A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403.
Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.


Treatment of advanced non-small cell lung cancer in the elderly.
Lung cancer is predominantly a disease that affects the elderly; about 30-40% of lung cancers are diagnosed in patients aged 70 or more. The increasing number of elderly patients over the next decades is generating a new social and health problem; despite that, these patients are underrepresented in clinical trials and undertreated in clinical practice. Areas covered: The main difficulty in treating elderly patients is to maximize the therapy benefits while minimizing the treatment risk. Elderly patients show a vulnerable clinical profile due to the higher prevalence of comorbid disease, higher polypharmacy interactions and aged organ dysfunction that increase the risk of mortality and toxicity with cancer treatments compared to younger patients. Expert commentary: The choice to treat or not to treat elderly patients cannot be taken only on the basis of the chronological age. Thus, the clinical approach should be to select patients who are effectively suitable for treatment having a better individual functional reserve and a better life expectancy. Elderly patients are a heterogeneous population and those who are fit to receive cancer treatment can be treated similarly to younger patients.


Microheterogeneity in regulatory circuits for T-cell alloresponsiveness.
Mixed leucocyte cultures of responder spleen cells from individual B10 mice, challenged with irradiated allogeneic B10.D2 or B10.BR spleen cells, were used to generate discrete pools of cytotoxic T lymphocytes (CTL) with which to immunize (B10 x B10.D2)F1 or (B10 x B10.BR)F1 animals. Aliquots of the original donor B10 spleen cells were stored at -70 degrees. Eighteen days after immunization of the F1 animals, spleen and serum preparations from these mice were tested, in reciprocal fashion, for their ability to affect the development of CTL from the thawed donor B10 spleen lymphocytes in fresh cultures challenged with either the original or a third party allogeneic stimulus. Evidence for individual specific suppression by F1-T lymphocytes or by F1-serum (antibody) molecules was obtained. By priming (B10 x B10.D2)F1 mice with B10 lymphoid cells the F1 animals can also be shown to resist the otherwise lethal GvHD induced by sublethal whole body irradiation followed by intravenous challenge with B10 lymphoid cells. Using F1 mice primed and subsequently challenged with lymphocytes prepared from individual donors, self-preference in the regulation of GvHD was also seen. A similar fine specificity of regulatory cells was observed using suppressor cells from individual mice rendered neonatally tolerant of histocompatible cells (by inoculation of F1 hybrid cells within 24 hr of birth). These findings suggest that the mouse T cell alloreceptor repertoire is subject to a process of somatic diversification during normal ontogenesis. By examining the regulation of alloresponsiveness in T lymphocytes of B10.Br origin which differentiate from the appropriate stem cells in a B10 or B10.Br host, we have uncovered evidence that the T-cell alloreceptor repertoire is, in part at least, determined by the host MHC environment.


Conductance of concentrated electrolytes: Multivalency and the Wien effect.
The electric conductivity of ionic solutions is well understood at low ionic concentrations of up to a few millimolar but becomes difficult to unravel at higher concentrations that are still common in nature and technological applications. A model for the conductivity at high concentrations was recently put forth for monovalent electrolytes at low electric fields. The model relies on applying a stochastic density-functional theory and using a modified electrostatic pair-potential that suppresses unphysical, short-range electrostatic interactions. Here, we extend the theory to multivalent ions as well as to high electric fields where a deviation from Ohm's law known as the Wien effect occurs. Our results are in good agreement with experiments and recent simulations.


Correlation between twinkling artifact and color Doppler carrier frequency: preliminary observations in renal calculi.
Color Doppler twinkling is a well-defined but not well-understood phenomenon that may assist in the detection of renal calculi. However, the relationship between the appearance of color Doppler twinkling and color Doppler carrier frequency has not been described systematically. To evaluate this relationship, a retrospective review was performed on 20 cases of renal calculi detected by twinkling on renal color Doppler sonography and confirmed with unenhanced computed tomography. The variable strength of twinkling at and behind renal calculi was observed with color Doppler carrier frequencies ranging from 1.75-4.0 MHz. All 20 calculi (100%) demonstrated twinkling when a low color Doppler carrier frequency, 1.75 or 2 MHz, was applied, whereas 12 of 20 cases (60%) were absent of twinkling when the highest carrier frequencies tested-3.5 or 4 MHz-were used. Quantitatively, there was a significant correlation between the amount of twinkling and carrier frequency (p = 0.002102). Hence, we conclude that the strength of the twinkling is color Doppler carrier frequency-dependent. The strength of the twinkling significantly increased when the color carrier frequency used for imaging decreased. Therefore, to improve renal calculi detection by enhancing the strength of the twinkling, the use of a lower color Doppler carrier frequency is recommended.


A multi-inverse approach for a holistic understanding of applied animal science systems.
Technological and mathematical advances have provided opportunities to investigate new approaches for the holistic quantification of complex biological systems. One objective of these approaches, including the multi-inverse deterministic approach proposed in this paper, is to deepen the understanding of biological systems through the structural development of a useful, best-fitted inverse mechanistic model. The objective of the present work was to evaluate the capacity of a deterministic approach, that is, the multi-inverse approach (MIA), to yield meaningful quantitative nutritional information. To this end, a case study addressing the effect of diet composition on sheep weight was performed using data from a previous experiment on saccharina (a sugarcane byproduct), and an inverse deterministic model (named Paracoa) was developed. The MIA successfully revealed an increase in the final weight of sheep with an increase in the percentage of corn in the diet. Although the soluble fraction also increased with increasing corn percentage, the effective nonsoluble degradation increased fourfold, indicating that the increased weight gain resulted from the nonsoluble substrate. A profile likelihood analysis showed that the potential best-fitted model had identifiable parameters, and that the parameter relationships were affected by the type of data, number of parameters and model structure. It is necessary to apply the MIA to larger and/or more complex datasets to obtain a clearer understanding of its potential.


A One-Bead-Per-Saccharide (1BPS) Model for Glycosaminoglycans.
Glycosaminoglycans (GAGs) are polysaccharide compounds that play key roles in various biological processes. GAGs are important structural components of cartilage and the extracellular matrix of the brain. Due to the large size of these polysaccharides, coarse-grained approaches are indispensable for modeling these biopolymers. We develop a one-bead-per-saccharide model of chondroitin sulfates and hyaluronic acid based on an existing three-bead-per-saccharide coarse-grained model. Our coarse graining is carried out by using iterative Boltzmann inversion (IBI), including an additional coupling potential to incorporate the correlation between dihedral angles. The predictions of the model are verified against those of the existing three-bead-per-saccharin model and the experimental radius of gyration for hyaluronic acid.


Human aldolase B serum levels: a marker of liver injury.
A solid-phase, noncompetitive radioimmunoassay has been developed for aldolase B in human serum and tissues. Aldolase B was purified from human liver, and specific antisera to purified aldolase B were obtained from chickens. Specific antihuman aldolase B IgG was purified by affinity chromatography. Disposable polypropylene plates were coated with affinity purified specific IgG antibody and used for radioimmunoassay with 125I-specific IgG antibody to aldolase B. The nonspecific binding was minimized by saturating the binding sites of the plates with 2% ovalbumin in 0.1% Tween 20. This radioimmunoassay is specific for the aldolase B subunit, with no cross-reactivity with human aldolase A or aldolase C subunits. Aldolase B is predominantly found in normal liver. Relatively high aldolase B levels are also observed in kidney. Serum levels of aldolase B in 21 normal subjects ranged from 21 to 39 ng per ml, with a mean of 28.7 +/- 8.6 (2 S.D.) ng per ml. Forty of 42 (95%) patients with acute and chronic hepatitis without cirrhosis had serum aldolase B levels greater than 40 ng per ml. Serum aldolase B levels correlated well with total serum aldolase enzyme activities (r = 0.967) and SGPT (r = 0.951) in patients with liver diseases. In cancer patients, serum aldolase B was slightly elevated in 15 of 26 (58%) patients with cancer metastatic to the liver or primary liver cell carcinoma, whereas no elevation of serum aldolase B was observed in 16 cancer patients without liver metastasis. Measurements of aldolase B serum levels by radioimmunoassay appear to be a useful measure of liver cell necrosis from benign or malignant liver diseases.


Prediction of susceptible biomarkers for end stage renal disease among North Indians.
Involvement of pro-inflammatory genes has been correlated with basic kidney diseases and end stage renal disease (ESRD). However, results at odds were often noted from such independent association studies. This study proposes a genome wide analysis approach to predict ESRD risk associated genes. We included 42 single nucleotide polymorphisms (SNPs) showing association among north Indian ESRD cases and controls. ESRD cases comprised chronic glomerulonephritis (CGN), chronic interstitial nephritis (CIN), hypertension (HTN) and autosomal dominant polycystic kidney disease (ADPKD). Genotyping data obtained from our prior published reports were compared with Genome-Wide Association Studies (GWAS) SNPs retrieved from HapMap and GWASCentral databases using R-statistical package SNPAssoc. Linkage disequilibrium (LD), gene-gene interaction, classification and regression tree (CART) and pathway analysis were carried out in the present study supplemented with IL-6 and TNF-α levels estimation using enzyme linked immunosorbent assay (ELISA). Comparison of genotyping data with GWAS SNPs revealed significant associations for interleukin (IL)1-RN, IL-6, MTHFR, tumour necrosis factor-α (TNF-α) and CCR3 genes with ESRD. Nine SNPs were commonly associated with CGN, CIN, HTN, ADPKD and ESRD. LD (D = 0.9) and gene-gene interaction (P = 0.0002) analyses revealed significant associations for IL-6 and TNF-α genes. In a consistent manner, CART analysis and functional analysis servers predict predisposing effects for TNF-α and IL-6 with ESRD. Finally, higher body circulating levels were observed for mutant TNF-α and IL-6 alleles among ESRD. The study indicates significance for IL-6 and TNF-α gene with basic kidney diseases and ESRD. Extensive statistical tests, pathway analysis and functional assays also reflect attenuated level of significance for these SNPs. In future these may be brought from bench side to clinical practice as diagnostic biomarkers upon external and prospective replication and confirmation among other cohorts.


A measure of and predictors for veterinarian trust developed with veterinary students in a simulated companion animal practice.
To gain a better understanding of the role of interpersonal trust in veterinarian-client interactions during routine health-care visits, develop a measure of trust uniquely suited to the context of veterinary medicine, and interpret the actions, beliefs, and perceptions that capture client trust toward veterinarians. Correlational study. 103 veterinary students and 19 standardized clients with pets from a college of veterinary medicine at a large public Midwestern university. measure of trust specific to veterinarian-client interactions was constructed on the basis of preexisting conceptualizations of the construct and administered to veterinary students and standardized clients following interactions in 2 medical scenarios in a high-fidelity simulated animal health clinic. Exploratory and confirmatory factor analytic techniques were used to validate the measure of trust, and hierarchic linear modeling was used to explore indicators of standardized client trust perceptions in one of the scenarios. Factor analysis revealed that the measure captured 2 perceptions indicative of trust in veterinary contexts: professionalism and technical candor. Students who had behaviors reflecting these factors as well as those who were perceived as more technically competent were seen as more trustworthy by standardized clients. The development of trustworthy relationships between clients and veterinarians is important to the continued growth and success of the profession. By identifying characteristics of veterinarian trustworthiness and developing related measurement tools, proactive approaches to monitoring veterinarian-client relations can be implemented and incorporated into veterinary training and practice programs to identify areas for improvement.


Prediction and early biomarkers of cognitive decline in Parkinson disease and atypical parkinsonism: a population-based study.
The progression of cognitive decline is heterogeneous in the three most common idiopathic parkinsonian diseases: Parkinson disease, multiple system atrophy and progressive supranuclear palsy. The causes for this heterogeneity are not fully understood, and there are no validated biomarkers that can accurately identify patients who will develop dementia and when. In this population-based, prospective study, comprehensive neuropsychological testing was performed repeatedly in new-onset, idiopathic parkinsonism. Dementia was diagnosed until 10 years and participants (N = 210) were deeply phenotyped by multimodal clinical, biochemical, genetic and brain imaging measures. At baseline, before the start of dopaminergic treatment, mild cognitive impairment was prevalent in 43.4% of the patients with Parkinson disease, 23.1% of the patients with multiple system atrophy and 77.8% of the patients with progressive supranuclear palsy. Longitudinally, all three diseases had a higher incidence of cognitive decline compared with healthy controls, but the types and severity of cognitive dysfunctions differed. In Parkinson disease, psychomotor speed and attention showed signs of improvement after dopaminergic treatment, while no such improvement was seen in other diseases. The 10-year cumulative probability of dementia was 54% in Parkinson disease and 71% in progressive supranuclear palsy, while there were no cases of dementia in multiple system atrophy. An easy-to-use, multivariable model that predicts the risk of dementia in Parkinson disease within 10 years with high accuracy (area under the curve: 0.86, P < 0.001) was developed. The optimized model adds CSF biomarkers to four easily measurable clinical features at baseline (mild cognitive impairment, olfactory function, motor disease severity and age). The model demonstrates a highly variable but predictable risk of dementia in Parkinson disease, e.g. a 9% risk within 10 years in a patient with normal cognition and CSF amyloid-β42 in the highest tertile, compared with an 85% risk in a patient with mild cognitive impairment and CSF amyloid-β42 in the lowest tertile. Only small or no associations with cognitive decline were found for factors that could be easily modifiable (such as thyroid dysfunction). Risk factors for cognitive decline in multiple system atrophy and progressive supranuclear palsy included signs of systemic inflammation and eye movement abnormalities. The predictive model has high accuracy in Parkinson disease and might be used for the selection of patients into clinical trials or as an aid to improve the prevention of dementia.


An immunoelectron microscopic study of von Willebrand factor in the thoracic duct endothelium of rats.
The localization of Von Willebrand factor-like immunoreactivity (VWFI) in the thoracic duct endothelium was investigated by means of preembedding immunoelectron microscopy. In the endothelial cells, VWFI was observed within rod-shaped Weibel-Palade bodies (WPBs) with an occasional tadpole-like appearance. The WPBs occasionally appeared to be associated with Golgi complexes of the endothelial cells. Some cisternae of the rough endoplasmic reticulum located in the perikarya of the endothelial cells also exhibited VWFI. There was a small number of large VWFI vesicles in the periphery of the endothelial cells. These findings provide morphological evidence for the thoracic duct as a site of VWF synthesis and suggest further that VWF is produced in the rough endoplasmic reticulum and transported into the WPBs and large vesicles occasionally via the Golgi apparatus.


Impact of beneficial bacteria supplementation on the gut microbiota, colony development and productivity of Apis mellifera L.
Honey bees are important pollinators of several crops and ecosystems, having a great ecological and economic value. In Europe, the restricted use of chemicals and therapeutic agents in the beekeeping sector has stimulated the search for natural alternatives with a special focus on gut symbionts. The modulation of the gut microbiota has been recognised as a practical and successful approach in the entomological field for the management of insect-related problems. To date, only a few studies have investigated the effect of bacterial supplementation on the health status of colonies, colony productivity and gut symbionts. To this purpose, a preparation of sugar syrup containing bifidobacteria and lactobacilli isolated from bee gut was sprayed on the frames of an apiary located in open field once a week for four weeks. Treated and control hives were monitored for two months for brood extension, honey and pollen harvest. The presence of beneficial gut microorganisms within bee gut was investigated with denaturing gradient gel electrophoresis and next generation sequencing. The administered bacteria led to a significant increase of brood population (46.2%), pollen (53.4%) and harvestable honey in honey supers (59.21%). Analysis of the gut microbiota on the new generation of bees in treated hives showed an increase in relative abundance of Acetobacteraceae and Bifidobacterium spp., which are known to be involved in bee nutrition and protection.


Complications of intravitreal injections.
Over the past few years, the results of many studies have highlighted the risks and benefits of intravitreal injection of a number of medications, the most common being triamcinolone, antivascular endothelial growth factor (VEGF) agents, antibiotics, antivirals, antifungals, and methotrexate. The purpose of this review is to highlight the complications associated with these injections. Elevated intraocular pressure and glaucoma are the most common complications of intraocular triamcinolone. There is also an increased incidence of cataract formation/progression over time. The immunosuppressive effect of triamcinolone does not appear to increase the risk of endophthalmitis. Recent reports suggest that intravitreal anti-VEGF injections have a low complication rate. Similarly, antimicrobials also have low rates of injection-associated complications. Intravitreal injections play a critical role in daily ophthalmic practice. The overall risk of endophthalmitis and retinal detachment appears to be low and most of the commonly used drugs are well tolerated, even with repeat injection. Further long-term studies need to be performed to elucidate ways of increasing the safety of these procedures and medications.


Comparison of pain catastrophizing and anxiety in patients with dyspareunia and healthy women: a cross-sectional study.
Despite the prominent role of cognitive-affective variables, such as pain catastrophizing and anxiety in chronic pain, little is known about their relationship with dyspareunia. This study compared pain-catastrophizing and anxiety in reproductive-aged women with and without dyspareunia. A controlled cross-sectional study was conducted on 398 married women in Iran selected by convenience sampling. Sampling was performed both online and in person. Data were collected using a checklist designed for the study, including background characteristics, self-reported dyspareunia, and two standard questionnaires: the Pain Catastrophizing Scale (PCS) and the Spielberger State-Trait Anxiety Inventory-6 (STAI-6). Results showed that 49.5% of the women reported dyspareunia in the previous six months, with a reduced figure of 42% and 31% when using more specific criteria for dyspareunia. Women with dyspareunia had significantly higher scores for pain catastrophizing and anxiety than the control group without dyspareunia. Pain-catastrophizing was associated with aversion to genital contact and body image dissatisfaction. Anxiety was correlated with age, marriage duration, and sexual abuse. Managing anxiety and catastrophizing thoughts may help dyspareunia patients better cope with pain.


Computational classification of mitochondrial shapes reflects stress and redox state.
Dynamic variations in mitochondrial shape have been related to function. However, tools to automatically classify and enumerate mitochondrial shapes are lacking, as are systematic studies exploring the relationship of such shapes to mitochondrial stress. Here we show that during increased generation of mitochondrial reactive oxygen species (mtROS), mitochondria change their shape from tubular to donut or blob forms, which can be computationally quantified. Imaging of cells treated with rotenone or antimycin, showed time and dose-dependent conversion of tubular forms to donut-shaped mitochondria followed by appearance of blob forms. Time-lapse images showed reversible transitions from tubular to donut shapes and unidirectional transitions between donut and blob shapes. Blobs were the predominant sources of mtROS and appeared to be related to mitochondrial-calcium influx. Mitochondrial shape change could be prevented by either pretreatment with antioxidants like N-acetyl cysteine or inhibition of the mitochondrial calcium uniporter. This work represents a novel approach towards relating mitochondrial shape to function, through integration of cellular markers and a novel shape classification algorithm.


The Effect of Proprioceptive Training on Directional Dynamic Stabilization.
Significant loss of playing time and the impact of treatment costs due to lower limb injury in football demonstrates a need for improved protocols for injury risk reduction. The aim of the present study is to assess the effect of a proprioceptive training program on the lower limb dynamic stability of elite footballers. A total of 16 elite premier league footballers were randomly allocated by matched pair design to a 8-week proprioception training group (group A, n = 8) or nontraining group (group B, n = 8), to determine the effect of this training over a 16-week period. Group A completed 8 weeks of bilateral proprioceptive training, 5 times per week for 10 minutes. The Biodex Stability System measures of overall stability index, anterior-posterior (A-P), and medial-lateral stability (M-L) at levels 8-6-4-1 were taken for both groups at baseline, 4, 8, and 16 weeks. Main effects of time, level of stability, and direction of stability were determined, with comparisons of effect made between the 2 groups. The training group displayed significant differences for multidirectional stability at week 8 (P ≤ .05). The A-P stability within the training group displayed significant differences between baseline measures and 16 weeks (P > .05), with significant increases in scores displayed for M-L and A-P stability between weeks 8 and 16 (P ≤ .05), representing a detraining effect. No significant differences were detected at any time point for the nontraining group (P > .05). Proprioceptive training over 8 weeks has a positive effect on all directions of stability. Greater declines in A-P stability were evident at 16 weeks when compared with M-L and overall stability index. Consideration must be given to the increased stability scores presented pretesting for A-P when compared with M-L. Findings of this work present implications for training design.


Ultrasound-guided core needle biopsy for differential diagnosis of thyroid nodules: A systematic review and meta-analysis.
Ultrasound-guided core needle biopsy (US-CNB) of thyroid nodules is a relatively new technique used in surgical workup. However, no systematic review of this method has yet been performed. In the present meta-analysis, literature databases consisting of Cochrane Library, Medline, Embase, Scopus and Google Scholar were searched. Following eligibility assessments of the studies, quality appraisals were performed on the included studies using the Quality Assessment Tool for Diagnostic Accuracy Studies-2 method. The data were systematically analyzed by using Review Manager (version 5.3) and Meta-Disc (version 1.4). Eight investigations were included, and the study qualities were good. There were 1,621 nodules included in the final meta-analysis. The summary estimated that US-CNB had a sensitivity of 0.96 [95% confidence interval (CI)=0.94-0.97] and a specificity of 0.96 (95% CI=0.94-0.97). Positive and negative likelihood ratios, and the diagnostic odds ratio of US-CNB were 18.20 (95% CI=2.21-156.41), 0.08 (95% CI=0.02-0.27) and 250.60 (95% CI=19.11-3286.76), respectively. The area under the summary receiver operating characteristic curve was 0.979. Therefore, US-CNB may be considered as a reliable method in the assessment of thyroid nodules, and has an acceptable risk of complications.


[Metabolism of bioactive lipids].
In addition to their well-known roles as structural elements (amphiphilic lipids of the cell membranes) and as energetic reserve (essentially triglycerides), the lipids function as "second messengers" is increasingly recognised. Indeed, they are also endogenous mediators with specific biological activities, synthesized "on request", often in response to a primary cellular signal. Most of the bio-active lipids originate from cleavage of the membrane structures under the action of phospholipases A2, C, D and of sphigomyelinases. Several products of lipolysis are involved in cell activation, signalling, apoptosis or proliferation. One of the major cascades of bio-active lipid production involves the release of arachidonic acid followed by the formation of prostanoids, e.g.: prostaglandins, thromboxanes, and of leukotrienes and related products. These molecules play major roles in such biological processes as inflammation or thrombosis. Arachidonic acid is also the substrate for cytochrome P450-dependent mono-oxygenases, producing molecules regulating ion fluxes in cell membranes. Action of sphingomyelinases leads to the release of ceramides, associated with apoptosis. Further hydrolysis of ceramides produces fatty acids and sphingosine; the latter being able, in its phosphorylated form, to induce cell proliferation and re-equilibrate the balance between cell death and cell renewal.


Abdominal compartment syndrome secondary to megarectum and megasigmoid.
A 31-year-old male patient with chronic constipation of unknown aetiology presented emergently with worsening nausea, vomiting and abdominal distension of one week duration. On examination, his abdomen was distended with minimal tenderness. A plain film of the abdomen demonstrated severe faecal loading. The patient was haemodynamically unstable on admission and appeared sick. An urgent CT abdomen and pelvis was conducted showing extensive rectal dilatation and associated proximal colonic stercoral perforation. The patient proceeded straight to theatre for laparotomy as his general condition was deteriorating rapidly. On transfer to the operating table, the patient suffered cardiopulmonary arrest. Resuscitation was immediately commenced. Abdominal compartment syndrome was suspected. Cardiac output was re-established following a midline laparotomy which acted relieve the abdominal pressure. The rectosigmoid faecal content was decompressed via an enterotomy. The perforated segment of transverse colon was resected and an end colostomy fashioned. A year later, the continuity of the bowel was re-established.


Intraoperative evaluation of coronary anastomosis by transit-time ultrasonic flow measurement.
Intraoperative assessment of the anastomosis is important during coronary bypass on a beating heart. The purpose of this study is to predict the quality of anastomosis using transit-time flow measurement and to find out the most accurate indicator. Eight swine underwent internal thoracic-anterior descending coronary artery bypass grafting on a beating heart. Flow measurement and angiography were performed at various degrees of stenosis created on the graft. As flow parameters, total flow, systolic flow, diastolic flow, diastolic/total flow ratio, systolic peak flow, diastolic peak flow, systolic/diastolic peak flow index, and pulsatility index were used. Mixed procedure and probability test (negative means successful anastomosis) were used to analyze the diagnostic ability. Diastolic flow, diastolic/total flow ratio, diastolic peak flow, systolic/diastolic peak flow index, and pulsatility index showed significant variance with increased stenosis. Among these measures, diastolic/total flow ratio showed the highest value of area under the curve (0.91) and the highest specificity (82%) at 90% sensitivity with actual value of 42%. Diastolic/total flow ratio was the most reliable indicator to predict critical stenosis in coronary artery bypass grafting.


Comparison of in-vitro production of progestagens by the corpora lutea of early pregnancy of the rat and hamster.
Immature rats and adult hamsters were killed on Days 2, 4 or 8 of pregnancy (Day 1 = sperm positive vaginal smear). Dispersed luteal cells (5 X 10(4) cells) were incubated for 2 h in the absence or presence of graded doses of ovine LH. In the absence of LH, incubation of rat luteal cells compared to hamster cells produced about 3-6-fold as much progesterone, 26-66 times as much 20 alpha-dihydroprogesterone and about the same amounts of 17 alpha-hydroxyprogesterone. For the rat, 1 ng LH was the minimal dose which stimulated synthesis of progesterone and 17 alpha-hydroxyprogesterone by luteal cells on Days 2 and 4 whereas 10 ng LH stimulated maximal production of progesterone by Day-8 luteal cells. As pregnancy progressed from Day 2 to Day 8, there was an inverse relationship between the levels of progesterone and 20 alpha-dihydroprogesterone accumulated by rat luteal cells. For the hamster, 1 ng LH significantly stimulated accumulation of progesterone and 17 alpha-hydroxyprogesterone by Day-2 luteal cells but not by Day-4 or Day-8 cells. Hamster luteal cells on Day 4 produced the highest levels of progesterone in response to 10 or 100 ng LH, with a maximal rate of accumulation by Day-8 cells with 10 ng LH.


Identification and validation of reference genes for qRT-PCR analysis in mulberry (Morus alba L.).
Mulberry (Morus alba L.) is an important economic tree species in many countries. Quantitative real time PCR (qRT-PCR) has become a widely used method for gene expression studies in plants. A suitable reference gene is essential to ensure accurate and reliable results for qRT-PCR analyses. However, no reports describing the selection of reference genes have been published for mulberry. In this work, we evaluated the stability of twenty candidate reference genes in different plant tissues and under different stress conditions by qRT-PCR in mulberry using algorithms in two programs-geNorm and NormFinder. The results revealed that TUB2, UBI4, ACTIN3 and RPL4 were ranked as the most stable reference genes in the samples subsets, whereas EF1α4 and TUB3showed the least stability with both algorithms. To further validate the stability of the reference genes, the expression patterns of six genes of mulberry were analyzed by normalization with the selected reference genes. Our study will benefit future analyses of gene expression in mulberry.


Age-related differences in head impact exposure of 9-13 year old football players.
While more than two-thirds of football players are under the age of 14, little biomechanics research has been conducted to quantify head impact exposure for players in this age range. The objective of this study was to quantify head impact exposure and the influence of age for 9-13 year old football players. Kinematic data from over 4400 head impacts were collected from 25 youth football players on two teams for one season using in-helmet accelerometers. The 50th and 95th percentile magnitudes for linear and rotational head acceleration and the number of impacts sustained were determined for each player. Comparisons were made for each metric by team and by player age. Players on the 9-11 year old team sustained an average of 154 ± 126 impacts with a 95th percentile linear acceleration magnitude of 40 g. On the 10 to 13 year old team, players sustained an average of 193 ± 158 impacts with a 95th percentile linear acceleration magnitude of 47 g. Players on the older team sustained slightly more and higher magnitude impacts than those on the younger team. These differences in head impact exposure were not significant due to large variation between players within each team.


Radiotherapy for stage I and II testicular seminomas: Secondary malignancies and survival.
Testicular seminoma affects relatively young men with excellent survival outcomes. There has been increasing concern that radiotherapy (RT) leads to secondary malignant neoplasms (SMNs) and subsequent mortality. We evaluated the effect of RT on incidence of SMNs and quantified cancer-related mortality and other causes of death for patients with stage I and II testicular seminoma. A national sample of men (1988-2013) diagnosed with stage IA/IB/IS/IIA/IIB/IIC testicular seminomas from Surveillance, Epidemiology, and End Results were evaluated. Use of RT over time and survival curves (5/10/15-year) was stratified by stage. Log-binomial regression determined relative risk of developing SMNs. Incidence rate ratios (IRR) and age-adjusted Cox proportional hazards models compared overall, cancer-specific survival (CSS), and other cancer-specific survival. Competing-risks regression generated cumulative incidence functions. Prevalence ratios explored excess deaths owing to specific causes. A total of 16,463 men were included with 9,126 (55.4%) undergoing RT with markedly decreased use for stage I seminoma in recent years (<20%) and ~50% for stage IIA. RT increased risk of SMNs (relative risk = 1.84 [95% CI: 1.61-2.10, P<0.01]). Survival rates were excellent (15-year CSS for stage I [≥99%], stage IIA [98.1%], stage IIB-C [96%-97%]). RT was associated with improved CSS for stage IB and IIA, but demonstrated less benefit for stage IA (IRR = 0.63 [95% CI: 0.35-1.14, P = 0.10]) with worse other cancer-specific survival (IRR = 1.80 [95% CI: 0.97-3.59, P = 0.05]). Gastrointestinal, respiratory, urinary, and hematologic malignances accounted for 84% of SMN deaths. RT offers excellent CSS for men with stage I/II seminoma and an increased risk of SMN later in life. Future studies should better evaluate risk-stratification for stage IB patients.


Effects of penicillin G on local metabolic changes in skeletal muscle following high velocity missile injury.
The effect of systemic penicillin G treatment on the local tissue damage 12 h after a high velocity missile injury in skeletal muscle has been studied in pigs (n = 13). Blood pressure, rectal temperature, hemoglobin concentrations, hematocrits, blood gases and acid base balances were followed and the tissue levels of ATP, creatine phosphate, glucose-6-phosphate, glucose and lactate were determined in control skeletal muscle as well as in muscle samples taken from the wound area. After 12 h all devitalized tissue was debrided and weighed. Penicillin G treatment slightly diminished the local tissue metabolic deterioration and significantly reduced the amount of debrided tissue as compared to untreated animals. It may be concluded that early treatment with penicillin G will considerably diminish the local tissue damage during the first 12-hour period following a high velocity missile injury.


Continuum electrostatic model for the binding of cytochrome c2 to the photosynthetic reaction center from Rhodobacter sphaeroides.
Electrostatic interactions are important for protein-protein association. In this study, we examined the electrostatic interactions between two proteins, cytochrome c(2) (cyt c(2)) and the reaction center (RC) from the photosynthetic bacterium Rhodobacter sphaeroides, that function in intermolecular electron transfer in photosynthesis. Electrostatic contributions to the binding energy for the cyt c(2)-RC complex were calculated using continuum electrostatic methods based on the recent cocrystal structure [Axelrod, H. L., et al. (2002) J. Mol. Biol. 319, 501-515]. Calculated changes in binding energy due to mutations of charged interface residues agreed with experimental results for a protein dielectric constant epsilon(in) of 10. However, the electrostatic contribution to the binding energy for the complex was close to zero due to unfavorable desolvation energies that compensate for the favorable Coulomb attraction. The electrostatic energy calculated as a function of displacement of the cyt c(2) from the bound position showed a shallow minimum at a position near but displaced from the cocrystal configuration. These results show that although electrostatic steering is present, other short-range interactions must be present to contribute to the binding energy and to determine the structure of the complex. Calculations made to model the experimental data on association rates indicate a solvent-separated transition state for binding in which the cyt c(2) is displaced approximately 8 A above its position in the bound complex. These results are consistent with a two-step model for protein association: electrostatic docking of the cyt c(2) followed by desolvation to form short-range van der Waals contacts for rapid electron transfer.


Enzymatic Production and Characterization of Pectic Oligosaccharides Derived from Citrus and Apple Pectins: A GC-MS Study Using Random Forests and Association Rule Learning.
Pectic oligosaccharides (POS) from citrus and apple pectin hydrolysis using ViscozymeL and Glucanex200G have been obtained. According to the results, maximum POS formation was achieved from citrus pectin after 30 min of hydrolysis with ViscozymeL, with a yield of 652 mg g-1 and average molecular mass ( Mw) of 0.8-2.5 kDa, while with Glucanex200G, the yield was 518 mg g-1 and Mw was 0.8-7.1 kDa. Digalacturonic and trigalacturonic acids were identified among other low Mw compounds as di- and tri-POS. In addition, differences in GC-MS spectra of all oligosaccharides found in the hydrolysates were studied by employing random forests and other algorithms to identify structural differences between the obtained POS, and high prediction rates were shown for new samples. Chemical structures were proposed for some influential m/ z ions, and 12 association rules that explain differences according to pectin and enzyme origin were built. This information could be used to establish structure-function relationships of POS.


Visualization of specific antibody and C1q binding to hapten-sensitized lipid vesicles.
Specific IgG antibodies directed against the spin-label nitroxide group present as a lipid hapten in single-compartment lipid vesicles have been visualized by using freeze-etch electron microscopy. Individual "particles" with diameters of the order of 20 nm are identified as single IgG molecules bound to lipid hapten. No significant aggregation of these IgG molecules was observed over a period of 1 hr in a dipalmitoyl phosphatidylcholine vesicle at 22 degrees. Binding of the human complement component C1q results in the formation of large (approximately 50-100 nm) asymmetric particles having a partially resolved substructure that may arise from individual IgG molecules bound to the membranes as well as to C1q. The binding of C1q appears to result in a clustering of membrane-bound IgG molecules. Samples containing a serum factor (perhaps anti-IgG antibodies) exhibit some IgG clustering distinct from that produced by Clq.


Emergent roles for intercellular adhesion molecule-1 in the restructuring of the blood-testis barrier during spermatogenesis in the mammal.
Mammalian spermatogenesis is comprised of a series of molecular, cellular, and morphological events that underscore the movement of developing germ cells across the blood-testis barrier. These events involve the restructuring of tight junctions, basal ectoplasmic specializations, gap junctions, and desmosomes, which constitute blood-testis barrier function. Previous studies show that preleptotene/leptotene spermatocytes traverse the blood-testis barrier while transiently trapped within an intermediate compartment, which sequesters primary spermatocytes away from basal and adluminal compartments of the seminiferous epithelium. Preleptotene/leptotene spermatocytes enter the adluminal compartment when stable junctions ahead of spermatocytes disassemble, while new junctions assemble behind them. While there is enormous restructuring of the seminiferous epithelium, the mechanism of germ cell movement is incompletely understood. In this perspective, the significance of intercellular adhesion molecule-1 in the restructuring of the blood-testis barrier during spermatogenesis in the mammal is discussed.


Effects of a Statewide Tobacco Cessation Program Among Individuals Involved With Arkansas Community Correction.
In response to a critical need for tobacco cessation services among justice-involved populations, Arkansas Community Correction (ACC) partnered with the University of Colorado's Behavioral Health & Wellness Program in 2013 to implement the DIMENSIONS: Tobacco Free Program within all probation, parole, and drug court units. In the first 2 years of this statewide, evidence-based program, more than 1,100 individuals from 33 ACC area office locations attended tobacco-free group sessions and provided data on tobacco use and readiness to quit. Results demonstrated a significant reduction in tobacco use among participants as well as increased knowledge, confidence, and intent to quit. This study provides some of the first evidence that members of this vulnerable population will attend tobacco-free group sessions with regularity and make progress toward tobacco cessation.


Imaging of Pericardial Diseases.
Given the widespread use of cross-sectional imaging modalities, specifically multidetector computed tomography and magnetic resonance, to evaluate thoracic disease, the pericardium is frequently imaged. Knowledge of the normal appearance and anatomical boundaries is vital for radiologists to avoid confusion with more sinister pathology. A variety of disorders and diseases of the pericardium can bring a patient to clinical attention from inflammatory conditions, resulting in pericarditis and pericardial effusion, to malignancy. This article discusses the anatomy and conditions that affect the pericardium, emphasizing the role imaging plays in diagnosis and management.


Efficient and automated quantum chemical calculation of rovibrational nonresonant Raman spectra.
An outline of a newly developed program for the simulation of rovibrational nonresonant Raman spectra is presented. This program is an extension of our recently developed code for rovibrational infrared spectra [Erfort et al., J. Chem Phys. 152, 244104 (2020)] and relies on vibrational wavefunctions from variational configuration interaction theory to allow for an almost fully automated calculation of such spectra in a pure ab initio fashion. Due to efficient contraction schemes, this program requires modest computational resources, and it can be controlled by only a few lines of input. As the required polarizability surfaces are also computed in an automated fashion, this implementation enables the routine application to small molecules. For demonstrating its capabilities, benchmark calculations for water H2 16O are compared to reference data, and spectra for the beryllium dihydride dimer, Be2H4 (D2h), are predicted. The inversion symmetry of the D2h systems lead to complementary infrared and Raman spectra, which are both needed for a comprehensive investigation of this system.


Investigation of Entropy Production with Thermal Analysis under Soret and Dufour Effects in MHD Flow between Convergent and Divergent Channels.
Hydromagnetic flow and heat transport have sustainable importance in conventional system design along with high-performance thermal equipment and geothermal energy structures. The current computational study investigates the energy transport and entropy production due to the pressure-driven flow of non-Newtonian fluid filled inside the wedge-shaped channel. The nonlinear radiation flux and uniform magnetic field are incorporated into the flow analysis. To be more precise, non-Newtonian fluid initiates from an inlet with the bound of the parabolic profile and leaves at outlet of a convergent/divergent channel. We assume that the channel flow is adiabatic and influenced by the wall friction. The leading flow equations are modeled via the Carreau fluid model using fundamental conservation laws. The thermodynamical aspect of the system is visualized using a two-phase model and analyses of the entropy equation due to fluid friction, ohmic heating, and diffusion of heat and mass fluxes. The modeled system of equations is normalized using a dimensionless variable mechanism. The system was elevated for the significant variation of controlling parameters. The outcomes obtained from the computational investigation are validated with the theoretical results that are available in the literature. An increasing semivertex angle and Reynolds number increase the converging channel flow. In the core flow zone, an increase in the divergent semiangle causes the flow to decelerate, while near and at the channel wall it causes a slight acceleration. Outcomes designate that the main contribution to the irreversibility is due to ohmic loss, frictional loss, and heat loss. The thermal performance and entropy production is dominant for a diverging flow. The outcomes of this research will assist in comprehending the process of entropy minimization in conjunction with the flow of nanomaterials in a nonuniform channel, which is essential in engineering processes such as the creation of micro machines, supersonic Jets, nozzles, and clean energy.


The management of coronavirus disease 2019 (COVID-19).
In December 2019, a novel coronavirus causing severe acute respiratory disease occurred in Wuhan, China. It is an emerging infectious disease with widespread and rapid infectiousness. The World Health Organization declared the coronavirus outbreak to be a public health emergency of international concern on 31 January 2020. Severe COVID-19 patients should be managed and treated in a critical care unit. Performing a chest X-ray/CT can judge the severity of the disease. The management of COVID-19 patients includes epidemiological risk and patient isolation; treatment entails general supportive care, respiratory support, symptomatic treatment, nutritional support, psychological intervention, etc. The prognosis of the patients depends upon the severity of the disease, the patient's age, the underlying diseases of the patients, and the patient's overall medical condition. The management of COVID-19 should focus on early diagnosis, immediate isolation, general and optimized supportive care, and infection prevention and control.


Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with an overall survival rate of less than 5%. The poor patient outcome in PDAC is largely due to the high prevalence of systemic metastasis at the time of diagnosis and lack of effective therapeutics that target disseminated cells. The fact that the underlying mechanisms driving PDAC cell migration and dissemination are poorly understood have hindered drug development and compounded the lack of clinical success in this disease. Recent evidence indicates that mutational activation of K-Ras up-regulates eIF5A, a component of the cellular translational machinery that is critical for PDAC progression. However, the role of eIF5A in PDAC cell migration and metastasis has not been investigated. We report here that pharmacological inhibition or genetic knockdown of eIF5A reduces PDAC cell migration, invasion, and metastasis in vitro and in vivo. Proteomic profiling and bioinformatic analyses revealed that eIF5A controls an integrated network of cytoskeleton-regulatory proteins involved in cell migration. Functional interrogation of this network uncovered a critical RhoA/ROCK signaling node that operates downstream of eIF5A in invasive PDAC cells. Importantly, eIF5A mediates PDAC cell migration and invasion by modulating RhoA/ROCK protein expression levels. Together our findings implicate eIF5A as a cytoskeletal rheostat controlling RhoA/ROCK protein expression during PDAC cell migration and metastasis. Our findings also implicate the eIF5A/RhoA/ROCK module as a potential new therapeutic target to treat metastatic PDAC cells.


Assessing Bone Marrow Activity in Patients with Myelofibrosis: Results of a Pilot Study of 18F-FLT PET.
An emerging noninvasive approach to assess tissue proliferation uses the PET tracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT). To evaluate the diagnostic value of this technique in myelofibrosis, 18F-FLT PET imaging results were compared with bone marrow histology and bone marrow scintigraphy (BMS), the gold standard techniques in this clinical situation. Methods: Fifteen patients with histology-proven myelofibrosis were included consecutively in the study. Tracers' distributions were assessed using a visual grading assessment score of the uptake in the axial skeleton, proximal and distal limbs, liver, and spleen. This visual score was used to define patterns of tracer distribution and to compare the information provided either by PET or by BMS. A semiquantitative analysis with determination of SUVmax in the same localizations was performed for 18F-FLT PET. Results: The histology grade of fibrosis correlated with the SUVmax in the axial skeleton (spine and iliac crests) and proximal limbs. 18F-FLT uptake in these areas was much lower in patients with grade 3 fibrosis than in patients with grade 1 or 2 fibrosis. 18F-FLT PET showed the same distribution of uptake as BMS in 13 of 14 patients (1 patient did not undergo BMS). In 1 patient, 18F-FLT PET clearly showed an intense abnormal splenic uptake, whereas spleen uptake was inconclusive with BMS. Conclusion:18F-FLT PET appears to be a reliable and convenient technique to assess hematopoietic activity in bone marrow. It yields results close to those observed with BMS. In our study population, 18F-FLT uptake in the axial skeleton and proximal limbs assessed by SUVmax correlated with the grade of fibrosis. Thus, 18F-FLT PET may be a useful tool to measure the severity of myelofibrosis, and to monitor noninvasively the patients' status during follow-up. Finally, 18F-FLT PET may be foreseen as an alternative to BMS.


Synthesis and Biological Evaluation of Ginsenoside Compound K Derivatives as a Novel Class of LXRα Activator.
Compound K is one of the active metabolites of Panaxnotoginseng saponins, which could attenuate the formation of atherosclerosis in mice modelsvia activating LXRα. We synthesized and evaluated a series of ginsenoside compound K derivatives modified with short chain fatty acids. All of the structures of this class of ginsenoside compound K derivative exhibited comparable or better biological activity than ginsenoside compound K. Especially structure 1 exhibited the best potency (cholesteryl ester content: 41.51%; expression of ABCA1 mRNA: 319%) and low cytotoxicity.


Staging and treatment of osteoblastoma in the mobile spine: a review of 51 cases.
To define the role of Enneking staging system and of the consequent different treatment options on the outcome of osteoblastoma (OBL) of the spine. A retrospective review of 51 patients with OBL of the mobile spine conducted to compare the outcomes among the different types of treatments at long term follow-up (25-229 months, av.90). These 51 patients were previously staged according to Enneking staging system and treatment selected accordingly. 10 stage two (st.2) OBLs were treated with intralesional excision and 41 stage three (st.3) OBLs were treated either by intralesional excision or en bloc resection. The intralesional excision group was divided considering the use or not of radiation therapy after surgery. The recurrence rate was compared among these groups and also considering previous open surgery ("non intact" vs. "intact"). The statistical significance was defined using the Fisher Exact test. No local recurrence occurred in the st.2 patients treated by intralesional excision. Considering the st.3 patients, 2 local recurrences out of 13 patients occurred in the en bloc resection (15.4 %) group. All occurred in "non intact" cases (67 %). In the intralesional group, 5 local recurrences out of 27 patients occurred (18 %) being none in the group that received radiation therapy after surgery. Two occurred in the "intact" (7 %) and three in the "non intact" group (75 %). Considering all patients, the difference between the recurrence rate between "intact" and "non intact" groups was statistically significant (p < 0.002). Intralesional excision proved to be effective in st.2 lesions and en bloc resection in st.3. Radiotherapy seems to be an effective adjuvant treatment when en bloc resection is not feasible or requires unacceptable functional sacrifices. The first treatment significantly affects the prognosis as previously treated patients have worse prognosis.


Short-term oral administration of polybrominated biphenyls enhances the development of hepatic enzyme-altered foci in initiated rats.
FireMaster BP-6 (FM), a commercial mixture of polybrominated biphenyls (PBB), has been shown to act as a tumor promoter in hepatocarcinogenesis assays in rats. Most hepatic tumor promoters must be administered for many weeks or months. Because FM is highly persistent in animal tissues, it was hypothesized that very short-term administration of FM would result in tumor promotion. Female Sprague-Dawley rats weighing 185-215 g were initiated by a two-thirds partial hepatectomy followed by 10 mg diethylnitrosamine/kg body weight (BW) 24 h later. Thirty days later, rats were gavaged with FM in corn oil, at total doses of 0, 13, or 130 mg FM/kg BW. Half the dose was given on d 30, and the remaining half was given 24 h later. At 120 d after gavage the rats were killed and necropsied. Five liver sections from each animal were histochemically stained for gamma-glutamyl transpeptidase-positive enzyme-altered foci (EAF). EAF were significantly increased over control values in initiated rats given 130 mg FM/kg. In animals given 13 mg FM/kg, EAF were increased to a lesser extent but not significantly above controls. Enhancement of these EAF in initiated rats reflects tumor-promoting activity. In this study, 24-h administration of FM in initiated rats was sufficient to enhance hepatic EAF measured 120 d later in an rats was sufficient to enhance hepatic EAF measured 120 d later in an initiation-promotion protocol, and a dose of 13 mg FM/kg was apparently close to a possible no-effect threshold level for enhancement of EAF.


A cheat sheet to navigate the complex maze of pharmaceutical exclusivities in Europe.
As the two leading markets for pharmaceutical and biotech companies, the USA and Europe offer incentives to stimulate drug innovation, including patent and regulatory exclusivities. These exclusivities extend periods during which companies can market their products free of generic or other competition and recoup their investment. Pharmaceutical and biotech companies should carefully assess the different types of exclusivities available when developing regulatory submissions, patent filing strategies. The authors have previously summarized the USA exclusivities in an earlier publication. This article focuses on European exclusivities. Due to space limitations, it focuses on small molecule drugs. Analogously to the format previously used, we have provided a cheat sheet of European exclusivities for small molecule drugs in Figure 1 .


Assessing behavioral health using OASIS: part 2: cognitive impairment, problematic behaviors, and anxiety.
This article is the second of a two-part series on assessing behavioral health in adult and elderly home care patients using OASIS. Part 1 presented an assessment approach for depressive symptoms and suicidality. This article presents the assessment of cognitive impairment, problematic behaviors, and anxiety using OASIS as a framework and stresses the importance of direct questioning. Case scenarios and guidelines for referral for further evaluation and possible treatment are provided.


Calcium dependency and free calcium concentrations during insulin secretion in a hamster beta cell line.
Using a glucose-responsive beta cell line, we tested the hypothesis that the free cytosolic Ca2+ concentration ([Ca2+]i) is the primary signal that couples a stimulus to insulin secretion, and examined the involvement of the extracellular Ca2+ pool in this process. Glucose or depolarization of the beta cell with 40 mM K+ stimulated a monophasic release of insulin directly proportional to the extracellular Ca2+ concentration. 40 mM K+ increased 45Ca2+ uptake and increased [Ca2+]i, which was measured with quin 2, 4.7-fold, from 56 +/- 3 to 238 +/- 17 nM. With high glucose, 45Ca2+ uptake did not increase, and [Ca2+]i was unchanged or fell slightly. There was a striking correlation between inhibitory effects of verapamil, the Ca2+ channel blocker, on insulin secretion and the rise in [Ca2+]i evoked by K+. Higher concentrations of verapamil were required to inhibit glucose- than K+-stimulated insulin secretion (dose giving half-maximal effect of 1.4 X 10(-4) M vs. 6.0 X 10(-7) M). Incubation in Ca2+-free, 1 mM EGTA buffer for 30 min lowered [Ca2+]i to 14 +/- 2 nM, and inhibited acute insulin release to both secretagogues. If high glucose was present in the Ca2+-free period, reintroduction of 2.5 mM Ca2+ in high glucose restored insulin secretion only to the basal rate. However, if low glucose was present during the Ca2+-free period, high glucose and 2.5 mM Ca2+ triggered a full first-phase insulin response. These data suggest that high glucose generates a non-Ca2+ signal that turns over rapidly and provide direct evidence that K+ triggers insulin release by drawing extracellular Ca2+ into the beta cell through verapamil-sensitive Ca2+ channels. However, an increase [Ca2+]i is not the primary signal that evokes glucose-stimulated insulin release in this beta cell line.


Major vault protein in cardiac and smooth muscle.
Major vault protein (MVP) is the major component of the vault particle whose functions are not well understood. One proposed function of the vault is to serve as a mechanism of drug transport, which confers drug resistance in cancer cells. We show that MVP can be found in cardiac and smooth muscle. In human airway smooth muscle cells, knocking down MVP was found to cause cell death, suggesting that MVP serves as a cell survival factor. Further, our laboratory found that MVP is S-glutathionylated in response to ligand/receptor-mediated cell signaling. The S-glutathionylation of MVP appears to regulate protein-protein interactions between MVP and a protein called myosin heavy chain 9 (MYH9). Through MYH9 and Vsp34, MVP may form a complex with Beclin-1 that regulates autophagic cell death. In pulmonary vascular smooth muscle, proteasome inhibition promotes the ubiquitination of MVP, which may function as a mechanism of proteasome inhibition-mediated cell death. Investigating the functions and the regulatory mechanisms of MVP and vault particles is an exciting new area of research in cardiovascular/pulmonary pathophysiology.


Preferential usage of T-cell receptor V beta 17 by dengue virus-specific human T lymphocytes in a donor with immunity to dengue virus type 4.
In order to better understand human T-cell responses to dengue viruses (DV), we analyzed T-cell receptor (TCR) V beta gene usage in DV-specific T lymphocytes. Peripheral blood T lymphocytes from a DV type 4 immune donor were stimulated in vitro with DV type 4 antigen, and TCR usage was examined by reverse transcriptase PCR. TCR V beta 17 was preferentially used (P = 0.020) among T cells stimulated by DV type 4 in bulk culture. Furthermore, 8 of 19 DV type 4-specific CD4+ T-cell clones established from the peripheral blood mononuclear cells expressed V beta 17 (P = 0.008). Preferential usage of TCR V alpha was not found among T cells expressing V beta 17. These results indicate that there is preferential usage of TCR V beta 17 among DV-specific T cells in this donor and suggest that T cells with certain TCRs may be important in immune responses to DV.


Specific receptor-mediated stimulation of progesterone secretion and cGMP accumulation by rat atrial natriuretic factor in cultured human granulosa-lutein (G-L) cells.
The effect of rat atrial natriuretic factor (ANFIV102-126) on the regulation of steroidogenesis in human G-L cells have been studied in vitro. The treatment of cells with ANF (1 X 10(-8)M) resulted in a 3- to 4-fold increase in progesterone secretion compared to the controls. ANF in combination with LH (200 ng/ml) increased progesterone secretion more than six-fold over controls. Concomitantly, ANF stimulated the accumulation of cGMP 30-fold, whereas the level of cAMP was either unchanged or fell slightly (10-15%). Mono[125I]-iodo-ANF bound to G-L cell surface specific receptors with a Kd of 1.8 X 10(-10)M at a density (Bmax) of 160,000-190,000 sites/cell. The binding of [125I]-iodo-ANF was competed by unlabeled ANF in a dose-dependent manner, and hormones unrelated to ANF, such as angiotensins, ACTH or LH, were unable to compete with [125I]-iodo-ANF. The results indicate that ANF can stimulate progesterone secretion and cGMP accumulation in ovarian G-L cells without affecting the level of cAMP and that the stimulatory effects of ANF on G-L cell steroidogenesis may proceed via mechanism(s) involving an intracellular messenger other than cAMP.


Comparison of three different COVID-19 vaccine platforms (CoronaVac, BTN162b2, and Ad5-nCoV) in individuals with and without prior COVID-19: Reactogenicity and neutralizing antibodies.
Neutralizing antibodies (NAbs) can be indicators of collective immunity, vaccine efficacy, and the longevity of the humoral response. This study aimed to compare reactogenicity and NAbs generated by three different COVID-19 vaccine platforms in individuals with and without prior COVID-19. 336 individuals vaccinated (112 with CoronaVac [inactivated virus], 112 with BNT162b2 [messenger RNA], and 112 with Ad5-nCoV [non-replicating viral vector]) were included. NAbs were quantified with the cPass SARS-CoV-2 kit. Individuals immunized with the Ad5-nCoV showed higher reactogenicity than those immunized with the other vaccines (p < 0.001). The BTN162b2 vaccine-induced NAbs with higher inhibition capacity than the other platforms in the first dose. In individuals without prior COVID-19, the Ad5-nCoV vaccine generated lower NAbs against SARS-CoV-2 than those induced by two doses of the BTN162b2 (Ad5-nCoV 72.10 [55.6-93.4] vs. BTN162b2 98.41 [98.16-98.56], p < 0.0001). One individual did not generate NAbs (0.89%) after a complete immunization with CoronaVac; in BTN162b2, all generated these antibodies, and in the Ad5-nCoV group, four individuals (3.57%) did not generate NAbs. Comorbidities, gender, age, and reactogenicity did not significantly influence the generation of NAbs (p > 0.05); however, a history of COVID-19 before vaccination was associated with antibodies with greater neutralizing capacity after the first dose (p < 0.01). In conclusion, the mRNA vaccine (BTN162b2) had a remarkable better ability to produce NAbs and lower reactogenicity than the other platforms, whereas the Ad5-nCov vaccine induced the lowest NAbs response in individuals without a history of COVID-19; therefore, we suggest that a booster could benefit these individuals.


Effect of early use of low-dose aspirin therapy on late-onset preeclampsia.
Low-dose aspirin (LDA) therapy has been found to be effective in preventing the development of early-onset preeclampsia. However, its effect on late-onset preeclampsia has not been described. Our study was aimed at determining if LDA therapy prescribed from early in pregnancy modified the severity of late-onset preeclampsia. A retrospective analysis of all women who were screened for early-onset preeclampsia at 11-13+6 weeks' gestation between April 2012 and October 2014 at our institution, and who subsequently developed late-onset preeclampsia. The treatment group consisted of women who were prescribed LDA therapy from early in pregnancy as a result of the screening. The control group consisted of women who did not receive LDA therapy. The aspirin group was associated with earlier delivery at 38.0 (37.5-38.5) weeks' gestation versus 39.0 (38.7-39.4) weeks' gestation for the nonaspirin group (p < .01). The aspirin group was also associated with lower absolute birth weight 2851 (2646-3055) versus 3215 (3068-3362) grams in the nonaspirin group (p < .01). However, when normalised for gestational age at delivery, the proportion of foetuses that were small for gestation age (< 10th centile) were not significantly different between the two groups [28% in aspirin group versus 23% in nonaspirin group; p = .62]. No other significant difference was noted. There was no difference in the clinical severity of late-onset preeclampsia between women screened as high risk for early-onset preeclampsia and subsequently prescribed LDA during their pregnancy, compared to women found to be at low risk and not prescribed LDA.


Spontaneous splenic rupture in an acute leukemia patient with splenic tuberculosis: A case report.
Spontaneous splenic rupture, also referred to as atraumatic splenic rupture, is a rare but life-threatening emergency condition. Without timely diagnosis and treatment, the mortality rate of splenic rupture approaches 100%. The etiology of atraumatic splenic rupture varies; it is reportedly associated with neoplasms or splenic infection, but is rarely encountered in patients with both conditions. We herein report the case of a 58-year-old male patient with acute myeloid leukemia (AML) complicated by splenic tuberculosis (TB), who presented with spontaneous rupture of the spleen. Pathological examination of the resected spleen revealed multifocal granulomatosis with caseous necrosis. However, with timely diagnosis and surgical intervention, the patient recovered successfully and is currently on consolidation therapy. To the best of our knowledge, this is the first case of spontaneous splenic rupture in AML with splenic TB. The relevant literature on spontaneous splenic rupture was also reviewed and the potential etiology and treatment were discussed.


Acetylation of NDPK-D Regulates Its Subcellular Localization and Cell Survival.
Nucleoside diphosphate kinases (NDPK) are ubiquitous enzymes that catalyze the reversible phosphotransfer of γ-phosphates between di- and triphosphonucleosides. NDPK-D (Nm23-H4) is the only member of the NDPK family with a mitochondrial targeting sequence. Despite the high expression of NDPK-D in the developing central nervous system, its function remains to be determined. In this study, we show that NDPK-D knockdown induces apoptosis in neuroblastoma cells as well as in mouse cortex, suggesting that NDPK-D is required for neuronal survival. We identified NDPK-D as a binding partner of NAD+-dependent histone deacetylase, SIRT1, by yeast two-hybrid screening. NDPK-D co-localized with SIRT1, and the association of these molecules was confirmed by co-immunoprecipitation. Inhibition of SIRT1 increases the acetylation of NDPK-D. Overexpression of NDPK-D along with SIRT1, or mutation in the acetylated lysine residues in NDPK-D, increases its nuclear accumulation. Furthermore, the NDPK-D acetylation-mimic mutant increased apoptosis in N1E-115 cells. Our data demonstrate that acetylation regulates the shuttling of NDPK-D between nucleus and cytoplasm, and increased acetylation of NDPK-D causes apoptosis.


Role of contrast-enhanced color Doppler ultrasonography and dynamic flow in the evaluation of hepatic tumors treated with radiofrequency.
The contribution of contrast-enhanced color Doppler ultrasonography (CDUS) and dynamic flow (DF) (Toshiba) in the evaluation following treatment of hepatic tumors with radiofrequency (RF) is discussed. Twenty-seven patients with 34 hepatic tumors were included in this prospective study. The treated tumors measured 10-58 mm in diameter (mean diameter 29 mm). Two tumors were treated twice and one three times, comprising a total of 38 target lesions treated with RF and evaluated by 127 contrast-enhanced CDUS. The results of CDUS follow-up were compared to those of the dynamic MRI at 2 months, 4 months, 6 months and 1 year. Before RF, the injection of Levovist raised the number of vascularized lesions seen with unenhanced Doppler from 44% to 79%. All the non-vascularized lesions were metastases. Twenty-four hours after RF, four tumors presented an enhancement with Levovist, in which two were insufficiently treated lesions. Twenty-one treated tumors have been followed-up jointly by CDUS and MRI at the same time at 2 months, 20 at 4 months, 12 at 6 months and nine at 1 year. Compared to the MRI and the evolution, the CDUS presented a sensitivity of 100% and a specificity of 90% for the detection of progressive recurrence. The preliminary results show that the CDUS is useful to confirm the absence of detectable vascularity after treatment with RF ablation, whereas the presence of enhancement must be confirmed by MRI.


[Research progress on chemical constituents and pharmacological activities of Potentilla].
There are 200-500 species of Potentilla(Rosaceae) worldwide, among which 90 species are widely distributed in China and have a long history of ethnic medicinal use. According to our statistics, a total of 367 compounds have been isolated and identified from plants of this genus, including terpenoids, flavonoids, phenolic acids, tannins, and phenylpropanoids. The medicinal materials made from these plants mainly have antioxidative, blood sugar-lowering, anti-inflammatory, anti-tumor, cardiovascular system-protecting, neuroprotective, and hepatoprotective activities. This study systematically reviews the research progress on chemical constituents and pharmacological activities of Potentilla plants to provide a basis for further research and clinical application.


Molecular cloning and differential expression of three GnRH genes during ovarian maturation of spotted halibut, Verasper variegatus.
In this study, the gonadotropin-releasing hormone (GnRH) genes in spotted halibut were cloned and sequenced by isolating their cDNAs. The species expressed three molecular forms of GnRH in the brain: chicken-type GnRH-II (cGnRH-II), seabream-type GnRH (sbGnRH), and salmon-type GnRH (sGnRH). Phylogenetic analysis divided the molecular forms of GnRHs into three branches: cGnRH-II branch, sGnRH branch, and fish-specific GnRH branch. The spatial expression showed that they had the highest expression levels in the brain. cGnRH-II was exclusively detected in the brain, while sbGnRH had a global expression pattern in all examined organs. sGnRH was detected in the brain, pituitary, and ovary. The temporal changes of brain GnRH mRNA expression levels were examined during ovarian maturation and postspawning, and the serum steroid hormones and gonadosomatic index (GSI) were recorded. Amounts of sbGnRH mRNA substantially elevated (P < 0.05) during ovarian maturation, which concomitant with considerable elevation of GSI and serum steroids levels. On the contrary, neither sGnRH nor cGnRH-II mRNA levels showed significant changes during ovarian maturation in this study. These results suggested that these three GnRH genes are the important regulators for the differential expression of GnRH in spotted halibut, and would help us better understand the reproductive endocrine mechanism of spotted halibut.


"Agriculture at risk: A report to the nation"--a historical review, critical analysis, and implications for future planning.
"Agricultural at Risk: A Report to the Nation" is a proceedings document of a three-year (1987-1990) policy development process entitled "Agricultural Occupational and Environmental Health: Policy Strategies for the Future." That process culminated in the emergence of occupational health and safety in agriculture as a public health policy issue in the U.S. Several agricultural health and safety programs evolved as direct or indirect consequences of this process, including, but not limited to, the NIOSH agricultural occupational health programs, The Kellogg Foundation agricultural health grants programs, and the prospective chronic health studies of pesticides (EPA-NlH funded). The Agriculture at Risk report resulted in 86 specific recommendations. The authors of this article reviewed each of these recommendations and rated them on a subjective scale as to their degree of attainment. They found that 44% of the recommendations had received moderate to substantial action. Most of the positive action was in the areas of research and coalition building. A noticeable lack of action was in the areas of standards and regulation, occupational health service delivery, and education categories. This article concludes with an analysis of the limitations of the AAR report, changes in exposed populations over the past decade, and specific recommendations on future actions to address the issues.


Comparison of prostate set-up accuracy and margins with off-line bony anatomy corrections and online implanted fiducial-based corrections.
The aim of the study was to determine prostate set-up accuracy and set-up margins with off-line bony anatomy-based imaging protocols, compared with online implanted fiducial marker-based imaging with daily corrections. Eleven patients were treated with implanted prostate fiducial markers and online set-up corrections. Pretreatment orthogonal electronic portal images were acquired to determine couch shifts and verification images were acquired during treatment to measure residual set-up error. The prostate set-up errors that would result from skin marker set-up, off-line bony anatomy-based protocols and online fiducial marker-based corrections were determined. Set-up margins were calculated for each set-up technique using the percentage of encompassed isocentres and a margin recipe. The prostate systematic set-up errors in the medial-lateral, superior-inferior and anterior-posterior directions for skin marker set-up were 2.2, 3.6 and 4.5 mm (1 standard deviation). For our bony anatomy-based off-line protocol the prostate systematic set-up errors were 1.6, 2.5 and 4.4 mm. For the online fiducial based set-up the results were 0.5, 1.4 and 1.4 mm. A prostate systematic error of 10.2 mm was uncorrected by the off-line bone protocol in one patient. Set-up margins calculated to encompass 98% of prostate set-up shifts were 11-14 mm with bone off-line set-up and 4-7 mm with online fiducial markers. Margins from the van Herk margin recipe were generally 1-2 mm smaller. Bony anatomy-based set-up protocols improve the group prostate set-up error compared with skin marks; however, large prostate systematic errors can remain undetected or systematic errors increased for individual patients. The margin required for set-up errors was found to be 10-15 mm unless implanted fiducial markers are available for treatment guidance.


Results From Three Performance Validity Tests in Children With Intellectual Disability.
If we wish to conclude that failure on a performance validity test (PVT) is a false positive for poor effort, we must have evidence that the person is truly incapable of passing the test because of cognitive impairment. We must show that they have a diagnostic condition that is sufficient to account fully for failure on that test. The purpose of the current study was to evaluate the performance of children with a primary diagnosis of intellectual disability (ID) on the Word Memory Test (WMT), the Medical Symptom Validity Test (MSVT), and the Nonverbal Medical Symptom Validity Test (Green, 2003 , 2004 , 2008b ; Green & Astner, 1995 ). If a Full-Scale IQ (FSIQ) less than 70 could account for failure on these tests in adults, then children with ID would also fail them. In fact, the children with ID in the current study did not fail the WMT or MSVT as long as they had at least a Grade 3 reading level. Also, the children with ID did not fail these tests any more often than did children of significantly higher intelligence. The data suggest that an FSIQ in the range of 48 to 70 is not sufficient to explain failure on these PVTs by children or adults.


Fatal malignant melanoma in a child with neurofibromatosis type 1.
Neurofibromatosis type 1 is an autosomal dominant disease and is considered one of the most commonly inherited diseases in humans. Malignant melanoma has been reported in up to 5% of patients with neurofibromatosis type 1. We report a young Saudi boy with neurofibromatosis type 1 who developed fatal metastatic malignant melanoma arising from giant melanocytic nevi within speckled lentiginous nevus (SLN).


[Medical treatment of early breast cancer: chemotherapy].
In general, chemotherapy improves recurrence-free and overall survival in patients with early breast cancer, but the possible benefits should be weighted against toxicities and the socio-economic burden for the individual patient. The benefits appear to be less in patients with hormone receptor positive tumours aged 59 or older and endocrine therapy alone might be preferred in these patients. A regimen containing anthracyclines and taxanes, the most active drugs in primary breast cancer, is preferable if chemotherapy is to be used, e.g. epirubicin and cyclophosphamide followed by docetaxel.


FungiScope™ -Global Emerging Fungal Infection Registry.
Rare invasive fungal diseases (IFD) are challenging for the treating physicians because of their unspecific clinical presentation, as well as the lack of standardised diagnostic and effective treatment strategies. Late onset of treatment and inappropriate medication is associated with high mortality, thus, urging the need for a better understanding of these diseases. The purpose of FungiScope™ is to continuously collect clinical information and specimens to improve the knowledge on epidemiology and eventually improve patient management of these orphan diseases. FungiScope™ was founded in 2003, and today, collaborators from 66 countries support the registry. So far, clinical data of 794 cases have been entered using a web-based approach. Within the growing network of experts, new collaborations developed, leading to several publications of comprehensive analyses of patient subgroups identified from the registry. Data extracted from FungiScope™ have also been used as the sole control group for the approval of a new antifungal drug. Due to the rarity of these diseases, a global registry is an appropriate method of pooling the scarce and scattered information. Joining efforts across medical specialities and geographical borders is key for researching rare IFD. Here, we describe the structure and management of the FungiScope™ registry.


Nephropathy in type 1 diabetes.
Nephropathy is the major life-threatening complication of type 1 diabetes. It is due to the adverse effects of glucose-induced preglomerular vasodilation on glomerular hemodynamics. Glomerulosclerosis is initiated early in the course of diabetic nephropathy by exacerbated expression of cytokines like tumor growth factor beta1. Not all type 1 diabetes patients are at risk of nephropathy, probably because some polymorphisms in the various factors involved in its pathogenesis can modulate the course of this disease from one individual to another. Blocking the course of nephropathy by blockers of the renin-angiotensin system relies on solid pathophysiological hypotheses and has proved to be efficacious for improving the prognosis of type 1 diabetes nephropathy.


Postoperative pain management after total knee arthroplasty in elderly patients: treatment options.
Total knee arthroplasty (TKA) is a common surgical procedure in the elderly and is associated with severe pain after surgery and a high incidence of chronic pain. Several factors are associated with severe acute pain after surgery, including psychological factors and severe preoperative pain. Good acute pain control can be provided with multimodal analgesia, including regional anesthesia techniques. Studies have demonstrated that poor acute pain control after TKA is strongly associated with development of chronic pain, and this emphasizes the importance of attention to good acute pain control after TKA. Pain after discharge from hospital after TKA is currently poorly managed, and this is an area where increased resources need to be focused to improve early pain control. This is particularly as patients are often discharged home within 4-5 days after surgery. Chronic pain after TKA in the elderly can be managed with both pharmacological and non-pharmacological techniques. After excluding treatable causes of pain, the simplest approach is with the use of acetaminophen combined with a short course of non-steroidal anti-inflammatory drugs (NSAIDs). Careful titration of opioid analgesics can also be helpful with other adjuvants such as the antidepressants or antiepileptic medications used especially for patients with neuropathic pain. Topical agents may provide benefit and are associated with fewer systemic side effects than oral administration. Complementary or psychological therapies may be beneficial for those patients who have failed other options or have depression associated with chronic pain.


Effect of sex and age on the association between suicidal behaviour and obesity in Korean adults: a cross-sectional nationwide study.
To examine the hypothesis that the relationship between obesity and the risk of suicidal behaviour would differ according to sex and age. Data from the 2007-2012 Korean National Health and Nutrition Examination Survey (KNHANES) were used. 36 211 adults with body mass index (BMI) data were included and the mean age was 49.6 years. BMI. Suicide ideation and attempts. A cross-sectional study was performed. Multiple logistic regressions after controlling for socioeconomic variables and concomitant diseases were applied to see the relationship between obesity level and suicidal ideation or attempt. Women with severe obesity had the highest prevalence of suicide attempts and ideation, whereas among males, underweight men had the highest prevalence. After adjustment, obese men had a lower OR for suicide ideation (OR=0.87, 95% CI 0.76 to 1.00). Among women, the ORs of severely obese and underweight women were 1.27 (95% CI 1.06 to 1.52) and 1.24 (95% CI 1.06 to 1.45), respectively. When grouped by age category, the ORs for suicide ideation in severely obese women aged 18 to <30 years or attempts in severely obese women aged 30 to <50 years were 2.30 (95% CI 1.36 to 3.89) and 3.07 (95% CI 1.50 to 6.31), respectively. However, overweight and obese women aged more than 50 years exhibited significantly less ORs of suicide ideation, when compared with counterparts of normal weight. The association between obesity and suicidal behaviour exhibited a different pattern by sex and age in South Korea. In particular, severely obese young women had a substantial risk of suicidal behaviour. Our study results highlighted the importance of obesity management in the prevention of suicide among young women, and may be helpful for the drafting of the health agenda in Asian countries with an obesity prevalence and culture similar to those in Korea.


Prenatal exposure to selenium may protect against wheezing in children by the age of 3.
It has been suggested that human in utero exposure to heavy metals such as selenium can reduce the prevalence of childhood asthma and allergic diseases. However, data on this topic are scarce. The objective of the present study was to assess the putative associations between maternal selenium level during pregnancy and the risk of asthma, wheezing, allergic rhinitis, and atopic dermatitis in children from the EDEN birth cohort by the age of 1 and 3 years. Plasma selenium concentrations were measured in maternal blood during mid-pregnancy (24-28 weeks of gestation) in 861 mothers. Cohort children were followed up from birth to 3 years using health questionnaires filled out by the parents for asthma, wheezing, allergic rhinitis, and atopic dermatitis. Maternal plasma selenium was related to the childhood outcomes by the age of 1 and 3 years. Our results showed a significant negative association between a high maternal plasma selenium level during pregnancy and the risk of wheezing in the child by the age of 1 and 3 years. However, maternal plasma selenium during pregnancy was not associated with the prevalence of asthma, allergic rhinitis or atopic dermatitis. The results of this study suggest that the level of fetal exposure to maternal selenium could have an influence on the risk of wheezing in infancy and potentially on the risk of developing asthma later in life.


Cell death: programmed, apoptosis, necrosis, or other?
There are at least two major types of active or physiological cell death. The most well-known form, apoptosis or Type I, involves early nuclear collapse, condensation of chromatin, generation of nucleosomal ladders, and cell fragmentation with little or no early alteration of lysosomes. It is most commonly seen in cells deriving from highly mitotic lines, and the cells are phagocytosed by neighboring cells or infiltrating macrophages. In metamorphosing or secretory cells, and under conditions where the majority of cells die, the bulk of the cytoplasm is consumed by expansion of the lysosomal system well before nuclear collapse is manifest. This form of cell death has been termed Type II cell death, and we revert to this terminology. The requirement for protein synthesis is more characteristic of Type II cell death in developmental situations than it is for Type I cell death. The variations seen force a reassessment of those aspects of physiological cell death that are truly universal, thereby focusing attention on the biology of the process. A better understanding of the biology and morphology of dying cells will help clarify the significance of the molecular and biochemical findings.


Nigral neurodegeneration triggered by striatal AdIL-1 administration can be exacerbated by systemic IL-1 expression.
Neuroinflammation has been proposed as an important component of Parkinson's Disease (PD) aetiology and/or progression. However, the inflammatory components and the mechanisms underlying their effects are only partially known. By injecting an adenovirus expressing IL-1 in the striatum, we provoked progressive neurodegeneration of dopaminergic cells in the substantia nigra, motor symptoms and microglial activation. All these effects were attenuated by an anti-inflammatory treatment. Interestingly, peripheral inflammatory stimuli exacerbated IL-1beta induced neurodegeneration and the central inflammatory reaction. These data provide evidence that central, chronic IL-1beta expression can trigger and systemic IL-1beta exacerbate nigral neurodegeneration and highlight the functional relevance of this cytokine in PD.


Causes of death in patients diagnosed with gastric adenocarcinoma in Sweden, 1970-2014: A population-based study.
The causes of death in patients with gastric adenocarcinoma have not been well characterized. This nationwide population-based cohort study included 56 240 patients diagnosed with gastric adenocarcinoma in 1970-2014 in Sweden. We used competing-risks regression to compare cause-specific risks of death in patients with different characteristics and a multiple-cause approach to assess proportions of deaths attributable to each cause. Among 53 049 deaths, gastric cancer was the main (77.7% of all deaths) underlying cause. Other major underlying causes were nongastric malignancies (8.0%), ischemic heart disease or cerebrovascular disease (6.5%), and respiratory diseases (1.4%). Risk of death from gastric cancer steadily decreased in patients with cardia adenocarcinoma over the study period, but remained relatively stable in patients with noncardia adenocarcinoma since the 1980s. Risk of death from other malignancies increased during later calendar periods (subhazard ratio [SHR] = 2.16, 95% confidence interval [CI] 1.97-2.38, comparing 2001-2014 with 1970-1980). Compared with men, the risk of death in women with cardia adenocarcinoma was higher from gastric cancer (SHR = 1.18, 95% CI 1.10-1.27), but lower from other malignancies (SHR = 0.80, 95% CI 0.71-0.91). In multiple-cause models, 60.4%-71.2% of all deaths were attributable to gastric cancer and 9.5%-12.1% to other malignancies. The temporal trends of cause-specific risks from multiple-cause models were similar to those of underlying causes. Our findings suggest that although most deaths in patients with gastric adenocarcinoma are due to gastric cancer, other causes of death are common. Patients with cardia adenocarcinoma face considerable increasing risk of death from other causes over time, particularly from other malignancies.


Locality constrained joint dynamic sparse representation for local matching based face recognition.
Recently, Sparse Representation-based Classification (SRC) has attracted a lot of attention for its applications to various tasks, especially in biometric techniques such as face recognition. However, factors such as lighting, expression, pose and disguise variations in face images will decrease the performances of SRC and most other face recognition techniques. In order to overcome these limitations, we propose a robust face recognition method named Locality Constrained Joint Dynamic Sparse Representation-based Classification (LCJDSRC) in this paper. In our method, a face image is first partitioned into several smaller sub-images. Then, these sub-images are sparsely represented using the proposed locality constrained joint dynamic sparse representation algorithm. Finally, the representation results for all sub-images are aggregated to obtain the final recognition result. Compared with other algorithms which process each sub-image of a face image independently, the proposed algorithm regards the local matching-based face recognition as a multi-task learning problem. Thus, the latent relationships among the sub-images from the same face image are taken into account. Meanwhile, the locality information of the data is also considered in our algorithm. We evaluate our algorithm by comparing it with other state-of-the-art approaches. Extensive experiments on four benchmark face databases (ORL, Extended YaleB, AR and LFW) demonstrate the effectiveness of LCJDSRC.


Post-war development of emergency medicine in Kosovo.
To (1) investigate emergency medical care priorities in Kosovo, (2) assess Kosovo's post-war development of emergency medical services and (3) identify expectations. An instrument with seven open-ended questions, approved by the institutional review board, was designed for in-person interviews (preferred) or written survey. The survey was administered in October 2003 at the Kosovo University Clinical Center, Pristina, Kosovo, and one regional hospital. Targeted participants were emergency care providers, clinical consultants and health policy consultants. Surveys were conducted by interview with simultaneous interpretation by a native Albanian speaker, an orthopaedic surgeon or in written Albanian form. The responses were evaluated quantitatively and qualitatively. 13 respondents participated in the study: 10 gave interviews and 3 provided written response; 7 were emergency care providers, 4 were emergency care consultants and 2 were health policy consultants. Emergency care priorities were defined as trauma, cardiac disease and suicide. Most respondents believed that emergency medicine as a specialised field was a post-war development. The international community was credited with the provision of infrastructure, supplies and training. Most respondents denied any harm from international assistance. However, some respondents described instances of inappropriate international investment. Ongoing needs are training of providers and equipping of facilities and vehicles. Improved hospital management, political administration and international involvement are thought to be necessary for continued development. Survey respondents agreed on priorities in emergency care, credited the international community with development to date, and identified administrative structures and international training support as the keys to ongoing development.


Regional White Matter Scaling in the Human Brain.
Anatomical organization of the primate cortex varies as a function of total brain size, where possession of a larger brain is accompanied by disproportionate expansion of associative cortices alongside a relative contraction of sensorimotor systems. However, equivalent scaling maps are not yet available for regional white matter anatomy. Here, we use three large-scale neuroimaging datasets to examine how regional white matter volume (WMV) scales with interindividual variation in brain volume among typically developing humans (combined N = 2391: 1247 females, 1144 males). We show that WMV scaling is regionally heterogeneous: larger brains have relatively greater WMV in anterior and posterior regions of cortical white matter, as well as the genu and splenium of the corpus callosum, but relatively less WMV in most subcortical regions. Furthermore, regions of positive WMV scaling tend to connect previously-defined regions of positive gray matter scaling in the cortex, revealing a coordinated coupling of regional gray and white matter organization with naturally occurring variations in human brain size. However, we also show that two commonly studied measures of white matter microstructure, fractional anisotropy (FA) and magnetization transfer (MT), scale negatively with brain size, and do so in a manner that is spatially unlike WMV scaling. Collectively, these findings provide a more complete view of anatomic scaling in the human brain, and offer new contexts for the interpretation of regional white matter variation in health and disease.SIGNIFICANCE STATEMENT Recent work has shown that, in humans, regional cortical and subcortical anatomy show systematic changes as a function of brain size variation. Here, we show that regional white matter structures also show brain-size related changes in humans. Specifically, white matter regions connecting higher-order cortical systems are relatively expanded in larger human brains, while subcortical and cerebellar white matter tracts responsible for unimodal sensory or motor functions are relatively contracted. This regional scaling of white matter volume (WMV) is coordinated with regional scaling of cortical anatomy, but is distinct from scaling of white matter microstructure. These findings provide a more complete view of anatomic scaling of the human brain, with relevance for evolutionary, basic, and clinical neuroscience.