Disrespect and abuse during facility-based childbirth in central Ethiopia.
Respectful maternity care is a fundamental human right, and an important component of quality maternity care. The aim of this study was to quantify the frequency and categories of D&A and identify factors associated with reporting D&A among women in north Showa zone of Ethiopia. A cross-sectional study was conducted with 435 randomly selected women who had given birth at public health facility within the previous 12 months in North Showa zone of Ethiopia. A digital (tablet-based) structured and researcher administered tool was used for data collection. Frequencies of D&A items organised around the Bowser and Hill categories of D&A and presented in the White Ribbon Alliance's Universal Rights of Childbearing Women Framework were calculated. Multivariable logistic regression was used to identify the association between experience of disrespect and abuse and interpersonal and structural factors at p-value <0.05 and odds ratio values with 95% confidence interval. All participants reported at least one form of disrespect and abuse during childbirth. Types of disrespect and abuse experienced by participants were physical abuse 435 (100%), non-consented care 423 (97.2%), non-confidential care 288 (66.2%), abandonment/neglect (34.7%), non-dignified care 126 (29%), discriminatory care 99 (22.8%) and detention 24 (5.5%). Hospital birth [AOR: 3.04, 95% CI: 1.75, 5.27], rural residence [AOR: 1.44, 95% CI: 0.76, 2.71], monthly household income less than 1,644 Birr (USD 57) [AOR: 2.26, 95% CI: 1.20, 4.26], being attended by female providers [AOR: 1.74, 95% CI: 1.06, 2.86] and midwifery nurses [AOR: 2.23, 95% CI: 1.13, 4.39] showed positive association with experience of disrespect and abuse. Hospital birth showed consistent association with all forms of disrespect and abuse. Expanding the size and skill mix of professionals in the hospitals, sensitizing providers consequences of disrespect and abuse could promote dignified and respectful care.


Intra- and Interskeletal Proteome Variations in Fresh and Buried Bones.
Proteomic methods are acquiring greater importance in archaeology and palaeontology due to the longevity of proteins in skeletal remains. There are also developing interests in forensic applications, offering the potential to shed light on post-mortem intervals and age at death estimation. However, our understanding of intra- and interskeletal proteome variations is currently severely limited. Here, we evaluated the proteomes obtained from five distinct subsamples of different skeletal elements from buried pig carcasses to ascertain the extent of variation within and between individuals. We found that reproducibility of data depends on the skeletal element used for sampling and that intrabone differences exceed those observed between the same skeletal element sampled from different individuals. Interestingly, the abundance of several serum proteins appeared to correlate with biological age with relative concentrations of alpha-1 antitrypsin and chromogranin-A increasing and those of fetuin-A decreasing. We also observed a surprising level of divergence in data from different LC-MS/MS runs on aliquots of similar samples analyzed months apart, adding constraints to the comparison of results of such methods across different studies.


Aggressive behaviour of solid-pseudopapillary tumor of the pancreas in adults: a case report and review of the literature.
Solid-pseudopapillary tumor (SPT) is a rare neoplasm of the pancreas that usually occurs in young females. It is generally considered a low-grade malignant tumor that can remain asymptomatic for several years. The occurrence of infiltrating varieties of SPT is around 10%-15%. Between 1986 and 2006, 282 cystic tumors of the pancreas were observed. Among them a SPT was diagnosed in 8 patients (2.8%) with only one infiltrating variety. This was diagnosed in a 49-year-old female 13 years after the sonographic evidence of a small pancreatic cystic lesion interpreted as a pseudocyst. The tumor invaded a long segment of the portal-mesenteric vein confluence, and was removed with a total pancreatectomy, resection of the portal vein and reconstruction with the internal jugular vein. Histological examination confirmed the R-0 resection of the primary SPT, although a vascular invasion was demonstrated. The postoperative course was uneventful, but 32 mo after surgery the patient experienced diffuse liver metastases. Chemotherapy with different drugs was started. The patient is alive and symptom-free, with stable disease, 75 mo after surgery. Twenty-five patients with invasion of the portal vein and/or of mesenteric vessels were retrieved from the literature, 16 recent patients with tumor relapse after potentially curative resection were also retrieved. The best treatment remains a radical resection whenever possible, even in locally advanced or metastatic disease. The role of chemotherapy, and/or radiotherapy, is still to be defined.


Effects of intracranial trochlear neurectomy on the structure of the primate superior oblique muscle.
PURPOSE. Although cyclovertical strabismus in humans is frequently attributed to superior oblique (SO) palsy, anatomic effects of SO denervation have not been studied. Magnetic resonance imaging (MRI) and orbital histology was used to study the effects of acute trochlear (CN4) denervation on the monkey SO. METHODS. Five juvenile macaque monkeys were perfused with formalin for 5 weeks: 15 months after unilateral or bilateral 10-mm intracranial trochlear neurectomy. Denervated and fellow orbits were imaged by MRI, embedded whole in paraffin, serially sectioned at 10-mum thickness, and stained with Masson trichrome. Whole muscle and individual fiber cross sections were quantified in SO muscles throughout the orbit and traced larger fibers in one specimen where they were present. RESULTS. MRI demonstrated marked reduction in midorbital cross section in denervated SO muscles, with anterior shift of SO mass preserving overall volume. Muscle fibers exhibited variable atrophy along their lengths. Denervated orbital layer (OL) fiber cross sections were slightly but significantly reduced from control at most anteroposterior locations, but this reduction was much more profound in global layer (GL) fibers. Intraorbital and intramuscular CN4 were uniformly fibrotic. In one animal, there were scattered clusters of markedly hypertrophic GL fibers that exhibited only sparse myomyous junctions only anteriorly. CONCLUSIONS. CN4 denervation produces predominantly SO GL atrophy with relative OL sparing. Overall midorbital SO atrophy was evident by MRI as early as 5 weeks after denervation, as denervated SO volume shifted anteriorly. Occasional GL fiber hypertrophy suggests that at least some SO fibers extend essentially the full muscle length after trochlear neurectomy.


Today's improvement in asthma treatment: role of MART and Easyhaler.
Asthma affects more than 330 million people worldwide, but many analyses have shown that there are still a lot of unmet needs for both patients and physicians in the treatment of asthma: poor adherence to treatment is one of the main causes of sub-optimal clinical results. Maintenance and Reliever Therapy (MART) with the combination of formoterol and inhaled corticosteroids (ICS) has an established scientific rationale and demonstrated to reduce asthma exacerbations. The aim of this review is to highlight how in asthmatic patients MART can be able to express its maximum therapeutic potential when administered through an 'ideal inhaler'. Since the treatment may be necessary several times a day, the use of a single combination inhaler simplifies the management, potentially improving adherence; moreover, easiness of use and comfort in administration of asthma treatment devices are not secondary aspects. Asthmatic patients are often young, with a normal relational and working life and they could request for a comfortable and not too noticeable device. Finally to the "ideal inhaler" is requested to guarantee accuracy, dose consistency, and resistance to stress conditions. Easyhaler® more closely demonstrates many expected characteristics: effective, consistent performance regardless of inspiration rate, stability, versatility, with several patient acceptability advantages. Asthma control is enhanced by a strong adherence obtained through the combination in a single inhaler of both maintenance and reliever therapy and the availability of a device as close as possible to the characteristics of the ideal inhaler.


Diverse changes in microglia morphology and axonal pathology during the course of 1 year after mild traumatic brain injury in pigs.
Over 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long-term neurological dysfunction. The mechanical forces that are caused by TBI propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acute to chronic time points after injury, altering the homeostasis of the brain. However, the relationship between the hallmark axonal pathology of diffuse TBI and potential changes in glial cell activation or morphology have not been established in a clinically relevant large animal model at chronic time points. In this study, we assessed the tissue from pigs subjected to rapid head rotation in the coronal plane to generate mild TBI. Neuropathological assessments for axonal pathology, microglial morphological changes, and astrocyte reactivity were conducted in specimens out to 1-year post-injury. We detected an increase in overall amyloid precursor protein pathology, as well as periventricular white matter and fimbria/fornix pathology after a single mild TBI. We did not detect the changes in corpus callosum integrity or astrocyte reactivity. However, detailed microglial skeletal analysis revealed changes in morphology, most notably increases in the number of microglial branches, junctions, and endpoints. These subtle changes were most evident in periventricular white matter and certain hippocampal subfields, and were observed out to 1-year post-injury in some cases. These ongoing morphological alterations suggest persistent change in neuroimmune homeostasis. Additional studies are needed to characterize the underlying molecular and neurophysiological alterations, as well as potential contributions to neurological deficits.


Down-modulation of SEL1L, an unfolded protein response and endoplasmic reticulum-associated degradation protein, sensitizes glioma stem cells to the cytotoxic effect of valproic acid.
Valproic acid (VPA), an histone deacetylase inhibitor, is emerging as a promising therapeutic agent for the treatments of gliomas by virtue of its ability to reactivate the expression of epigenetically silenced genes. VPA induces the unfolded protein response (UPR), an adaptive pathway displaying a dichotomic yin yang characteristic; it initially contributes in safeguarding the malignant cell survival, whereas long-lasting activation favors a proapoptotic response. By triggering UPR, VPA might tip the balance between cellular adaptation and programmed cell death via the deregulation of protein homeostasis and induction of proteotoxicity. Here we aimed to investigate the impact of proteostasis on glioma stem cells (GSC) using VPA treatment combined with subversion of SEL1L, a crucial protein involved in homeostatic pathways, cancer aggressiveness, and stem cell state maintenance. We investigated the global expression of GSC lines untreated and treated with VPA, SEL1L interference, and GSC line response to VPA treatment by analyzing cell viability via MTT assay, neurosphere formation, and endoplasmic reticulum stress/UPR-responsive proteins. Moreover, SEL1L immunohistochemistry was performed on primary glial tumors. The results show that (i) VPA affects GSC lines viability and anchorage-dependent growth by inducing differentiative programs and cell cycle progression, (ii) SEL1L down-modulation synergy enhances VPA cytotoxic effects by influencing GSCs proliferation and self-renewal properties, and (iii) SEL1L expression is indicative of glioma proliferation rate, malignancy, and endoplasmic reticulum stress statuses. Targeting the proteostasis network in association to VPA treatment may provide an alternative approach to deplete GSC and improve glioma treatments.


Study, Design, and Rationale of Noncommunicable Diseases in Nepal (NCD Nepal) Study: A Community-Based Prospective Epidemiological and Implementation Study in Rural Nepal.
Noncommunicable diseases (NCDs) are the leading causes of deaths globally. Currently, there are limited high-quality data on the epidemiology and usefulness of community-based screening and treatment of NCDs in low-to-middle-income countries (LMIC), like Nepal. We describe the protocol of a community-based, longitudinal epidemiological study of screening and management of NCDs in rural Nepal. We organize monthly mobile health clinics to screen NCDs among 40- to 75-year-old residents from municipal subdivision wards 3, 4, 6, and 7 of Ghorahi submetropolitan city, Dang, Nepal (approximately 406 km west of the capital, Kathmandu). We estimate a total of 7052 eligible participants. After obtaining informed consent, trained personnel will collect sociodemographic and lifestyle data, medical, medication, and family history using validated questionnaires, plus anthropometric measures and capillary glucose levels. We will screen for hypertension, diabetes, obesity, dyslipidemia, tobacco and alcohol use, self-reported physical activity, dietary habits, cardiovascular disease, stroke, chronic lung disease, cancer, and chronic kidney disease. We will also check hemoglobin A1C, lipid panel, serum creatinine, sodium, potassium, urine dipstick, and urine albumin-to-creatinine ratio in high-risk participants. We will offer lifestyle counseling, pharmacotherapy or refer to higher level care, where appropriate; routinely follow participants with NCDs for continuity of care; and follow individuals without NCDs but with elevated glucose, prehypertension or other risk factors every year, and those without risk factors every 2 years. We will monitor participants in the community to reduce attrition and to track all-cause and disease-specific mortality. Understanding the community burden of NCDs in resource-limited setting and testing effectiveness of community-based screening and management of NCDs will provide insights to develop national policy to address NCD burden in LMIC like Nepal.


Functional analysis of archaeal MBF1 by complementation studies in yeast.
Multiprotein-bridging factor 1 (MBF1) is a transcriptional co-activator that bridges a sequence-specific activator (basic-leucine zipper (bZIP) like proteins (e.g. Gcn4 in yeast) or steroid/nuclear-hormone receptor family (e.g. FTZ-F1 in insect)) and the TATA-box binding protein (TBP) in Eukaryotes. MBF1 is absent in Bacteria, but is well- conserved in Eukaryotes and Archaea and harbors a C-terminal Cro-like Helix Turn Helix (HTH) domain, which is the only highly conserved, classical HTH domain that is vertically inherited in all Eukaryotes and Archaea. The main structural difference between archaeal MBF1 (aMBF1) and eukaryotic MBF1 is the presence of a Zn ribbon motif in aMBF1. In addition MBF1 interacting activators are absent in the archaeal domain. To study the function and therefore the evolutionary conservation of MBF1 and its single domains complementation studies in yeast (mbf1Δ) as well as domain swap experiments between aMBF1 and yMbf1 were performed. In contrast to previous reports for eukaryotic MBF1 (i.e. Arabidopsis thaliana, insect and human) the two archaeal MBF1 orthologs, TMBF1 from the hyperthermophile Thermoproteus tenax and MMBF1 from the mesophile Methanosarcina mazei were not functional for complementation of an Saccharomyces cerevisiae mutant lacking Mbf1 (mbf1Δ). Of twelve chimeric proteins representing different combinations of the N-terminal, core domain, and the C-terminal extension from yeast and aMBF1, only the chimeric MBF1 comprising the yeast N-terminal and core domain fused to the archaeal C-terminal part was able to restore full wild-type activity of MBF1.However, as reported previously for Bombyx mori, the C-terminal part of yeast Mbf1 was shown to be not essential for function. In addition phylogenetic analyses revealed a common distribution of MBF1 in all Archaea with available genome sequence, except of two of the three Thaumarchaeota; Cenarchaeum symbiosum A and Nitrosopumilus maritimus SCM1. The absence of MBF1-interacting activators in the archaeal domain, the presence of a Zn ribbon motif in the divergent N-terminal domain of aMBF1 and the complementation experiments using archaeal- yeast chimeric proteins presented here suggests that archaeal MBF1 is not able to functionally interact with the transcription machinery and/or Gcn4 of S. cerevisiae. Based on modeling and structural prediction it is tempting to speculate that aMBF1 might act as a single regulator or non-essential transcription factor, which directly interacts with DNA via the positive charged linker or the basal transcription machinery via its Zn ribbon motif and the HTH domain. However, also alternative functions in ribosome biosynthesis and/or functionality have been discussed and therefore further experiments are required to unravel the function of MBF1 in Archaea.


Conditioning cattle to graze broom snakeweed (Gutierrezia sarothrae).
Broom snakeweed (Gutierrezia sarothrae) is the most widespread range weed in North America. We attempted to positively condition cattle to graze broom snakeweed to create a biological tool to decrease the competitive ability of snakeweed in a plant community. Fifteen yearling heifers were divided into three treatment groups receiving different supplements: 1) cornstarch, 2) starch with ground snakeweed, and 3) a control (no supplements). Heifers were fed fresh snakeweed, and then were gavaged with the respective supplements to provide positive feedback to enhance their acceptance of snakeweed. The starch group consumed more snakeweed in the pen conditioning trial (P = 0.02). The starch and control groups were then taken to the field for two grazing trials. In the spring grazing trial, there was no snakeweed consumed in the free-ranging part of the trial; however, when the pasture size was decreased, the heifers started to consume snakeweed as alternative forages became less abundant. In the second small pasture trial, heifers in the positively conditioned group consumed more snake-weed than those in the control group (16 vs. 5% of bites, P < 0.001). In the fall grazing trial, little snakeweed was consumed in the free-ranging part of the trial. When the pasture size was decreased, both positively conditioned and control groups increased snakeweed consumption up to 35% of bites. In the small pastures of both the spring and fall grazing trials, 36 to 59% of snakeweed plants were grazed. Cattle can be forced to graze snake-weed in a short-duration, high-intensity grazing strategy.


[Long-term use of prazosin alone and combined with propranolol in patients with essential hypertension].
Therapeutic efficiency and hemodynamic effects of prazosin were examined in 42 patients with essential hypertension in the course of prolonged treatment. Where the adrenoblocker showed low efficiency, the beta-blocker propranolol was added to the treatment scheme. The mechanism of the hypotensive effect was shown to be dependent on correlations between arteriolo- and venodilatation. In the presence of prevailing precapillary dilatation, BP dropped owing to reduced total and regional vascular resistance. If venodilatation was more pronounced, the hypotensive effect was due to reduced minute volume. The addition of propranolol eliminated the manifestations of sympathetic stimulation, enhanced the hypotensive effect and improved general condition of the patients. Combined treatment is indicated particularly in those cases of stable hypertension where prazosin alone has failed to produce an adequate effect.


The collaboration of both humoral and cellular HER-2/neu-targeted immune responses is required for the complete eradication of HER-2/neu-expressing tumors.
HER-2/neu (neu) transgenic mice (neu-N mice), which express the nontransforming rat proto-oncogene, demonstrate immunological tolerance to neu that is similar to what is encountered in patients with neu-expressing breast cancer. We have shown previously that a significant increase in neu-specific T cells, but no induction of neu-specific antibody, is seen after neu-specific vaccination in neu-N mice. In contrast, a significant induction of both neu-specific T-cell and antibody responses is found in nontoleragenic FVB/N mice after vaccination. These mice are fully protected from a s.c. challenge with NT cells, a mammary tumor cell line derived from a spontaneous tumor that arose in a neu-N mouse, whereas neu-N mice are not. In this study, we demonstrate that CD4+ T cell-depleted FVB/N mice show no induction of neu-specific IgG after vaccination and are unable to reject an NT challenge (0 of 10 mice were tumor free). Conversely, the depletion of natural killer cells has no effect on vaccine-mediated tumor rejection (100% of mice were tumor free). In CD8+ T cell-depleted animals, where vaccine-induced neu-specific IgG titers were normal, NT growth was delayed, but only 10% of mice remained tumor free, demonstrating that neu-specific IgG alone is insufficient for protection from NT challenge. To directly assess the necessity for the combination of neu-specific cellular and humoral immune responses, severe combined immunodeficient mice were given an adoptive transfer of CTLs plus IgG derived from FVB/N mice. Animals that were given CTLs that recognized an irrelevant antigen plus neu-specific IgG developed tumors at a rate similar to CD8+ T cell-depleted FVB/N mice. Animals receiving an adoptive transfer of neu-specific CTLs plus control IgG derived from naive FVB/N mice were only partially protected from NT challenge (50% of animals were tumor free). However, only animals receiving the combination of neu-specific CTLs and neu-specific IgG were fully protected from NT challenge (100% of animals were tumor free). These studies specifically define the immunological requirements for the eradication of neu-expressing tumors in this model system, demonstrating that both cellular and humoral neu-specific responses are necessary for protection from an NT challenge. These data suggest that vaccines optimized to induce maximal T- and B-cell immunity to neu, and possibly to similar putative tumor-rejection antigens, may lead to more potent in vivo antitumor immunity.


An attenuated LC16m8 smallpox vaccine: analysis of full-genome sequence and induction of immune protection.
The potential threat of smallpox bioterrorism has made urgent the development of lower-virulence vaccinia virus vaccines. An attenuated LC16m8 (m8) vaccine was developed in 1975 from the Lister strain used in the World Health Organization smallpox eradication program but was not used against endemic smallpox. Today, no vaccines can be tested with variola virus for efficacy in humans, and the mechanisms of immune protection against the major intracellular mature virion (IMV) and minor extracellular enveloped virion (EEV) populations of poxviruses are poorly understood. Here, we determined the full-genome sequences of the m8, parental LC16mO (mO), and grandparental Lister (LO) strains and analyzed their evolutionary relationships. Sequence data and PCR analysis indicated that m8 was a progeny of LO and that m8 preserved almost all of the open reading frames of vaccinia virus except for the disrupted EEV envelope gene B5R. In accordance with this genomic background, m8 induced 100% protection against a highly pathogenic vaccinia WR virus in mice by a single vaccination, despite the lack of anti-B5R and anti-EEV antibodies. The immunogenicity and priming efficacy with the m8 vaccine consisting mainly of IMV were as high as those with the intact-EEV parental mO and grandparental LO vaccines. Thus, mice vaccinated with 10(7) PFU of m8 produced low levels of anti-B5R antibodies after WR challenge, probably because of quick clearance of B5R-expressing WR EEV by strong immunity induced by the vaccination. These results suggest that priming with m8 IMV provides efficient protection despite undetectable levels of immunity against EEV.


Diffusion tensor imaging of cerebral white matter integrity in cognitive aging.
In this article we review recent research on diffusion tensor imaging (DTI) of white matter (WM) integrity and the implications for age-related differences in cognition. Neurobiological mechanisms defined from DTI analyses suggest that a primary dimension of age-related decline in WM is a decline in the structural integrity of myelin, particularly in brain regions that myelinate later developmentally. Research integrating behavioral measures with DTI indicates that WM integrity supports the communication among cortical networks, particularly those involving executive function, perceptual speed, and memory (i.e., fluid cognition). In the absence of significant disease, age shares a substantial portion of the variance associated with the relation between WM integrity and fluid cognition. Current data are consistent with one model in which age-related decline in WM integrity contributes to a decreased efficiency of communication among networks for fluid cognitive abilities. Neurocognitive disorders for which older adults are at risk, such as depression, further modulate the relation between WM and cognition, in ways that are not as yet entirely clear. Developments in DTI technology are providing a new insight into both the neurobiological mechanisms of aging WM and the potential contribution of DTI to understanding functional measures of brain activity. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.


Postprandial hyperglycemia and glycemic variability: should we care?
The aim of this article is to evaluate the pros and cons of a specific impact of postprandial hyperglycemia and glycemic variability on the--mainly cardiovascular (CV)--complications of diabetes, above and beyond the average blood glucose (BG) as measured by HbA(1c) or fasting plasma glucose (FPG). The strongest arguments in favor of this hypothesis come from impressive pathophysiological studies, also in the human situation. Measures of oxidative stress and endothelial dysfunction seem to be especially closely related to glucose peaks and even more so to fluctuating high and low glucose concentrations and can be restored to normal by preventing those glucose peaks or wide glucose excursions. The epidemiological evidence, which is more or less confined to postprandial hyperglycemia and postglucose load glycemia, is also rather compelling in favor of the hypothesis, although certainly not fully conclusive as there are also a number of conflicting results. The strongest cons are seen in the missing evidence as derived from randomized prospective intervention studies targeting postprandial hyperglycemia longer term, i.e., over several years, and seeking to reduce hard CV end points. In fact, several such intervention studies in men have recently failed to produce the intended beneficial outcome results. As this evidence by intervention is, however, key for the ultimate approval of a treatment concept in patients with diabetes, the current net balance of attained evidence is not in favor of the hypothesis here under debate, i.e., that we should care about postprandial hyperglycemia and glycemic variability. The absence of a uniformly accepted standard of how to estimate these parameters adds a further challenge to this whole debate.


Amantadine and rimantadine for influenza A in children and the elderly.
Although amantadine (AMT) and rimantadine (RMT) are used to relieve or treat influenza A symptoms in healthy adults, little is known about the effectiveness and safety of these antivirals in preventing and treating influenza A in children and the elderly. The aim of this review was to systematically consider evidence on the effectiveness and safety of AMT and RMT in preventing and treating influenza A in children and the elderly. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2007, issue 3); MEDLINE (1966 to July 2007) and EMBASE (1980 to July 2007). Randomised or quasi-randomised trials comparing AMT and/or RMT in children and the elderly with placebo, control, other antivirals or comparing different doses or schedules of AMT and/or RMT or no intervention. Two review authors independently selected trials for inclusion and assessed methodological quality. Disagreements were resolved by consensus. In all comparisons except for one, the trials in children and in the elderly were analysed separately. Data were analysed and reported using Cochrane Review Manager 4.2. software. In children, RMT was effective in the abatement of fever on day three of treatment. AMT showed a prophylactic effect against influenza A infection. AMT and RMT were not related to an increase in the occurrence of adverse effects. RMT also was considered to be well tolerated by the elderly, but showed no prophylactic effect. Different doses were comparable in the prophylaxis of influenza in the elderly, as well as in reporting adverse effects. Zanamivir prevented influenza A more effectively than RMT in the elderly. AMT was effective in the prophylaxis of influenza A in children. As confounding matters might have affected our findings, caution should be taken when considering which patients should to be given this prophylactic. Our conclusions about effectiveness of both antivirals for the treatment of influenza A in children were limited to a proven benefit of RMT in the abatement of fever on day three of treatment. Due to the small number of available studies we could not reach a definitive conclusion on the safety of AMT or the effectiveness of RMT in preventing influenza in children and the elderly.


Chronopharmaceutics: gimmick or clinically relevant approach to drug delivery?
Due to advances in chronobiology, chronopharmacology, and global market constraints, the traditional goal of pharmaceutics (e.g. design drug delivery systems with a constant drug release rate) is becoming obsolete. However, the major bottleneck in the development of drug delivery systems that match the circadian rhythm (chronopharmaceutical drug delivery systems: ChrDDS) may be the availability of appropriate technology. The last decade has witnessed the emergence of ChrDDS against several diseases. The increasing research interest surrounding ChrDDS may lead to the creation of a new sub-discipline in pharmaceutics known as chronopharmaceutics. This review introduces the concept of chronopharmaceutics, addresses theoretical/formal approaches to this sub-discipline, underscores potential disease-targets, revisits existing technologies and examples of ChrDDS. Future development in chronopharmaceutics may be made at the interface of other emerging disciplines such as system biology and nanomedicine. Such novel and more biological approaches to drug delivery may lead to safer and more efficient disease therapy in the future.


Differentiated neuroblastoma cells remain epigenetically poised for de-differentiation to an immature state.
Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for a significant share of childhood cancer deaths. Prior studies utilizing RNA sequencing of bulk tumor populations showed two predominant cell states characterized by high and low expression of neuronal genes. Although cells respond to treatment by altering their gene expression, it is unclear whether this reflects shifting balances of distinct subpopulations or plasticity of individual cells. Using neuroblastoma cell lines lacking MYCN amplification, we show that the antigen CD49b distinguishes these subpopulations. CD49b expression marks proliferative cells with an immature gene expression program, while CD49b-negative cells express differentiated neuronal marker genes and are non-cycling. Sorted populations spontaneously switch between CD49b expression states in culture, and CD49b-negative cells can generate rapidly growing, CD49b-positive tumors in mice. Though doxorubicin treatment selectively kills CD49b-positive cells in culture, the CD49b-positive population recovers when treatment is withdrawn. We profiled H3K27ac to identify enhancers and super enhancers that are specifically active in each population and find that CD49b-negative cells maintain the priming H3K4me1 mark at elements that are active in CD49b-high cells. Improper maintenance of primed enhancer elements thus may underlie cellular plasticity in neuroblastoma, representing potential therapeutic targets for this lethal tumor.


[Thoracoscopic longitudinal myotomy of the esophagus. Successful alternative treatment for diffuse esophageal spasm].
A 55-year-old woman had for 5 years been suffering from severe burning thoracic pain. She had typical risk factors for cardiovascular disease, namely hypertension, chronic smoking, obesity and hypercholesterolaemia. She had been hospitalized several times for suspected myocardial infarction, but coronary heart disease had been excluded by cardiac examination, including angiocardiography. The only contributory admission finding was epigastric pain on pressure. Gastroscopy revealed a non-erosive duodenitis and chronic antral gastritis. The cardia was tightly closed and there were no signs of reflux oesophagitis. Manometry in the oesophagus showed frequent simultaneous contractions and marked increase in pressure amplitude, predominantly in the distal segment, indicating diffuse oesophageal spasms. Drug treatment with calcium channel blockers gave only brief relief from the thoracic pain. But longitudinal oesophageal myotomy via thoracoscopy brought about complete pain relief, which has now persisted for 3 years. Thoracoscopic longitudinal oesophageal myotomy can provide a therapeutic alternative in patients with oesophageal spasms when drug therapy and pneumatic oesophageal dilatation have failed.


Religion and spirituality in coping with breast cancer: perspectives of Chilean women.
This study examined the roles of religion and spirituality in relation to coping with breast cancer in Chilean women. Specifically, the purpose of the study was to examine how these patients used religion and spirituality to cope with their illness; how their illness changed the roles of religion and spirituality in their lives; and their views regarding whether, and if so how, spiritual faith can help patients recuperate from breast cancer. Twenty-seven women with breast cancer who were patients at a clinic in Santiago, Chile were recruited to participate in one-on-one interviews. The transcribed interviews were analyzed using the "constant comparative method" to seek patterns and organize the content into specific themes. Women viewed religion and spirituality as primary resources for themselves and others to use in coping with breast cancer. Women's use of religion and spirituality was manifested in praying, in their perceived dependence on God to intercede and guide them through their illness, and in obtaining social support from other persons in their faith community. Half (13/26) of the women reported that their cancer prompted an increased emphasis on religion and spirituality in their lives by deepening their faith in God. Almost all (26/27) participants endorsed the belief that spiritual faith can help cancer patients to recuperate. These findings suggest that health care providers working should be aware of the culturally dependent roles that religion and spirituality play in women's coping with breast cancer.


The trastuzumab and vinorelbine combination: an alternative to taxane-based chemotherapy for early-stage and locally advanced her2-positive breast cancer.
Anthracyclines and taxanes have historically constituted the backbone of chemotherapy regimens for patients with breast cancer positive for the human epidermal growth factor receptor 2 (her2). For a subset of patients who categorically refuse alopecia, or for those with a contraindication to those drugs, there is an urgent need to define alternative regimens. Here, we report our institutional experience with trastuzumab and vinorelbine (tv), a combination with good clinical activity and a good side effect profile for patients with her2-positive breast cancer. In a retrospective analysis, outcomes data were extracted for patients receiving tv as their only chemotherapy in the non-metastatic setting at the Jewish General Hospital. For the most part, tv was administered weekly for 6 months, followed by trastuzumab for 6 months. The analysis identified 46 patients (mean age: 64 years) who received tv between 2003 and 2012 (n = 36 adjuvant, n = 10 neoadjuvant). Of the patients in the adjuvant group, 81% had stage i disease. In the neoadjuvant group, 3 patients experienced a complete pathologic response. Only 1 patient experienced local recurrence after a short course (3 months) of adjuvant tv. Overall survival and breast cancer-specific survival were 94% and 98% respectively at a median 5 years of follow-up. Febrile neutropenia-induced sepsis resulted in the death of 1 patient with significant medical comorbidities; 2 other patients died of comorbidities unrelated to their cancer or treatment. Grades 3 or 4 adverse events included neutropenia (23%), febrile neutropenia (10%), fatigue (2%), and anemia (2%). For patients with non-metastatic breast cancer refusing alopecia, or for patients who are not candidates for standard chemotherapy, tv is a reasonable alternative to standard adjuvant chemotherapy.


Bestrophin-2 mediates bicarbonate transport by goblet cells in mouse colon.
Anion transport by the colonic mucosa maintains the hydration and pH of the colonic lumen, and its disruption causes a variety of diarrheal diseases. Cholinergic agonists raise cytosolic Ca2+ levels and stimulate anion secretion, but the mechanisms underlying this effect remain unclear. Cholinergic stimulation of anion secretion may occur via activation of Ca2+-activated Cl- channels (CaCCs) or an increase in the Cl- driving force through CFTR after activation of Ca2+-dependent K+ channels. Here we investigated the role of a candidate CaCC protein, bestrophin-2 (Best2), using Best2-/- mice. Cholinergic stimulation of anion current was greatly reduced in Best2-/- mice, consistent with our proposed role for Best2 as a CaCC. However, immunostaining revealed Best2 localized to the basolateral membrane of mucin-secreting colonic goblet cells, not the apical membrane of Cl--secreting enterocytes. In addition, in the absence of HCO3-, cholinergic-activated current was identical in control and Best2-/- tissue preparations, which suggests that most of the Best2 current was carried by HCO3-. These data delineate an alternative model of cholinergic regulation of colonic anion secretion in which goblet cells play a critical role in HCO3- homeostasis. We therefore propose that Best2 is a HCO3- channel that works in concert with a Cl:HCO3- exchanger in the apical membrane to affect transcellular HCO3- transport. Furthermore, previous models implicating CFTR in cholinergic Cl- secretion may be explained by substantial downregulation of Best2 in Cftr-/- mice.


Chinese patients with transient ischemic attacks.
In 123 cases of transient ischemic attacks, 72 were followed up for 22 years. The percentage of complete stroke was 46.5% and the fatality rate 47.9%. Causes of death, survival rate by life table, limitation of indication of neurovascular surgical operation and rehabilitation of survived patients were studied. The causes of death were mainly cerebral strokes. The long-term follow-up showed that the range for neurovascular surgical operation was limited to only 17.9%. The 95% confidence interval of the 20-year survival rate was 17.7-53.6%. Ninety-four, 48 and 44 cases were examined by B-mode Doppler tomography, cerebral CT scanning and echocardiography, respectively.


Competition Between Tumor and Mononuclear Phagocyte System Causing the Low Tumor Distribution of Nanoparticles and Strategies to Improve Tumor Accumulation.
In the past few decades, nanoparticles have shown their advantages in anti-cancer therapy. After intravenous injection, they could preferentially arrive at tumor tissue either by extravasation from tumor vasculature or targeting vascular endothelial cells. But at the same time, their quantity in mononuclear phagocyte system (MPS) is far more than that in tumor. In this review, we discuss the advantages of MPS in spleen and liver over tumor on competing nanoparticles. The biophysical causes of spleen and liver help the MPS to capture nanoparticles, such as sufficient flux of blood stream, capillary network with fenestrations in liver and venous sinuses in spleen. Meanwhile, liver and spleen are the two major organs that contain MPS. Various properties of nanoparticles may affect their biodistribution. It is suggested that nanoparticles with proper size and shape, suitable charge, polyethyleneglycol and ligands will minimize the clearance by MPS. Several novel and promising approaches for cancer therapy are introduced in this review. This review seeks to provide guidelines for improving nanoparticles accumulation in tumor through both optimizing nanoparticles design and novel ways to design nanodelivery system for cancer therapy.


The effects of red yeast rice dietary supplement on blood pressure, lipid profile, and C-reactive protein in hypertension: A systematic review.
Interest is increasing regarding the potential health effects of red yeast rice (RYR) consumption, which is described as a "natural statin" in China. This review aims to evaluate the efficacy of RYR on blood pressure (BP), lipid profile, and C-reactive protein (CRP) in treating hypertension. Seven electronic databases including the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, the Chinese National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal Database (VIP), the Chinese Biomedical Literature Database (CBM), and the Wanfang database were searched. To investigate the role of RYR for hypertension, randomized controlled trials for the use of RYR either as monotherapy or in combination with conventional medicine versus placebo, no intervention, or conventional medicine for hypertension were identified. A total of 21 trials containing 4558 patients were analyzed, the majority of which had low methodological quality. "RYR plus conventional therapy" exhibited significant lowering effects on serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and CRP but exhibited no significant effect on systolic BP, diastolic BP, triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) compared with "placebo plus conventional therapy." "RYR plus conventional therapy" showed significant lowering effects on systolic BP, TC, LDL-C, and CRP but no effect on diastolic BP, TG, and HDL-C compared with "placebo plus conventional therapy." No significant difference in BP and lipid profile between "RYR plus conventional therapy" and "statins plus conventional therapy" was observed. "RYR plus statins" appeared to be more effective in lowering BP, TC, TG, and LDL-C but without a significant difference in HDL-C compared to statins. No serious adverse events were reported. The results of this meta-analysis suggested some supportive but limited evidence regarding RYR for hypertension. Further rigorously designed trials are warranted before RYR could be recommended to hypertensive patients.


HIV-associated neurocognitive disorders: recent advances in pathogenesis, biomarkers, and treatment.
HIV-associated neurocognitive disorders (HAND) remain prevalent despite plasma viral suppression by antiretroviral agents. In fact, the prevalence of milder subtypes of cognitive impairment is increasing. Neuropsychologic testing remains the "gold standard" of diagnosis; however, this is time consuming and costly in a resource-poor environment. Recently developed screening tools, such as CogState and the revised HIV dementia scale, have very good sensitivity and specificity in the more severe stages of HAND. However, questions remain regarding the utility of, optimal population for, and insensitivity of tests in mild HAND. Recognition of ongoing viral persistence and the inflammatory milieu in the central nervous system (CNS) has advanced our understanding of the pathogenesis of HAND and facilitated the development of biomarkers of CNS disease. The importance of the monocyte-macrophage lineage cell and the astrocyte as viral reservoirs, HIV viral proteins, self-perpetuating CNS inflammation, and CCR5 chemokine receptor neurotropism has been identified. Whilst biomarkers demonstrate monocyte activation, inflammation, and neuronal injury, they remain limited in their clinical utility. The improved understanding of pathogenic mechanisms has led to novel approaches to the treatment of HAND; however, despite these advances, the optimal management is still undefined.


Tocotrienol rich fraction (TRF) supplementation protects against oxidative DNA damage and improves cognitive functions in Wistar rats.
Oxidative stress is caused by imbalance between the productions of reactive oxygen species (ROS) and antioxidant defense mechanisms. Palm oil antioxidants such as tocotrienol rich fraction (TRF) is known to have neuroprotective effects on neurones by acting against free radical induced neuronal cell death. This study was undertaken to elucidate the effect of TRF on oxidative DNA damage and cognitive functions in experimental rats. A total of 20 male Wistar rats (aged 3 months) were divided into 2 groups: (i) control group fed with distilled water and (ii) experimental group fed with TRF (200 mg/ kg body weight) for 8 months. DNA damage was determined using Comet assay. Antioxidant enzymes like superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were assessed in the blood. The Morris Water Maze (MWM) test was used to evaluate the cognitive functions. DNA damage was significantly reduced in the experimental group supplemented with TRF compared to the control group (p <0.05). In the group supplemented with TRF, the percentage of DNA damage was 2.87 ± 0.48% compared to 5.96 ± 0.43% in the control group. SOD, GPx, and CAT enzyme activities increased in experimental group. Results from MWM showed improvement in cognitive functions as determined by latency to target platform, swim path and average speed between TRF and control groups. Continuous supplementation of TRF for 8 months reduced DNA damage and exhibited positive influence in spatial learning and memory.


Variability in antenatal prognostication of fetal diaphragmatic hernia across the North American Fetal Therapy Network (NAFTNet).
To evaluate variability in antenatal sonographic prognostication of congenital diaphragmatic hernia (CDH) within the North American Fetal Therapy Network (NAFTNet). NAFTNet centre were invited to complete a questionnaire and participate in videoconference calls, during which participants were observed while measuring lung area by ultrasound using the anteroposterior (AP) method, longest method, and trace method. Each center identified 1-2 experienced fetal medicine specialist(s) or medical imaging specialists locally to participate in the study. Practices were compared among NAFTNet centre within and without the fetal endoscopic tracheal occlusion (FETO) consortium. Nineteen participants from 9 FETO center and 30 participants from 17 non-FETO center completed the survey and 31 participants were interviewed and observed while measuring sonographic lung area. All Centres measured observed-to-expected lung-to-head ratio (o/e LHR) or LHR for CDH prognostication. Image selection criteria for lung area measurement were consistent, including an axial section of the chest with clear lung borders and a 4-chamber cardiac view. Lung area measurement methods varied across NAFTNet, with most centre using longest (4/9 FETO vs. 13/29 non-FETO) or trace (3/9 FETO vs. 11/29 non-FETO) method. Centres differed in expected reference ranges for o/e LHR determination and whether the lowest, highest or average o/e LHR was utilized. Variability in antenatal sonographic prognostication of CDH was identified across NAFTNet, indicating a need for consensus-based standardization.


Phase II trial of intracarotid BCNU and cisplatin in primary malignant brain tumors.
Intracarotid BCNU (100 mg/m2) and cisplatin (60 mg/m2) were administered to 36 patients with malignant brain tumors recurrent or progressive after cranial irradiation. Courses of therapy were repeated at 4-6 week intervals. Of 23 evaluable patients with recurrent glioma, 9 (39%) had tumor regression by CT scan and 3 had stable disease. The median time to tumor progression for responding patients was 37 weeks. For all patients with primary tumors it was 14 weeks. Six of 9 patients with no prior chemotherapy had a response and 1 had stable disease. Of 14 patients who had received prior chemotherapy, 3 had a response and 2 had stable disease. Survival ranged from 9 weeks to 95+ weeks (median 34 weeks) from start of therapy. Six of 23 patients with primary tumors are alive 1 year or more following therapy. Four of 11 patients with brain metastases had a response and 2 had stable disease. Major neurologic toxicity of intracarotid BCNU and cisplatin appeared cumulative and consisted of reversible hemiparesis in 3% of 118 courses, TIA in 1%, expressive aphasia in 9%, lethargy in 3%, seizures in 12%, and reversible confusion in 1%. Retinal toxicity consisted of mild blurring of vision in 4 patients and ipsilateral blindness in 5 patients. Three of 22 patients who had received supraophthalmic infusion later developed evidence of leukoencephalopathy. Intracarotid BCNU and cisplatin appears to have modest increase in activity over intracarotid cisplatin alone (Cancer 54:794, 1984), however, neurologic and retinal toxicity may also be increased.


Radical trachelectomy: a fertility-sparing option for early invasive cervical cancer.
For the past 15 years gynecological oncologists have been seeking ways to preserve woman's fertility when treating invasive cervical cancer. For some women with small localized invasive cervical cancers, there is now hope for pregnancy after treatment. Many cases of cervical cancer are diagnosed in young woman who wish to preserve their fertility. As more women are delaying childbearing, fertility preservation has become an important consideration. The standard surgical treatment for stage IA2-IB1 cervical cancer is a radical hysterectomy and bilateral pelvic lymphadenectomy. This surgery includes removal of the uterus and cervix, radical resection of the parametrial tissue and upper vagina, and complete pelvic lymphadenectomy. Obviously, the standard treatment does not allow future childbearing. Radical trachelectomy is a fertility-sparing surgical approach developed in France in 1994 by Dr. Daniel Dargent for the treatment of early invasive cervical cancer. Young women wishing to bear children in the future may be candidates for fertility-preservation options. The radical trachelectomy operation has been described and performed abdominally, assisted vaginally by laparoscopy and robotically. In this review we discuss the selection criteria for radical trachelectomy, the various possible techniques for the operation, the oncological and obstetric outcomes, and common complications.


Frequency of snoring, rather than apnea-hypopnea index, predicts both cognitive and behavioral problems in young children.
Primary snoring (PS) and obstructive sleep apnea (OSA) not only affect the quality of sleep in a large number of young children, but have also been repeatedly associated with a variety of behavioral and cognitive problems. However, little is known about the potentially differing relationships of behavioral and cognitive pathology within the sleep disordered breathing (SDB) spectrum. This study examined data from an enriched for snoring community sample of 631 children aged between 4 and 10 years. Multivariate mixed models were used to assess the relationship between both snoring and the apnea-hypopnea index (AHI). Numerous cognitive and behavioral variables were used, while adjusting for several important demographic variables. These were followed by univariate analyses of individual measures and sensitivity analyses. Results indicated that snoring status is a significant predictor of general behavioral (p = 0.008) and cognitive (p = 0.013) domains, even after adjusting for baseline covariates and AHI severity. More frequent snoring was associated with poorer outcomes independent of AHI. However, AHI did not emerge as a significant predictor of the overall cognitive functioning domain (p = 0.377). Additionally, although AHI was a significant predictor of the general behavioral functioning domain (p = 0.008), the significance pattern and nature of its relationship with individual behavioral measures were inconsistent in post-hoc analyses. The findings of this study suggest that general behavioral and cognitive function may decline with greater snoring severity. Further, snoring should not simply be assumed to represent a lower severity level of SDB, but should be examined as a potential predictor of relevant outcomes.


A murine model of hypertonic saline as a treatment for acute spinal cord injury: effects on autonomic outcome.
spinal cord injury (SCI) continues to be a problem without a definitive cure. Research based on improved understanding of the immunological aspects of SCI has revealed targets for treating and ameliorating the extent of secondary injury. Hypertonic saline (HTS), a substance both easy to create and to transport, has been investigated as an immunologically active material that can be used in a clinically relevant interval after injury. In this pilot study, HTS was investigated in a murine model for its abilities to ameliorate secondary injury after a severe spinal cord contusion. female C57Bl/6 mice with severe T8-10 contusion injuries were used as the model subjects. A group of 41 mice were studied in a blinded fashion. Mice received treatments with HTS (HTS, 7.5%) or normal saline solution (NSS, 0.9%) at 2 discreet time points (3 and 24 hours after injury.) A separate group of 9 untreated animals were also used as controls. Animals were assessed for autonomic outcome (bladder function). In a group of 33 mice, histological assessment (cellular infiltration) was also measured. bladder function was found to be improved significantly in those treated with HTS compared with those who received NSS and also at later treatment times (24 hours) than at earlier treatment times (3 hours). Decreased cellular infiltration in each group correlated with bladder recovery. the increased effectiveness of later administration time of the more osmotically active and immunomodulatory substance (HTS) suggests that interaction with events occurring around 24 hours after injury is critical. These events may be related to the invasion of leukocytes peaking at 8-24 hours postinjury and/or the peak benefit time of subject rehydration.


Localization of insulin-like growth factor-I (IGF-I) and IGF-I receptor (IGF-IR) in equine testes.
The insulin-like growth factor-I (IGF-I) is a key regulator of reproductive functions. IGF-I actions are primarily mediated by IGF-IR. The main objective of this research was to evaluate the presence of IGF-I and IGF-I Receptor (IGF-IR) in stallion testicular tissue. The hypotheses of this study were (i) IGF-I and IGF-IR are present in stallion testicular cells including Leydig, Sertoli, and developing germ cells, and (ii) the immunolabelling of IGF-I and IGF-IR varies with age. Testicular tissues from groups of 4 stallions in different developmental ages were used. Rabbit anti-human polyclonal antibodies against IGF-I and IGF-IR were used as primary antibodies for immunohistochemistry and Western blot. At the pre-pubertal and pubertal stages, IGF-I immunolabelling was present in spermatogonia and Leydig cells. At post-pubertal, adult and aged stages, immunolabelling of IGF-I was observed in spermatogenic cells (spermatogonia, spermatocyte, spermatid, and spermatozoa) and Leydig cells. Immunolabelling of IGF-IR was observed in spermatogonia and Leydig cells at the pre-pubertal stage. The immunolabelling becomes stronger as the age of animals advance through the post-pubertal stage. Strong immunolabelling of IGF-IR was observed in spermatogonia and Leydig cells at post-puberty, adult and aged stallions; and faint labelling was seen in spermatocytes at these ages. Immunolabelling of IGF-I and IGF-IR was not observed in Sertoli cells. In conclusion, IGF-I is localized in equine spermatogenic and Leydig cells, and IGF-IR is present in spermatogonia, spermatocytes and Leydig cells, suggesting that the IGF-I may be involved in equine spermatogenesis and Leydig cell function as a paracrine/autocrine factor.


Fos immunoreactivity in the diagonal band and the perinuclear zone of the supraoptic nucleus after hypertension and hypervolaemia in unanaesthetized rats.
We used Fos immunocytochemistry to study the effects of hypertension and hypervolaemia on neurones in the diagonal band of Broca and the perinuclear zone of the supraoptic nucleus, two nuclei that are both involved in the baroreceptor regulation of vasopressin neurones in the supraoptic nucleus. In addition, we used sino-aortic denervation to examine the role of arterial baroreceptors in the response to these haemodynamic changes. Sham-operated and sino-aortic denervated rats were infused with phenylephrine sufficient to increase blood pressure for 2 h. Control rats were infused with the same volume of isontonic saline. Only Sham sino-aortic denervated rats showed reflex bradycardia in response to the increased blood pressure. Volume expansion was produced by infusing the rats with isotonic saline equal to 10% of their body weight for 10 min, which significantly increased central venous pressure. In the diagonal band of Broca and the perinuclear zone, the number of Fos-positive neurones was significantly increased after phenylephrine infusion. Sino-aortic denervation blocked the significant increase in both regions. After volume expansion, a significant increase in Fos staining was observed only in the perinuclear zone of the supraoptic nucleus. This increase was not blocked by sino-aortic denervation. Our results indicate that both the diagonal band of Broca and the perinuclear zone of the supraoptic nucleus are activated by stimulating arterial baroreceptors; however, the perinuclear zone of the supraoptic nucleus is stimulated during volume expansion. Furthermore, the activation of perinuclear zone of the supraoptic nucleus after volume expansion is not dependent on intact arterial baroreceptors.


[Sphincter surgery. Etiology and therapy of the anal fissure (author's transl)].
Anal fissures belong to the autonomic diseases. A raised sympathicotonus (spasm dystrophy) is responsible for the origin, the poor healing tendency and the burning pain. This excessive effect of the sympathetic leads first to functional and later to organic disorders of the sphincter in the form of an achalasia. The empirically developed methods of operation have intervention in the autonomic nervous system in common, and only differ in the extent of this "invasion of the autonomic". Functional changes must be treated with local anesthetics or by stretching the sphincter, organic changes by sphincterotomy.


Differential diagnosis of gingival hyperplasia based on IFN-gamma-stimulated gene expression using RT-PCR.
Epulus is a benign gingival tumour of unknown aetiopathogenesis. Classification is inconsistent, and standard management strategies are lacking. Epuli are generally believed to be inflammatory rather than neoplastic lesions. The literature does not present any molecular analysis of the tumour characteristics. The purpose of the present study was to compare benign (epulus) and malignant (cancer) gingival hyperplasias with regard to the activity of the genes of apoptosis, proliferation, and inflammation using RT-PCR. The investigation involved 70 patients with epuli and 15 patients with gingival squamous cell carcinoma. Each subject had specimens collected from the tumour, tissue margin (incision line), and healthy tissue. Molecular investigations by RT-PCR were used to evaluate expression levels of the genes associated with apoptosis (Bcl-2, Bax, Bcl-2/Bax), proliferation (H3 histone), and inflammatory processes (IFN-gamma, IFNgamma-R1, IFN-gammaR2, IFN-gammaR1/IFN-gammaR2). Correlations have been disclosed between apoptosis and proliferation genes expression in giant cell epuli and high-differentiated gingival squamous cell carcinoma. In RT-PCR molecular analysis, giant cell epulus shows characteristics of a neoplastic lesion, while other epulus types seem to be inflammatory tumours.


Rebleeding prophylaxis improves outcomes in patients with hepatocellular carcinoma. A multicenter case-control study.
Outcome of variceal bleeding (VB) in patients with hepatocellular carcinoma (HCC) is unknown. We compared outcomes after VB in patients with and without HCC. All patients with HCC and esophageal VB admitted between 2007 and 2010 were included. Follow-up was prolonged until death, transplantation, or June 2011. For each patient with HCC, a patient without HCC matched by age and Child-Pugh class was selected. A total of 292 patients were included, 146 with HCC (Barcelona Classification of Liver Cancer class 0-3 patients, A [in 25], B [in 29], C [in 45], and D [in 41]) and 146 without HCC. No differences were observed regarding previous use of prophylaxis, clinical presentation, endoscopic findings, and initial endoscopic treatment. Five-day failure was similar (25% in HCC versus 18% in non-HCC; P = 0.257). HCC patients had greater 6-week rebleeding rate (16 versus 7%, respectively; P = 0.025) and 6-week mortality (30% versus 15%; P = 0.003). Fewer patients with HCC received secondary prophylaxis after bleeding (77% versus 89%; P = 0.009), and standard combination therapy was used less frequently (58% versus 70%; P = 0.079). Secondary prophylaxis failure was more frequent (50% versus 31%; P = 0.001) and survival significantly shorter in patients with HCC (median survival: 5 months versus greater than 38 months in patients without HCC; P < 0.001). Lack of prophylaxis increased rebleeding and mortality. On multivariate analysis Child-Pugh score, presence of HCC, portal vein thrombosis, and lack of secondary prophylaxis were predictors of death. Patients with HCC and VB have worse prognosis than patients with VB without HCC. Secondary prophylaxis offers survival benefit in HCC patients.


[The change in readmission rate, length of stay and hospital charge after performance reporting of hip hemiarthroplasty].
We assessed impact of performance reporting information about the readmission rate, length of stay and cost of hip hemiarthroplasty. The data are from a nationwide claims database, National Quality Improvement Project database, of Health Insurance Review & Assessment Service in Korea. From January 2006 to April 2008, we received information of length of stay, readmission within 30 days, cost of 22 851 hip hemiarthroplasty episodes. Each episodes has retained the diagnoses of comorbidities and demographics. We used time-series analysis to assess the shifting of patients selections, between high volume(over 16 operations in a year) and low volume institutions, after performance reporting (december 2007). The changes of quality (readmission, length of stay) and cost were evaluated by multilevel analysis with adjustment of patient's factors and institutional factors after performance reporting. As compared with the before performance reporting, the proportion of patients who choose the high volume institution, increased 3.45% and the trends continued 4 months at marginal significance (p=0.059). After performance reporting, national average readmission rate, length of stay were decreased by 0.49 OR (95% CI=0.25-0.95) and 10% (β=-0.102 p<0.01) and cost was not changed (β=-0.01, p<0.27). The high volume institutions were more decreased than low volume in length of stay. After performance reporting, readmission rate, length of stay were decreased and the patient selections were marginal shifted from low volume institutions to high volume institutions.


Pulmonary regurgitation: the effects of varying pulmonary artery compliance, and of increased resistance proximal or distal to the compliance.
Pulmonary regurgitation is common after repair of tetralogy of Fallot, predisposing to right ventricular dilatation and potentially fatal arrhythmias. Magnetic resonance studies of such patients led us to hypothesize that the amount of regurgitation, in the absence of an effective valve, depends on pulmonary arterial compliance and on the location of resistance relative to the compliance. Using a pre-existing mathematical model representing the cardiovascular system, removal of the virtual pulmonary valve gave a triphasic pulmonary artery flow curve similar in shape to those recorded in patients with free regurgitation, with a regurgitant fraction of 30%. There was no reversal of flow at pulmonary capillary level, the regurgitant volume originating entirely from the compliance of the virtual pulmonary arteries and arterioles. Doubling their compliance increased regurgitation to 35%, whereas halving it decreased regurgitation to 23%. Doubling the total pulmonary vascular resistance by increasing arteriolar resistance increased regurgitation to 46%, whereas doubling it by simulating pulmonary annular stenosis proximal to the compliance limited regurgitation to 10%, but at the cost of a 32 mmHg peak systolic pressure drop. The model supported our hypotheses, indicating the relevance to pulmonary regurgitation of previously overlooked variables. The virtual pulmonary regurgitation was exacerbated by pulmonary artery compliance and by elevated resistance distal to it, but was limited by more proximal resistance. These relationships merit careful clinical investigation as they would have implications for the initial management, subsequent investigation and decisions on re-intervention in patients with pulmonary regurgitation.


Neuroimaging markers for early neurologic deterioration in single small subcortical infarction.
Early neurological deterioration (END) occurs in ≥20% of single small subcortical infarctions (SSSIs; axial diameter ≤20 mm in the perforator territories) and deters functional recovery. Both microvasculopathies and atherosclerosis have been proposed to independently contribute to the occurrence of END in SSSI cases. We hypothesized that the occurrence of END in SSSIs differs according to the pathological process. We collected data from 587 patients with SSSI within 48 hours of onset from a prospective stroke registry containing 4961 case records. Independent reviewers, blinded to END information, rated neuroimaging characteristics, including relevant artery stenosis (0% to 50% stenosis of the adjacent arteries on magnetic resonance angiography), branch atheromatous lesions (≥4 consecutive axial cuts or extensions from the basal surface of the pons), white matter hyperintensities, old lacunar infarctions, and cerebral microbleeds. END occurred in 79 (13.5%) cases, including 6 recurrences, 68 progressions, 1 symptomatic hemorrhagic transformation, 1 others, and 3 unknowns. END increased the National Institutes of Health Stroke Scale score by 2.3±1.4 points. Patients with END showed higher frequencies of modified Rankin Scale scores of 3 to 6 after 3 months compared with patients without END (49% versus 23%). Patients with relevant artery stenosis (adjusted odds ratio, 1.91; 95% confidence interval, 1.13-3.21) and branch atheromatous lesions (adjusted odds ratio, 2.98; 95% confidence interval, 1.80-4.93) had significantly higher odds of exhibiting END. However, such an association was not detected with small vessel disease markers. Our analysis indicated a potential contribution of the localized atherosclerotic process to END in SSSIs. Precautionary measures might be used for SSSIs suggestive of atherosclerotic pathologies.


Occludin is required for TRPV1-modulated paracellular permeability in the submandibular gland.
Occludin plays an important role in maintaining tight junction barrier function in many types of epithelia. We previously reported that activation of transient receptor potential vanilloid subtype 1 (TRPV1) in rabbit submandibular gland promoted salivary secretion, partly by an increase in paracellular permeability. We have now explored the role of occludin in TRPV1-modulated paracellular permeability in a rat submandibular gland cell line SMG-C6. Both TRPV1 and occludin were expressed in SMG-C6 cells, and capsaicin induced redistribution of occludin, but not claudin-3, claudin-4 or E-cadherin, from the cell membrane into the cytoplasm. Capsaicin also decreased transepithelial electrical resistance (TER) and increased the Trypan Blue and FITC-dextran flux. Capsazepine (CPZ), a TRPV1 antagonist, inhibited the capsaicin-induced occludin redistribution and TER decrease. Moreover, occludin knockdown by shRNA suppressed, whereas occludin re-expression restored, the TER response to capsaicin. Mechanistically, TRPV1 activation increased ERK1/2 and MLC2 phosphorylation. PD98059, an ERK1/2 kinase inhibitor, abolished the capsaicin-induced MLC2 phosphorylation, whereas ML-7, an MLC2 kinase inhibitor, did not affect ERK1/2 phosphorylation, suggesting that ERK1/2 is the upstream signaling molecule of MLC2. Capsaicin also induced F-actin reorganization, which was abolished by CPZ, PD98059 and ML-7, indicating that TRPV1 activation altered F-actin organization in an ERK1/2- and MLC2-dependent manner. Furthermore, either PD98059 or ML-7 could abolish the capsaicin-induced TER response and occludin redistribution, whereas knockdown of ERK1/2 further confirmed that the TRPV1-modulated paracellular permeability was ERK1/2 dependent. Taken together, these results identified a crucial role of occludin in submandibular epithelial cells, and more importantly, demonstrated that occludin was required to mediate TRPV1-modulated paracellular permeability.


Glycyrrhizic acid ameliorates HMGB1-mediated cell death and inflammation after renal ischemia reperfusion injury.
Renal ischemia reperfusion injury (IRI) leads to acute kidney injury (AKI) and the death of tubular epithelial cells (TEC). The release of high-mobility group box-1 (HMGB1) and other damage-associated molecular pattern moieties from dying cells may promote organ dysfunction and inflammation by effects on TEC. Glycyrrhizic acid (GZA) is a functional inhibitor of HMGB1, but its ability to attenuate the HMGB1-mediated injury of TEC has not been tested. In vitro, hypoxia and cytokine treatment killed TEC and resulted in the progressive release of HMGB1 into the supernatant. GZA reduced the hypoxia-induced TEC death as measured by annexin-V and propidium iodide. Hypoxia increased the expression of MCP-1 and CXCL1 in TEC, which was reduced by GZA in a dose-dependent manner. Similarly, the HMGB1 activation of effector NK cells was inhibited by GZA. To test the effect of HMGB1 neutralization by GZA in vivo, mice were subjected to renal IRI. HMGB1 protein expression increased progressively in kidneys from 4 to 24 h after ischemia and was detected in tubular cells by 4 h using immunohistochemistry. GZA preserved renal function after IRI and reduced tubular necrosis and neutrophil infiltration by histological analyses and ethidium homodimer staining. Importantly, these data demonstrate for the first time that AKI following hypoxia and renal IRI may be promoted by HMGB1 release, which can reduce the survival of TEC and augment inflammation. Inhibition of the interaction of HMGB1 with TEC through GZA may represent a therapeutic strategy for the attenuation of renal injury following IRI and transplantation.


Secreted proteins from adipose tissue and skeletal muscle - adipokines, myokines and adipose/muscle cross-talk.
White adipose tissue and skeletal muscle are the largest organs in the body and both are composed of distinct cell types. The signature cell of adipose tissue is the adipocyte while myocytes are the defining cell of skeletal muscle. White adipocytes are major secretory cells and this is increasingly apparent also for myocytes. Both cells secrete a range of bioactive proteins, generally termed adipokines in the case of adipocytes and myokines for muscle cells. There has, however, been some confusion over nomenclature and we suggest that the name myokine is restricted to a protein that is secreted from myocytes, while the term adipokine should be used to describe all proteins secreted from any type of adipocyte (white, brown or brite). These definitions specifically exclude proteins secreted from other cells within adipose tissue and muscle, including macrophages. There is some commonality between the myokines and adipokines in that both groups include inflammation-related proteins - for example, IL-6, Il-8 and MCP-1. Adipokines and myokines appear to be involved in local autocrine/paracrine interactions within adipose tissue and muscle, respectively. They are also involved in an endocrine cross-talk with other tissues, including between adipose tissue and skeletal muscle, and this may be bi-directional. For example, IL-6, secreted from myocytes may stimulate lipolysis in adipose tissue, while adipocyte-derived IL-6 may induce insulin resistance in muscle.


Thermodynamics and stoicheiometry of the binding of substrate analogues to uricase.
The subunit composition, metal content, substrate-analogue binding and thermal stability of Aspergillus flavus uricase were determined. A. flavus uricase is a tetramer and contains no copper, iron or any other common prosthetic group. Analytical-gel-filtration and equilibrium-dialysis experiments showed one binding site per subunit for urate analogues. The free energy of xanthine binding was -30.5 kJ (-7.3 kcal)/mol of subunit by equilibrium dialysis and -30.1 kJ (-7.2 kcal)/mol of subunit by microcalorimetry. The enthalpy change for xanthine binding was -15.9 kJ (-3.8 kcal)/mol of subunit when determined from the temperature-dependence of the equilibrium constant and -18.0 kJ (-4.3 kcal)/mol of subunit when measured microcalorimetrically. The thermal inactivation rate of A. flavus uricase increases as protein concentration is decreased. This concentration-dependent instability is not due to subunit dissociation.


Improved Integrated Whole Proteomic and Phosphoproteomic Profiles of Severe Acute Pancreatitis.
Severe acute pancreatitis (SAP) is caused by complicated biological factors, and revealing its complex pathogenesis by single-target analysis is difficult. Systematic studies have developed slowly because extraction of degradable pancreatic proteins exposed to multiple proteases is challenging. We present integrated whole proteomic and phosphoproteomic profiles of SAP rats based on a modified protein extraction strategy with less protein degradation. Data-dependent acquisition (DDA) and data-independent acquisition (DIA) strategies were applied to select an appropriate method. Total 275 differentially expressed proteins and 757 differentially expressed phosphorylated proteins were identified by DIA-based quantitative proteomics. Several signal transduction pathways, including the AMPK, MAPK, and PI3K-Akt pathways, were enriched in SAP. Up-regulation of phosphorylated proteins involved in the process of TNFA signaling and inflammatory response was also detected in SAP. Our results improve the understanding of SAP development and progression.


Isolated splenic tuberculosis presenting with pyrexia of unknown origin.
We report a case of a 62-y-old man who presented with fever, malaise and weight loss. He was diagnosed with pyrexia of unknown origin due to tuberculosis of the spleen. Combination anti-tuberculous therapy was administered and fever gradually subsided after 6 weeks. A 12-month course of anti-tuberculous treatment would appear to be appropriate for the treatment of most patients with splenic tuberculosis.


Reconstitution of a bacterial/plant polyamine biosynthesis pathway in Saccharomyces cerevisiae.
Polyamine synthesis in most organisms is initiated by the decarboxylation of ornithine to form putrescine via ornithine decarboxylase (ODC). Plants, some bacteria and some fungi and protozoa generate putrescine from arginine, via arginine decarboxylase (ADC) and agmatine ureohydrolase (AUH) or agmatine iminohydrolase. A polyamine-requiring strain of Saccharomyces cerevisiae with a mutation in the gene encoding ODC was transformed with plasmids bearing genes encoding Escherichia coli ADC and AUH. Transformants regained the ability to grow in the absence of exogenous polyamines and contained enzyme activities consistent with the presence of both prokaryotic enzymes. Similar results were obtained when a plasmid containing a gene encoding oat (Avena sativa L.) ADC was substituted for the E. coli gene. These data demonstrate the successful complementation of a yeast biosynthetic polyamine synthesis defect by genes encoding an alternative pathway found in bacteria; they also show that plant ADC can substitute for the bacterial enzyme in this pathway. The recombinant yeast provides a tool for the study of the functional properties of these enzymes and for discovery of compounds that specifically inhibit this pathway.


Strategies for handling ethical problems in end of life care: obstacles and possibilities.
In end of life care, ethical problems often come to the fore. Little research is performed on ways or strategies for handling those problems and even less on obstacles to and possibilities of using such strategies. A previous study illuminated stroke team members' experiences of ethical problems and how the teams managed the situation when caring for patients faced with sudden and unexpected death from stroke. These findings have been further explored in this study. The aim of the study was to illuminate obstacles and possibilities perceived by stroke team members in using strategies for handling ethical problems when caring for patients afflicted by sudden and unexpected death caused by stroke. A qualitative method with combined deductive and inductive content analysis was utilized. Data were collected through individual interviews with 15 stroke team members working in stroke units of two associated county hospitals in western Sweden. The study was approved by the Regional Ethics Review Board, Gothenburg, Sweden. Permission was also obtained from the director of each stroke unit. All the studied strategies for handling of ethical problems were found to have both obstacles and possibilities. Uncertainty is shown as a major obstacle and unanimity as a possibility in the use of the strategies. The findings also illuminate the value of the concept "the patient's best interests" as a starting point for the carers' ethical reasoning. The concept "the patient's best interests" used as a starting point for ethical reasoning among the carers is not explicitly defined yet, which might make this value difficult to use both as a universal concept and as an argument for decisions. Carers therefore need to strengthen their argumentation and reflect on and use ethically grounded arguments and defined ethical values like dignity in their clinical work and decisions.


Xanthium spinosum L. Extracts Inhibit Breast Cancer in Mice by Apoptosis Induction and Immune System Modulation.
Plants have been considered for many years as an important source of medicine to treat different diseases. Xanthium spinosum L. (Asteraceae, Compositae) is known for its diuretic, anti-inflammatory, and sedative effects. It is also used in the treatment of several ailments, such as cancer. In order to evaluate the anticancer and immunomodulatory activities, crude ethanol extract was prepared from the aerial part of X. spinosum and then fractionated using solvents with different polarities. As well, the chemical composition of X. spinosum extract and fractions were identified using LC-MS analysis. The antitumor effect of X. spinosum was assessed in both in vitro and in vivo models. Apoptosis induction was measured in vitro using a caspase-3 activity kit. Lymphocyte proliferation and phagocytosis and pinocytosis induction were used to quantify the effect of the plant extract and fractions on acquired and innate immunity, respectively. The effect of X. spinosum extract, and fractions on the levels of cytokines (IFN-γ, IL-2, IL-4, and IL-10) in murine lymphocytes was determined using a mouse-uncoated TH1/TH2 ELISA kit. Results showed that ethanol extract had the highest antiproliferative activity (IC₅₀ = 2.5 mg mL-1) against EMT6/P cell lines, while the aqueous and chloroform fractions had the highest apoptotic activity with 2.2 and 1.7 folds, respectively. On the other hand, the n-hexane fraction was the most effective in stimulating lymphocyte proliferation, whereas ethanol extract, aq. Methanol and aqueous fractions exhibited the highest phagocytic activity. As well, X. spinosum extract and fractions were able to modulate the expression of IL-2, IL-4, and IFN-γ. A remarkable decrease in tumor size was accomplished following the treatment of tumor-bearing mice with X. spinosum extract and fractions. Both aq. Methanol and chloroform fractions showed the highest percentage change in tumor size with -58 and -55%, respectively. As well, tumor-bearing mice treated with chloroform fraction demonstrated a high curable percentage with a value of 57.1%. Anyway, X. spinosum extract and fractions exhibited no toxic impact on the liver or kidney functions of the mice-treated groups. These findings may confirm that X. spinosum has favorable anticancer and immunomodulatory effects. However, additional studies are required to fully understand the mechanisms of action of this plant and the signaling pathways involved in its effects. Moreover, more testing is needed to have better insight into the apoptotic pathway and to know the exact concentration of active compounds.


Dynamics of within-, inter-, and cross-modal attentional modulation.
Numerous studies have demonstrated effects of spatial attention within single sensory modalities (within-modal spatial attention) and the effect of directing attention to one sense compared with the other senses (intermodal attention) on cortical neuronal activity. Furthermore, recent studies have been revealing that the effects of spatial attention directed to a certain location in a certain sense spread to the other senses at the same location in space (cross-modal spatial attention). The present study used magnetoencephalography to examine the temporal dynamics of the effects of within-modal and cross-modal spatial and intermodal attention on cortical processes responsive to visual stimuli. Visual or tactile stimuli were randomly presented on the left or right side at a random interstimulus interval and subjects directed attention to the left or right when vision or touch was a task-relevant modality. Sensor-space analysis showed that a response around the occipitotemporal region at around 150 ms after visual stimulation was significantly enhanced by within-modal, cross-modal spatial, and intermodal attention. A later response over the right frontal region at around 200 ms was enhanced by within-modal spatial and intermodal attention, but not by cross-modal spatial attention. These effects were estimated to originate from the occipitotemporal and lateral frontal areas, respectively. Thus the results suggest different spatiotemporal dynamics of neural representations of cross-modal attention and intermodal or within-modal attention.


[Spread of tropical malaria in the Republic of Tajikistan (1994-2008)].
Tropical malaria occurred in the Republic of Tajikistan in 1994 after 40-year absence and spread in 28 regions of Tajikistan and in 3 cities (Dushanbe, Kulyab, and Kurgan-Tyube), peaking in 2000 (831 cases). A total of 3585 cases of tropical malaria were notified in 602 foci during a 15-year period. Migrants imported the pathogenic agent by the route of Pakistan-Afghanistan-Tajikistan during armed conflicts and in trading activities continually.The emergence of Asian Plasmodium falciparum phenotypes was accompanied by the clinical complications of the disease: the high percentage of moderate and severe forms of the disease was observed in preschool children in the absence of fatal outcomes. The rising incidence of malaria was associated with not only with the intensive import of the infection and the flight of infected malaria mosquitoes, but also with the active examination of the population during homestead rounds and with the timely laboratory diagnosis of malaria pathogens. The long-term goal antimalarial measures in the Republic of Tajikistan in 2009 resulted in the pause in the local transmission of tropical malaria, which meant its elimination in the country.


Environmentally benign and efficient Ag2S-ZnO nanowires as photoanodes for solar cells: comparison with CdS-ZnO nanowires.
In this work, we develop a low-temperature, facile solution reaction route for the fabrication of quantum-dot-sensitized solar cells (QDSSCs) containing Ag(2)S-ZnO nanowires (NWs), simultaneously ensuring low manufacturing costs and environmental safety. For comparison, a CdS-ZnO NW photoanode was also prepared using the layer-by-layer growth method. Ultraviolet photoelectron spectroscopy analysis revealed type-II band alignments for the band structures of both photoanodes which facilitate electron transfer/collection. Compared to CdS-ZnO QDSSCs, Ag(2)S-ZnO QDSSCs exhibit a considerably higher short-circuit current density (J(sc)) and a strongly enhanced light-harvesting efficiency, but lower open-circuit voltages (V(oc)), resulting in almost the same power-conversion efficiency of 1.2 %. Through this work, we demonstrate Ag(2)S as an efficient quantum-dot-sensitizing material that has the potential to replace Cd-based sensitizers for eco-friendly applications.


Determination of Hg and Se in swordfish (Xiphias gladius) from Mediterranean Sea: Implications for nutritional recommendations during pregnancy and childhood.
Swordfish (Xiphias gladius) are important marine predators facing potential mercury (Hg) contamination. This study analyzed Hg levels in swordfish muscle tissue from two Mediterranean Sea stocks. Italian specimens showed significantly higher Hg concentrations (1.4 ± 0.8 mg kg-1 ww) than Spanish ones (0.8 ± 0.5 mg kg-1 ww), with many samples exceeding EU's safety limit (1 mg kg-1 ww). Selenium (Se) content and Se:Hg ratios were examined, along with the maximum safe fish meals per month for vulnerable consumers. These results highlight the urgent need for monitoring and mitigation strategies to reduce health risks, especially for susceptible populations.


Incidence and predictors of incisional hernia after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
Background and objectives: The incidence of incisional hernia (IH) after cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is largely unknown. Methods: We conducted a retrospective study to identify patients who underwent CRS/HIPEC from 2001 to 2016. Patients were followed postoperatively for a minimum of two years. The primary outcome was the occurrence of an IH identified either on CT scan or physical examination. Univariate and multivariable logistic regression models were used to test associations with IH. Results: We identified 155 patients who underwent CRS/HIPEC; 26 patients (17%) were diagnosed with an IH at a median time of 245 days (Interquartile range [IQR] 175 - 331 days). On multivariable analysis, older age [50-64 vs. 18-49 years: hazard ratio (HR) = 0.08; 95% confidence interval (CI), 0.01 to 0.64)], female gender (HR = 0.09; 95% CI, 0.01 to 0.75), and increased BMI (>30 vs. <25; HR = 0.03; 95% CI, 0.01 to 0.37) were significant independent predictors of IH. Conclusions: The incidence of IH in this high-risk patient population treated with CRS/HIPEC is similar to that after other abdominal cancer operations. Nevertheless, the occurrence of IH is an important patient outcome, so alternative closure techniques for reducing IH should be studied in this patient population. Synopsis In a single-institutional study, the incidence of incisional hernia was 17% after cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy. Independent risk factors of incisional hernia were older age, female gender and obesity.


CD8+ lymphocytes are critical for early control of tuberculosis in macaques.
The functional role of CD8+ lymphocytes in tuberculosis remains poorly understood. We depleted innate and/or adaptive CD8+ lymphocytes in macaques and showed that loss of all CD8α+ cells (using anti-CD8α antibody) significantly impaired early control of Mycobacterium tuberculosis (Mtb) infection, leading to increased granulomas, lung inflammation, and bacterial burden. Analysis of barcoded Mtb from infected macaques demonstrated that depletion of all CD8+ lymphocytes allowed increased establishment of Mtb in lungs and dissemination within lungs and to lymph nodes, while depletion of only adaptive CD8+ T cells (with anti-CD8β antibody) worsened bacterial control in lymph nodes. Flow cytometry and single-cell RNA sequencing revealed polyfunctional cytotoxic CD8+ lymphocytes in control granulomas, while CD8-depleted animals were unexpectedly enriched in CD4 and γδ T cells adopting incomplete cytotoxic signatures. Ligand-receptor analyses identified IL-15 signaling in granulomas as a driver of cytotoxic T cells. These data support that CD8+ lymphocytes are required for early protection against Mtb and suggest polyfunctional cytotoxic responses as a vaccine target.


Are you ready to execute your facility's emergency management plans?
Within the context of emergency management, the difference between preparedness and readiness is discussed. A 5-step approach is presented to help identify the readiness of individuals to execute their facility's emergency management plans. Step 1 is a 10-question self-evaluation. Suggestions for identifying individual and plan deficiencies are also presented. A short discussion regarding emergency management exercises/drills and their importance is provided. In addition, information regarding Hospital Emergency Incident Command System III and the new Hospital Emergency Incident Command System IV compliance with the National Incident Management System is also presented. The argument can be made that no one is ever fully prepared or is 100% ready because readiness is an ongoing development process. Although that may be true, one can reasonably prepare for identified potential events. Readiness certainly falls within the scope of continuous quality improvement.


A novel compound active against SARS-CoV-2 targeting uridylate-specific endoribonuclease (NendoU/NSP15): in silico and in vitro investigations.
NendoU (NSP15) is an Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond. Our in-house library was subjected to high throughput virtual screening (HTVS) to identify compounds with potential to inhibit NendoU enzyme, high-rank compounds (those that bound to multiple target structures) were further subjected to 100 nanoseconds MD simulations. Among these, one was found to be bound highly stable within the active site of the NendoU protein structure. Here, we are reporting a derivative of piperazine based '(2S,3S)-3-amino-1-(4-(4-(tert-butyl)benzyl)piperazin-1-yl)-4-phenylbutan-2-ol' (IV) from our in-house libraries having potential efficacy against SARS-CoV-2 in in vitro assays. This compound demonstrated inhibition of viral replication at the same level as Ivermectin, a known SARS-CoV-2 inhibitor, which is not used due to its toxicity at a higher than the currently approved dosage. Compound IV was not toxic to the cell lines up to a 50 μM concentration and exhibited IC50s of 4.97 μM and 8.46 μM in viral entry and spread assay, respectively. Therefore, this novel class of NendoU inhibitor could provide new insights for the development of treatment options for COVID-19.


Economic benefits of reducing somatic cell count under the milk quality program of Ontario.
An empirical stochastic model for monthly bulk milk SCC was used to determine the impact of bulk milk SSC on the probability and cost of penalties under the milk quality program of Ontario, Canada. Under this program, milk price is reduced by $1 (Canadian)/hl each time bulk milk SCC exceeds 500,000 cells/ml three times in a 4-mo period. The model included herd average bulk milk SCC, effects of season, five autoregressive terms for bulk milk SCC in previous months, and a random variable with a standard deviation that depended on herd average SCC. Probabilities of receiving a penalty were 20, 13, 7, 4, 1.5, and 0.4%/mo for herd average bulk milk SCC of 450,000, 400,000, 350,000, 300,000, 250,000, and 200,000 cells/ml, respectively. Associated average penalty costs were $0.81, 0.47, 0.17, 0.04, 0.002, and 0.000/hl, respectively. Marginal return functions for reducing herd average linear somatic cell score were derived also. Marginal values were minimal for herd average linear scores < 3. For the population, the marginal value of reducing average linear score by one unit from a mean of 3 was $19.60/yr per cow. Results indicated that efforts to reduce bulk milk SCC resulted in substantial extra milk revenues. A bulk milk SCC target of 250,000 cells/ml was advocated.


A Classification System for Assessment and Home Monitoring of Tremor in Patients with Parkinson's Disease.
Tremor is one of the most common symptoms of Parkinson's disease (PD), which is widely being used in the diagnosis procedure. Accurate estimation of PD tremor based on Unified PD Rating Scale (UPDRS) provides aid for physicians in prescription and home monitoring. This article presents a robust design of a classification system to estimate PD patient's hand tremors and the results of the proposed system as compared to the UPDRS. A smartphone accelerometer sensor is used for accurate and noninvasive data acquisition. We applied short-time Fourier transform to time series data of 52 PD patients. Features were extracted based on the severity of PD patients' hand tremor. The wrapper method was employed to determine the most discriminative subset of the extracted features. Four different classifiers were implemented for achieving best possible accuracy in the estimation of PD hand tremor based on UPDRS. Of the four tested classifiers, the Naive Bayesian approach proved to be the most accurate one. The classification result for the assessment of PD tremor achieved close to 100% accuracy by selecting an optimum combination of extracted features of the acceleration signal acquired. For home health-care monitoring, the proposed algorithm was also implemented on a cost-effective embedded system equipped with a microcontroller, and the implemented classification algorithm achieved 93.8% average accuracy. The accuracy result of both implemented systems on MATLAB and microcontroller is acceptable in comparison with the previous works.


Evaluation of culturing and molecular assay for detection of Mycoplasma gallisepticum in chicken suffering from chronic respiratory disease.
Mycoplasma gallisepticum (M. gallisepticum) is a bacterium that causes chronic respiratory disease (CRD) and infectious sinusitis (IS) in chicken and turkeys .Therefore, rapid and immediate diagnosis or regular detection of Mycoplasma may be of great help to early detection. 120 chicken layers, Within Karbala city was carried out during their laying period on breeding flocks. The study proposed a promising method for isolation of M. gallisepticum, 120 tracheal swabs and blood samples from chicken in different dairy farms were used to analyze M. gallisepticum utility of PCR and culture. Compared with ELISA anti-IgG M. gallisepticum, the clinical specificity of PCR detection is 89.66%, the sensitivity is 86.36%, and the kappa coefficient is 0.817. Compared with the culture method, the specificity is 100%, the specificity is 45%, and the kappa coefficient is 0.543. Demonstrate the method's effectiveness and applicability as a standard method for mycoplasmas field diagnosis.


Patients with antiphospholipid antibodies: CT and MR findings of the brain.
The purpose of this study was to determine the spectrum of neuroradiologic findings in patients with antiphospholipid antibodies (APA) and to compare findings in systemic lupus erythematosus (SLE) and non-SLE patients. We identified 110 patients with APA who underwent CT or MR imaging, of whom 59 (54%) had abnormal studies. Of these 59 patients, abnormalities were categorized as large infarcts, cortical infarcts, lacunar infarcts, hyperintense white matter foci on T2-weighted images, or dural sinus thrombosis. White matter foci were designated as small (< 5mm) or large (> 5 mm). Large infarcts were the most common abnormality, seen in 24 of 110 (22%) patients, followed in frequency by hyperintense white matter foci, seen in 19 of 110 (17%) patients. Ninety-five percent of patients with hyperintense white matter foci had at least one large lesion, and 76% had five or more small foci, three or more large foci, or both. Small cortical infarcts and lacunar infarcts were seen in 11 of 110 (10%) and 10 of 110 (9%) patients, respectively. Dural sinus thrombosis was seen in five patients. The frequency of abnormalities was high in both the SLE (57%) and the non-SLE (41%) groups. Large infarcts were more common in the non-SLE group (26%) than in the SLE group (5%). Although hyperintense white matter foci and cortical infarcts were more common in SLE patients, the differences were not statistically significant. Infarcts of various sizes and hyperintense white matter foci are the most common abnormalities seen on CT and MR imaging in patients with APA. We found no significant differences in frequencies of abnormalities seen between non-SLE and SLE patients.