Entanglement between the future and the past in the quantum vacuum.
We note that massless fields within the future and past light cone may be quantized as independent systems. The vacuum is shown to be a nonseparable state of these systems, exactly mirroring the known entanglement between the spacelike separated Rindler wedges. This leads to a notion of timelike entanglement. We describe an inertial detector which exhibits a thermal response to the vacuum when switched on at t=0, due to this property. The feasibility of detecting this effect is discussed, with natural experimental parameters appearing at the scale of 100 GHz.


Epigenetic pacemaker: closed form algebraic solutions.
DNA methylation is widely used as a biomarker in crucial medical applications as well as for human age prediction of very high accuracy. This biomarker is based on the methylation status of several hundred CpG sites. In a recent line of publications we have adapted a versatile concept from evolutionary biology - the Universal Pacemaker (UPM) - to the setting of epigenetic aging and denoted it the Epigenetic PaceMaker (EPM). The EPM, as opposed to other epigenetic clocks, is not confined to specific pattern of aging, and the epigenetic age of the individual is inferred independently of other individuals. This allows an explicit modeling of aging trends, in particular non linear relationship between chronological and epigenetic age. In one of these recent works, we have presented an algorithmic improvement based on a two-step conditional expectation maximization (CEM) algorithm to arrive at a critical point on the likelihood surface. The algorithm alternates between a time step and a site step while advancing on the likelihood surface. Here we introduce non trivial improvements to these steps that are essential for analyzing data sets of realistic magnitude in a manageable time and space. These structural improvements are based on insights from linear algebra and symbolic algebra tools, providing us greater understanding of the degeneracy of the complex problem space. This understanding in turn, leads to the complete elimination of the bottleneck of cumbersome matrix multiplication and inversion, yielding a fast closed form solution in both steps of the CEM.In the experimental results part, we compare the CEM algorithm over several data sets and demonstrate the speedup obtained by the closed form solutions. Our results support the theoretical analysis of this improvement. These improvements enable us to increase substantially the scale of inputs analyzed by the method, allowing us to apply the new approach to data sets that could not be analyzed before.


Histology of the canine urethra II. Morphometry of the male pelvic urethra.
Urinary bladders and pelvic urethrae were collected from six adult and two juvenile male dogs. Within two vesical and six urethral sampling regions, volume densities were estimated for smooth and striated muscle, connective tissue and elastic fibers, stratum cavernosum, luminal epithelium, and prostate. The neck had significantly less smooth muscle and more connective tissue than the body of the bladder. In the prostatic urethra, smooth muscle was associated principally with trabeculae surrounding prostate lobules. Smooth muscle was sparse superficially in the prostatic capsule and practically absent in relation to the mid-prostatic urethra. Thus there was no mechanism for active closure of the middle prostatic urethra, and elastic fiber density was correspondingly high in this region. The smooth muscle sphincter needed to maintain urinary continuence and prevent semen reflux was primarily the vesical neck. Caudal to the body of the prostate, striated muscle comprised more than 40% of the urethral wall. Juvenile and adult postprostatic urethrae were similar except for a decreased quantity of stratum cavernosum in the pups.


Laboratory techniques for the diagnosis of chlamydial infections.
Yolk-sac inoculation of embryonated eggs was superseded 25 years ago by the use of cell cultures (often McCoy) for the isolation of Chlamydia trachomatis. Centrifugation of specimens onto the cell monolayers was shown to increase sensitivity, but little of late has further improved sensitivity which is at least ten-fold greater than that of eggs. However, culture is slow and labour intensive so that non-cultural techniques without these drawbacks have come to dominate. Direct fluorescent antibody (DFA) tests are rapid and have sensitivities that range from 70% to 100% for men and 68% to 100% for women, and specificities that range from 87% to 99% for men and 82% to 100% for women; if the tests are read by competent observers the values are at the top end of the ranges. The detection rate may be enhanced even further by relatively low-speed centrifugation of specimens before staining. Skilled reading is not a feature of enzyme immunoassays (EIAs) which according to the literature have sensitivities that range from 62% to 97% for men and 64% to 100% for women, and specificities that range from 92% to 100% for men and 89% to 100% for women. However, comparison against poor reference tests is responsible for most of the higher values and the clinician should not be misled into believing that EIAs have excellent sensitivity; the lower values in the ranges are closer to reality. Furthermore, EIAs that are being designed for use by general practitioners should be regarded with the greatest caution since lack of sensitivity means that chlamydia-positive patients will go undetected. The polymerase chain reaction (PCR) is not bedevilled by insensitivity but it is no more sensitive than the most sensitive cell culture or DFA tests. PCR is unsuitable for routine diagnosis but has a place as a research tool. For men, examination of "first-catch" urine samples by the best of the non-cultural procedures provides an acceptable non-invasive approach to diagnosis; for women, the value of examining urine may be less, but needs to be thoroughly tested. However, there is little doubt that a Cytobrush used to obtain cervical specimens holds no practical advantage over a swab. Serological tests are reliant on the provision of paired sera for making a diagnosis; high antibody titres in single sera may be suggestive of an aetiological association in deep-seated chlamydial infections (epididymitis, arthritis, salpingitis, etc), but unequivocal interpretation is unusual, particularly in an individual case, since the distinction between a current and past infection is problematical.


Inadequate health literacy among paid caregivers of seniors.
Many seniors rely on paid non-familial caregivers to maintain their independence at home. Caregivers often assist with medication reminding and activities of daily living. No prior studies have examined the health literacy levels among paid non-familial caregivers. To determine health literacy levels and the health-related responsibilities of paid non-familial caregivers of seniors. One-on-one face-to-face surveys. The Test for Functional Health Literacy (TOFHLA) was administered to identify health literacy levels. Caregivers were asked to demonstrate their skill in medication use by following directions on pill bottles and sorting medications into pill boxes. Ninety-eight paid unrelated caregivers of seniors recruited at physician offices, caregiver agencies, senior shopping areas, and independent living facilities. Average age of caregivers was 49.5 years, and 86.7% were female. Inadequate health literacy was found in 35.7% of caregivers; 60.2% of all caregivers made errors with the pillbox test medications, showing difficulty in following label directions. Health-related tasks (i.e., medication reminding, sorting, dispensing, and accompanying seniors to physician appointments) were performed by 85.7% of caregivers. The mean age of their seniors was 83.9 years (range 65-99 years), and 82.1% were female. Paid non-familial caregivers are essential for many seniors to remain independent and maintain their health. Many caregivers perform health-related duties, but over 1/3 have inadequate health literacy and have difficulties following medication-related instructions. Educating caregivers and ascertaining their health literacy levels prior to assigning health-related tasks may be an important process in providing optimal care to seniors.


Improving Hepatitis B Care in the US: A Case for a New "Ryan White" Program.
Chronic hepatitis B infection is common in the United States, yet only a minority of eligible people are screened, vaccinated, and receive treatment. The Ryan White HIV/AIDS program has been a key tool for ensuring that socioeconomically disadvantaged HIV-infected patients have access to care. Many of the same disease and patient attributes that make the Ryan White program necessary and effective for HIV exist in chronic hepatitis B. Thus, we believe that the current Ryan White program should be expanded to care for people with hepatitis B under similar regulations. Considering recent changes proposed to the health insurance marketplace, policymakers should strongly consider inclusion of chronic hepatitis B in the safety-net Ryan White Program.


[Origin of the adenohypophysis and of the olfactory system in toads: demonstration by chimera method].
Localisation of the primordium of the olfactory system and its topographical relationships with the primordium of the hypothalamic-hypophyseal system were determined on the embryos of the toad Bufo japonicus by generating chimeric embryos. Different parts of the neural ridge and the neural plate were taken up from normal embryos and grafted on the same region of albino embryos of the same developmental stage. The melanin granules contained in the grafts permitted to trace the developmental fate. The anteriormost region of the neural ridge (ANR) was found to be the origin of all the parts of the adenohypophysis as well as some of the neurons in the preoptic region. The infundibulum differentiated from the central portion of the neural plate, just posterior to the adenohypophyseal primordium. The primordium of the olfactory system, including the olfactory sacs and the olfactory bulbs, was found to be situated on the neural ridge on both sides of the ANR. The present results showed that the central and peripheral parts of each of the two systems constitute a closely apposed cell population at the neurula stage. It seems that the periphero-central connection in these systems reflect a clonal origin of the presumptive cells. If the olfactory primordium was removed at the neurula stage, the olfactory sac regenerated from the adenohypophyseal primordium. In conclusion, these results demonstrate that the olfactory primordium is related not only topographically but also ontogenetically to the adenohypophyseal primordium.


Application of evolution strategies for the solution of an inverse problem in near-field optics.
We introduce an inversion procedure for the characterization of a nanostructure from near-field intensity data. The method proposed is based on heuristic arguments and makes use of evolution strategies for the solution of the inverse problem as a nonlinear constrained-optimization problem. By means of some examples we illustrate the performance of our inversion method. We also discuss its possibilities and potential applications.


Effects of empagliflozin and target-organ damage in a novel rodent model of heart failure induced by combined hypertension and diabetes.
Type 2 diabetes mellitus and hypertension are two major risk factors leading to heart failure and cardiovascular damage. Lowering blood sugar by the sodium-glucose co-transporter 2 inhibitor empagliflozin provides cardiac protection. We established a new rat model that develops both inducible diabetes and genetic hypertension and investigated the effect of empagliflozin treatment to test the hypothesis if empagliflozin will be protective in a heart failure model which is not based on a primary vascular event. The transgenic Tet29 rat model for inducible diabetes was crossed with the mRen27 hypertensive rat to create a novel model for heart failure with two stressors. The diabetic, hypertensive heart failure rat (mRen27/tetO-shIR) were treated with empagliflozin (10 mg/kg/d) or vehicle for 4 weeks. Cardiovascular alterations were monitored by advanced speckle tracking echocardiography, gene expression analysis and immunohistological staining. The novel model with increased blood pressure und higher blood sugar levels had a reduced survival compared to controls. The rats develop heart failure with reduced ejection fraction. Empagliflozin lowered blood sugar levels compared to vehicle treated animals (182.3 ± 10.4 mg/dl vs. 359.4 ± 35.8 mg/dl) but not blood pressure (135.7 ± 10.3 mmHg vs. 128.2 ± 3.8 mmHg). The cardiac function was improved in all three global strains (global longitudinal strain - 8.5 ± 0.5% vs. - 5.5 ± 0.6%, global radial strain 20.4 ± 2.7% vs. 8.8 ± 1.1%, global circumferential strain - 11.0 ± 0.7% vs. - 7.6 ± 0.8%) and by increased ejection fraction (42.8 ± 4.0% vs. 28.2 ± 3.0%). In addition, infiltration of macrophages was decreased by treatment (22.4 ± 1.7 vs. 32.3 ± 2.3 per field of view), despite mortality was not improved. Empagliflozin showed beneficial effects on cardiovascular dysfunction. In this novel rat model of combined hypertension and diabetes, the improvement in systolic and diastolic function was not secondary to a reduction in left ventricular mass or through modulation of the afterload, since blood pressure was not changed. The mRen27/tetO-shIR strain should provide utility in separating blood sugar from blood pressure-related treatment effects.


Bombesin stimulation of inositol 1,4,5-trisphosphate generation and intracellular calcium release is amplified in a cell line overexpressing the N-ras proto-oncogene.
Bombesin stimulation of T15 cells in which the inducible N-ras oncogene is overexpressed caused elevated production of inositol phosphates compared to uninduced cells [Wakelam, Davies, Houslay, McKay, Marshall & Hall (1986) Nature (London) 323, 173-176]. This elevated response is shown here to result from increased generation of inositol 1,4,5-trisphosphate leading to an elevated release of intracellular stored Ca2+. Single-cell analysis of Ca2+ release showed that the elevated response is not a consequence of an increased fraction of responding cells. These amplifications are consistent with p21N-ras acting like a guanine nucleotide coupling protein in this cell line.


Rhythmic expression of an egr-1 transgene in rats distinguishes two populations of photoreceptor cells in the retinal outer nuclear layer.
Nocturnal rhythms of gene expression in the retina are known to be both darkness- and circadian clock-dependent, but their role and cellular location are not well defined. In the present study we have used a new transgenic rat model (early growth response gene 1-destablized, enhanced green fluorescent protein 2; egr-1-d2EGFP) to investigate the rhythmic regulation of darkness-related gene expression. Adult transgenic rats were sampled during the light and dark phases of a standard laboratory lighting schedule. The cellular location of transgene expression in retinal sections was detected either via immunohistochemistry for green fluorescent protein (GFP) or via direct microscopy. The GFP expression pattern was compared to endogenous proteins (Egr-1, melanopsin, rhodopsin) via dual fluorophore immunohistochemistry. Day-night changes in GFP and Egr-1 expression were quantified by western blot analysis of retinal protein extracts. Nocturnal transgene expression was abundant in the outer nuclear layer (ONL) of the retina, recapitulating expression of the endogenous Egr-1 protein. The transgene provided greatly enhanced visualization of the ONL cellular expression pattern, in part due to cellular filling by GFP molecules that pervade rod photoreceptor cells including inner and outer segments. The transgene was also expressed in isolated (Egr-1-positive) cells of the inner nuclear layer and the ganglion cell layer. In the ONL, a marked day-night rhythm in transgene expression was found to be predominantly within an inner zone of this retinal nuclear layer. This concentration of rhythmic GFP/Egr-1 to the inner ONL was not associated with differential localization of rhodopsin. Analysis of a novel transgenic rat strain has identified subpopulations of rod photoreceptor cells that differ with respect to rhythmic nocturnal expression of egr-1. These studies demonstrate the value of this genetic approach that has provided a model for the functional characterization of retinal rhythms, specifically addressing the role of Egr-1 within nocturnal transcriptional events in a rod photoreceptor population. Because the darkness-dependent induction of Egr-1 is gated by a circadian clock, this model can also provide insights into the cellular mechanisms of circadian regulation in the retina.


Management of behavioural change in patients presenting with a diagnosis of dementia: a video vignette study with Australian general practitioners.
To test the impact of feedback on the proposed management of standardised patients presenting with behavioural change with a diagnosis of dementia in Australian primary care. A video vignette study was performed with Australian general practitioners (GPs) in 2013. Participants viewed six pairs of matched videos depicting people presenting changed behaviour in the context of a dementia diagnosis in two phases. In both phases GPs indicated their diagnosis and management. After phase 1, GPs were offered feedback on management strategies for the patients depicted. Analyses focused on identification of change in management between the two phases of the study. Factors impacting on the intention to coordinate care for such patients were tested in a questionnaire based on the Theory of Planned Behaviour. Forty-five GPs completed the study. There was significant improvement in the proposed management of three of the six scenarios after the intervention. Older GPs were more likely to refer appropriately (OR=1.11 (1.01 to 1.23), p=0.04.). Overall referral to support agencies was more likely after the intervention (OR=2.52 (1.53 to 4.14), p<0.001). Older GPs were less likely to intend to coordinate care for such patients (OR=0.89 (0.81 to 0.98) p=0.02). Participants who felt confident about their ability to coordinate care were more likely to do so (OR=3.79 (1.08 to 13.32) p=0.04). The intervention described in this study promoted multidisciplinary management of patients with behavioural problems with a diagnosis of dementia. Increasing practitioner confidence in their ability to coordinate care may increase the proportion of GPs who will respond to patients and carers in this context. Older GPs may benefit in particular.


Assisted suicide and the discrimination argument: Can people with mental illness fulfill beneficence- and autonomy-based eligibility criteria?
According to the "discrimination argument," it would be discriminatory and hence impermissible to categorically exclude people with mental illness (PMI) from access to assisted suicide (AS) if AS is accessible to people with somatic illnesses. In objection to this, it could be argued that excluding PMI is not discriminatory, but rather based on their inability to meet certain eligibility criteria for AS. Which criteria are deemed necessary depends on the approach taken to justifying AS. In this article, we describe two distinct ethical approaches to justifying AS and the eligibility criteria they entail and examine whether PMI can fulfill these criteria. A widespread "joint" approach based on beneficence and autonomy assumes that AS is justified when it alleviates the severe and irremediable suffering of a person who autonomously requests AS. An alternative, exclusively autonomy-based approach assumes that providing AS is justified when a person's request is autonomous, regardless of whether AS is in her best interests. The latter approach underlies an important judgment of the German Federal Constitutional Court from 2020. We argue that PMI can in principle fulfill both beneficence- and autonomy-based eligibility criteria for AS, and that a blanket exclusion of all PMI from AS is thus discriminatory on either approach. However, depending on which approach is taken, there are differences regarding the subgroups of PMI that would be eligible for AS. Whether the exclusion of specific PMI is discriminatory therefore depends on how we understand and justify AS.


Understanding the role of men in women's use of the vaginal ring and oral PrEP during pregnancy and breastfeeding: multi-stakeholder perspectives.
We examined men's influence on women's interest in biomedical HIV prevention during pregnancy and breastfeeding through structured questionnaires and focus group discussions with currently or recently pregnant and breastfeeding (P/BF) women (n = 65), men with P/BF partners (n = 63) and mothers/mothers-in-law of P/BF women (n = 68) in eastern and southern Africa. Data were transcribed, coded and summarised into analytical memos. Men were depicted by most participants as joint decision-makers and influencers of women's use of HIV prevention. Cultural and religious norms depicting men as heads, breadwinners and protectors of the family were cited to legitimise their involvement in decision-making. Male partner education and engagement were recommended to garner their support in women's HIV prevention. This study elucidates how P/BF women's ability to prevent HIV is shaped by traditional and contemporary gender norms in social settings and locations where the study was conducted. Findings may aid intervention design to engage men for P/BF women's effective use of microbicide and oral PrEP.


The effects of transcutaneous electrical nerve stimulation on experimental pain and sympathetic nervous system response.
Transcutaneous electrical nerve stimulation (TENS) is a technique widely used in clinical practice to control pain, although its clinical efficacy remains controversial. Though many mechanisms have been proposed for its analgesic effects, there is a conspicuous lack of experimentally controlled research investigating whether TENS analgesia is related to its effects on the sympathetic nervous system (SNS). Using an established psychophysiological paradigm, the present study investigated the effects of high-frequency/low-intensity TENS, low-frequency/high-intensity TENS, and sham TENS on the perception of experimental pain and SNS function in healthy volunteers. Measures of heart rate, digital pulse volume, and skin conductance were recorded during a 20-minute TENS stimulation period and in anticipation of a series of painful electric shocks prior to and following TENS stimulation. Healthy volunteers rated the intensity of the shocks using a 0-10-point verbal pain rating scale. The three TENS conditions failed to differentially effect SNS responses during either the 20-minute TENS treatment period or the shock anticipation periods, and TENS did not affect ratings of pain intensity to the shock stimuli. While these results may not generalize to acute or chronic pain patients, within the limitations of the present experimental paradigm, no support was found for TENS affecting either SNS function or acute experimental pain perception.


Gut microbiota and probiotics in chronic liver diseases.
There is a strong relationship between liver and gut: the portal system receives blood from the gut, and intestinal blood content activates liver functions. The liver, in turn, affects intestinal functions through bile secretion into the intestinal lumen. Alterations of intestinal microbiota seem to play an important role in induction and promotion of liver damage progression, in addition to direct injury resulting from different causal agents. Bacterial overgrowth, immune dysfunction, alteration of the luminal factors, and altered intestinal permeability are all involved in the pathogenesis of complications of liver cirrhosis, such as infections, hepatic encephalopathy, spontaneous bacterial peritonitis, and renal failure. Probiotics have been suggested as a useful integrative treatment of different types of chronic liver damage, for their ability to augment intestinal barrier function and prevent bacterial translocation. This review summarizes the main literature findings about the relationships between gut microbiota and chronic liver disease, both in the pathogenesis and in the treatment by probiotics of the liver damage.


Differential targeting of the L-type Ca2+ channel alpha 1C (CaV1.2) to synaptic and extrasynaptic compartments in hippocampal neurons.
In central nervous system neurons L-type Ca2+ channels are involved in developmental processes, the integration and conduction of postsynaptic electric activity and synaptic plasticity. However, little is known about the channel isoforms underlying each of these functions or about the exact localization and targeting properties of the major L-type channel isoform alpha1C (CaV1.2) in neurons. We addressed these questions using high-resolution immunofluorescence analysis of the endogenous alpha1C and epitope-tagged recombinant channel isoforms expressed in mouse hippocampal neurons. Endogenous alpha1C and surface-expressed hemagglutinin (HA)-tagged alpha1C-HA were localized in small clusters distributed between the axon initial segment and the apical branches of the dendritic tree. The average cluster size was estimated to be eight channels per alpha1C-HA cluster. Analysis of the subcellular localization of alpha1C-HA clusters relative to known synaptic markers suggested the existence of two distinct populations of alpha1C clusters, extrasynaptic and synaptic, the latter associated with glutamatergic synapses in dendritic spines. Both glutamatergic and GABAergic neurons expressed alpha1C in the soma and dendrites. In contrast to the N-type channel GFP-alpha1B, GFP-alpha1C was excluded from distal axons and nerve terminals of mature neurons. In developing neurons, however, alpha1C and alpha1C-HA were robustly expressed in the growth cone, indicating that specific targeting properties of neuronal compartments change during differentiation. Synaptic and extrasynaptic localizations of alpha1C correspond to putative roles of L-type Ca2+ currents in synaptic modulation and in the propagation of dendritic Ca2+ spikes, respectively. The transiently expressed alpha1C in the growth cone may be involved in neurite extension and axonal pathfinding.


Two regulatory elements required for enhancing ospA expression in Borrelia burgdorferi grown in vitro but repressing its expression during mammalian infection.
During cycling between the tick vector and a mammal, the Lyme disease spirochaete Borrelia burgdorferi must coordinate expression of outer-surface proteins (Osps) A and B to quickly respond to environmental changes. The pathogen abundantly produces OspA/B in the tick, but represses their expression during mammalian infection. This paper reports a regulatory structure, consisting of two sequences flanking the ospAB promoter, that is required for enhancing ospA expression in B. burgdorferi grown in vitro, but repressing its expression during murine infection. Deletion or replacement of either the upstream or downstream sequence of the ospAB promoter caused a significant decrease in ospA expression in vitro, but a dramatic increase during murine infection. Fusion of either sequence with the flaB reporter promoter led to increased expression of an ospA reporter gene in vitro, but a decrease in the murine host. Furthermore, simultaneous fusion of both sequences with the reporter promoter showed a synergistic effect in enhancing expression of the ospA reporter in vitro, but repressing its expression during murine infection. Taken together, the results demonstrate that the regulatory structure functions oppositely in the two different environments and potentially provides B. burgdorferi with a molecular mechanism to quickly adapt to the distinct environments during its enzootic life cycle.


Purification and partial characterization of the OmpA family of proteins of Pasteurella haemolytica.
This study was conducted to partially characterize and identify the purity of two major outer membrane proteins (OMPs) (with molecular weights of 32,000 and 35,000 [32K and 35K, respectively]) of Pasteurella haemolytica. The 35K and 32K major OMPs, designated Pasteurella outer membrane proteins A and B (PomA and PomB, respectively), were extracted from P. haemolytica by solubilization in N-octyl polyoxyl ethylene. The P. haemolytica strain used was a mutant serotype A1 from which the genes expressing the 30-kDa lipoproteins had been deleted. PomA and PomB were separated and partially purified by anion-exchange chromatography. PomA but not PomB was heat modifiable. The N-terminal amino acid sequences of the two proteins were determined and compared with reported sequences of other known proteins. PomA had significant N-terminal sequence homology with the OmpA protein of Escherichia coli and related proteins from other gram-negative bacteria. Moreover, polyclonal antiserum raised against the E. coli OmpA protein reacted with this protein. PomA was surface exposed, was conserved among P. haemolytica biotype A serotypes, and had porin activity in planar bilayers. No homology between the N-terminal amino acid sequence of PomB and those of other known bacterial proteins was found. Cattle vaccinated with live P. haemolytica developed a significant increase in serum antibodies to partially purified PomA, as shown by enzyme-linked immunosorbent assays, and to purified PomA and PomB, as detected on Western blots and by densitometry.


Monolayer MXenes: promising half-metals and spin gapless semiconductors.
Half-metals and spin gapless semiconductors are promising candidates for spintronic applications due to the complete (100%) spin polarization of electrons around the Fermi level. Based on recent experimental and theoretical findings of graphene-like monolayer transition metal carbides and nitrides (also known as MXenes), we demonstrate using first-principles calculations that monolayers Ti2C and Ti2N exhibit nearly half-metallic ferromagnetism with the magnetic moments of 1.91 and 1.00μB per formula unit, respectively, while monolayer V2C is a metal with unstable antiferromagnetism, and monolayer V2N is a nonmagnetic metal. Interestingly, under a biaxial strain, there is a phase transition from a nearly half-metal to truly half-metal, spin gapless semiconductor, and metal for monolayer Ti2C. Monolayer Ti2N is still a nearly half-metal under a suitable biaxial strain. Large magnetic moments can be induced by the biaxial tensile and compressive strains for monolayer V2C and V2N, respectively. We also show that the structures of these four monolayer MXenes are stable according to the calculated formation energy and phonon spectrum. Our investigations suggest that, unlike monolayer graphene, monolayer MXenes Ti2C and Ti2N without vacancy, doping or external electric field exhibit intrinsic magnetism, especially the half-metallic ferromagnetism and spin gapless semiconductivity, which will stimulate further studies on possible spintronic applications for new two-dimensional materials of MXenes.


Leukemogenic activity of filtrates from radiation-induced lymphoid tumors of mice.
Cell-free filtrates of x-ray-induced lymphoid tumors of strain C57BL/ Ka mice have elicited, on injection into newborn isologous hosts, a lymphoma incidence of 15 to 19 percent. In control mice of the same subline, the incidence of spontaneous lymphoma is about 1 percent. No leukemogenic activity could be detected in filtrates from thymi harvested at 2 to 32 days following completion of x-ray treatment. Activity was evident at 64 days and was perhaps somewhat greater at 128 days. Serial cell-free passage of filtrates in newborn F(1) hybrid mice resulted in a marked increase in lymphoma incidence (69 percent), coupled with a shortening of the median latency. Supplementary x-irradiation failed to enhance the activity of filtrates after neonatal injection.


Calcitonin gene-related peptide terminates long-lasting vasopressor responses to endothelin 1 in vivo.
Slow dissociation of endothelin 1 from its endothelin A receptors is responsible for the long-lasting vasoconstrictor effects of the peptide. We showed recently that calcitonin gene-related peptide selectively terminates long-lasting contractile responses to endothelin 1 in isolated rat mesenteric arteries. Here we assessed whether the antiendothelinergic effect of calcitonin gene-related peptide is vascular bed specific and may terminate long-lasting pressor responses to exogenous and locally produced endothelin 1 in vivo. Regional heterogeneity of the calcitonin gene-related peptide/endothelin A receptor cross-talk was explored in arteries isolated from various rat organs. Endothelin A receptor-mediated arterial contractions were terminated by calcitonin gene-related peptide in rat mesenteric, renal, and spermatic arteries but not in basilar, coronary, epigastric, gastric, splenic, and saphenous arteries. Endothelin A receptor antagonism only ended endothelin 1-induced contractions in spermatic arteries. In anesthetized rats, instrumented with Doppler flow probes to record regional blood flows, long-lasting pressor and vasoconstrictor responses to an intravenous bolus injection of endothelin 1 or big endothelin 1 were transiently reduced by sodium nitroprusside (NO donor) but terminated by intravenously administered calcitonin gene-related peptide. In conscious rats, calcitonin gene-related peptide but not sodium nitroprusside terminated prolonged (>60-minute) pressor responses to endothelin 1 but not those to intravenous infusion of phenylephrine. In conclusion, pressor responses to circulating and locally produced endothelin 1 that are resistant to endothelin receptor antagonism and NO can be terminated by a regionally selective effect of calcitonin gene-related peptide. Calcitonin gene related peptide receptor agonism may represent a novel strategy to treat endothelin 1-associated cardiovascular pathologies.


Longitudinal Changes of Physical Activity and Sedentary Time in the Middle-Aged and Older Japanese Population: The Hisayama Study.
The purpose of this study was to describe changes in physical activity volumes and sedentary time over 3 years in the middle-aged and older Japanese population. Study participants included 1151 Japanese community-dwelling residents aged ≥40 years in 2009 who underwent 2 sets of health examinations (2009 and 2012). Using a triaxial accelerometer, longitudinal changes in sedentary time, light physical activity volume, moderate to vigorous physical activity volume, number of steps, and total physical activity volume were evaluated according to sex, age (40-49, 50-59, 60-69, 70-79, and ≥80 y), and obese (nonobese and obese) categories. Sedentary time significantly increased, and all physical activity volumes significantly decreased among all participants. Although most variables did not change significantly in the 40-49 and 50-59 year age categories, similar changes as all participants were observed across all other categories. In the correlation analyses, changes in sedentary time correlated, at most, only modestly for each change in physical activity volumes, indicating that increased physical activity volume does not always lead to decreased sedentary time, and vice versa. Strategies to reduce sedentary time and promote physical activity are needed in Japan, particularly for people aged ≥60 years.


Chronic Q Fever Infections in Israeli Children: A 25-year Nationwide Study.
Q fever is a zoonosis caused by the bacterium Coxiella burnetii (C. burnetii) with a worldwide distribution. Our aim was to assess the epidemiology, clinical manifestations and treatment regimens of chronic Q fever infections in Israeli children during the past 25 years. Cases were collected from the national Q fever reference laboratory database. Demographic, epidemiologic and clinical data were reviewed using a structured questionnaire sent to the referring physician. Cases were defined according to the new Dutch Consensus Guidelines. A total of 16 children originating from all regions of the country were found positive for chronic Q fever infections. The most common infection site was bone or joint (8/16, 50%), all in previously healthy children. Endovascular infections were found in 5 children (31%), all with an antecedent cardiac graft insertion. According to the new Consensus Guidelines, 9 children (56%) had a proven infection, 3 (19%) a probable infection and 4 (25%) a possible chronic Q fever infection. Almost all cases were treated with a long-term antibiotic regimen, often necessitating a change in medication because of persistent or rising titers. Although pediatric chronic Q fever infections are rare, incidence has been rising. The most common infection site was bone or joint. A high index of suspicion is necessary, even in cases of previously healthy children without a possible exposure history. Use of the relatively new diagnostic tools in combination with serologic methods is helpful in diagnosing proven cases. There is no consensus as to the selection or duration of antibiotic treatment.


Thoracic irrigation prevents retained hemothorax: A prospective propensity scored analysis.
Thoracic trauma resulting in hemothorax (HTx) is typically managed with thoracostomy tube (TT) placement; however, up to 20% of patients develop retained HTx which may necessitate further intervention for definitive management. Although optimal management of retained HTx has been extensively researched, little is known about prevention of this complication. We hypothesized that thoracic irrigation at the time of TT placement would significantly decrease the rate of retained HTx necessitating secondary intervention. A prospective, comparative study of patients with traumatic HTx who underwent bedside TT placement was conducted. The control group consisted of patients who underwent standard TT placement, whereas the irrigation group underwent standard TT placement with immediate irrigation using 1 L of warmed sterile 0.9% saline. Patients who underwent emergency thoracotomy, those with TTs removed within 24 hours, or those who died within 30 days of discharge were excluded. The primary end point was secondary intervention defined by additional TT placement or operative management for retained HTx. A propensity-matched analysis was performed with scores estimated using a logistic regression model based on age, sex, mechanism of injury, Abbreviated Injury Scale chest score, and TT size. In over a 30-month period, a total of 296 patients underwent TT placement for the management of traumatic HTx. Patients were predominantly male (79.6%) at a median age of 40 years and were evenly split between blunt (48.8%) and penetrating (51.2%) mechanisms. Sixty (20%) patients underwent thoracic irrigation at time of initial TT placement. The secondary intervention rate was significantly lower within the study group (5.6% vs. 21.8%; OR, 0.16; p < 0.001). No significant differences in TT duration, ventilator days, or length of stay were noted between the irrigation and control cohort. Thoracic irrigation at the time of initial TT placement for traumatic HTx significantly reduced the need for secondary intervention for retained HTx. Therapeutic Study, Level III.


Enhanced recovery after surgery with laparoscopic radical gastrectomy for stomach carcinomas.
To study the efficacy of the enhanced recovery after surgery (ERAS) program in laparoscopic radical gastrectomy for stomach carcinomas. From June 2010 to December 2012, 61 gastric cancer patients who underwent laparoscopic-assisted radical gastrectomy with D2 lymphadenectomy at First Hospital of Jilin University were enrolled in this randomized controlled trial. (Clinical Trials.gov, registration ID: NCT01955096). The subjects were divided into the ERAS program group and the conventional control group. The clinical characteristics, recovery variables, and complications of patients were analyzed. The time to first ambulation, oral food intake, and time to defecation were significantly shorter in the ERAS group (n = 30), compared to the conventional group (n = 31; P = 0.04, 0.003, and 0.01, respectively). The postoperative hospital stay was less in the ERAS group (6.8 ± 1.1 d) compared to the conventional group (7.7 ± 1.1 d) (P = 0.002). There was no significant difference in postoperative complications between the ERAS (1/30) and conventional care groups (2/31) (P = 1.00). There were no readmissions or mortality during the 30-d follow-up period. The ERAS program is associated with a shorter hospital stay in gastric cancer patients undergoing laparoscopic radical gastrectomy. The ERAS protocol is useful in the treatment of gastric cancer.


Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot-Marie-Tooth disease and related peripheral neuropathies.
During the last decade, 18 genes and 11 additional loci harboring candidate genes have been associated with Charcot-Marie-Tooth disease (CMT) and related peripheral neuropathies. Ten of these 18 genes have been identified in the last 2 years. This phenomenal pace of CMT gene discovery has fomented an unprecedented explosion of information regarding peripheral nerve biology and its pathologic manifestations in CMT. This review integrates molecular genetics with the clinical phenotypes and provides a flowchart for molecular-based diagnostics. In addition, we discuss rational approaches to molecular therapeutics, including novel biologic molecules (eg, small interfering ribonucleic acid [siRNA], antisense RNA, and ribozymes) that potentially could be used as drugs in the future. These may be applicable in attempts to normalize gene expression in cases of CMT type 1A, wherein a 1.5 Mb genomic duplication causes an increase in gene dosage that is associated with the majority of CMT cases. Aggresome formation by the PMP22 gene product, the disease-associated gene in the duplication cases, could thus be avoided. We also discuss alternative therapeutics, in light of other neurodegenerative disorders, to disrupt such aggresomes. Finally, we review rational therapeutic approaches, including the use of antioxidants such as vitamin E, coenzyme Q10, or lipoic acid to relax potential oxidative stress in peripheral nerves, for CMT management.


An update of the salmon louse (Lepeophtheirus salmonis) reference genome assembly.
Salmon lice have plagued the salmon farming industry and have negatively impacted salmon populations in the wild. In response, researchers have generated high density genetic maps, genome assemblies, transcriptomes, and whole-genome resequencing data to better understand this parasite. In this study, we used long-read sequencing technology to update the previous genome assemblies of Atlantic Ocean salmon lice with a more contiguous assembly and a more comprehensive gene catalog of Pacific Ocean salmon lice. We were also able to further characterize genomic features previously identified from other studies by using published resequenced genomes of 25 Atlantic and 15 Pacific salmon lice. One example was further characterizing the ZW sex chromosomes. For both the Atlantic and Pacific Ocean salmon lice subspecies, we found that the female W-chromosome is only a small fraction of the Z-chromosome and that the vast majority of the W and Z-chromosome do not contain conserved regions (i.e. pseudoautosomal regions). However, conserved orthologous protein sequences can still be identified between the W- and Z-chromosomes.


[Sacrococcygeal teratoma: single center experience and functional long-term follow-up].
To propose long-term follow-up protocol to analyse clinical and functional aspects and evaluate the Quality of Life (QoL) of patients with Sacrococcygeal Teratoma (SCT). The long-term follow-up of 14 out of 28 patients has been assessed through the retrospective review of data related to antenatal diagnosis, obstetric pathology and surgery, collected from July 1985 to December 2009. It has been accomplished by analysing functional and aesthetic outcomes and the QoL experienced by the patients with an average observation range of 121 months for each patient. Concerning the anorectal functionality, 14% of patients reported impairment of fecal continence while 36% had completely normal bowel habits. Other health problems varying from urinary incontinence to neurogenic bladder were reported by 36% of patients. Dealing with the functionality of lower limbs, 20% of patients exhibited minor dysfunctions while 7% major ones. Optimal aesthetic outcome of the surgical scar has been reported only by 21% of the specimen. The evaluation of QoL pointed out that 64% of patients are moderately satisfied while 36% presented problems. We believe that functional sequelae should play an important role during antenatal counselling and that the urological and anorectal follow-up for SCT patients should be long-term evaluated. Furthermore, aesthetic aspects and psychological support should be taken into account carefully especially during childhood.


Radiation therapy in the last month of life.
We sought to survey a large, multi-center patient sample to better characterize/quantify RT utilization at the end of life. Few objective data exist for radiation therapy (RT) delivery at end of life (EOL). Data were retrieved for all patients receiving RT in calendar year 2010 in the Department of Radiation Oncology at Indiana University (IU) and Howard University (HU) hospitals. Specific attention was made of the group of patients receiving RT in the last 30 days of life. A total of 852 patients received all or part of their RT during 2010 (HU: 139, IU: 713). At time of analysis in early 2012, 179 patients had died (21%). Fifty-four patients (6.3% of total; 30% of expired patients) died within 30 days of receiving their last treatment. Twenty patients (2.3% of total; 11.2% of expired patients) received RT within their last week of life. For both sites, the median time until death from completion of therapy was 12.5 days (range 2-30 days). Radiation in the last month of life is likely to provide minimal palliation or survival benefit. This, coupled with the financial implications, time investment, and physical costs, suggests that physicians and patients should more strongly consider hospice, and minimize duration of palliative RT courses as far as possible. As with chemotherapy, RT utilization at EOL should be considered for collection as an overuse metric.


Effects of alpha-difluoromethylornithine on the growth of experimental Wilms' tumor and renal adenocarcinoma.
Because polyamines are essential for cellular growth and differentiation, and because human renal carcinomas have spermidine levels that are higher than those in normal renal tissue, effects of 2-difluoromethylornithine (DFMO) on the growth of experimental renal tumors were investigated. DFMO is a specific enzyme-activated irreversible inhibitor of ornithine decarboxylase, the rate-limiting enzyme controlling polyamine biosynthesis. DFMO (2%) in drinking water was administered to BALB/c mice with intrarenal transplants of a renal adenocarcinoma cell suspension and to Wistar/Furth rats with s.c. transplants of a Wilms' tumor. At 28 days, renal carcinomas in DFMO-fed mice weighed 72% less than those in control animals (p less than 0.001). Wilms' tumor weight was not affected by DFMO feeding. DFMO caused 72 to 75% inactivation of ornithine decarboxylase activity and reduced putrescine levels in renal carcinoma and Wilms' tumor, reduced spermidine levels in Wilms' tumor, and apparently raised spermine levels in the latter as a consequence. DNA content was not affected by DFMO feeding. The mean number of lung metastases in DFMO-fed, renal carcinoma-bearing mice was 0.1 and in controls was 1.4 (p less than 0.001). DFMO feeding increased survival of mice bearing renal carcinomas by 3.0 +/- 0.8 (S.E.) days (p less than 0.05), i.e., from 30.5 +/- 0.8 days to 33.5 +/- 1.2 days. DFMO did not affect the growth of Wilms' tumor; however, in renal adenocarcinoma, it reduced growth, prevented lung metastases, and increased survival.


Exon resequencing of the gene encoding UCma/GRP reveals a common carboxy-terminal 138Thr > Ser polymorphism.
The upper zone of growth plate and cartilage matrix-associated protein (UCMA), also called G1a-rich protein (GRP), is a novel protein found at sites affected by pathological calcifications. We performed a full exon resequencing on DNA samples from 17 chronic kidney disease (CKD) patients (stage 5) and compared the results with 121 healthy controls in a Swedish population. A novel non-synonymous single nucleotide polymorphism (SNP) causing a carboxy-terminal amino acid exchange was found. This SNP involves an alteration of the last ACC codon for threonine in exon 5 (adjacent to the stop codon) to an AGC serine codon (138Thr > Ser). Six controls and two CKD patients were heterozygous for the 138Thr > Ser polymorphism. Both patients had histories of vascular calcification; however, it is uncertain whether this SNP has any significance for the functional domains of the UCMA protein. In addition, a heterozygous transversion mutation was found in a patient at SNP rs4750328 (A/G) in intron 2, involving an exchange of the ancestral A allele to a T base. The 138Thr > Ser polymorphism seems to be the only non-synonymous SNP found in the UCMA gene in a Swedish population.


Novel Molecular Mechanism of Regulation of CD40 Ligand by the Transcription Factor GLI2.
The interaction between tumor cells and their surrounding microenvironment is essential for the growth and persistence of cancer cells. This interaction is mediated, in part, by cytokines. Although the role of cytokines in normal and malignant cell biology is well established, many of the molecular mechanisms regulating their expression remain elusive. In this article, we provide evidence of a novel pathway controlling the transcriptional activation of CD40L in bone marrow-derived stromal cells. Using a PCR-based screening of cytokines known to play a role in the biology of bone marrow malignancies, we identified CD40L as a novel GLI2 target gene in stromal cells. CD40L plays an important role in malignant B cell biology, and we found increased Erk phosphorylation and cell growth in malignant B cells cocultured with CD40L-expressing stromal cells. Further analysis indicated that GLI2 overexpression induced increased CD40L expression, and, conversely, GLI2 knockdown reduced CD40L expression. Using luciferase and chromatin immunoprecipitation assays, we demonstrate that GLI2 directly binds and regulates the activity of the CD40L promoter. We found that the CCR3-PI3K-AKT signaling modulates the GLI2-CD40L axis, and GLI2 is required for CCR3-PI3K-AKT-mediated regulation of the CD40L promoter. Finally, coculture of malignant B cells with cells stably expressing human CD40L results in increased Erk phosphorylation and increased malignant B cell growth, indicating that CD40L in the tumor microenvironment promotes malignant B cell activation. Therefore, our studies identify a novel molecular mechanism of regulation of CD40L by the transcription factor GLI2 in the tumor microenvironment downstream of CCR3 signaling.


Co-Amorphization of Ibuprofen by Paracetamol for Improved Processability, Solubility, and In vitro Dissolution.
Co-amorphous (COAM) systems of ibuprofen (IB) and paracetamol (PA), in clinical dose ratios, were prepared by ball milling to enhance solubility and dissolution of IB. Subsequently, COAM were characterized by solubility, processability, XRPD, DSC, ATR-FTIR, SEM, in-vitro dissolution and accelerated stability studies. Maximum increase in aqueous solubility of IB was seen in 500:200 mg dose ratio (COAM 1) with 6.7 fold rise from 78.3 ± 1.1 to 522.6 ± 1.29 ∆g/ml. COAM 1 exhibited 99.80 ± 0.58% dissolution of IB at 20 min in phosphate buffer, significantly high (P < 0.05) compared to plain IB. Thus saturation solubility and dissolution rate of IB was found significantly improved unlike PA. The flowability/ processability of COAM system was remarkably improved compared to pure IB, speculated due to as formation of miniscular forms of PA-IB, having strong adhesive interactions. XRPD and DSC results confirmed amorphization of IB. ATR-FTIR results evidenced hydrogen bonding interactions between both the drugs. In accelerated stability studies, flowability, XRPD, DSC and in-vitro dissolution studies demonstrated insignificant changes, thus confirming successful stabilisation of IB by PA.


Nanowire Oligomer Waveguide Modes towards Reduced Lasing Threshold.
Semiconductor nanowires offer a promising route of realizing nanolasers for the next generation of chip-scale optoelectronics and photonics applications. Established fabrication methods can produce vertical semiconductor nanowires which can themselves act both as a gain medium and as a Fabry-Pérot cavity for feedback. The lasing threshold in such nanowire lasers is affected by the modal confinement factor and end facet reflectivities, of which the substrate end reflectivity tends to be limited due to small refractive index contrast between the nanowire and substrate. These modal properties, however, also depend strongly on the modal field profiles. In this work, we use numerical simulations to investigate waveguide modes in vertical nanowire oligomers (that is, arrangements of few vertical nanowires close to each other) and their modal properties compared to single nanowire monomers. We solve for the oligomer waveguide eigenmodes which are understood as arising from interaction of monomer modes and further compute the reflectivity of these modes at the end facets of the nanowires. We consider either the nanowires or an additional coating layer as the gain medium. We show that both types of oligomers can exhibit modes with modal properties leading to reduced lasing threshold and also give directions for further research on the topic.


[Compound osteosynthesis as treatment for an osteoporotic LWK-1 burst fracture in a 76 year old female patient].
The surgical treatment of osteoporotic vertebral compression fractures is rarely necessary and is mostly done in fractures with neurological deficit. We present a case of compound osteosynthesis in an osteoporotic fracture of the first lumbar vertebra as a "salvage procedure" after a dislocation of a dorsal internal fixator in a 76 year old female sustaining incomplete paraplegia. In this case, an additional ventral stabilization using a vertebral body replacement was not practicable because of old age and previous pneumonia. We performed an additional compound osteosynthesis using bone cement because of insufficient stability when only using cement for augmentation of the pedicle screws.


Evidence that the recessive bymovirus resistance locus rym4 in barley corresponds to the eukaryotic translation initiation factor 4E gene.
SUMMARY Recent studies have shown that resistance in several dicotyledonous plants to viruses in the genus Potyvirus is controlled by recessive alleles of the plant translation initiation factor eIF4E or eIF(iso)4E genes. Here we provide evidence that the barley rym4 gene locus, controlling immunity to viruses in the genus Bymovirus, corresponds to eIF4E. A molecular marker based on the sequence of eIF4E was developed and used to demonstrate that eIF4E and rym4 map to the same genetic interval on chromosome 3HL in barley. Another genetic marker was developed that detects a polymorphism in the coding sequence of eIF4E and consistently distinguishes between rym4 and susceptible barley cultivars of diverse parentage. The eIF4E gene product from barley genotypes carrying rym4 and allelic rym5 and rym6 genes, originating from separate exotic germplasm, and a novel resistant allele that we identified through a reverse genetics approach all contained unique amino acid substitutions compared with the wild-type protein. Three-dimensional models of the barley eIF4E protein revealed that the polymorphic residues identified are all located at or near the mRNA cap-binding pocket, similarly to recent findings from studies on recessive potyvirus resistance in dicotyledonous plants. These new data complement our earlier observations that specific mutations in bymovirus VPg are responsible for overcoming rym4/5-controlled resistance. Because the potyviral VPg is known to interact with eIF4E in dicotyledonous plants, it appears that monocotyledonous and dicotyledonous plants have evolved a similar strategy to combat VPg-encoding viruses in the family Potyviridae.


A novel role of microRNA in late preconditioning: upregulation of endothelial nitric oxide synthase and heat shock protein 70.
MicroRNAs (miRNAs) are noncoding RNAs of 18 to 24 nucleotides that are involved in posttranscriptional regulation of protein expression. Their role in ischemic preconditioning (IPC) is currently unknown. We hypothesized that miRNAs induced after IPC in the heart may create a preconditioned phenotype through upregulating proteins including endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) and heat shock protein (HSP)70, which are implicated in the late-phase protection of IPC. miRNAs were extracted from hearts of ICR mice following IPC. The purified miRNAs were injected in vivo into the left ventricular wall of mice, and, 48 hours later, the hearts were subjected to regional ischemia/reperfusion injury by left anterior descending artery ligation for 30 minutes followed by reperfusion for 24 hour. IPC caused no changes in miRNA-23b and miRNA-483 whereas miRNA-1, miRNA-21and miRNA-24 were significantly increased. The IPC-miRNA treatment caused an increase in eNOS mRNA and protein, whereas iNOS was not changed. HSF-1 (heat shock transcription factor 1) and HSP70 were also increased with IPC-miRNA treatment versus control. Moreover, injection of IPC-miRNA protected the hearts against ischemia/reperfusion injury, as shown by a reduction of infarct size as compared with saline or non-IPC miRNA-treated control. We conclude that IPC-induced miRNAs trigger cardioprotection similar to the delayed phase of IPC, possibly through upregulating eNOS, HSP70, and the HSP70 transcription factor HSF-1.


Maximizing the Role of Emergency Medical Services in COVID-19 Response.
The Centers for Disease Control and Prevention define 6 intervals of a pandemic: (1) investigation of cases, (2) recognition of the increased potential for ongoing transmission, (3) initiation of a pandemic wave, (4) acceleration of a pandemic wave, (5) deceleration of a pandemic wave, and (6) preparation for future pandemic waves. Each of these stages has 8 domains. Following China's coronavirus disease 2019 (COVID-19) outbreak announcement, Israel's National Emergency Medical Services (EMS) Organization immediately began working in conjunction with the Ministry of Health (MOH) to address the threat of the COVID-19 outbreak. This article will describe how a national EMS organization acted according to these pandemic intervals and domains. In the initial stages, EMS managed a checkpoint in the international airport voluntarily testing people for febrile symptoms. Calls to the dispatch centers that aroused the suspicion of COVID-19 resulted in EMS transport to the hospital with protective gear. During the period of first exposure, the scope of the medical emergency number was increased to include questions concerning coronavirus, telemedicine, and home sampling by protected EMS workers. In the contagion stages, epidemiological tests were conducted by the MOH, and EMS began operating dedicated telephone triage, mass drive-through sampling, and finally, administration of vaccinations.


[The endocrinology of the human placenta].
The human placenta performs various, important functions essential for the maintenance of pregnancy and development of the fetus. Its secretory diversity surpasses any of the other endocrine organs. The placenta is provided with precursors of hormones by the mother as well as by the fetus. It synthesizes and secretes steroid and protein hormones, growth factors, cytokines. The paper is the review of the present knowledge of steroid hormones (progesterone, estrogens), in particular their synthesis and functions in fetoplacental unit. The protein hormones (chorionic gonadotropin, placental lactogen) are also discussed. The last findings concerning placental gonadotropin-releasing hormone, corticotropin-releasing hormone, leptin, activin, inhibin, follistatin and urocortin are presented. The endocrinology of the placenta is considered to be a progressive field of science. The performed studies elucidate the role of the newly identified hormones in the placenta. It is believed, that research on endocrinology of the placenta contributes to the development of perinatology and, moreover, they improve the prenatal care.


Germ cell expression of an isolated human endogenous retroviral long terminal repeat of the HERV-K/HTDV family in transgenic mice.
In contrast to most other human endogenous retroviral families, various HERV-K members have open reading frames that code for functional viral proteins which can form noninfectious particles in some germ cell tumors. The HERV-K viral genes are highly transcribed in germ cell tumors but are transcribed to lower or undetectable levels in most other tissue and tumor types. To further analyze the expression patterns of these proviruses, long terminal repeats (LTRs) were isolated from the human genome and used in reporter gene assays. Expression of some HERV-K LTRs was found to be high in human and murine germ cell tumors (testicular teratocarcinomas) and low in non-germ-cell tumors. Furthermore, upon differentiation of a teratocarcinoma cell line, the expression of an active LTR dropped dramatically, suggesting developmental regulation of these proviral LTRs. Transgenic mice harboring an active LTR driving lacZ expression were generated and analyzed. Adult mouse testes showed the highest levels of expression, and the transgene staining appeared to be restricted primarily to the more undifferentiated spermatocytes. Most other tissues analyzed revealed very low or undetectable levels of expression both by reverse transcription-PCR and by Northern blot analysis. Whether the restricted expression of HERV-K in germ cells and in germ cell-derived tumors is of significant importance during development or tumorigenesis remains to be elucidated. Germ line expression of these viruses would allow for their expansion and movement, while somatic repression would ensure limited insertional mutagenesis and misexpression in an individual.


Peer effects in learning HIV results.
How do neighbors positively or negatively influence individuals living in rural Malawi to learn their HIV results? Using data of location of homes and distance to neighbors, we measure the social network effects of neighbors' learning their HIV results on individuals own learning. Using the fact that neighbors were randomly offered monetary incentives of varying amounts to learn their HIV results, we find positive effects of neighbors attending clinics on others living nearby: a 10 percentage point increase of the percentage of neighbors (approximately 2.4 individuals) learning their HIV results increases the probability of learning HIV results by 1.1 percentage points. The strongest network effects are among closest neighbors; we find no effect among religious social networks. We also find a negative interaction between direct cash incentives and peers: the effect of peers doubles among those who were not offered any individual financial incentive to learn their HIV results.


The antagonistic effect of the sigma 1 receptor ligand (+)-MR200 on persistent pain induced by inflammation.
The sigma 1 (σ1) receptor, which is widely distributed in the CNS in areas that are known to be important for pain control, may play a role in persistent pain characterized by the hypersensitivity of nociceptive transmission. Here, we investigated the effect of σ1 blockade in an inflammatory pain model. An intraplantar injection of carrageenan (2 %) was used to induce paw inflammation. The effects of the σ1 antagonist (+)-MR200, given subcutaneously at a dose of 0.1, 0.25, 0.5,1, 1.5, and 2 mg/kg prior to injection of carrageenan, on inflammatory pain and inflammation were assessed. Mechanical allodynia with von Frey filaments, thermal hyperalgesia with the plantar test and edema evaluation with a plethysmometer were measured. Intergroup comparisons were assessed by one- or two-way analysis of variance when appropriate, followed by post-hoc tests (Dunnett's test for one-way or Bonferroni for two-way ANOVA). (+)-MR200 dose-dependently prevented allodynia and hyperalgesia induced by carrageenan. Furthermore, it reduced paw edema with a significant inhibition percentage of 37.82 % at 3 h after carrageenan treatment. The blockade of the σ1 receptor with the selective antagonist (+)-MR200 may contribute to the suppression of the typical symptoms of inflammatory pain.


Intentional Forgetting in Organizations: The Importance of Eliminating Retrieval Cues for Implementing New Routines.
To cope with the already large, and ever increasing, amount of information stored in organizational memory, "forgetting," as an important human memory process, might be transferred to the organizational context. Especially in intentionally planned change processes (e.g., change management), forgetting is an important precondition to impede the recall of obsolete routines and adapt to new strategic objectives accompanied by new organizational routines. We first comprehensively review the literature on the need for organizational forgetting and particularly on accidental vs. intentional forgetting. We discuss the current state of the art of theory and empirical evidence on forgetting from cognitive psychology in order to infer mechanisms applicable to the organizational context. In this respect, we emphasize retrieval theories and the relevance of retrieval cues important for forgetting. Subsequently, we transfer the empirical evidence that the elimination of retrieval cues leads to faster forgetting to the forgetting of organizational routines, as routines are part of organizational memory. We then propose a classification of cues (context, sensory, business process-related cues) that are relevant in the forgetting of routines, and discuss a meta-cue called the "situational strength" cue, which is relevant if cues of an old and a new routine are present simultaneously. Based on the classification as business process-related cues (information, team, task, object cues), we propose mechanisms to accelerate forgetting by eliminating specific cues based on the empirical and theoretical state of the art. We conclude that in intentional organizational change processes, the elimination of cues to accelerate forgetting should be used in change management practices.


Genomics and autism spectrum disorder.
To present the current state of the evidence regarding translation of genetics (the study of single genes) and genomics (the study of all genes and gene-gene or gene-environment interactions) into health care of children with autism spectrum disorder (ASD). This article presents an overview of ASD as an international health challenge, the emerging science related to broad diagnostic criteria, and the role of the nurse in research, education, and practice. Much progress is being made in the understanding of genetics and genomics of ASD. Environmental factors are thought to contribute to the risk of developing ASD by interacting with a number of genes in different ways, thus suggesting causal heterogeneity. The rising identified prevalence of ASD, the changing diagnostic criteria for ASD, and the complexity of the core and associated features have made it difficult to define the ASD phenotype (observable behaviors that result from gene-environment interaction). Because early identification improves opportunities for intervention, researchers are looking for a useful biomarker to detect ASD. This search is complicated by the likelihood that there are multiple causes for multiple expressions that are defined as the autism spectrum. To date, genetic and genomic research on ASD have underscored the complexity of the causes of ASD indicating that there are very complex genetic processes involved that are still not well understood. Nurses will benefit from new knowledge related to early identification, diagnosis, and implications for the family to promote early intervention. Families who have a child with ASD will require nursing support for advocacy for optimal health outcomes.


Effect of a Diet-Induced Obesity on the Progeny Response in a Murine Model.
Diet-induced obesity could have detrimental effects on adults and their progeny. The aim of this study was to determine the effect of a high-energy diet on both F1 mice body weight and tissue/organ weight and F2 offspring growth. A simple murine model for obesity was developed using a high-energy diet and mice reared in litters of five or ten, from 30 dams receiving a cafeteria diet of either commercial chow (low energy), or a mixture of commercial chow, chocolate (50% cacao), and salty peanuts (high energy). This diet continued from mating until weaning, when the pups were allocated according to sex into eight groups based on maternal diet, litter size, and post-weaning diet. On day 74, the males were slaughtered, and the females were bred then slaughtered after lactation. As a result, the high-energy maternal diet increased the F1 offspring growth during lactation, while the high-energy post-weaning diet increased the F1 adult body weight and tissue/organ weight. The high-energy maternal diet could negatively affect the onset of the F1 but not the maintenance of breastfeeding of F1 and F2 offspring. For F2 offspring growth, the high energy overlapped the low-energy post-weaning diet, due to problems of gaining weight during lactation.


Multi-triggered and enzyme-mimicking graphene oxide/polyvinyl alcohol/G-quartet supramolecular hydrogels.
Supramolecular hydrogels with stimuli-responsive behaviors under aqueous environments are attractive for their potential applications in controlled drug delivery, clinical diagnostics, and tissue engineering. However, there still remain challenges in developing multicomponent hydrogels as a new generation of "smart" soft materials with multiple intelligent functions toward complex biochemical stimuli. In this work, a three dimensional (3D)-nanostructured supramolecular hydrogel was fabricated using a simple and facile strategy via the self-assembly of graphene oxide (GO) nanosheets, poly(vinyl alcohol) (PVA) chains, and G-quartet/hemin (G4/H) motifs. The as-prepared GO/PVA/G4/H hydrogel exhibited a honeycomb-like 3D GO network architecture as well as excellent mechanical properties. Importantly, the hydrogel demonstrated pH-inducing reversible and cyclic phase transitions between solution and hydrogel states, which could be used as "ink" for injectable 3D printing of different shaped patterns. Also, binary AND and OR logic gates were successfully built by encapsulating enzymes into the hydrogels, which responded to a variety of biochemicals. In addition, the hydrogels showed excellent peroxidase-like activity, achieving the ultrasensitive detection of H2O2 at a concentration as low as 100 nM by their deposition on an electrochemical electrode. The design of multicomponent hydrogels opens up an avenue to fabricate novel "smart" soft matter for biological and medical applications.


The role of transforming growth factor beta isoforms in tendon-to-bone healing.
The purpose of this study was to examine the role of two of the three transforming growth factor beta (TGF-β) isoforms at the healing tendon-to-bone insertion. The supraspinatus tendons of 64 rats were transected at their bony insertions and repaired to the humeral head. One shoulder of each rat received an osmotic pump for sustained delivery of the following factors at the repair site: (1) TGF-β1 and neutralizing antibodies to TGF-β2 and 3 (TGF-β1 group), (2) TGF-β3 and neutralizing antibodies to TGF-β1 and 2 (TGF-β3 group), (3) neutralizing antibodies to TGF-β1, 2, and 3 (anti-TGF-β group), and (4) saline (saline group). The contralateral shoulders received saline to serve as paired controls. The repairs were evaluated at multiple time points postmortem using histology-based assays and biomechanical testing. Treated shoulders in the TGF-β1 group showed increased type III collagen production compared to the paired control shoulders, indicative of a scar-mediated response. There was a trend toward reduced mechanical properties in the TGF-β1 group, but these changes did not reach statistical significance. The anti-TGF-β group showed no difference in tissue volume, but significantly inferior mechanical properties, compared to the paired control shoulders. The TGF-β3 group did not show any differences compared to the paired control shoulders. Although TGF-β isoforms play important roles in tendon-to-bone development and healing, application of exogenous TGF-β isoforms and neutralizing antibodies to the subacromial space using osmotic pumps did not improve supraspinatus tendon-to-bone healing.


Morphometric, histopathological and molecular findings of Macracanthorhynchus hirudinaceus infection in wild boar (Sus scrofa) from continental Italy.
Although Macracanthorhynchus hirudinaceus is a neglected acanthocephalan of suids occasionally responsible for severe infections in humans, the spread of wild boar (Sus scrofa) populations in Europe could promote the circulation. Herein, we report the first morphometric, histological and molecular characterization of a severe M. hirudinaceus infection in a boar from continental Italy. The boar's intestine displayed granulomatous enteritis due to 24 helminths (14 females, 10 males), identified as adults of M. hirudinaceus by a combined morphometric/molecular approach. The phylogenetic analysis of the cox1 gene revealed a close relationship of the M. hirudinaceus sequence type found herein with those from Hungary and insular Italy. The high haplotype diversity and low nucleotide diversity of M. hirudinaceus specimens would suggest its rapid demographic expansion in the Mediterranean basin. More research is needed to assess the presence of M. hirudinaceus in susceptible beetle species and the role of boars in the epidemiology of infection.


Osteopetrosis: a single centre experience of stem cell tranisplantation and prenatal diagnosis.
Malignant osteopetrosis (MOP) is an autosomal recessive disease in which osteoclast dysfunction results in excessive bone deposition and early infant death. Thirteen children suffering from MOP from four related families all belonging to one Bedouin tribe, were studied. The disease was diagnosed as early as at a few days postnatal to 5 months. Nine children underwent BMT, four of whom are still alive; one is blind and two have markedly reduced vision. Four children who did not undergo BMT died between 4 and 6 months of age. Recently, the gene for MOP has been mapped for this Bedouin tribe allowing prenatal diagnosis. Seven pregnancies were subsequently prenatally diagnosed and two fetuses were found to be affected. Pregnancy was electively terminated in one case. In the other case the parents refused and after establishing the diagnosis, the newborn was transplanted at the age of 7 days.


Comparison of response rates to a postal questionnaire from a general practice and a research unit.
A postal questionnaire study was carried out in an urban general practice to determine the effect of the introductory letter being sent by the participants' own general practitioner compared with that from a letter sent directly from a research unit. By sequential sampling 409 individuals aged between 40 and 59 were assigned to one of two groups. The people in one group were written to by their own general practitioner and those in the other by a doctor from a research unit. Husbands and wives were paired and were always sent the same letter. A second letter was sent to nonresponders after one month. The response rate to the general practitioner was significantly higher than that to the doctor in the research unit (85% compared with 75%) and differed by age and sex. The results have important implications for other research workers and suggest that general practitioners are in a key position in the conduct of medical and epidemiological research.


Dynamic Assessment of Narratives: Efficient, Accurate Identification of Language Impairment in Bilingual Students.
This study investigated the classification accuracy of a concentrated English narrative dynamic assessment (DA) for identifying language impairment (LI). Forty-two Spanish-English bilingual kindergarten to third-grade children (10 LI and 32 with no LI) were administered two 25-min DA test-teach-test sessions. Pre- and posttest narrative retells were scored in real time. Using a structured intervention approach, examiners taught children missing story grammar elements and subordination. A posttest was administered using a parallel story. Four classification predictors were analyzed: posttest scores, gain scores, modifiability ratings, and teaching duration. Discriminant function analysis indicated that an overall modifiability rating was the best classifier, with 100% sensitivity and 88% specificity after 1 DA session and 100% sensitivity and specificity after 2 sessions. Any 2 combinations of posttest scores, modifiability ratings, and teaching duration for just 1 session resulted in sensitivity and specificity rates over 90%. Receiver operating characteristic analyses were used to identify clinically usable cutoff points. Post hoc exploration indicated that similar results could be obtained after only one 5-10-min teaching cycle, potentially further abbreviating the DA process. Concentrated English narrative DA results in high classification accuracy for bilingual children with and without LI. This efficient version of DA is amenable to clinical use.


ZEB1: A Critical Regulator of Cell Plasticity, DNA Damage Response, and Therapy Resistance.
The predominant way in which conventional chemotherapy kills rapidly proliferating cancer cells is the induction of DNA damage. However, chemoresistance remains the main obstacle to therapy effectivity. An increasing number of studies suggest that epithelial-to-mesenchymal transition (EMT) represents a critical process affecting the sensitivity of cancer cells to chemotherapy. Zinc finger E-box binding homeobox 1 (ZEB1) is a prime element of a network of transcription factors controlling EMT and has been identified as an important molecule in the regulation of DNA damage, cancer cell differentiation, and metastasis. Recent studies have considered upregulation of ZEB1 as a potential modulator of chemoresistance. It has been hypothesized that cancer cells undergoing EMT acquire unique properties that resemble those of cancer stem cells (CSCs). These stem-like cells manifest enhanced DNA damage response (DDR) and DNA repair capacity, self-renewal, or chemoresistance. In contrast, functional experiments have shown that ZEB1 induces chemoresistance regardless of whether other EMT-related changes occur. ZEB1 has also been identified as an important regulator of DDR by the formation of a ZEB1/p300/PCAF complex and direct interaction with ATM kinase, which has been linked to radioresistance. Moreover, ATM can directly phosphorylate ZEB1 and enhance its stability. Downregulation of ZEB1 has also been shown to reduce the abundance of CHK1, an effector kinase of DDR activated by ATR, and to induce its ubiquitin-dependent degradation. In this perspective, we focus on the role of ZEB1 in the regulation of DDR and describe the mechanisms of ZEB1-dependent chemoresistance.


Dual actions of brain-derived neurotrophic factor on GABAergic transmission in cerebellar Purkinje neurons.
The ability to regulate inhibitory synapses is a critical feature of the nervous system and a growing body of evidence indicates that brain-derived neurotrophic factor (BDNF) acutely modulates the efficacy of GABA synaptic transmission. Although the neuronal potassium-chloride cotransporter 2 (KCC2) has been implied in this BDNF-induced ionic plasticity, the reports about actions of BDNF on GABA signaling remain conflicting. Here we show dual effects of BDNF on GABAergic synaptic transmission in Purkinje neurons in rat cerebellar slices. BDNF decreased the amplitude of evoked outward IPSCs postsynaptically. It induced a depolarizing shift in the reversal potential (E(IPSC)), which reduced the driving force for outward IPSCs. However, in the absence of KCC2 activity, BDNF directly potentiated rather than inhibited GABA(A) receptor, which was reflected by an increase in the amplitude of outward IPSCs. This action of BDNF coincided with its effect in increasing the amplitude of inward IPSCs. Furthermore, an interaction between GABA(A) receptor and KCC2 was revealed by co-immunoprecipitation. The effects of BDNF on both GABA(A) receptor and KCC2 were dependent on TrkB and also activation of cyclin-dependent kinase 5 (Cdk5). However, only the effect of BDNF on KCC2 activity was dependent on a rise of intracellular calcium. Taken together, these data highlight distinct actions of BDNF on KCC2 and GABA(A) receptor in the regulation of GABAergic synaptic transmission.


Post-thoracotomy pain syndrome and sensory disturbances following thoracotomy at 6- and 12-month follow-ups.
Persistent pain affects a large proportion of patients after thoracotomy and is associated with sensory disturbances. The objective of this prospective study was to investigate the time course of pain and sensory disturbances over a 12-month period. Patients scheduled for thoracotomy were recruited. Data were collected on the day before surgery, including baseline characteristics and the presence of any preoperative pain. At 6- and 12-month follow-ups, data on pain were collected using the Brief Pain Inventory-Short Form, and perceived sensory disturbances around the thoracotomy scar were recorded from a self-exploration test. At 12 months after surgery, 97 patients had complete data including baseline and 6-and 12-month measurements. Almost half of the patients reported post-thoracotomy pain at the follow-ups. However, 20% of the patients not reporting post-thoracotomy pain at 6 months did report it at 12 months. Between 40% and 60% of patients experienced some kind of sensory disturbance at 6 months. A small decline in some kind of sensory disturbance was reported by 20%-50% of patients at 12 months. A proportion of patients experienced either resolved or delayed onset of pain. Sensory changes were strongly associated with post-thoracotomy pain syndrome, but were also present in a large proportion of patients without it.


Effect of actinomycin D and cycloheximide on Epstein-Barr virus early antigen induction in lymphoblastoid cells.
The effect of inhibitors of RNA (actinomycin D, Act. D) and protein synthesis (cycloheximide, CH) on induction of Epstein-Barr virus (EBV) antigens by the tumour promoter TPA and by EBV superinfection has been analysed. The data indicate that (i) concomitant treatment of cells with Act. D and TPA leads to complete suppression of virus antigen induction. Subsequent treatment of the cells with Act. D after prior exposure to TPA results in some virus antigen induction, the amount depending on the time of TPA treatment. (ii) Simultaneous treatment of the cells with TPA and CH blocks antigen expression completely. Removal of the inhibitor results in antigen expression at a comparable rate to that of CH-untreated cells. (iii) If Ch treatment is followed by addition of Act. D, virus antigen induction by TPA is completely inhibited. In contrast, superinfection of the cells with P3HR-1 EBV in the presence of CH for the same period followed by removal of the inhibitor and addition of Act. D leads to virus antigen expression by 3 h after Act. D addition. (iv) Concomitant treatment with CH and TPA followed by addition of either iododeoxyuridine or n-butyric acid results in 'superinduction'. Virtually all cells exhibit EBV-specified antigens. This implies that induction of virus antigens by tumour promoters requires the synthesis of a specific RNA, that this RNA increases in concentration during the induction period and that the same RNA is not required for EBV transcription after exogenous infection.


Access to Radiation Therapy: From Local to Global and Equality to Equity.
The discipline of radiation oncology is the most resource-intensive component of comprehensive cancer care because of significant initial investments required for machines, the requirement of dedicated construction, a multifaceted workforce, and recurring maintenance costs. This review focuses on the challenges associated with accessible and affordable radiation therapy (RT) across the globe and the possible solutions to improve the current scenario. Most common cancers globally, including breast, prostate, head and neck, and cervical cancers, have a RT utilization rate of > 50%. The estimated annual incidence of cancer is 19,292,789 for 2020, with > 70% occurring in low-income countries and low-middle-income countries. There are approximately 14,000 teletherapy machines globally. However, the distribution of these machines is distinctly nonuniform, with low-income countries and low-middle-income countries having access to < 10% of the global teletherapy machines. The Directory of Radiotherapy Centres enlists 3,318 brachytherapy facilities. Most countries with a high incidence of cervical cancer have a deficit in brachytherapy facilities, although formal estimates for the same are not available. The deficit in simulators, radiation oncologists, and medical physicists is even more challenging to quantify; however, the inequitable distribution is indisputable. Measures to ensure equitable access to RT include identifying problems specific to region/country, adopting indigenous technology, encouraging public-private partnership, relaxing custom duties on RT equipment, global/cross-country collaboration, and quality human resources training. Innovative research focusing on the most prevalent cancers aiming to make RT utilization more cost-effective while maintaining efficacy will further bridge the gap.


Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy.
Fasting reduces glucose levels and protects mice against chemotoxicity, yet drugs that promote hyperglycemia are widely used in cancer treatment. Here, we show that dexamethasone (Dexa) and rapamycin (Rapa), commonly administered to cancer patients, elevate glucose and sensitize cardiomyocytes and mice to the cancer drug doxorubicin (DXR). Such toxicity can be reversed by reducing circulating glucose levels by fasting or insulin. Furthermore, glucose injections alone reversed the fasting-dependent protection against DXR in mice, indicating that elevated glucose mediates, at least in part, the sensitizing effects of rapamycin and dexamethasone. In yeast, glucose activates protein kinase A (PKA) to accelerate aging by inhibiting transcription factors Msn2/4. Here, we show that fasting or glucose restriction (GR) regulate PKA and AMP-activated protein kinase (AMPK) to protect against DXR in part by activating the mammalian Msn2/4 ortholog early growth response protein 1 (EGR1). Increased expression of the EGR1-regulated cardioprotective peptides atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in heart tissue may also contribute to DXR resistance. Our findings suggest the existence of a glucose-PKA pathway that inactivates conserved zinc finger stress-resistance transcription factors to sensitize cells to toxins conserved from yeast to mammals. Our findings also describe a toxic role for drugs widely used in cancer treatment that promote hyperglycemia and identify dietary interventions that reverse these effects.


Cantharidin poisoning.
Cantharidin, or Spanish fly, is a lipid soluble irritant extracted from the blister beetle. Manifestations of cantharidin poisoning range from local vesiculobullous formation to gross hematuria, myocardial damage, denudation of the gastrointestinal tract, and occasionally death. Despite the wide spectrum of clinical symptomatology, the available information on this subject is extremely scanty. We have attempted the first review of this subject in this century. Currently cantharidin is the active ingredient in various wart removal compounds. The blister beetle has a ubiquitous distribution, with many species found in the southeastern United States. Although most case reports concern adults, the potential for pediatric poisoning is great. Treatment is primarily supportive.


Structure and stability of icosahedral particles of a covalent coat protein dimer of bacteriophage MS2.
Particles formed by the bacteriophage MS2 coat protein mutants with insertions in their surface loops induce a strong immune response against the inserted epitopes. The covalent dimers created by fusion of two copies of the coat protein gene are more tolerant to various insertions into the surface loops than the single subunits. We determined a 4.7-A resolution crystal structure of an icosahedral particle assembled from covalent dimers and compared its stability with wild-type virions. The structure resembled the wild-type virion except for the intersubunit linker regions. The covalent dimer orientation was random with respect to both icosahedral twofold and quasi-twofold symmetry axes. A fraction of the particles was unstable in phosphate buffer because of assembly defects. Our results provide a structural background for design of modified covalent coat protein dimer subunits for use in immunization.


Apolipoprotein E-/- mice have delayed skeletal muscle healing after hind limb ischemia-reperfusion.
Classic studies of limb ischemia-reperfusion injury have been performed using young healthy mice. However, patients with peripheral vascular disease are older and often exhibit metabolic derangements that may delay healing after revascularization. Mice with genetic deletion of apolipoprotein E (ApoE(-/-)) have been used as a model in various experimental scenarios of hypercholesterolemia. These experiments evaluated the inflammatory response and changes in skeletal muscle morphology during the acute and chronic phases of limb ischemia-reperfusion injury in aged ApoE(-/-) mice. Age-matched ApoE(-/-) and wild-type (Wt) mice underwent 1.5 hours of unilateral hind limb ischemia, followed by 1, 7, or 14 days of reperfusion (DR). Histologic analysis of skeletal muscle fiber injury was assessed at 1DR. Morphologic evidence of muscular fiber maturation was assessed at 14DR. Levels of MyoD and myogenin, markers of skeletal muscle differentiation, were assessed at 7 and 14DR using Western blots. Markers of inflammation, including myeloperoxidase, macrophage inflammatory protein-2 (MIP-2), monocyte chemotactic protein-1 (MCP-1), and osteopontin, were assayed using enzyme-linked immunosorbent assay and chemokine (C-C motif) receptor 2 (CCR2) using Western blots at 1, 7, and 14DR. After 1DR, tissue adenosine 5'-triphosphate (ATP) levels were measured to assess metabolic activity. Unpaired t test and Mann-Whitney test were used for comparisons. Histologic evaluation of skeletal muscle after 1DR showed no difference in the degree of injury between Wt and ApoE(-/-) mice. However, at 14DR, ApoE(-/-) mice had higher percentage of immature muscle fibers than Wt mice. Myogenin level was lower in the ApoE(-/-) mice at 7DR. Injured skeletal muscle of ApoE(-/-) mice had lower levels of myeloperoxidase than Wt mice at 7 DR and higher levels of MCP-1 at 14DR. There was no difference in the levels of tissue ATP, MIP-2, osteopontin, or CCR2 at all experimental intervals. Although there was no difference between the injured muscle of Wt and ApoE(-/-) mice during the acute phase of reperfusion, ApoE(-/-) mice showed delay in skeletal muscle healing during the chronic phase of reperfusion. This lag in muscle regeneration was associated with lower levels of myogenin at 7DR and an increased level of MCP-1 at 14DR in the ApoE(-/-) mice. The delay in skeletal muscle healing in the ApoE(-/-) mice may have broader implications for poor tissue healing and functional recovery in elderly patients who have vascular risk factors such as hypercholesterolemia.


The economic returns to hospital admitting privileges.
Legal suits contesting the denial or termination of hospital staff privileges are the most common antitrust cases involving medical markets. There is, however, very little evidence about the economic implications for the physicians of having staff privileges. Using a nationally representative sample of self-employed physicians from 1992, this article presents estimates of the effects of hospital admitting privileges on physician earnings. The results indicate that for nonprimary care specialists with few admitting privileges, gaining an additional privilege increase earnings. This effect diminishes as the number of admitting privileges increases, however, and there are no economic gains beyond having three to four admitting privileges. Among primary care physicians, we detect no statistically significant effect of hospital admitting privileges on earnings. With the growing emphasis on managed care, physicians are being scrutinized both in terms of the quality of care they deliver and their impact on the economic performance of hospitals and managed care organizations. This suggests that the frequency of lawsuits involving the denial or rescission of medical staff privileges may assume even greater importance.


Immunosuppressive Therapies in Ear, Nose, and Throat Involvement in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results From a Multicenter Retrospective Cohort Study.
The aim of this study was to evaluate the response of ear, nose, and throat (ENT) symptoms to different immunosuppressive therapies in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). In this cohort study, patients with AAV treated between January 2010 and April 2020 at 2 Dutch hospitals were included. Clinical, histological, and laboratory data were collected retrospectively. ENT involvement was defined as follows: (1) ≥ 1 ENT symptom according to the Birmingham Vasculitis Activity Score (version 3; BVAS3), and/or (2) presence of saddle nose deformity. Associations between therapy and ENT activity were assessed using logistic regression analysis. A total of 320 patients with AAV were included, of whom 209 (65.3%) had ENT involvement at some point throughout the disease course. In these 209 patients, median age at disease onset was 52.0 years (IQR 40.0-62.0) and 45.5% were male. Median BVAS3 was 12.0 (IQR 6.0-18.0) at diagnosis. Despite immunosuppressive therapy, 50% (n = 77) of the patients had ENT symptoms at relapse and 29.1% (n = 59) had ENT activity at their last visit. No statistically significant difference in ENT activity at last visit was observed between patients treated with oral or intravenous cyclophosphamide (CYC, n = 137) compared to rituximab (RTX, n = 55; adjusted odds ratio 0.59, 95% CI 0.33-1.06; P = 0.08). Lower age at disease onset and female sex were independently associated with ENT activity at last follow-up. In this cohort, CYC and RTX therapy had similar therapeutic effects on ENT symptoms in AAV. Persistent ENT activity is a common feature despite immunosuppressive therapy.


[Hereditary angioedema. Review and presentation of 2 cases in a family].
The clinical records of two patients (mother and son) who had hereditary angioedema of type 1 since childhood are studied. The angioedema was present in each case after trauma, they both had history of chronic allergic rhinitis and the son had of spastic bronchitis. In each of these two patients the level of C4 and CH50 was low, C3 was normal and C1 INH was absent. In a twin (bivitaline) brother and one mother's sister as well as in the son's father the level of C1 INH was normal. They were treated every time successfully with steroids and antiallergic medicine.


Identification and characterization of large-scale genomic rearrangements during wheat evolution.
Following allopolyploidization, nascent polyploid wheat species react with massive genomic rearrangements, including deletion of transposable element-containing sequences. While such massive rearrangements are considered to be a prominent process in wheat genome evolution and speciation, their structure, extent, and underlying mechanisms remain poorly understood. In this study, we retrieved ~3500 insertions of a specific variant of Fatima, one of the most dynamic gypsy long-terminal repeat retrotransposons in wheat from the recently available high-quality genome drafts of Triticum aestivum (bread wheat) and Triticum turgidum ssp. dicoccoides or wild emmer, the allotetraploid mother of all modern wheats. The dynamic nature of Fatima facilitated the identification of large (i.e., up to ~ 1 million bases) Fatima-containing insertions/deletions (indels) upon comparison of bread wheat and wild emmer genomes. We characterized 11 such indels using computer-assisted analysis followed by PCR validation, and found that they might have occurred via unequal intra-strand recombination or double-strand break (DSB) events. Additionally, we observed one case of introgression of novel DNA fragments from an unknown source into the wheat genome. Our data thus indicate that massive large-scale DNA rearrangements might play a prominent role in wheat speciation.