powder diffraction data and single-crystal diffuse scattering measurements as means of characterising disorder in these systems, and we suggest a number of opportunities for future research in the field.


Correlation of D-dimer and Outcomes in COVID-19 Patients.
The coronavirus disease 2019 (COVID-19) global pandemic has impacted daily life and medical practices around the world. Hospitals are continually making observations about this unique population as it relates to laboratory data and outcomes. Plasma D-dimer levels have been shown to be promising as a prognostic factor for outcomes in COVID-19 patients. This single institution retrospective study investigates the correlation between D-dimer and patient outcomes in our inpatient COVID-19 patient population. COVID-19 confirmed positive patients who were admitted between March 2020 and May 2020 at our hospital were identified. Admission and peak D-dimer values and patient outcomes, including intubation and mortality, were retrospectively analyzed. Ninety-seven patients met criteria for inclusion in the study Mean age was 63.2 years, median admission D-dimer 2.35ug/mL, and median peak D-dimer 2.74ug/mL. Average time to peak D-dimer was 3.2 days. Patient's requiring intubation had higher admission D-dimers (3.79ug/mL vs. 1.62 ug/mL). Higher admission and peak D-dimer values were associated with worsening clinical outcomes, specifically with higher rates of intubation and mortality. Noting D-dimer trends early in a patients' COVID course, regardless of patients' clinical condition, may allow opportunities for physicians to provide early intervention to prevent these outcomes.


Metastable states and quasicycles in a stochastic Wilson-Cowan model of neuronal population dynamics.
We analyze a stochastic model of neuronal population dynamics with intrinsic noise. In the thermodynamic limit N→∞ , where N determines the size of each population, the dynamics is described by deterministic Wilson-Cowan equations. On the other hand, for finite N the dynamics is described by a master equation that determines the probability of spiking activity within each population. We first consider a single excitatory population that exhibits bistability in the deterministic limit. The steady-state probability distribution of the stochastic network has maxima at points corresponding to the stable fixed points of the deterministic network; the relative weighting of the two maxima depends on the system size. For large but finite N , we calculate the exponentially small rate of noise-induced transitions between the resulting metastable states using a Wentzel-Kramers-Brillouin (WKB) approximation and matched asymptotic expansions. We then consider a two-population excitatory or inhibitory network that supports limit cycle oscillations. Using a diffusion approximation, we reduce the dynamics to a neural Langevin equation, and show how the intrinsic noise amplifies subthreshold oscillations (quasicycles).


Characterization of the proteins of guinea-pig hair and hair-follicle tissue.
This work forms a part of a study of the mechanism and control of protein synthesis in the hair follicle and concerns the characterization of the proteins of hair-follicle tissue and for comparative reasons those of the hair itself. 1. Five different groups of reduced carboxymethylated proteins were delineated from both tissues; these were: group 1A proteins, which appeared to be aggregates of the group 2 proteins; group 1B proteins, soluble at pH4.4, which were thought to originate from the medulla and inner-rootsheath layers; group 2 proteins, which were defined as the main low-sulphur keratin proteins insoluble at pH4.4; group 3 proteins, the precise origin of which is not known; and the group 4 proteins, which were defined as the main high-sulphur keratin proteins soluble at pH4.4. 2. With the single exception of the group 1B proteins, the types and properties of all hair and hair-follicle proteins were identical as far as could be determined by use of such criteria as multiplicity of components, molecular charge, molecular weight and amino acid composition. 3. Two significant quantitative differences were noted: in follicle extracts there were more group 2 proteins but less group 3 and group 4 proteins than in hair extracts; and secondly, in the follicle group 4 proteins, there were more proteins of lowest molecular weight and S-carboxymethylcysteine content, but fewer proteins of the highest molecular weight and S-carboxymethylcysteine conent than in the hair group 4 proteins. 4. These quantitative differences are discussed in terms of the mechanism of synthesis of the keratin proteins. 5. Follicle group 1B proteins are postulated to have arisen from the trichohyalin droplets of the developing medulla and inner-root-sheath layers of the follicle and may be precursors of the proteins of the mature medulla and inner root sheath.


Induction of the ara operon of Escherichia coli B-r.
The inducer specificity and kinetics of induction of the ara operon were examined in Escherichia coli B/r. A difference in the kinetics of induction was found between our B/r strains and the K-12 strain previously described by Schleif. The roles of active transport and metabolism of inducer, and of cell density, in induction were studied. d-Fucose and beta-methyl-l-arabinoside were competitive inhibitors of induction. No inducer of the wild-type strain other than l-arabinose was found. However, a procedure for selecting mutants with altered inducer affinity or specificity was developed. The properties of one such mutant (inducible by d-fucose) are described.


Octogenarians in the ICU: are you ever too old?
Long-term morbidity and mortality rates for older patients admitted to the ICU remain substantial. In this issue of Critical Care, Roch and colleagues describe a retrospective study evaluating factors associated with survival and quality-of-life of octogenarians (aged ≥80 years) admitted to a medical ICU. This study proposes to address a highly relevant and increasingly encountered scenario in ICUs - what factors can best estimate prognosis for elderly patients at the time of evaluation for ICU admission? While perhaps not unique to octogenarians, such data have the potential to better inform on decision-making regarding advanced life support along with facilitating discussion on the perceived benefit and on patient treatment preferences concerning intensive care.


Chromosome dynamics during interphase: a biophysical perspective.
The dynamic nature of chromosome organization plays a central role in the regulation of many crucial processes, such as DNA transcription and replication. However, the molecular bases of the link between genomic function, structure and dynamics remain elusive. In this review, we focus on how biophysical modelling can be instrumentally used to rationalize experimental studies of chromosome dynamics, and to probe the impact of putative mechanisms on genome folding kinetics during interphase. We introduce the general connection between chromatin internal organization and dynamics, and outline the potential effects of passive interactions mediated by architectural proteins and of active, energy-dependent processes on chromatin motion. Finally, we discuss current ambiguities emerging from in vivo observations, in particular related to ATP depletion and transcriptional activation, and highlight future perspectives.


PIGMENTED VILLONODULAR SYNOVITIS IN A RETICULATED GIRAFFE (GIRAFFA CAMELOPARDALIS).
: A 17-yr-old, female, captive-born reticulated giraffe ( Giraffa camelopardalis ) presented with acute-onset lameness of the right metacarpophalangeal (fetlock) joint. Despite multiple courses of treatment, the lameness and swelling progressively worsened over a 3.5-yr period, and the giraffe was euthanized. At necropsy, gross and microscopic changes in the right, front fetlock and associated flexor tendon sheath included villous synovial hyperplasia and the formation of discrete pigmented nodules within synovial membranes. Histologically, the nodules were composed of abundant, fibrous connective tissue with heavy macrophage infiltration, hemosiderin deposition, and distinctive, multinucleated cells that resembled osteoclasts. These findings were consistent with pigmented villonodular synovitis (PVNS), a rare condition affecting both humans and animals. Although the pathophysiology of PVNS is poorly understood, lesions exhibit features of both neoplastic and reactive inflammatory processes. This case report represents, to the authors' knowledge, the first description of PVNS in a nondomestic ungulate.


Deficit Effect Sizes and Correlations of Auditory Event-Related Potentials at First Hospitalization in the Schizophrenia Spectrum.
The N1, P2, and P3 event-related potentials (ERPs) are impaired in first-episode schizophrenia (FESz). Reduced pitch-deviant mismatch negativity (MMN) is present in chronic schizophrenia but not FESz. We examined effect sizes of, and correlations between, N1, P2, P3, and MMN in 106 FESz and 114 matched psychiatrically well controls to determine which ERPs maximally differentiated groups, and whether late sensory/perceptual deficits (N1, P2) affected preattentive memory (MMN) and conscious attention (P3). Furthermore, we compared hallucinators and nonhallucinators within FESz. Participants completed 1 of 3 oddball tasks, silently counting target tones among standard tones. Sixty-seven FESz and 72 matched participants also completed pitch-deviant MMN testing. Measures were z-scored from task appropriate controls before merging samples. Mean z-scores for N1, P2, and P3 were significantly abnormal in FESz, while pitch-deviant MMN was not. N1 showed the largest deficit (z = 0.53), and only N1 was smaller in hallucinators (n = 71) than nonhallucinators (n = 27). Among all participants, early sensory processing (N1, P2) correlated with later cognitive processing (P3), and P2 and P3 also correlated with automatic preattentive memory (pitch-deviant MMN). In well individuals, N1 was associated with MMN. These data are consistent with bottom-up sensory/perceptual processes affecting more cognitive processes. However, N1 and MMN were not associated in FESz, suggesting different auditory cortex physiology underlie these ERPs, which is differentially affected in FESz. Larger P2 and P3 with greater estimated premorbid intellect in patients indicate a possible neuroprotective effect of intellect in FESz.


How is whole body protein turnover perturbed in growth hormone-deficient adults?
Adult patients with GH deficiency have reduced lean body mass (LBM), muscle mass, and muscle strength, suggesting an underlying abnormality of protein metabolism. As acute GH administration has previously been reported to decrease protein oxidation and increase protein synthesis in GH-deficient (GHD) adults, we investigated whether the converse might occur in untreated GH deficiency by undertaking studies of whole body protein turnover in 10 GHD and 13 normal subjects using a 3-h primed constant infusion of 1-[13C]leucine. Dual energy x-ray absorptiometry was used to quantify LBM and fat mass (FM). In normal subjects, LBM was the major, independent determinant of leucine appearance (Ra; r=0.80; P=0.0009), leucine oxidation (r=0.81; P=0.0008), and leucine incorporation into protein (r=0.75; P= 0.003). However, in an analysis of covariance, FM was also a significant independent determinant of leucine Ra (P=0.002) and leucine incorporation into protein (P=0.003). After correcting for LBM and FM, GHD patients had significantly reduced rates of leucine Ra (109.9+/-4.4 vs. 125.5+/-3.7 micromol/min, respectively; P=0.02) and leucine incorporation into protein (87.0+/-3.9 vs. 100.3+/-3.3 mmol/ min; P=0.02) compared to normal subjects. There was no significant difference in the corrected rates of leucine oxidation between the two groups (22.9+/-1.3 vs. 25.2+/-1.0, GHD vs. normal; P=0.20). In summary, GHD adults have reduced rates of protein synthesis and protein breakdown, but normal rates of irreversible oxidative loss; these findings are discordant with what was predicted from the acute changes in protein metabolism observed with GH administration. We conclude that normalization of protein oxidation may be a homeostatic mechanism that operates to constrain protein loss in GHD adults.


Comparing Machine Learning Techniques for Blood Glucose Forecasting Using Free-living and Patient Generated Data.
Managing a chronic disease like Type 1 diabetes (T1D) is both challenging and time consuming, but new technologies that allow continuous measurement of glucose and delivery of insulin have led to significant improvements. The development of an artificial pancreas (AP), which algorithmically determines insulin dosing and delivers insulin in a fully automated way, may transform T1D care but it is not yet widely available. Patient-led alternatives, like the Open Artificial Pancreas (OpenAPS), are being used by hundreds of individuals and have also led to a dramatic increase in the availability of patient generated health data (PGHD). All APs require an accurate forecast of blood glucose (BG). While there have been efforts to develop better forecasts and apply new ML techniques like deep learning to this problem, methods are often tested on small controlled datasets that do not indicate how they may perform in reality - and the most advanced methods have not always outperformed the simplest. We introduce a rigorous comparison of BG forecasting using both a small controlled research dataset and large heterogeneous PGHD. Our comparison advances the state of the art in BG forecasting by providing insight into how methods may fare when moving beyond small controlled studies to real-world use.


The association of cannabis use and cardiac dysrhythmias: a systematic review.
Introduction: Cannabis use results in elevation of heart rate and blood pressure immediately after use, primarily due to sympathetic nervous system stimulation and parasympathetic nervous system inhibition. These effects may precipitate cardiac dysrhythmia. The objective of our study was to analyze systematically the pertinent medical literature regarding the putative association between cannabis use and cardiac dysrhythmia.Methods: We queried PubMed, Google Scholar, and OpenGrey, and reviewed results for relevance. We graded clinical trials, observational and retrospective studies, case series and reports using Oxford Centre for Evidence-Based Medicine guidelines.Results: The relevant publications identified included one Level I systematic review and meta-analysis of six human studies, 16 Level II studies with 6,942 subjects, nine Level III studies with 3,797,096 subjects and two systematic and scoping reviews with 30 cases. Cannabis-induced tachycardia was highlighted in 17 of 28 (61%) Level I-III articles followed by a generalized description of dysrhythmia in eight (29%). Specific dysrhythmias noted in the Level I-III articles included atrial fibrillation, atrial flutter, atrioventricular block, premature ventricular contractions, premature atrial contractions, ventricular tachycardia, and ventricular fibrillation. Other reported findings on electrocardiogram included ST segment elevation, P, and T wave changes. Only one Level III study reported a decreased risk of atrial fibrillation from cannabis use in patients hospitalized for heart failure (Odds ratio = 0.87). There were 39 case series (Level IV) and case reports (Level V) with 42 subjects. Average age was 30 ± 12 years, and only ten (24%) were female. The most common dysrhythmia mentioned in the Level IV and V articles was ventricular fibrillation (21%), followed by atrial fibrillation (19%), ventricular tachycardia (12%), third degree atrioventricular block (12%), and asystole (12%). There were four cases (10%) of symptomatic bradycardia. Notable electrocardiographic changes included ST segment elevation (29%), Brugada pattern in leads V1, V2 (14%), and right bundle branch block (12%). There were eight cases of cardiac arrest, of whom five expired.Conclusion: Cannabis use is associated with increased risk of cardiac dysrhythmia, which is rare but may be life-threatening. Clinicians and nurses should inquire about acute and chronic cannabis use in their patients presenting with tachycardia, bradycardia, dysrhythmia, chest pain, and/or unexplained syncope. Patients who use cannabis should be educated on this deleterious association, especially those with underlying cardiac disease or risk factors.


Heart rate-dependent stiffening of large arteries in intact and sympathectomized rats.
In the anesthetized rat, acute increases in heart rate are accompanied by a reduction in arterial distensibility, which is a significant phenomenon in elastic-type vessels such as the common carotid but much less evident in muscle-type vessels such as the femoral artery. Because the sympathetic nervous system importantly reduces arterial distensibility, the present study aimed to determine whether sympathetic influences (1) are involved in the heart rate-dependent changes in arterial distensibility and (2) exert differential effects on elastic-type versus muscle-type arteries. To address this issue, 9 sympathectomized (6-hydroxydopamine) and 10 vehicle-treated, 12-week-old, pentobarbitone-anesthetized Wistar-Kyoto rats were subjected to atrial pacing via a transjugular catheter at 5 different randomly sequenced rates (280, 310, 340, 370, and 400 bpm). After each step, spontaneous sinus rhythm was allowed to return to normal. Common carotid and femoral artery diameters were measured by an echo Doppler device (NIUS 01), and blood pressure was measured via catheter inserted into the contralateral vessel. Arterial distensibility was calculated over the systolic-diastolic pressure range according to the Langewouters formula. In the common carotid artery, progressive increases in heart rate determined progressive and marked reductions of distensibility (range, 15% to 43%) in sympathectomized and intact rats. In the femoral artery, the stiffening effect of tachycardia was present in sympathectomized rats (range, 21% to 42%), at variance with the inconsistent changes observed in intact rats. In conclusion, our experiments support the notions (1) that in predominantly elastic-type arteries, the stiffening effect of tachycardia is exerted independently of sympathetic modulation of the vessel wall properties and (2) that in predominantly muscle-type arteries, removal of sympathetic influences unmasks the stiffening effect of tachycardia.


[Bacteriophage T2 DNA modification by O-methylhydroxylamine].
A comparative study of the reactivities of free 5-hydroxymethylcytosine (5-HMC) and 5-HMC found in the composition of native, denaturated and intraphage DNA of the T2 phage with that of O-methylhydroxylamine (OMHA) demonstrated that the DNA secondary structure in situ is partially disturbed. The interaction DNA-protein in the phage particle channels the reaction into a predominant formation of 4N-methoxy-6-methoxyamino-5,6-dihydro-5-hydroxymethyl cytosine, but not 4N-methoxy-5-hydroxymethyl cytosine, which is formed in vitro. In the course of the reaction the interaction DNA-protein is probably fixed by covalent binding.


Cathelicidin LL-37: LPS-neutralizing, pleiotropic peptide.
Human organism, constantly exposed to a large variety of pathogenic microorganisms and their products, such as lipopolysaccharide (LPS), developed innate immunity as a first line of defence. One of the compartments of our organism well equipped with these defence mechanisms is the respiratory system. The cells lining the airways respond to the presence of virulent microorganisms by producing natural antimicrobial peptides, including the only member of the cathelicidins family found to date in humans, peptide LL-37. LL-37 is a small peptide of 37 amino acid residues. The peptide, in addition to its bactericidal effect, plays numerous roles in inflammatory and tissue remodelling processes. It stimulates angiogenesis, induces proliferation of lung epithelial cells, accelerates wound closure of the airway epithelium, and provokes cytokine release (e.g. IL-8) and cell migration. LL-37 is also able to neutralize LPS, a heteropolymer associated with organic dust, produced by Gram-negative bacteria. LPS (commonly referred to as endotoxin) plays an important role in pathogenesis of many respiratory diseases caused by organic dust, including organic dust toxic syndrome and chronic illnesses such as chronic obstructive pulmonary disease (COPD), asthma or allergic alveolitis (hypersensitivity pneumonitis). LPS is a strong pro-inflammatory stimulus, inducing in respiratory airways expression of antimicrobial peptides, including LL-37, which is in turn a potent LPS-neutralizing factor. The article discusses the complex interplay between endotoxin and the LPS-neutralizing, pleiotropic peptide LL-37 in pathogenic mechanisms of lung diseases, with regard to closer perspectives of using LL-37 and its derivatives as therapeutic agents.


Fumitoxins, new mycotoxins from Aspergillus fumigatus Fres.
Extracts of cultures of Aspergillus fumigatus isolated from silage were lethal to chicken embryos. Using this test and thin-layer chromatography, four UV-absorbing toxins, designated as fumitoxins A, B, C and D, were isolated. Analysis and mass spectrometry of crystallized fumitoxin A, the most abundant in the extract, established its molecular formula to be C31H42O8. Infrared, UV spectroscopy, and chemical reactions suggested that fumitoxin A is a steroid. Fumitoxins appear to be clearly different from the previously described toxins recognized in A. fumigatus.


Does acute-phase beta blockade reduce left atrial appendage function in patients with chronic nonvalvular atrial fibrillation?
To investigate whether acute-phase beta-blocker therapy has a harmful effect on left atrial appendage (LAA) function in patients with chronic nonvalvular atrial fibrillation by transesophageal echocardiography (TEE), we evaluated 21 patients with normal left ventricular systolic function and a poorly controlled ventricular rate, despite the use of digoxin. Baseline parameters that were obtained included heart rate, blood pressure, LAA emptying velocities, and left atrial spontaneous echo contrast intensity. Then, each patient was given a bolus dose of 5 mg metoprolol. Ten minutes later, a second set of assessments was performed. After the first TEE studies, each patient began treatment with metoprolol (50 mg orally twice daily for 1 week). A second TEE study was performed after 1 week of continuous oral metoprolol therapy at maintenance dose, and values were again determined. The average resting apical heart rate was 91 +/- 7 bpm. As expected, beta-blocker therapy showed a marked decrease in heart rate at 10 minutes (79 +/- 6 bpm, P <.001) and at 1 week (71 +/- 4 bpm, P <.001). Beta-blocker therapy caused a significant reduction in systolic and diastolic blood pressures (144 +/- 16 / 93 +/- 6 mm Hg at baseline, 137 +/- 16 / 87 +/- 9 mm Hg at 10 minutes, and 135 +/- 12 / 86 +/- 8 mm Hg at 1 week, P <.001). With the beta-blocker therapy, the baseline transesophageal Doppler parameter of LAA emptying velocities (at baseline 24 +/- 7 cm/s) fell significantly at 10 minutes (19 +/- 7 cm/s, P <.001) and at 1 week (17 +/- 6 cm/s, P <.001) after initiation of beta-blocker therapy. After a bolus of metoprolol, spontaneous echo contrast intensity did not change in any patients, but 1 week later, it increased in 1 patient. In 2 patients who had not been found to have an LAA thrombus at baseline TEE study, the second TEE examination demonstrated new thrombi in the LAA. In conclusion, our findings suggest that in patients with chronic nonvalvular atrial fibrillation who have normal left ventricular systolic function and a poorly controlled ventricular rate despite the use of digoxin, acute-phase beta blockade may have a harmful effect on LAA function.


Recent advances in osmium-catalyzed hydrogenation and dehydrogenation reactions.
CONSPECTUS: A current issue in metal-catalyzed reactions is the search for highly efficient transition-metal complexes affording high productivity and selectivity in a variety of processes. Moreover, there is also a great interest in multitasking catalysts that are able to efficiently promote different organic transformations by careful switching of the reaction parameters, such as temperature, solvent, and cocatalyst. In this context, osmium complexes have shown the ability to catalyze efficiently different types of reactions involving hydrogen, proving at the same time high thermal stability and simple synthesis. In the catalytic reduction of C═X (X = O, N) bonds by both hydrogenation (HY) and transfer hydrogenation (TH) reactions, the most interest has been focused on homogeneous systems based on rhodium, iridium, and in particular ruthenium catalysts, which have proved to catalyze chemo- and stereoselective hydrogenations with remarkable efficiency. By contrast, osmium catalysts have received much less attention because they are considered less active on account of their slower ligand exchange kinetics. Thus, this area remained almost neglected until recent studies refuted these prejudices. The aim of this Account is to highlight the impressive developments achieved over the past few years by our and other groups on the design of new classes of osmium complexes and their applications in homogeneous catalytic reactions involving the hydrogenation of carbon-oxygen and carbon-nitrogen bonds by both HY and TH reactions as well as in alcohol deydrogenation (DHY) reactions. The work described in this Account demonstrates that osmium complexes are emerging as powerful catalysts for asymmetric and non-asymmetric syntheses, showing a remarkably high catalytic activity in HY and TH reactions of ketones, aldehydes, imines, and esters as well in DHY reactions of alcohols. Thus, for instance, the introduction of ligands with an NH function, possibly in combination with a pyridine ring, led to a new family of [OsCl2(PP)(NN)] (NN = diamine, 2-aminomethylpyridine; PP = diphosphine) and pincer [OsCl(CNN)(PP)] (HCNN = 6-aryl-2-aminomethylpyridine, 2-aminomethylbenzo[h]quinoline) complexes, which are outstanding catalysts for (asymmetric) HY and TH of carbonyl compounds and DHY of alcohols with turnover numbers and turnover frequencies up to 10(5) and 10(6) h(-1), respectively. In addition, PNN osmium complexes containing the 2-aminomethylpyridine motif have been found to be among the most active catalysts for HY of esters. These complexes have shown catalytic activities that are comparable and in some cases superior to those reported for analogous ruthenium systems. These results give an idea of the potential of Os complexes for the design of new highly productive and robust catalysts for the synthesis of chiral and nonchiral alcohols and amines as well as ketones from alcohols. Thus, we hope that this report will promote increased interest in the chemistry of these metal complexes, opening novel opportunities for new catalytic processes as well as the improvement of existing ones.


No strings attached!
Many governors want to convert medicaid to a block grant and do away with the myriad federal rules that have vastly expanded the program's reach in recent years. Congress may oblige them. But groups that fought for the rules aren't going to sit still.


Safety and efficacy of low molecular weight heparins for hemodialysis in patients with end-stage renal failure: a meta-analysis of randomized trials.
Low molecular weight heparins (LWMH) are the preferred initial treatment for many thromboembolic disorders but are renally excreted and relatively contraindicated in patients with renal failure because of concerns of increased bleeding risks. The purpose of this study was to evaluate the safety and efficacy of LMWH compared with unfractionated heparin (UFH) for preventing thrombosis of the extracorporeal dialysis circuit. Studies were identified with the use of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and FirstSearch; reference lists were reviewed; and pharmaceutical companies were contacted. Randomized, controlled trials that compared an LMWH with another anticoagulant during hemodialysis in patients with ESRD and reported at least one of bleeding, extracorporeal circuit thrombosis, or anti-Xa levels were chosen. Two reviewers independently extracted data on methodologic quality, study design, clinical outcomes, and anti-Xa levels. Seventeen trials were included in this systematic review, 11 of which were included in the meta-analysis. It was found that LMWH did not significantly affect the number of bleeding events (relative risk, 0.96; 95% confidence interval [CI], 0.27 to 3.43), bleeding assessed by vascular access compression time (weighted mean difference, -0.87; 95% CI, -2.75 to 1.02), or extracorporeal circuit thrombosis (relative risk, 1.15; 95% CI, 0.70 to 1.91) as compared with UFH. LMWH seem to be as safe as UFH in terms of bleeding complications and as effective as UFH in preventing extracorporeal circuit thrombosis. However, inferences from these trials assessing anticoagulation for patients who undergo hemodialysis will continue to be weak until larger, more rigorous randomized trials are conducted.


Combined treatment with sustained-release basic fibroblast growth factor and heparin enhances neovascularization in hypercholesterolemic mouse hindlimb ischemia.
Whether the combined treatment with sustained-release basic fibroblast growth factor (bFGF) and heparin enhances neovascularization in hypercholesterolemic mouse hindlimb ischemia was investigated. Wild-type C57BL/6 and low density lipoprotein receptor-deficient mice were assigned to 1 of the following 4 experimental groups and treated for 2 weeks after femoral artery extraction: group N, no treatment; group H, daily subcutaneous injection of heparin calcium; group F, single intramuscular injection of the sustained-release bFGF microspheres; and group FH, combined treatment with sustained-release bFGF and heparin. Among the wild-type mice at 4 weeks after femoral artery extraction, the laser Doppler perfusion image index (LDPII) in groups H, F, and FH was significantly higher than that in group N. The vascular density in group FH was the highest among the 4 groups. The maturation index in the 3 treated groups was significantly higher than that in group N. Among the hypercholesterolemic mice, the LDPII in group FH was significantly higher than that in the other 3 groups. The vascular density and maturation index in group FH were the highest among the 4 groups. Combined treatment with sustained-release bFGF and heparin enhanced neovascularization in the hypercholesterolemic hindlimb ischemia model.


The encephalomyocarditis virus internal ribosome entry site allows efficient coexpression of two genes from a recombinant provirus in cultured cells and in embryos.
Rous sarcoma virus-based retroviral vectors were constructed to compare three different approaches for coexpressing two genes in individual infected cells. All vectors expressed the upstream gene (lacZ) from the Rous sarcoma virus long terminal repeat, while the downstream gene (the chloramphenicol acetyltransferase gene [cat] or v-src) was expressed in one of three ways: from a subgenomic mRNA generated by regulated splicing, from a strong internal promoter, or from the encephalomyocarditis virus internal ribosome entry site (IRES). Both biochemical and immunohistochemical assays of cultured cells showed that the encephalomyocarditis virus IRES provided the most efficient means for coexpressing two genes from a single provirus. Most importantly, most cells infected by a LacZ-IRES-CAT virus expressed both LacZ and CAT, whereas most cells infected by internal promoter or regulated splicing vectors expressed either LacZ or CAT but not both. In addition, viral titers were highest with IRES vectors. Presumably, use of the IRES avoids transcriptional controls and RNA processing steps that differentially affect expression of multiple genes from internal promoter and regulated splicing vectors. Finally, we injected a LacZ-IRES-v-Src virus into chicken embryos and then identified the progeny of infected cells with a histochemical stain for LacZ. LacZ-positive cells in both skin and mesenchyme displayed morphological abnormalities attributable to expression of v-src. Thus, IRES vectors can be used to coexpress a reporter gene and a bioactive gene in vivo.


A developmental dose-response analysis of the effects of methylphenidate on the peer interactions of attention deficit disordered boys.
Mixed dyads of 42 normal and 42 ADD boys were videotaped in free play, co-operative task, and simulated classrooms. ADD boys received placebo, 0.15 mg/kg, and 0.50 mg/kg of methylphenidate. ADD boys were more active and off task, watched peers less, and scored lower on mathematics and visual-motor tasks. Older boys interacted less, ignored peer interactions and play more frequently, were less controlling, and more compliant. In class, methylphenidate improved visual motor scores, and reduced the controlling behaviour, activity level, and off task behaviour of ADD boys. Normal peers displayed reciprocal reductions in controlling behaviour, activity level, and off task behaviour.


Private Facial Prediagnosis as an Edge Service for Parkinson's DBS Treatment Valuation.
Facial phenotyping for medical prediagnosis has recently been successfully exploited as a novel way for the preclinical assessment of a range of rare genetic diseases, where facial biometrics is revealed to have rich links to underlying genetic or medical causes. In this paper, we aim to extend this facial prediagnosis technology for a more general disease, Parkinson's Diseases (PD), and proposed an Artificial-Intelligence-of-Things (AIoT) edge-oriented privacy-preserving facial prediagnosis framework to analyze the treatment of Deep Brain Stimulation (DBS) on PD patients. In the proposed framework, a novel edge-based privacy-preserving framework is proposed to implement private deep facial diagnosis as a service over an AIoT-oriented information theoretically secure multi-party communication scheme, while data privacy has been a primary concern toward a wider exploitation of Electronic Health and Medical Records (EHR/EMR) over cloud-based medical services. In our experiments with a collected facial dataset from PD patients, for the first time, we proved that facial patterns could be used to evaluate the facial difference of PD patients undergoing DBS treatment. We further implemented a privacy-preserving information theoretical secure deep facial prediagnosis framework that can achieve the same accuracy as the non-encrypted one, showing the potential of our facial prediagnosis as a trustworthy edge service for grading the severity of PD in patients.


Factors associated with the use of seclusion in an inpatient psychiatric unit in Lilongwe, Malawi.
Data on the use of seclusion for psychiatric inpatients in sub-Saharan Africa are extremely limited. Though seclusion is sometimes necessary for patients that pose a threat to themselves or others, adverse physical and psychological sequelae from the experience are increasingly being recognized, leading to efforts to reduce its use. The purpose of this study was to calculate the frequency of seclusion in patients hospitalized in an inpatient psychiatric unit in Lilongwe, Malawi, and to identify factors associated with its use. Records of 419 psychiatric inpatients hospitalized at Kamuzu Central Hospital's Bwaila Psychiatric Unit in Lilongwe, Malawi, from January 1, 2011 to December 31, 2011, were reviewed. Multivariate logistic regression analysis was employed to identify factors associated with the use of seclusion. Seclusion was used for 30.3% (127/419) of patients during the study period. Male patients had increased odds of being secluded (aOR: 2.22, p=0.02). Assaulting other patients on the unit (aOR 7.92, p<0.01) and presenting to the unit in mechanical restraints (aOR 2.33, p<0.01) were also associated with seclusion. There was no association between seclusion and age; diagnosis of alcohol use disorder, marijuana use disorder, or schizophrenia; involuntary admission; presence of extra pyramidal side effects; presence of hallucinations; suicidality; or commission of violent acts prior to admission. Documentation about the rationale for the use of seclusion on the unit was minimal. Improved record keeping requirements will be essential to future efforts to study seclusion and reduce its use. Development of strategies to address patient violence on the unit could decrease the use of seclusion for aggressive patients. Patients arriving to the unit in restraints would benefit from increased efforts by staff to apply behavioural interventions or administer medications, in order to deescalate these individuals and limit the use of seclusion in their treatment.


Friedreich's ataxia (FA) associated with diabetes mellitus type 1 and hypertrophic cardiomyopathy: analysis of a FA family.
Progressive signs of ataxia in a eight year old girl with hypo-active knee and ankle jerks, prompted the analysis of the frataxin gene (FXN; 606829). The most common molecular abnormality--GAA trinucleotide repeat expansion in intron 1--was found with +300 GAA repeats (1490 bp) (normal individuals have 5 to 30 GAA repeats expansions, whereas affected individuals have from 70 to more than 1000 GAA triplets). Additionally she had unstable gait with incoordination of limb movements, impairment of position and vibratory senses, dysarthria, pes cavus, positive Babinski sign and scoliosis. At the age of fourteen the girl was referred in a comatose condition, in severe diabetic ketoacidosis. Insulin dependent diabetes mellitus was since treated with insulin preparations. Electrocardiogram showed diffuse T wave inversion with sinus bradycardia, while ultrasound revealed concentric, symmetric hypertrophy of the left ventricle leading to the diagnosis of hypertrophic cardiomyopathy. At the age of 14, she is bound to the wheelchair, unable to walk. Her brother started to show ataxia at the age of 8 years and subsequent analysis also showed hypertrophic cardiomyopathy. His mutational analysis revealed the same frataxin abnormality with +300 GAA repeats. So far, no signs of diabetes occurred. The parental DNA was not available for analysis.


Light transmission aggregometry using pre-coated microtiter plates and a Victor X5 plate reader.
Light transmission aggregometry (LTA) can be performed with microtiter plates (96-well LTA). When conducting LTA, an agonist is added to platelet-rich plasma and the sample is shaken for minutes after which absorbance readings are done. Platelet aggregation is detected as decrease in absorbance. However, the classical method is cumbersome and therefore microtiter plates can be used for concomitant testing of multiple samples. Furthermore, it would be convenient to prepare the plate in advance of platelet aggregation testing. Aim: The aim of the present study was to establish a simplified 96-well LTA protocol, where plates were pre-coated with agonists and stored at -80 C until use. We developed and validated a protocol for 96-well LTA using a Victor X5 plate reader and pre-coated microtiter plates. The minimum requirement of platelet-rich plasma was 45 μL per sample and the sample platelet count should not be below 100 x109/L. Optimal absorbance reading was 595 nm wavelengths. Platelet aggregation results were higher at 37°C than at room temperature. Platelet adherence to wells after stimulation was observed; it was not avoided by pre-coating of the wells with gelatin. A range of up to 7 concentrations for each agonist (collagen, arachidonic acid, adenosine diphosphate, thrombin receptor-activating peptide and protease-activated receptor-4) was tested concomitantly. A transient rise in platelet aggregation was observed after 2 minutes of shaking in some samples with low agonist concentration, and platelet aggregation was optimal after 10 minutes of shaking for samples with high agonist concentration. Plates could be stored at -80°C for 15 days without significant change in the platelet aggregation results. The 96-well LTA is suitable for platelet aggregation testing and a range of agonist concentrations can be concomitantly tested.


Processing of clustered DNA damage in human breast cancer cells MCF-7 with partial DNA-PKcs deficiency.
Complex DNA damage such as double strand breaks (DSBs) and non-DSB bistranded oxidative clustered DNA lesions (OCDL) (two or more DNA lesions within a short DNA fragment of 1-10bp on opposing DNA strands) are considered the hallmark of ionizing radiation. Clustered DNA lesions are hypothesized to be repair-resistant lesions challenging the repair mechanisms of the cell. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays an important role during the processing of DSBs. To evaluate the role of DNA-PKcs in the processing of complex DNA damage in human MCF-7 breast cancer cells we used small interfering RNAs (siRNAs) to target the silencing of the gene Prkdc coding for DNA-PKcs. MCF-7 cells with knockdown DNA-PKcs expression showed a marked decrease in their efficiency to process DSBs and OCDL after exposure to radiotherapy-relevant gamma ray doses. For the detection and measurement of complex DSBs and OCDL, we used the gamma-H2AX assay and an adaptation of pulsed field gel electrophoresis with Escherichia coli repair enzymes as DNA damage probes. An accumulation of all types of DNA damage was detected for the siRNA-treated MCF-7 cells compared to controls. These findings point to the important role of DNA-PKcs in the processing of complex DNA damage and its potential association with breast cancer development.


Acoustic reflectometry in the detection of middle ear effusion.
Acoustic reflectometry, a new technique for detecting middle ear effusion, was compared with results from tympanocentesis or myringotomy in 75 patients (141 ears). There was a highly significant association (P less than .0001) for ears having middle ear effusion with high reflectivity (5 through 9 units) and for ears having no middle ear effusion with low reflectivity (0 through 4 units). In a pediatric population with middle ear effusion present in 98 of 141 ears and using reflectivity readings greater than 4 to indicate middle ear effusion, the sensitivity of this technique was 86.7% and the specificity was 69.8%. False-positive errors usually occurred in ears with thick tympanic membranes, or in ears in which reflectivity was determined prior to the induction of anesthesia. False-negative errors usually occurred in ears with both air and fluid. This technique was validated by direct comparison with tympanocentesis or myringotomy and can be used with pneumatic otoscopy and impedance tympanometry to follow children with middle ear effusion.


Incorporation of 3H-amino acids into proteins in a partially purified fraction of axoplasm: evidence for transfer RNA-mediated, post-translational protein modification in squid giant axons.
Transfer RNA (tRNA) has been demonstrated to be present in axons of both invertebrates and the higher vertebrates, but nothing is known of its role in the metabolism of the axon. The present experiments were performed to determine whether tRNA functions in axons as a participant in post-translational protein modification of endogenous proteins. RNA was extracted from the axoplasm of squid giant axons and incubated with a variety of 3H-amino acids, aminoacyl-tRNA synthetases (obtained from squid optic lobe), and an appropriate reaction mixture. All of the amino acids tested were bound to an RNA fraction, but this reaction did not occur when samples were incubated in the presence of ribonuclease or in the absence of axoplasmic RNA. When radioactive RNA was chromatographed by polyacrylamide gel electrophoresis, the radioactivity comigrated with known tRNA markers, suggesting the presence of 3H-aminoacylated tRNA. Aminoacylation of RNA could also be demonstrated by incubating fresh axoplasm with labeled amino acids and a reaction mixture, minus exogenous aminoacyl-tRNA synthetases. These findings indicate the presence in axoplasm of a variety of species of aminoacyl-tRNAs as well as their corresponding synthetase enzymes. In the latter experiment no radioactivity was found associated with the protein fraction. This was also the finding when 3H-aminoacylated tRNA was either injected directly into the axon or incubated with extruded axoplasm. Thus, under the conditions described above, there is no evidence of transfer of amino acids from tRNA to proteins. In other experiments, axoplasm was pooled to a volume of 50 to 100 microliters, homogenized gently, and centrifuged at 150,000 X g for 1 hr. Some of the high speed supernatant was incubated with labeled amino acids and an appropriate reaction mixture, and the remainder was passed through an S-200 Sephacryl column before incubation with the same reaction mixture. There was no incorporation of amino acids into protein in the high speed supernatant fraction. However, in the S-200 purified fraction 3H-labeled Arg, Lys, Tyr, Leu, and Asp were all incorporated into proteins in amounts of 44, 30, 7, 5 and 3.5 times heat-inactivated controls. The reaction is not inhibited by Ca2+ or Ca2+-activated proteases, but appears to be dependent on the presence of tRNA. The addition of amino acids to protein is not protein synthesis since the reactions occurred in a partially purified fraction of the 150,000 X g supernatant, a fraction devoid of ribosomes and free amino acids.(ABSTRACT TRUNCATED AT 400 WORDS)


Administration of recombinant human growth hormone normalizes GH-IGF1 axis and improves malnutrition-related disorders in patients with anorexia nervosa.
High serum level of GH in the presence of low plasma level of insulin-like growth factor-I (IGF-I) is one of the endocrinological features of anorexia nervosa (AN). Whether the amount of endogenous GH is not enough to increase IGF-I is not certain. We studied the effect of recombinant human growth hormone (rhGH) on the GH-IGF-I axis and on malnutrition-related disorders in this syndrome. Twenty patients with AN were divided into two groups; one (N = 13) was given rhGH (0.33 mg/day), and the other (N = 7) was given placebo for 6 or 12 months, respectively. During each treatment, levels of serum GH, plasma IGF-I, serum thyroid hormones, serum cholesterol, fasting plasma glucose and cardiac function were monitored. Changes in body mass index (BMI) and calorie taken were also evaluated. Plasma IGF-I level increased from 74.4 +/- 41.9 to 269.0 +/- 31.2 microg/L (P<0.001) during administration of rhGH, which associated with a decrease in serum GH level from 17.0 +/- 15.0 to 1.6 +/- 0.8 microg/L (P<0.001). Administration of rhGH increased BMI, body temperature, fasting plasma glucose level, and food intake. Serum level of triiodothyronine, but not thyroxine, increased during treatment with rhGH. The treatment decreased serum levels of both total and HDL-cholesterol. Studies with echocardiography showed an increase in cardiac output during the treatment with rhGH. These improvements were not observed in patients treated with placebo. Administration of rhGH is recommended as one of the methods of managing the patients with AN.


Oxidative stress in preeclampsia and the role of free fetal hemoglobin.
Preeclampsia is a leading cause of pregnancy complications and affects 3-7% of pregnant women. This review summarizes the current knowledge of a new potential etiology of the disease, with a special focus on hemoglobin-induced oxidative stress. Furthermore, we also suggest hemoglobin as a potential target for therapy. Gene and protein profiling studies have shown increased expression and accumulation of free fetal hemoglobin in the preeclamptic placenta. Predominantly due to oxidative damage to the placental barrier, fetal hemoglobin leaks over to the maternal circulation. Free hemoglobin and its metabolites are toxic in several ways; (a) ferrous hemoglobin (Fe(2+)) binds strongly to the vasodilator nitric oxide (NO) and reduces the availability of free NO, which results in vasoconstriction, (b) hemoglobin (Fe(2+)) with bound oxygen spontaneously generates free oxygen radicals, and (c) the heme groups create an inflammatory response by inducing activation of neutrophils and cytokine production. The endogenous protein α1-microglobulin, with radical and heme binding properties, has shown both ex vivo and in vivo to have the ability to counteract free hemoglobin-induced placental and kidney damage. Oxidative stress in general, and more specifically fetal hemoglobin-induced oxidative stress, could play a key role in the pathology of preeclampsia seen both in the placenta and ultimately in the maternal endothelium.


Albuminuria and kidney function as prognostic marker of left ventricular mass among South Asians with hypertension.
We aimed to evaluate the association of albuminuria and estimated glomerular filtration rate (eGFR) at baseline and changes in these parameters with left ventricular mass index (LVMI) at 7 years in adults with hypertension from communities in Pakistan. A nested cohort of 539 hypertensives aged 40 years and older from a community-living population in Karachi, Pakistan, followed up for 7 years in the Control of Blood Pressure and Risk Attenuation trial. Urine spot albumin-to-creatinine ratio (UACR) and serum creatinine-based eGFR were assessed at baseline and 7 years, and echocardiography at 7 years. Mean age of participants was 50.9 ± 9.1 (standard deviation) years; 63% were female. Mean eGFR was 91.0 ± 15.9 (standard deviation) mL/min/1.73 m2 and median (interquartile range) UACR 6.2 (3.9, 11.3) mg/g. In multivariate analysis, although baseline eGFR was marginally associated with LVMI, a strong association was found between higher LVMI with greater rate of decline in eGFR (β = -1.05; 95% confidence interval [CI]: [-1.94, -0.17]). Higher baseline UACR was significantly associated with higher follow-up LVMI (β = 2.26; 95% CI: [0.87, 3.65]), as was rate of UACR increase of ≥1.07 mg/g/y versus of <0.14 mg/g/y. (β = 4.19; 95% CI: [0.75, 7.63]). Associations with developing left ventricular hypertrophy were found for reduced baseline eGFR, higher baseline UACR, and greater rate of UACR increase, but not for rate of eGFR decline. Comparable results were observed for the outcomes of posterior wall thickness and septal wall thickness. Higher baseline albuminuria, lower baseline eGFR, and their longitudinal worsening were significantly associated with higher LVMI or the development of left ventricular hypertrophy among individuals with hypertension in Pakistan.


Experimental characterization of magnetically focused electron contamination at the surface of a high-field inline MRI-linac.
The fringe field of the Australian MRI-linac causes contaminant electrons to be focused along the central axis resulting in a high surface dose. This work aims to characterize this effect using Gafchromic film and high-resolution detectors, MOSkinTM and microDiamond. The secondary aim is to investigate the influence of the inline magnetic field on the relative dose response of these detectors. The Australian MRI-linac has the unique feature that the linac is mounted on rails allowing for measurements to be performed at different magnetic field strengths while maintaining a constant source-to-surface distance (SSD). Percentage depth doses (PDD) were collected at SSD 1.82 m in a solid water phantom positioned in a low magnetic field region and then at isocenter of the MRI where the magnetic field is 1 T. Measurements for a range of field sizes were taken with the MOSkinTM , microDiamond, and Gafchromic® EBT3 film. The detectors' relative responses at 1 T were compared to the near 0 T PDD beyond the region of electron contamination, that is, 20 mm depth. The near surface measurements inside the MRI bore were compared among the different detectors. Skin dose in the MRI, as measured with the MOSkinTM , was 104.5% for 2.1 × 1.9 cm2 , 185.6% for 6.1 × 5.8 cm2 , 369.1% for 11.8 × 11.5 cm2 , and 711.1% for 23.5 × 23 cm2 . The detector measurements beyond the electron contamination region showed agreement between the relative response at 1 T and near 0 T. Film was in agreement with both detectors in this region further demonstrating their relative response is unaffected by the magnetic field. Experimental characterization of the high electron contamination at the surface was performed for a range of field sizes. The relative response of MOSkinTM and microDiamond detectors, beyond the electron contamination region, were confirmed to be unaffected by the 1-T inline magnetic field.


[The sanitary status of natural waters on the territory of Moscow (according to the results of the examination of chemical and radionuclide composition)].
The paper presents the results of examination of the chemical and radionuclide composition of natural waters and snow cover in Moscow. Areas with abnormal contents of tritium are found in the underground and surface waters and snow cover. The high concentrations of strontium, boron, fluorine, and barium are ascertained to be associated with natural factors. Areas of technogenically polluted underground waters are identified. Recommendations are given for further studies. Particular emphasis is laid on that the artesian wells that are a reservoir source of water supply under emergency are to be revised.


Medication use and fall-risk assessment for falls in an acute care hospital.
A nested case-control study was carried out to examine relationships of a fall-risk score and the use of single medications and polypharmacy with falls among hospitalized patients aged 50 years and older in Taiwan. There were 83 patients who experienced a fall during hospitalization in an acute-care hospital. Matched by age and sex, five control patients for each case were randomly selected from all other inpatients who had not experienced any fall at the time of the index fall. Patients who took tricyclic antidepressants, diuretics, and narcotics were 3.36-, 1.83- and 2.09-fold, respectively, more likely to experience a fall than their counterparts. Conversely, patients who took beta-blockers were 0.34-fold more likely than those who did not take them to experience a fall. Patients taking ≥6 medications were 3.08-fold more likely than those taking fewer medications to experience a fall, whereas those with anxiety were 4.72-fold more likely to experience a fall than those without. A high fall-risk score was not significantly associated with the occurrence of falls. Among older hospitalized patients, tricyclic antidepressants, diuretics, narcotics, and polypharmacy should be mindfully prescribed and reviewed on a regular basis. A fall-risk scale developed from community-dwelling older people might not accurately predict falls in hospitalized patients. Further research to validate the negative effect of beta-blocker use on falls is required.


The elimination half-life of benzodiazepines and fall risk: two prospective observational studies.
the STOPP criteria advise against the use of long-acting benzodiazepines (LBs). to study whether LBs are associated with a higher fall risk than short-acting benzodiazepines (SBs) (elimination half-life ≤ 10 h). we used base-line data and prospective fall follow-up from the Longitudinal Aging Study Amsterdam, a longitudinal cohort study including 1,509 community-dwelling older persons (Study 1) and from a separate fall prevention study with 564 older persons after a fall (Study 2). Time to the first fall after inclusion and number of falls in the first year after inclusion were the primary endpoints. both in Study 1 and Study 2 the use of SBs was associated with time to the first fall, hazard ratio (HR) 1.62 (95% CI: 1.03-2.56) and HR 1.64 (95% CI: 1.19-2.26),respectively. LBs were not significantly associated with time to first fall, HR 1.40 (0.85-2.31) and HR 1.08 (0.72-1.62). In both studies, the use of SBs was also associated with number of falls, odds ratio (OR) 1.28 (95% CI: 1.01-1.61) and OR 1.37 (95% CI: 1.10-1.70). LBs were not significantly associated with number of falls, OR 1.23 (0.96-1.57) and 1.10 (0.82-1.48). the use of SBs is not associated with a lower fall risk compared with LBs. The use of both SBs and LBs by old persons should be strongly discouraged.


[Hydrolases in the large intestine in rats with various experimental pathologies].
In the colon mucous membrane, activity of a wide range of membrane and mainly intracellular enzymes was studied in the organism at different conditions. The data obtained suggest participation of digestive hydrolases in the colon not only on postdigestive processes but, in certain states of the organism, in digestive processes too.


Stiffness of the abdominal aorta in obese children.
Obesity is pathogenically related to clinical and subclinical disorders that contribute to the development of atherosclerotic plaques and their complications leading to onset of cardiovascular events. Arterial stiffness may be an indicator of early vascular changes signaling the development of vascular disease. The purpose of this study was to assess the stiffness of the abdominal aorta using transthoracic echocardiography in normotensive obese and hypertensive obese pediatric patients and a control group. The study group consisted of 25 healthy children (M/F: 13/12) as a control group (Group I), 25 normotensive obese children (M/F: 13/12) (Group II) and 25 hypertensive obese children (M/F: 14/11) (Group III). The mean ages were 12.1 +/- 1.8, 11.9 +/- 1.5 and 12.4 +/- 1.4 years, respectively. Aortic strain (S), pressure strain elastic modulus (Ep) and normalized Ep (Ep*) measurements were significantly different in the hypertensive obese group, and cholesterol levels and body mass index were higher in this group. These findings may be important in determining the relationship between obesity and cardiovascular risk factors at pediatric age.


Analysis of the impact of CSF-1 administration in adult rats using a novel Csf1r-mApple reporter gene.
Macrophages are present in large numbers in every tissue in the body where they play critical roles in development and homeostasis. They exhibit remarkable phenotypic and functional diversity, underpinning their adaptation to specialized roles in each tissue niche. CSF1, signaling through the CSF1 receptor, which is restricted to monocyte-macrophage lineage cells in adults, is a critical growth factor controlling macrophage proliferation, differentiation, and many aspects of mature macrophage function. We have generated a macrophage reporter rat, utilizing a construct containing elements of the mouse Csf1r promoter and the highly conserved Fms intronic regulatory element to drive mApple fluorescent protein expression. Csf1r-mApple was robustly expressed in monocyte-macrophage lineage cells in rat bone marrow (BM), peripheral blood, and tissues, with detectable expression in granulocytes and B cells and no evidence of expression in hematopoietic precursors or non-hematopoietic cells. Here, we use the Csf1r-mApple transgene to highlight and dissect the abundance and heterogeneity of rat tissue macrophage populations, and to demonstrate parallel increases in blood monocytes and multiple tissue macrophage populations, including BM, liver, spleen, and lung, in response to CSF1 treatment in vivo. The Csf1r-mApple rat is a novel tool enabling analysis of rat macrophages in situ by direct imaging and providing an additional phenotypic marker to facilitate exploration of rat tissue macrophage phenotypic and functional heterogeneity.


Sleep disorders in children: the Singapore perspective.
This review article summarises the current available literature on sleep patterns and sleep problems in Singapore children. Co-sleeping is a culturally dependent practice and its prevalence in Singapore has been determined to be 73%. Co-sleeping is not associated with significant sleep problems in Singapore children. Snoring and habitual snoring occur in 28.1% and 6.0% of Singapore children, respectively. Habitual snoring in Singapore children was significantly associated with obesity, allergic rhinitis, atopic dermatitis, maternal smoking and breastfeeding. Atopy was the strongest risk factor for habitual snoring in Singapore, and the effect was cumulative. Children attending psychiatric services in Singapore may also have sleep disorders, the highest prevalence being in children with attention deficit hyperactivity disorder. The knowledge on childhood sleep disorders (including obstructive sleep apnoea) amongst the public, patients, parents and future doctors in Singapore are inadequate and there is an urgent need for increased education in this area given the importance of good sleep in children. There is also a need to change parental attitudes about sleep disorders and encourage early medical consultation.


Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability.
The death receptor Fas undergoes a variety of post-translational modifications including S-palmitoylation. This protein acylation has been reported essential for an optimal cell death signaling by allowing both a proper Fas localization in cholesterol and sphingolipid-enriched membrane nanodomains, as well as Fas high-molecular weight complexes. In human, S-palmitoylation is controlled by 23 members of the DHHC family through their palmitoyl acyltransferase activity. In order to better understand the role of this post-translational modification in the regulation of the Fas-mediated apoptosis pathway, we performed a screen that allowed the identification of DHHC7 as a Fas-palmitoylating enzyme. Indeed, modifying DHHC7 expression by specific silencing or overexpression, respectively, reduces or enhances Fas palmitoylation and DHHC7 co-immunoprecipitates with Fas. At a functional level, DHHC7-mediated palmitoylation of Fas allows a proper Fas expression level by preventing its degradation through the lysosomes. Indeed, the decrease of Fas expression obtained upon loss of Fas palmitoylation can be restored by inhibiting the lysosomal degradation pathway. We describe the modification of Fas by palmitoylation as a novel mechanism for the regulation of Fas expression through its ability to circumvent its degradation by lysosomal proteolysis.


A case of the vibrant soundbridge stapes coupler in patients with mixed hearing loss.
The Vibrant Soundbridge (VSB) with stapes clip coupler placement at the stapes head has been used successfully to treat mixed hearing loss. Coupling between the floating mass transducer of the VSB and the stapes head is technically less demanding than incus vibroplasty and is more likely to generate a positive outcome without significantly changing residual hearing or resulting in medical or surgical complications. A 65-year-old man with bilateral mixed hearing loss and chronic otitis media underwent vibroplasty with a stapes clip coupler. Speech discrimination scores in both quiet and noise environments showed better functional gain with the VSB than with the use of a conventional hearing aid. The results of the present case show the feasibility of implanting a VSB with a stapes coupler in patients with mixed hearing loss due to chronic otitis media.


Temperature-mediated feeding between spring-associated and riverine-associated congeners, with implications for community segregation.
Freshwater fish communities segregate along water temperature gradients attributed in part to temperature-mediated physiological processes that affect species fitness. In spring complexes of southwest USA, spring complexes with narrow range of water temperatures are dominated by a community of fishes (i.e., spring-associated fishes), whereas riverine habitats with wide-range of water temperatures are dominated by a different community of fishes (i.e., riverine-associated fishes). The purpose of this study was to test a prediction of the concept that temperature-mediated species performance is a mechanism in maintaining community segregation. We predicted that a spring-associated fish (Largespring Gambusia Gambusia geiseri) would feed first and more often in a pairing with a riverine-associated fish (Western Mosquitofish G. affinis) at an average spring temperature (23 °C) and that the riverine-associated fish would feed first and more often in a pairing with the spring-associated fish at a warm riverine temperature (30 °C). Among four trails consisting of 30 pairings, at the spring complex temperature (23 °C), Largespring Gambusia had a greater number of first feeds (mean ± 1 SD, 5.0 ± 0.82) than Western Mosquitofish (2.5 ± 1.73) and had greater mean number of total feeds (1.9 ± 0.31) than Western Mosquitofish (0.81 ± 0.70). At the riverine environment temperature (30 °C), Western Mosquitofish had a greater number of first feeds (5.25 ± 1.71) than Largespring Gambusia (2.5 ± 1.73) and had greater mean number of total feeds (2.78 ± 1.05) than Largespring Gambusia (0.94 ± 0.68). Our findings suggest that temperature-mediated species performance could be maintaining segregation between the two fish communities. This study benefits our understanding of distributional patterns and improves threat assessments of stenothermal aquatic organisms.


Seasonal dynamics in mosquito abundance and temperature do not influence avian malaria prevalence in the Himalayan foothills.
We examined seasonal prevalence in avian haemosporidians (Plasmodium and Haemoproteus) in migrant and resident birds in western Himalaya, India. We investigated how infection with haemosporidians in avian hosts is associated with temporal changes in temperature and mosquito abundance along with host abundance and life-history traits (body mass). Using molecular methods for parasite detection and sequencing partial cytochrome b gene, 12 Plasmodium and 27 Haemoproteus lineages were isolated. Our 1-year study from December 2008 to December 2009 in tropical Himalayan foothills revealed a lack of seasonal variation in Plasmodium spp. prevalence in birds despite a strong correlation between mosquito abundance and temperature. The probability of infection with Plasmodium decreased with increase in temperature. Total parasite prevalence and specifically Plasmodium prevalence showed an increase with average avian body mass. In addition, total prevalence exhibited a U-shaped relationship with avian host abundance. There was no difference in prevalence of Plasmodium spp. or Haemoproteus spp. across altitudes; parasite prevalence in high-altitude locations was mainly driven by the seasonal migrants. One Haemoproteus lineage showed cross-species infections between migrant and resident birds. This is the first molecular study in the tropical Himalayan bird community that emphasizes the importance of studying seasonal variation in parasite prevalence. Our study provides a basis for further evolutionary study on the epidemiology of avian malaria and spread of disease across Himalayan bird communities, which may not have been exposed to vectors and parasites throughout the year, with consequential implications to the risk of infection to naïve resident birds in high altitude.


PD-1/PD-L1 Immune Checkpoint Inhibition with Radiation in Bladder Cancer: In Situ and Abscopal Effects.
The combination of radiation with immune checkpoint inhibitors was reported in some cancers to have synergic effects both locally and distally. Our aim was to assess this combined therapy on both radiated and nonradiated bladder tumors and to characterize the immune landscape within the tumor microenvironment. Murine bladder cancer cells (MB49) were injected subcutaneously in both flanks of C57BL/6 mice. Mice were randomly assigned to the following treatments: placebo, anti-PD-L1 (four intraperitoneal injections over 2 weeks), radiation to right flank (10 Gy in two fractions), or radiation+anti-PD-L1. Tumor digestion, flow cytometry, and qPCR were performed. Log-rank analysis was used for statistical significance. Radiation+anti-PD-L1 group demonstrated statistically significant slower tumor growth rate both in the radiated and nonirradiated tumors (P < 0.001). Survival curves demonstrated superior survival in the combination group compared with each treatment alone (P = 0.02). Flow cytometry showed increased infiltration of immunosuppressive cells as well as CTL in the radiation and combination groups (P = 0.04). Ratio of immunosuppressive cells to CTL shifted in favor of cytotoxic activity in the combination arm (P < 0.001). The qPCR analysis revealed downregulation of immunosuppressive genes (CCL22, IL22, and IL13), as well as upregulation of markers of CTL activation (CXCL9, GZMA, and GZMB) within both the radiated and distant tumors within the combination group. Combining radiation with immune checkpoint inhibitor provided better response in the radiated tumors and also the distant tumors along with a shift within the tumor microenvironment favoring cytotoxic activity. These findings demonstrate a possible abscopal effect in urothelial carcinoma with combination therapy.


Regulation of Matrix Remodeling by Peroxisome Proliferator-Activated Receptor-γ: A Novel Link Between Metabolism and Fibrogenesis.
The intractable process of fibrosis underlies the pathogenesis of systemic sclerosis (SSc) and other diseases, and in aggregate contributes to 45% of deaths worldwide. Because currently there is no effective anti-fibrotic therapy, a better understanding of the pathways and cellular differentiation programs underlying fibrosis are needed. Emerging evidence points to a fundamental role of the nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPAR-γ) in modulating fibrogenesis. While PPAR-γ has long been known to be important in lipid metabolism and in glucose homeostasis, its role in regulating mesenchymal cell biology and its association with pathological fibrosis had not been appreciated until recently. This article highlights recent studies revealing a consistent association of fibrosis with aberrant PPAR-γ expression and activity in various forms of human fibrosis and in rodent models, and reviews studies linking genetic manipulation of the PPAR-γ pathway in rodents and fibrosis. We survey the broad range of anti-fibrotic activities associated with PPAR-γ and the underlying mechanisms. We also summarize the emerging data linking PPAR-γ dysfunction and pulmonary arterial hypertension (PAH), which together with fibrosis is responsible for the mortality in patients in SSc. Finally, we consider current and potential future strategies for targeting PPAR-γ activity or expression as a therapy for controlling fibrosis.


The concentration of β-carotene in human adipocytes, but not the whole-body adipocyte stores, is reduced in obesity.
We have examined the concentration of β-carotene in the fat of isolated abdominal subcutaneous adipocytes obtained from lean (BMI<23 kg/m²), non-obese with higher BMI (23≤BMI<28 kg/m²), obese (BMI≥28 kg/m²), and from a group of obese subjects with type 2 diabetes. The concentration of β-carotene was 50% lower in the adipocytes from the obese and obese/diabetic groups compared with the lean and non-obese groups. Interestingly, the total amount of β-carotene in the adipocyte stores of each subject was constant among all groups. Triacylglycerol constituted 92±1% (by weight) of the adipocyte lipids in the lean group and this was increased to 99±2% in the obese group with diabetes (p<0.05). The concentration of cholesteryl esters was in all cases <0.1 g per 100 g of total lipids, demonstrating that mature human adipocytes have negligible stores of cholesteryl ester. Our findings demonstrate that adipocyte concentrations of β-carotene are reduced in obese subjects. The lower concentrations in adipocytes from subjects with type 2 diabetes apparently reflect subjects obesity. Our finding that whole-body stores of β-carotene in adipocytes are constant raises new questions regarding what function it serves, as well as the mechanisms for maintaining constant levels in the face of varied adipose tissue mass among individuals over a period of time.


High thick layer-by-layer 3D multiscale fibrous scaffolds for enhanced cell infiltration and it's potential in tissue engineering.
This work explains the fabrication and potential applicability of high thick three dimensional (3-D) electrospun multiscale fibrous scaffolds in tissue engineering by focusing on the possible fabrication techniques. Multiscale fibrous scaffold of poly(lactic acid) (PLA) was fabricated by combining nano and micro fibers in optimum concentrations. Finely chopped multiscale fibers were allowed to undergo compression, freeze-drying, resin embedding, cryo-grinding and layering techniques to make 3D scaffolds and the layer-by-layer method was found to be most suitable for 3-D scaffold fabrication. Cell studies in layered 3D scaffolds were performed using MG 63 cells and infiltration was observed using SEM and confocal microscope. Since the layered high thick 3D scaffold perfectly complies with the requirements, this could be proposed as one of the suitable methods for constructing 3D scaffolds for tissue engineering applications.


Cost of orthopedic injuries sustained in motorcycle accidents.
Fifty-one serial admissions to the orthopedic services at the University of California, Davis, Medical Center, Sacramento, for motorcycle accident trauma with open fractures were reviewed. Fifty-five percent of those tested were alcohol intoxicated at the time of admission. Seventy-five percent carried no insurance of any kind, and for the total group, 72% of the cost of acute hospitalization (+17,704 per patient) was paid by the state of California, with an additional 10% paid by other tax-based sources. Care of motorcycle trauma consumes a substantial portion of public health care funds in California. This could be reduced by legislative action concerning helmet use, licensing, and rigid enforcement of compulsory insurance.


Effect of short-term fasting on free/dissociable insulin-like growth factor I concentrations in normal human serum.
A small portion of circulating insulin-like growth factor I (IGF-I) is detected in the free or readily dissociable state, which is thought to be the metabolically active form. The amount of free/dissociable IGF-I in serum is dependent on a complex interplay between the production rate and the concentrations of IGF-I and IGF-binding proteins (IGFBPs). IGF availability is also influenced by posttranslational changes in IGFBPs that affect the affinity of IGFBPs for IGF-I. In the present study, we examined whether a short term fast (approximately 12 h) alters the serum concentration of free/dissociable IGF-I, and whether these changes are associated with alterations in IGFBP-1 and the proteolysis status of IGFBP-3. Circulating free/dissociable IGF-I concentrations, as assessed by a two-site immunoradiometric assay, did not differ between fasting and 4 h after a morning meal (1.48 +/- 0.07 vs. 1.50 +/- 0.07 microgram/L, respectively). Likewise, free/dissociable IGF-I levels measured by RIA after separation by centrifugal ultrafiltration were not different between the two groups (1.43 +/- 0.14 vs. 1.38 +/- 0.18 microgram/L, respectively). IGF-I bioactivity, as measured by thymidine incorporation by fibroblasts, did not differ in fasting and 4-h postprandial sera. There was no difference in IGFBP-3 and total acid-ethanol-extractable IGF-I concentrations in serum from fasted and fed subjects. In contrast, the concentration of IGFBP-1 in the serum was increased approximately 5-fold in the fasted state compared to fed values. IGFBP-1 existed in a highly phosphorylated form under fasting conditions. There was no change in IGFBP-3 proteolysis assessed either in vivo or in vitro between the fasting and fed states. The results indicate that a physiologically relevant short term overnight fast does not alter the circulating levels of free/dissociable IGF-I despite a marked elevation in IGFBP-1.


The Evaluation of Changes of Angles in Selected Joints During Topspin Forehand in Table Tennis.
The aims of this study were to evaluate movement patterns of topspin forehand, to define the main principles of performing this shot, and to determine the essential differences in individual types of topspin forehand. In total, 10 female high-level athletes participated in this study. The BTS analysis system was used with a novel model for the range-of-motion measurement. An acoustic sensor was attached to the racket for identification of a ball-racket contact. Players, performing topspin forehand, attempt to achieve maximal racket velocity based on the principles of proximal-to-distal sequences and summation of speed with a stretch-shortening character of cycle. The essential differences between type of topspin forehand occurred in the range of motion. Increased power of topspin shot was accompanied by a significant increase in range of motion in most of the studied joints and body segments, in particular in the rotation movement of the upper body, pelvis and shoulders, flexion and rotation in the shoulder and elbow joints, and flexion and rotation in knee joints.


A Case of Rare Diffuse Alveolar Hemorrhage and Review of Literature.
It is well known that some disorders can cause concomitant kidney dysfunction with lung involvement. These syndromes, characterized by the simultaneous presence of intra-alveolar hemorrhage and acute glomerulonephritis, are caused by numerous and variable disorders. The most frequent are the antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis and Goodpasture syndrome. A quick discerning of the underlying causes and initiation of adequate treatment is crucial to prevent acute respiratory failure and irreversible loss of renal function. We reported the case of a 33-year-old man having hemorrhagic alveolitis presenting a picture consistent with Goodpasture syndrome in the absence of anti-glomerular basement membrane (anti-GBM) antibodies or ANCA at lab test and a review of literature. This case highlights the need to consider the chances of falsely seronegative cases of anti-GBM disease, as well as the importance of using all available assay routine tests. These cases would appear indeed more common than before if just taken into consideration their existence. Several reports have shown false seronegatives especially in patients with relapses, in smokers, and in patients with predominantly pulmonary symptoms.


Variations in nurse practitioner use in Veterans Affairs primary care practices.
Increasingly, primary care practices include nurse practitioners (NPs) in their staffing mix to contain costs and expand primary care. To achieve these aims in U.S. Department of Veterans Affairs medical centers (VAMCs), national policy endorsed involvement of NPs as primary care (PC) providers. To evaluate the degree to which VAMCs incorporated NPs into PC practices between 1996 and 1999, and to identify the internal and external practice environment features associated with NP use. We surveyed 131 PC directors of all VAMCs in 1996 and 1999 to ascertain the staffing and characteristics of the PC practice and parent organization (e.g., academic affiliation, level of physician staffing, use of managed care arrangements), and drew on previously published studies and HRSA State Health Workforce Profiles to characterize each practice's regional health care environment (e.g., geographic region, state NP practice laws, state managed care penetration). Using multivariate linear regression, we evaluate the contribution of these environmental and organizational factors on the number of NPs/10,000 PC patients in 1999, controlling for the rate of NP use in 1996. From 1996-1999, NP use increased from 75 percent to 90 percent in VA PC practices. The mean number of NPs per practice increased by about 60 percent (2.0 versus 3.2; p<.001), while the rate of NPs/10,000 PC patients trended upward (2.2 versus 2.7; p=.09). Staffing of other primary care clinicians (e.g., physicians and physician assistants per practice) remained stable, while the NP-per-physician rate increased (0.2 versus 0.4; p<.001). After multivariate adjustment, greater reliance on managed-care-oriented provider education programs (p=.02), the presence of NP training programs (p=.05), and more specialty-trained physicians/10,000 PC patients (p=.09) were associated with greater NP involvement in primary care. Staffing models in VA PC practices have, in fact, changed, with NPs having a greater presence. However, we found substantial practice-based variations in their use, suggesting that more research is needed to better understand how they have been integrated into practice and what impact their involvement has had on the VA's ability to achieve its restructuring goals.


Isoflavones prevent bone loss following ovariectomy in young adult rats.
Soy protein, a rich source of phytoestrogens, exhibit estrogen-type bioactivity. The purpose of this study was to determine if ingestion of isoflavones before ovariectomy can prevent bone loss following ovariectomy. Twenty-four nulliparous Wistar rats were randomly divided into four groups. In the normal diet groups, a sham operation was performed on Group A, while ovariectomy was performed on Group B. For Groups C and D, all rats were fed with an isoflavone-rich (25 mg/day) diet for one month, then bilateral ovariectomy were performed. In the rats in Group C, a normal diet was begun following the ovariectomy. The rats in Groups D continued to receive the isoflavone-rich diet for two additional months postoperatively. All rats were sacrificed 60 days after surgery. The weight of bone ash of the long bones and whole lumbar spine were determined. A histological study of cancellous bone was done and biochemical indices of skeletal metabolism were performed and analyzed. The markers of bone metabolism exhibited no significant changes. When compared with the sham-operated rats fed a normal diet, the bone mass of ovariectomized rats decreased significantly; pre-ovariectomy ingestion of an isoflavone-rich diet did not prevent bone loss. The bone mass of rats treated with an isoflavone-rich diet for three months was higher than controls two months after ovariectomy. Dietary isoflavones did not prevent the development of post-ovariectomy bone loss, but long-term ingestion of an isoflavone-rich diet increased the bone mineral contents after ovariectomy in young rats.


HER2 Mediates PSMA/mGluR1-Driven Resistance to the DS-7423 Dual PI3K/mTOR Inhibitor in PTEN Wild-type Prostate Cancer Models.
Prostate cancer remains a major cause of male mortality. Genetic alteration of the PI3K/AKT/mTOR pathway is one of the key events in tumor development and progression in prostate cancer, with inactivation of the PTEN tumor suppressor being very common in this cancer type. Extensive evaluation has been performed on the therapeutic potential of PI3K/AKT/mTOR inhibitors and the resistance mechanisms arising in patients with PTEN-mutant background. However, in patients with a PTEN wild-type phenotype, PI3K/AKT/mTOR inhibitors have not demonstrated efficacy, and this remains an area of clinical unmet need. In this study, we have investigated the response of PTEN wild-type prostate cancer cell lines to the dual PI3K/mTOR inhibitor DS-7423 alone or in combination with HER2 inhibitors or mGluR1 inhibitors. Upon treatment with the dual PI3K/mTOR inhibitor DS-7423, PTEN wild-type prostate cancer CWR22/22RV1 cells upregulate expression of the proteins PSMA, mGluR1, and the tyrosine kinase receptor HER2, while PTEN-mutant LNCaP cells upregulate androgen receptor and HER3. PSMA, mGluR1, and HER2 exert control over one another in a positive feedback loop that allows cells to overcome treatment with DS-7423. Concomitant targeting of PI3K/mTOR with either HER2 or mGluR1 inhibitors results in decreased cell survival and tumor growth in xenograft studies. Our results suggest a novel therapeutic possibility for patients with PTEN wild-type PI3K/AKT-mutant prostate cancer based in the combination of PI3K/mTOR blockade with HER2 or mGluR1 inhibitors.


Restoration of reproductive capacity in a male patient with congenital adrenal hyperplasia and bilateral testicular adrenal rest tumors (TARTs) after six months of glucocorticoid intensification: A case report.
Congenital adrenal hyperplasia (CAH) is considered one of the most common inherited disorders. In about more than 95% of all CAH cases, the deficient enzyme is 21-hydroxylase. Infertility is an important complication of this disease, and although this topic has been studied more frequently in females, cases, and literature reviews of the causes of infertility in male patients are constantly increasing. A 28 old male with congenital adrenal hyperplasia (we assume to be a nonclassical type) presented to our institution with infertility and suspected bilateral testicular masses after 4 years of stopping dexamethasone. Testicular adrenal rest tumors. Dexamethasone was reapplied in a supraphysiologic dose (1.5 mg before bedtime) with periodic monitoring of the patient. Treatment with supraphysiologic dose of dexamethasone led to regression of these tumors and significant improvement in sperm count, resulting in being capable of having a child. There are many suspected causes of reduced male fertility in male CAH patients and the presence of testicular adrenal rest tumors is the main cause of infertility in this population. These benign tumors are believed to arise from ectopic adrenal cells in the testes, that grow under adrenocorticotropic hormone stimulation in poorly controlled patients. Annual scrotal ultrasound is recommended in all males with CAH for detection and treatment of these tumors as early as possible before they cause permanent damage to the seminiferous tubules and irreversible infertility.


Listeria monocytogenes as a Cause of Spontaneous Bacterial Peritonitis.
Spontaneous bacterial peritonitis is a common and often serious complication of long standing ascites in the presence of advanced liver disease. We report a case of a 74-year-old woman with alcoholic cirrhosis admitted to our emergency department with a 1-week history of diffuse abdominal pain and increased abdominal perimeter. On physical examination, she had a significant abdominal distention and a positive fluid wave consistent with ascites. A diagnosis of spontaneous bacterial peritonitis was made and empiric therapy with ceftriaxone was started but the patient's condition worsened. Four days later Listeria monocytogenes was detected in peritoneal fluid culture and ampicillin was initiated according to in vitro sensibility test. The patient completed 14 days of treatment with clinical and laboratory improvement. Listeria is an uncommon cause of spontaneous bacterial peritonitis. Clinicians should be aware of the uncommon agents of spontaneous bacterial peritonitis, mainly when there is not a proper response to therapy.