Anesthesia in patients with cancer disorders.
Along with the increasing population of elderly people in developed countries, anesthesiologists have increasing opportunities to anesthetize cancer patients in their routine work. However, no guideline of anesthesia procedures for cancer patients is available even though guidelines of operative procedures have been formulated for different types of cancer. This review provides recent findings related to the optimal choice of anesthetics and adequate anesthesia management for cancer patients. The intrinsic weapon fighting cancer cells is competent immune cells, particularly CD4+ T helper 1-type cells, CD8+ cytotoxic T cells, and natural killer cells. However, surgical inflammation, some anesthetics, and inadvertent anesthesia management suppress these effector cells and induce suppressive immune cells, which render cancer patients susceptible to tumor recurrence and metastasis after surgery. Accumulated basic and clinical data suggest that total intravenous anesthesia with propofol, cyclooxygenase antagonists, and regional anesthesia can decrease negative consequences associated with perioperative immunosuppression. Volatile anesthesia, systemic morphine administration, unnecessary blood transfusions, intraoperative hypoxia, hypotension, hypothermia, and hyperglycemia should be avoided.


Results of nonoperative management of full-thickness tears of the rotator cuff.
The results of nonoperative management of 53 patients with full-thickness tears of the rotator cuff proven by arthroscopic examination was as follows. Patients were treated with nonsteroidal antiinflammatory medication, stretching, strengthening, and occasional steroid injections. Average age at presentation was 62.2 years. Patients were evaluated at an average of 7.6 years. Forty patients were male, and the dominant limb was involved in 40 cases. Thirty-four patients were reviewed by questionnaire and physical examination, whereas 19 patients were evaluated by telephone interview only. In 40 patients, the onset of symptoms was associated with an injury. In 12 patients, workmen's compensation was involved. At follow-up evaluation, the 34 shoulders that were available for examination were evaluated for pain, range of motion, strength, and function. Thirty-nine of the 53 patients (74%) assessed subjectively had only slight or no shoulder discomfort. Of the 28 shoulders presenting within three months of injury, 24 (86%) were rated as satisfactory at the time of latest evaluation. Of the 16 patients who initially had had shoulder pain for over 6 months, only nine (56%) were rated as satisfactory. Most patients showed improvement with regard to their ability to perform activities of daily living. Average active total elevation was 149 degrees compared with 121 degrees at initial presentation. Thirty-two of the 34 patients examined (94%) had evidence of weakness on muscle testing and 19 (56%) had demonstrable muscle atrophy.


Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain.
Neuronal ELAV-like (nELAVL) RNA binding proteins have been linked to numerous neurological disorders. We performed crosslinking-immunoprecipitation and RNAseq on human brain, and identified nELAVL binding sites on 8681 transcripts. Using knockout mice and RNAi in human neuroblastoma cells, we showed that nELAVL intronic and 3' UTR binding regulates human RNA splicing and abundance. We validated hundreds of nELAVL targets among which were important neuronal and disease-associated transcripts, including Alzheimer's disease (AD) transcripts. We therefore investigated RNA regulation in AD brain, and observed differential splicing of 150 transcripts, which in some cases correlated with differential nELAVL binding. Unexpectedly, the most significant change of nELAVL binding was evident on non-coding Y RNAs. nELAVL/Y RNA complexes were specifically remodeled in AD and after acute UV stress in neuroblastoma cells. We propose that the increased nELAVL/Y RNA association during stress may lead to nELAVL sequestration, redistribution of nELAVL target binding, and altered neuronal RNA splicing.


Underdeveloped uterus and reduced estrogen responsiveness in mice with disruption of the estrogen-responsive finger protein gene, which is a direct target of estrogen receptor alpha.
The biological roles of estrogen-responsive finger protein (efp) in vivo were evaluated in mice carrying a loss-of-function mutation in efp by gene-targeted mutagenesis. Although efp homozygous mice were viable and fertile in both sexes, the uterus that expressed abundant estrogen receptor alpha exhibited significant underdevelopment. When the ovariectomized homozygotes were subjected to 17beta-estradiol treatment, they showed remarkably attenuated responses to estrogen, as exemplified by decreased interstitial water imbibition and retarded endometrial cell increase, at least, attributable to the lower ratio of G1 to S-phase progression in epithelial cells. These results suggest that efp is essential for the normal estrogen-induced cell proliferation and uterine swelling as one of the direct targets of estrogen receptor alpha.


Mpl traffics to the cell surface through conventional and unconventional routes.
Myeloproliferative neoplasms (MPNs) are often characterized by JAK2 or calreticulin (CALR) mutations, indicating aberrant trafficking in pathogenesis. This study focuses on Mpl trafficking and Jak2 association using two model systems: human erythroleukemia cells (HEL; JAK2V617F) and K562 myeloid leukemia cells (JAK2WT). Consistent with a putative chaperone role for Jak2, Mpl and Jak2 associate on both intracellular and plasma membranes (shown by proximity ligation assay) and siRNA-mediated knockdown of Jak2 led to Mpl trapping in the endoplasmic reticulum (ER). Even in Jak2 sufficient cells, Mpl accumulates in punctate structures that partially colocalize with ER-tracker, the ER exit site marker (ERES) Sec31a, the autophagy marker LC3 and LAMP1. Mpl was fused to miniSOG, a genetically encoded tag for correlated light and electron microscopy. Results suggest that a fraction of Mpl is taken up into autophagic structures from the ER and routed to autolyososomes. Surface biotinylation shows that both immature and mature Mpl reach the cell surface; in K562 cells Mpl is also released in exosomes. Both forms rapidly internalize upon ligand addition, while recovery is primarily attributed to immature Mpl. Mpl appears to reach the plasma membrane via both conventional ER-Golgi and autolysosome secretory pathways, as well as recycling.


Purification and kinetic properties of two soluble forms of calmodulin-dependent cyclic nucleotide phosphodiesterase from rat pancreas.
The calmodulin-dependent cyclic AMP phosphodiesterase and cyclic GMP phosphodiesterase (EC 220.127.116.11) activity of rat pancreas was purified 280-fold by affinity chromatography on calmodulin-Sepharose 4B. It then accounted for 15% of the total cytosol cyclic GMP nucleotide phosphodiesterase activity, in the presence of Ca2+, and represented a minor component of proteins specifically adsorbed by the column. This activity was resolved on a DEAE-Sephacel column into two fractions, termed PI and PII, on the basis of their order of emergence. After this step, PI and PII were purified 5650- and 3700-fold respectively. The molecular weight of PI was 175 000 and that of PII was 116 000, by polyacrylamide-gradient-gel electrophoresis. Both forms of phosphodiesterase could hydrolyse cyclic AMP and cyclic GMP, although PII displayed a higher affinity toward cyclic GMP than toward cyclic AMP. PI and PII exhibited negative homotropic kinetics in the absence of calmodulin. Upon addition of calmodulin, both enzymes displayed Michaelis-Menten kinetics and a 5-9-fold increase in maximal velocity, at physiological concentrations of cyclic GMP and cyclic AMP. When a pancreatic extract freshly purified by affinity chromatography was immediately analysed by high-performance gel-permeation chromatography on a TSK gel G3000 SW column, PII represented as much as 78% of the eluted activity. This percentage decreased to 52% when the sample was stored at 0 degrees C for 20 h before analysis, suggesting that PII, possibly predominant in vivo, was converted into the heavier PI form upon storage.


[Radiological and clinical considerations on the proximal sesamoid bones of young horses (author's transl)].
Several clinical and radiological studies of the proximal sesamoid bones were done in eleven horses from the age of one month to three years. The X-ray findings were found to be inconstant. The number of nutrient canals visualized increased or decreased, and the bone structure gradually became more irregular. Bone deposits along the borders of the sesamoid bones usually did not become apparent until the second or third year of life. Particularly this growth of new bone was found to be a significant clinical feature. On the other hand, nutrient canals and irregular bone structures were also observed in horses in which clinical examination failed to reveal any changes.


Enhancement of Macrophage Function by the Antimicrobial Peptide Sublancin Protects Mice from Methicillin-Resistant Staphylococcus aureus.
Methicillin-resistant Staphylococcus aureus (MRSA) is the major pathogen responsible for community and hospital bacterial infections. Sublancin, a glucosylated antimicrobial peptide isolated from Bacillus subtilis 168, possesses antibacterial infective effects. In this study, we investigated the role and anti-infection mechanism of sublancin in a mouse model of MRSA-induced sublethal infection. Sublancin could modulate innate immunity by inducing the production of IL-1β, IL-6, TNF-α, and nitric oxide, enhancing phagocytosis and MRSA-killing activity in both RAW264.7 cells and mouse peritoneal macrophages. The enhanced macrophage function by the peptide in vitro correlated with stronger protective activity in vivo in the MRSA-invasive sublethal infection model. Macrophage activation by sublancin was found to be partly dependent on TLR4 and the NF-κB and MAPK signaling pathways. Moreover, oral administration of sublancin increased the frequencies of CD4+ and CD8+ T cells in mesenteric lymph nodes. The protective activity of sublancin was associated with in vivo augmenting phagocytic activity of peritoneal macrophages and partly improving T cell-mediated immunity. Macrophages thus represent a potentially pivotal and novel target for future development of innate defense regulator therapeutics against S. aureus infection.


Novel calmodulin mutations associated with congenital arrhythmia susceptibility.
Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations. We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity. CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.


Bovine bile derivative treatment for cancer-a critical evaluation.
Bovine bile derivative, a material reported to be effective in cancer chemotherapy, was administered to 31 patients with malignant disease. In 22 cases the results were considered evaluable. In one of the 22 there was a suggestion of antitumor response. In almost all patients diarrhea and phlebitis developed and in 11 these complications necessitated cessation of therapy.


Changes in Life Circumstances and Mental Health Symptoms during the COVID-19 Pandemic among Midlife Women with Elevated Risk for Cardiovascular Disease.
Cardiovascular disease (CVD) remains the leading cause of death among women. During midlife (ages 40-60), universal aging processes, sex-specific factors such as menopause, psychological distress, and conditions such as hypertension substantially increase women's risk for CVD. The onset of the COVID-19 pandemic has impacted employment, social interactions, caregiving responsibilities, and overall well-being worldwide; however, little research has investigated how COVID-19 has affected women in midlife. The present study was designed to determine how COVID-19 has affected women in midlife with elevated risk for CVD, by examining changes in their mental health symptoms and life domains across three time points: prior to COVID-19 (2019), during stay-at-home orders (April-June 2020), and during initial reopening (August 2020). Women in midlife with one or more CVD risk conditions (e.g., hypertension; n = 35) responded to questions related to COVID-19, changes in life circumstances, and mental health symptoms at each time point. Findings showed meaningful changes in caregiving, medical visits, and employment status, as well as significant changes in depression and sleep quality scores across time. However, the findings also showed that women were distressed prior to COVID-19 and did not exhibit changes in perceived stress, body dissatisfaction, or anxiety symptoms over time. Findings from this study highlight the impact of the COVID-19 pandemic on an at-risk group of women, which may be used to help guide future health promotion efforts specifically tailored to this population.


Simultaneous localization of two linked disease susceptibility genes.
For diseases with complex genetic etiology, more than one susceptibility gene may exist in a single chromosomal region. Extending the work of Liang et al. ([2001] Hum. Hered. 51:64-78), we developed a method for simultaneous localization of two susceptibility genes in one region. We derived an expression for expected allele sharing of an affected sib pair (ASP) at each point across a chromosomal segment containing two susceptibility genes. Using generalized estimating equations (GEE), we developed an algorithm that uses marker identical-by-descent (IBD) sharing in affected sib pairs to simultaneously estimate the locations of the two genes and the mean IBD sharing in ASPs at these two disease loci. Confidence intervals for gene locations can be constructed based on large sample approximations. Application of the described methods to data from a genome scan for type 1 diabetes (Mein et al. [1998] Nat. Genet. 19:297-300) yielded estimates of two putative disease gene locations on chromosome 6, approximately 20 cM apart. Properties of the estimators, including bias, precision, and confidence interval coverage, were studied by simulation for a range of genetic models. The simulations demonstrated that the proposed method can improve disease gene localization and aid in resolving large peaks when two disease genes are present in one chromosomal region. Joint localization of two disease genes improves with increased excess allele sharing at the disease gene loci, increased distance between the disease genes, and increased number of affected sib pairs in the sample.


Recovery from exercise-induced desaturation in the quadriceps muscles of elite competitive rowers.
A simple muscle tissue spectrophotometer is adapted to measure the recovery time (TR) for hemoglobin/myoglobin (Hb/Mb) desaturation in the capillary bed of exercising muscle, termed a deoxygenation meter. The use of the instrument for measuring the extent of deoxygenation is presented, but the use of TR avoids difficulties of quantifying Hb/Mb saturation changes. The TR reflects the balance of oxygen delivery and oxygen demand in the localized muscles of the quadriceps following work near maximum voluntary contraction (MVC) in elite male and female rowers (a total of 22) on two occasions, 1 yr apart. TR ranged from 10 to 80 s and was interpreted as a measure of the time for repayment of oxygen and energy deficits accumulated during intense exercise by tissue respiration under ADP control. The Hb/Mb resaturation times provide a noninvasive localized indication of the degree of O2 delivery stress as evoked by rowing ergometry and may provide directions for localized muscle power output improvement for particular individuals in rowing competitions.


Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair.
Peroxisome proliferator-activated receptor γ (PPARγ) is a widely expressed ligand-modulated transcription factor that governs the expression of genes involved in inflammation, redox equilibrium, trophic factor production, insulin sensitivity, and the metabolism of lipids and glucose. Synthetic PPARγ agonists (e.g. thiazolidinediones) are used to treat Type II diabetes and have the potential to limit the risk of developing brain injuries such as stroke by mitigating the influence of comorbidities. If brain injury develops, PPARγ serves as a master gatekeeper of cytoprotective stress responses, improving the chances of cellular survival and recovery of homeostatic equilibrium. In the acute injury phase, PPARγ directly restricts tissue damage by inhibiting the NFκB pathway to mitigate inflammation and stimulating the Nrf2/ARE axis to neutralize oxidative stress. During the chronic phase of acute brain injuries, PPARγ activation in injured cells culminates in the repair of gray and white matter, preservation of the blood-brain barrier, reconstruction of the neurovascular unit, resolution of inflammation, and long-term functional recovery. Thus, PPARγ lies at the apex of cell fate decisions and exerts profound effects on the chronic progression of acute injury conditions. Here, we review the therapeutic potential of PPARγ in stroke and brain trauma and highlight the novel role of PPARγ in long-term tissue repair. We describe its structure and function and identify the genes that it targets. PPARγ regulation of inflammation, metabolism, cell fate (proliferation/differentiation/maturation/survival), and many other processes also has relevance to other neurological diseases. Therefore, PPARγ is an attractive target for therapies against a number of progressive neurological disorders.


Cigarette smoking and the risk of ovarian cancer in the Japanese population: findings from the Japanese Collaborate Cohort study.
The many studies into the relation between cigarette smoking and the risk of ovarian cancer have produced inconsistent results. Here we investigated this relation using data from the Japan Collaborative Cohort Study for Evaluation of Cancer Risk, initiated in 1988. A self-administered questionnaire on smoking habits and other risk factors for cancer was completed by 34 639 Japanese women. After 7.6 years of follow up, 39 cases of ovarian cancer were available for analyses. Cox proportional-hazards models were used to compute relative risks (RR) and to adjust for confounders. Relative to those who had never smoked, the RR of ovarian cancer were 1.63 (95% confidence interval [CI] = 0.21-12.50) for former smokers and 2.27 (95% CI = 0.85-6.08) for current smokers. Among current smokers, the RR were 1.48 (95% CI = 0.20-10.92), 5.56 (95% CI = 1.68-19.06), and 1.86 (95% CI = 0.25-14.30) among women who smoked <10, 10-19, and at least 20 pack-years ([number of cigarettes smoked per day/20] x number of years subject has smoked), respectively, relative to those who had never smoked. A test for trend was statistically significant (P = 0.044). These data indicate that cigarette smoking increases the risk of developing ovarian cancer in the Japanese population.


A stochastic model for discrete waves in the Limulus photoreceptor.
A stochastic model that links the absorption of a photon to the production of a discrete wave in the photoreceptor of the lateral eye of Limulus is proposed. By separating a discrete wave into an initial component due directly to the absorption of a photon, and a second quasi all-or-nothing component, a mathematical description of the latencies of discrete waves is deduced and some important features of their time courses are suggested. The predictions of the model are compared to observations from 60 different ommatidia.


Image-formation technique for scanning electron microscopy and electron probe microanalysis.
A technique is described for topographic images on the scanning electron microscope and the scanning electron probe microanalyzer. In this technique, the brightness of the oscilloscope is modulated by a signal obtained by mixing the signal (from secondary electrons or targets current) with its first derivative. This enhances minor topographic features which are poorly reproduced in the technique.


Playing with Others: Head Start Children's Peer Play and Relations with Kindergarten School Competence.
Time-sampled observations of Head Start preschoolers' (N = 264; 51.5% boys; 76% Mexican American; M = 53.11 and SD = 6.15 months of age) peer play in the classroom were gathered during fall and spring semesters. One year later, kindergarten teachers rated these children's school competence. Latent growth models indicated that, on average, children's peer play was moderately frequent and increased over time during preschool. Children with higher initial levels or with higher slopes of peer play in Head Start had higher levels of kindergarten school competence. Results suggest that Head Start children's engagement with peers may foster development of skills that help their transition into formal schooling. These findings highlight the importance of peer play, and suggest that peer play in Head Start classrooms contributes to children's adaptation to the demands of formal schooling.


Contrasting Perspectives of Anesthesiologists and Gastroenterologists on the Optimal Time Interval between Bowel Preparation and Endoscopic Sedation.
Background. The optimal time interval between the last ingestion of bowel prep and sedation for colonoscopy remains controversial, despite guidelines that sedation can be administered 2 hours after consumption of clear liquids. Objective. To determine current practice patterns among anesthesiologists and gastroenterologists regarding the optimal time interval for sedation after last ingestion of bowel prep and to understand the rationale underlying their beliefs. Design. Questionnaire survey of anesthesiologists and gastroenterologists in the USA. The questions were focused on the preferred time interval of endoscopy after a polyethylene glycol based preparation in routine cases and select conditions. Results. Responses were received from 109 anesthesiologists and 112 gastroenterologists. 96% of anesthesiologists recommended waiting longer than 2 hours until sedation, in contrast to only 26% of gastroenterologists. The main reason for waiting >2 hours was that PEG was not considered a clear liquid. Most anesthesiologists, but not gastroenterologists, waited longer in patients with history of diabetes or reflux. Conclusions. Anesthesiologists and gastroenterologists do not agree on the optimal interval for sedation after last drink of bowel prep. Most anesthesiologists prefer to wait longer than the recommended 2 hours for clear liquids. The data suggest a need for clearer guidelines on this issue.


Frequency-dependent enhancement of fluid intelligence induced by transcranial oscillatory potentials.
Everyday problem solving requires the ability to go beyond experience by efficiently encoding and manipulating new information, i.e., fluid intelligence (Gf) [1]. Performance in tasks involving Gf, such as logical and abstract reasoning, has been shown to rely on distributed neural networks, with a crucial role played by prefrontal regions [2]. Synchronization of neuronal activity in the gamma band is a ubiquitous phenomenon within the brain; however, no evidence of its causal involvement in cognition exists to date [3]. Here, we show an enhancement of Gf ability in a cognitive task induced by exogenous rhythmic stimulation within the gamma band. Imperceptible alternating current [4] delivered through the scalp over the left middle frontal gyrus resulted in a frequency-specific shortening of the time required to find the correct solution in a visuospatial abstract reasoning task classically employed to measure Gf abilities (i.e., Raven's matrices) [5]. Crucially, gamma-band stimulation (γ-tACS) selectively enhanced performance only on more complex trials involving conditional/logical reasoning. The present finding supports a direct involvement of gamma oscillatory activity in the mechanisms underlying higher-order human cognition.


Trends in immediate perioperative morbidity and delay in discharge after open and minimally invasive radical prostatectomy (RP): a 20-year institutional experience.
WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Standard clinical care pathways to discharge have been established for a number of operations including radical prostatectomy (RP). The pathway after RP has changed dramatically over the past two decades due to improvements in surgical technique, anaesthesia and most recently, the introduction of minimally invasive RP (MIRP). This study adds evidence that the emergence of MIRP is associated with a decrease in LOS for all patients undergoing RP. In addition, it catalogues the development of the clinical care pathway over 20 years at a large, tertiary care hospital with extensive experience in RP. Finally, it defines the common reasons patients fall 'off-pathway' (ileus, urine leak, anaemia and re-exploration for bleeding) and defines the immediate perioperative morbidity profile of RP. Specifically, it addresses approach-specific morbidities and indicates that MIRP is associated with higher rates of 'off-pathway' discharge, most often due to ileus. To investigate the development of the clinical care pathway to discharge after radical prostatectomy (RP) at a large, academic medical centre over the past 20 years, focusing on the rates and reasons for deviation. In all, 18 049 men were identified from the Johns Hopkins RP database who had undergone surgery since 1991. Patients in whom the length of stay (LOS) was ≤95th percentile, defined the clinical care pathway to discharge and those in whom LOS was ≥98th percentile were termed 'off-pathway'. The mean LOS decreased from 7.7 days in 1991 to 1.6 days in 2010. Of 7126 patients undergoing RP since 2005, 1803(25.3%), 4881(68.5%) and 312 (4.4%) were discharged on postoperative day (POD) 1, 2 and 3, respectively; 126 (1.8%) patients, discharged on POD4-21 were 'off-pathway'. The most common reasons for delay of discharge were ileus (44, 0.615%), urine leak (12, 0.17%), anaemia requiring blood transfusion (nine, 0.126%) and bleeding requiring re-exploration (six, 0.08%). The proportion of patients 'off-pathway' was 1.20%, 1.06% and 4.01% for retropubic RP (RRP), laparoscopic RP (LRP) and robot-assisted laparoscopic RP (RALRP), respectively (P < 0.001). Ileus delayed discharge in 0.28%, 0.37% and 1.9% of patients undergoing RRP, LRP and RALRP, respectively (P < 0.001). The clinical care pathway to discharge after RP has changed dramatically at our institution over the past 20 years. RALRP appears to result in a higher proportion of 'off-pathway' patients, primarily due to ileus, compared with RRP and LRP. However, very few patients were discharged 'off-pathway'.


Porcine Circovirus Type 2 Induces ORF3-Independent Mitochondrial Apoptosis via PERK Activation and Elevation of Cytosolic Calcium.
Our previous studies demonstrated that porcine circovirus type 2 (PCV2) triggers an unfolded protein response (UPR) in porcine kidney PK-15 cells by activating the protein kinase R-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α (eIF2α) pathway of endoplasmic reticulum (ER) stress, which in turn facilitates viral replication (Y. Zhou et al., Viruses 8:e56, 2016, https://doi.org/10.3390/v8020056; Y. Zhou et al., J Zhejiang Univ Sci B 18:316-323, 2017, https://doi.org/10.1631/jzus.B1600208). PCV2 is found to cause oxidative stress and upregulation of cytoplasmic Ca2+ levels. The virus is reported to employ its open reading frame 3 (ORF3) to induce apoptosis. We wondered whether and how PCV2-induced UPR would lead to apoptosis independent of ORF3. Using an ORF3-deficient PCV2 mutant (ΔORF3), apoptotic responses in infected PK-15 and porcine alveolar macrophage (PAM) cells were still apparent, although lower than in the parental PCV2 strain. We hypothesized that apoptosis induced by ΔORF3 might result from the UPR. We found that ΔORF3-induced apoptosis was significantly reduced when the infected cells were treated with the selective PERK blocker GSK2606414 (GSK) or the general ER stress attenuator 4-phenylbutyrate (4-PBA). Such treatments also ameliorated elevation of cytoplasmic Ca2+ and reactive oxygen species (ROS) levels in PK-15 and PAM cells, two predisposing factors for apoptosis via disruption of the ER-mitochondrion units. Treatment of ΔORF3-infected cells with GSK and 4-PBA also decreased the mitochondrial Ca2+ load and increased the mitochondrial membrane potential (MMP). With transient expression of the structural protein capsid (Cap) in combination with PERK silencing, we found that Cap induced MMP collapse and mitochondrial apoptosis could result from the UPR and elevation of Ca2+ and ROS levels, which were inhibitable by downregulation of PERK. We propose that PCV2-driven ER stress is Cap dependent and could lead to mitochondrial apoptotic responses independent of ORF3 via perturbation of intracellular Ca2+ homeostasis and accumulation of ROS.IMPORTANCE PCV2 encodes protein ORF3, a putative protein with proapoptotic activity. Our early studies showed that PCV2 infection triggers ER stress via selective activation of the PERK pathway, a branch of the ER stress pathways, in permissive cells for enhanced replication and infection increased cytosolic Ca2+ and ROS levels. Here we clearly show that PCV2 infection or Cap expression induces ORF3-independent apoptosis via increased cytosolic and mitochondrial Ca2+ levels and cellular ROS levels as a result of activation of the PERK pathway.


Synthesis of isoflavone aglycones and equol in soy milks fermented by food-related lactic acid bacteria and their effect on human intestinal Caco-2 cells.
One hundred and three strains of lactic acid bacteria, isolated from various food ecosystems, were assayed for β-glucosidase activity toward p-nitrophenyl-β-D-glucopyranoside substrate. Lactobacillus plantarum DPPMA24W and DPPMASL33, Lactobacillus fermentum DPPMA114, and Lactobacillus rhamnosus DPPMAAZ1 showed the highest activities and were selected as the mixed starter to ferment various soy milk preparations, which mainly differed for chemical composition, protein dispersibility index, and size dimension. The soy milk made with organically farmed soybeans (OFS) was selected as the best preparation. All selected strains grew well in OFS soy milk, reaching almost the same values of cell density (ca. 8.5 log cfu/mL). After 96 h of fermentation with the selected mixed starter, OFS soy milk contained 57.0 μM daidzein, 140.3 μM genistein, 20.4 μM glycitein, and 37.3 μM equol. Fermented and nonfermented OFS soy milks were used for the in vitro assays on intestinal human Caco-2/TC7 cells. Fermented OFS soy milk markedly inhibited the inflammatory status of Caco-2/TC7 cells as induced by treatment with interferon-γ (IFN-γ) (1000 U/mL) and lipopolysaccharide (LPS) (100 ng/mL), maintained the integrity of the tight junctions, even if subjected to negative stimulation by IFN-γ, and markedly inhibited the synthesis of IL-8, after treatment with interleukin-1β (2 ng/mL). As shown by using chemical standards, these effects were due to the concomitant activities of isoflavone aglycones and, especially, equol, which were synthesized in the fermented OFS soy milk preparation.


Design strategy for photoinduced electron transfer-based small-molecule fluorescent probes of biomacromolecules.
As the cardinal support of innumerable biological processes, biomacromolecules such as proteins, nucleic acids and polysaccharides are of importance to living systems. The key to understanding biological processes is to realize the role of these biomacromolecules in thte localization, distribution, conformation and interaction with other molecules. With the current development and adaptation of fluorescent technologies in biomedical and pharmaceutical fields, the fluorescence imaging (FLI) approach of using small-molecule fluorescent probes is becoming an up-to-the-minute method for the detection and monitoring of these imperative biomolecules in life sciences. However, conventional small-molecule fluorescent probes may provide undesirable results because of their intrinsic deficiencies such as low signal-to-noise ratio (SNR) and false-positive errors. Recently, small-molecule fluorescent probes with a photoinduced electron transfer (PET) "on/off" switch for biomacromolecules have been thoroughly considered. When recognized by the biomacromolecules, these probes turn on/off the PET switch and change the fluorescence intensity to present a high SNR result. It should be emphasized that these PET-based fluorescent probes could be advantageous for understanding the pathogenesis of various diseases caused by abnormal expression of biomacromolecules. The discussion of this successful strategy involved in this review will be a valuable guide for the further development of new PET-based small-molecule fluorescent probes for biomacromolecules.


l-2-oxothiazolidine-4-carboxylic acid modulates function of peritoneal mesothelial cells in vitro.
The influence of the glutathione precursor, l-2-oxothiazolidine-4-carboxylic acid (OTZ), on the function of human peritoneal mesothelial cells in vitro, in conditions that mimic the in vivo effect of peritoneal dialysis solutions on mesothelium, was studied. Mesothelial monolayers were exposed to dialysis fluids (Dianeal 1.36 or Dianeal 3.86; Baxter Healthcare Corp, Round Lake, IL) that were diluted gradually with pooled-effluent dialysate obtained from patients undergoing continuous ambulatory peritoneal dialysis. In vitro exposure of mesothelium to standard dialysis fluid enhances their susceptibility to injury by hydrogen peroxide. OTZ added to dialysis solution in concentrations of 1 mmol/L prevented the toxic effect of hydrogen peroxide, probably by increasing intracellular glutathione. Mesothelial cells exposed to dialysis fluid become activated, evidenced by increased release of interleukin-6 and hyaluronan. OTZ used in concentrations of 1 mmol/L reduced that effect. Furthermore, the addition of glucose to the culture medium in a concentration of 45 mmol/L inhibits the proliferation of mesothelial cells; the presence of OTZ, 1 mmol/L, partially prevents the inhibitory effect of glucose. The results presented in this report show that by augmenting the intracellular concentration of glutathione in mesothelial cells by the addition of OTZ to the dialysis fluid, we can increase their resistance to the acute toxicity of free radicals and long-term toxicity of glucose. In addition, mesothelial cells with an increased glutathione level are less activated after their exposure to dialysis fluid.


Interlist equivalencies for a numeral and a vowel/consonant multiple-choice monosyllabic test for severely/profoundly deaf young adults.
Conventional multiple-choice speech tests measuring discrimination of initial/final consonants, and the CID "Everyday" Sentences test are too difficult for many young adults whose hearing is severely/profoundly limited. Using the 6-choice closed-set paradigm, a new 12-item Numerals test was developed as well as a modification of the Pickett et al (Gallaudet) modified rhyme test of vowel and consonantal discrimination. This test, here called the Webster-Pickett (W/P) test, essentially expands the original 2 alternative lists to 6, with some further minor changes. Both these tests were administered to 35 students at the National Technical Institute for the Deaf (NTID). In combination, the new tests provided usable scores for the NTID population. Most of those who yielded scores of zero on the W-22, on the CID sentences tests and on the W/P test nevertheless scored above zero on Numerals, while those who scored 100% on Numerals scored between 0 and 100% on the W/P test. All 6 recorded lists of the Numerals test were equivalent. Slight corrections to those raw scores between 10 and 90% on the 6 lists of the W/P were proposed to yield interlist equivalence.


A Review of Topical Corticosteroid Foams
BACKGROUND: Topical corticosteroids are efficacious treatment options for multiple dermatoses. However, ointments and cream corticosteroid vehicles can be cumbersome to patients and may act as a barrier to adherence. Foam vehicles may be preferred by some patients. OBJECTIVE: To evaluate the efficacy and safety of topical corticosteroid foams. METHODS: A literature review was conducted using the keywords "clobetasol," "betamethasone," "propionate," "valerate," "topical," "foam," "vehicles," "desonide," and "clinical trial." Thirty-seven articles were chosen. RESULTS: For moderate plaque-type psoriasis, 68% of subjects using clobetasol propionate foam achieved a Physician Static Global Assessment score of 0 or 1 at week 2 compared with 21% in the control group (P<0.0001). For betamethasone valerate (BMV) foam, a 12-week regimen for alopecia areata yielded a mean Investigator Global Assessment score of 2.9 compared with placebo (4.6; P<0.001) and achieved ≥75% hair regrowth in 42.86% of subjects. Furthermore, BMV foam cleared or almost cleared 72% of scalp psoriasis subjects compared with BMV lotion (P≤0.005%). For calcipotriol plus betamethasone dipropionate foam, 38.3% of psoriasis subjects achieved treatment success compared with placebo (22.5%; P<0.001). Desonide 0.05% foam was superior to vehicle foam in pediatric atopic dermatitis subjects. CONCLUSION: Topical corticosteroid foams can be used for a variety of corticosteroid-responsive dermatoses. Topical corticosteroid foams are generally easy to apply and may improve patient adherence and, therefore, clinical outcome in patients who prefer a convenient and less messy topical therapy.


Preliminary Results of Branch Level, Brachial Plexus Peripheral Nerve Stimulation on a Non-Human Primate.
Restoring functional hand control is a priority for those suffering from neurological impairments. Functional electrical stimulation (FES) is commonly applied to assist with rehabilitation. However, FES applied intramuscularly typically results in complex surgeries requiring many implants. This paper presents the preliminary findings from a feasibility study focused on evaluating the potential to access the upper extremity peripheral nerves through a single surgical approach (axillary approach). A single Japanese macaque (macaca fuscata) monkey was used to validate the feasibility of this study. Four of the five peripheral nerves which control the upper extremity were exposed, and had multi-contact epineural cuffs implanted: median, radial, ulnar and musculocutaneous. The axillary nerve was not accessible for epineural cuff placement with the current surgical approach used in this study. Electrical stimuli were used to produce movement contraction patterns of muscles relevant to the innervated peripheral nerves. In addition, to assist in quantifying the outcome, evoked potentials were simultaneously recorded from five extrinsic forearm flexors during median nerve stimulation. This feasibility study demonstrated that the axillary approach enables electrode placement to four of the five peripheral nerves required for upper extremity control through a single skin incision.Clinical relevance- This study demonstrated that the electrode placement to most of the peripheral nerves that control the arm and hand can be done by a single surgical approach: axillary approach.


The mechanism of insulin action on islet amyloid polypeptide fiber formation.
The pathology of type II diabetes includes the presence of cytotoxic amyloid deposits in the islets of Langerhans. The main component of these deposits, islet amyloid polypeptide (IAPP), is a hormone involved in glucose metabolism and is normally co-secreted with insulin by the beta-cells of the pancreas. Here, we perform in vitro IAPP fibrillogenesis experiments in the presence and in the absence of insulin to elucidate the mechanism by which insulin acts on fiber formation. We find that insulin is an exceptionally potent inhibitor. In contrast to the vast excess of insulin over IAPP in vivo, substoichiometric amounts of insulin inhibit seeded and unseeded reactions by more than tenfold in vitro. Unusually, the magnitude of the inhibitory effect is dependent on the concentration of insulin, yet independent of the concentration of IAPP. In addition, insulin appears to bind non-specifically to fiber surfaces, giving rise to altered morphology. IAPP fiber formation in vitro requires a minimum of three steps: fiber-independent nucleation, elongation, and fiber-dependent nucleation. Furthermore, these steps are attenuated by the presence of a dispersed-phase transition. We interpret these data in the context of the phase-mediated fibrillogenesis model (PMF) and conclude through experiment and kinetic simulation that the dominant effect of insulin is to act on the elongation portion of the reaction. These results suggest that amyloid formation in type II diabetes involves either an additional agent that acts as an accelerant, or a step that segregates IAPP from insulin.


How many proteins are there in a typical mammalian cell?
There is a major disparity between the number of polysomal mRNA species found in mammalian cells and the number of polypeptides detected by high-resolution two-dimensional polyacrylamide gel electrophoresis. Here we show that technical factors are not responsible for the relative paucity of proteins, and that the translation products of rare mRNAs would be easily detectable if all mRNAs were translated in proportion to their abundance. We conclude that a large majority of rare mRNAs are translated at no more than a tenth the average translation rate, if they are translated at all. There may be no more than 2000 physiologically significant primary gene products (polypeptides) in a typical mammalian cell.


Journey through the Trials and Triumphs of Disability.
One Woman's journey through the Trials and Triumphs of Disability , Disabled Peoples International 8th World Assembly 2011 Durban, South Africa, October 10-13, 2011. When embarking on my career as a teacher at a special school in South Africa, I never thought that a motor vehicle accident would place me in the position where my learners with disabilities suddenly saw me as an ally. Little did I realise the chasm that exists between able-bodied people and people with disabilities, or the remarkable role I would find myself in whilst actively addressing disability and Inclusive Education issues. My experiences with disability in South Africa drew encouraging attention from delegates at the Disabled People's International 8th World Assembly when I shared my story. The resounding positive response affirmed that my experiences are not unique to nationality, gender, race or age, and are typical of the time and country in which I live, where people with disabilities are considered to have little potential, and woman with disabilities are further marginalised. In the infancy of our democracy, we are still in the early days of attending to equity amongst all South Africans. This story comprises both a narrative and a graphic presentation which run parallel, although not always telling an identical story; they complement one another and should be experienced simultaneously. Ultimately, it relates the success that can be achieved by pro-active people with disabilities as members of the South African society within their own spheres of knowledge and skill to change attitudes and practices of people without disabilities in education and local communities.


Amphiphilic Nanoaggregates with Bimodal MRI and Optical Properties Exhibiting Magnetic Field Dependent Switching from Positive to Negative Contrast Enhancement.
Mixed micelles based on amphiphilic gadolinium(III)-DOTA and europium(III)-DTPA complexes were synthesized and evaluated for their paramagnetic and optical properties as potential bimodal contrast agents. Amphiphilic folate molecule for targeting the folate receptor protein, which is commonly expressed on the surface of many human cancer cells, was used in the self-assembly process in order to create nanoaggregates with targeting properties. Both targeted and nontargeted nanoaggregates formed monodisperse micelles having distribution maxima of 10 nm. The micelles show characteristic europium(III) emission with quantum yields of 2% and 1.1% for the nontargeted and targeted micelles, respectively. Fluorescence microscopy using excitation at 405 nm and emission at 575-675 nm was employed to visualize the nanoaggregates in cultured HeLa cells. The uptake of folate-targeted and nontargeted micelles is already visible after 5 h of incubation and was characterized with the europium(III) emission, which is clearly observable in the cytoplasm of the cells. The very fast longitudinal relaxivity r1 of ca. 26 s-1 mM-1 per gadolinium(III) ion was observed for both micelles at 60 MHz and 310 K. Upon increasing the magnetic field to 300 MHz, the nanoaggregates exhibited a large switching to transversal relaxivity with r2 value of ca. 52 s-1 mM-1 at 310 K. Theoretical fitting of the 1H NMRD profiles indicate that the efficient T1 and T2 relaxations are sustained by the favorable magnetic and electron-configuration properties of the gadolinium(III) ion, rotational correlation time, and coordinated water molecule. These nanoaggregates could have versatile application as a positive contrast agent at the currently used magnetic imaging field strengths and a negative contrast agent in higher field applications, while at the same time offering the possibility for the loading of hydrophobic therapeutics or targeting molecules.


[Cognitive disorders in patients with myotonic dystrophy type I: a clinical and magnetic resonance study].
We studied 20 patients with myotonic dystrophy (MD) type I, mean age 34.4±12.3 years. A control group consisted of 10 healthy people, mean age 35.2±13.7 years. Cognitive status was assessed using the Brief Cognitive Rating Scale (BCRS), the Frontal Assessment battery (FAB), the Clock drawing test, the Luria memory ten-word retrieval test. The characteristic signs for cognitive deficit in MD were disturbances of visual-spatial functions revealed even in patients with high score on BCRS and FAD, the decrease in verbal fluency, generalization ability and the volume of auditory-speech memory. MRI data indicate the involvement of the gray matter (cortex athrophy) and the white matter (dilatation of the ventricular system, strengthening of the perivascular spaces, areas of T2 and FLAIR hyperintensity) in the pathological process. The lesion of the white matter in MD is similar to the imaging of demyelinization that should be taken into account in making the diagnosis by experts in neuroimaging, neurologists and geneticists.


Comparative analysis of mouse skeletal muscle fibre type composition and contractile responses to calcium channel blocker.
In this study, we examined the correlation between excitation-contraction coupling characteristics and skeletal muscle fibre type by (1) localizing the distribution of dihydropyridine receptor (DHPR) protein and (2) comparing the effect of DHPR blocker on muscles with different fibre type composition, in order to better understand the differences between contractile phenotypes of fibres and to explain the contradictory reports to date on the interaction of dihydropyridines with skeletal muscle isoform of DHPR. Histochemical experiments revealed that fluorophore conjugated dihydropyridines stain selectively the membranes of muscle fibres. The staining was most evident in type IIA fibres. The major fibre type in gluteus and femoris, revealed by mATPase staining, was IIA (45.0 and 38.1 %, respectively). In gastrocnemius the content of IIA fibres was 22.7 %. Contraction forces before and after the addition of blocker for the three muscles investigated were: gluteus 0.075 +/- 0.017 N vs. 0.052 +/- 0.011 N, femoris 0.045 +/- 0.005 N vs. 0.033 +/- 0.005 N and gastrocnemius 0.089 +/- 0.016 N vs. 0.075 +/- 0.014 N, respectively. The attenuation of contraction force proportional to the cross-sectional area of the muscle was significantly (P = 0.023) higher in gluteus (28.3 +/- 3.5 %) and femoris (27.6 +/- 3.2 %) as compared to gastrocnemius (16.1 +/- 2.5 %). However, no significant change in the control measurements was observed ruling out the possibility of fatigue. The results indicate that the attenuation of the contraction force was largest in muscles with a high percentage of type IIA fibres. This supports our finding that the abundance of dihydropyridine receptors of IIA fibres outnumbers that in the other fibre types. The present data show that the correlation of density of dihydropyridine receptors can be one of the important factors influencing the overall contractile properties of the muscle and for its part explain the contradictory results of previous studies on coupling process.


Schizophrenia, bipolar disorder and depression. A discriminant analysis, using 'lifetime' psychopathology ratings.
Discriminant and canonical variate analyses were performed using 302 patients, on whom ratings of lifetime psychopathology and course of illness has been made. DSM-III diagnoses were used to form the criterion groups. Bipolar disorder emerged as a distinct grouping, but there are reasons for dissatisfaction with its definition. The remaining patients formed a 'schizodepressive continuum', but this also had a tendency to bimodality. It is possible that the distinction between schizophrenia and depression was obscured by inadequacies in the data and the inclusion of excessive numbers of patients with schizoaffective depression in this study.


Recent advances in controlled release pulmonary therapy.
Delivering therapeutic agents to the airways maximizes their concentration in lung tissue, decreasing systemic exposure or facilitating systemic absorption as desired. Many formulations exist for the treatment of respiratory illnesses however, no controlled release inhalation formulation exists to-date. This review is an update of the current advances in controlled release inhalation formulations and evaluation. The major successful particle engineering strategies are discussed along with potential in vitro and in vivo methodologies required for their characterisation. Controlled release formulation has many challenges to overcome, specific to this kind of medicament for inhalation. With small particle size and thus an increase in surface area, it becomes more difficult to achieve an effective controlled release profile. In addition, the physiology of the lung and its impact on resident particles need to be considered. An important issue when developing controlled release inhalation formulation is the toxic, inflammatory and accumulation effects of the release modifying agents used. These effects will need to be scrutinized in much greater detail in order to bring these formulations to the market. Currently, strategies for controlling the release of inhalation therapy include molecular dispersions (liposomal-based systems), solid lipid microparticles, coating or encapsulating drug particles in a lipid outer shield, solid biodegradable (synthetic and natural excipient-based matrices), conjugates and viscous semisolid vehicles. However, the availability of standardized pharmacopoeia methodologies to test the in vitro release rates or in vivo methodologies to evaluate deposition, pharmacokinetics and clearance of controlled release systems are not available. These methodologies are presented and discussed in this review.


Efficient one-pot synthesis of amino-benzotriazolodiazocinone scaffolds via catalyst-free tandem Ugi-Huisgen reactions.
Herein we describe a catalyst-free, one-pot procedure employing an Ugi-4CR between propargyl glycine, functionalised 2-azidoanilines, different isocyanides and aldehydes, followed by a thermal azide-alkyne Huisgen cycloaddition to generate a 14-member set of amino-benzotriazolodiazocine-bearing dipeptides with multiple points of diversification and high atom economy. These structures were derivatized by means of Suzuki-Miyaura cross-coupling reactions at two positions with good to excellent yields, leading to conformationally constrained tricyclic structures. In silico and NMR conformational analysis studies demonstrated that turn conformations are adopted by these structures.


Irinotecan Plus Gemcitabine and Fluorouracil in Advanced Biliary Tract Cancer: A Retrospective Study.
Since 2010, combination therapy with gemcitabine and cisplatin is the standard treatment for patients with biliary tract cancer (BTC) based on the ABC-02 trial. However, treatment after first-line progression is less clearly defined. We therefore retrospectively analyzed the efficacy of a 3-drug chemotherapy regimen in patients with advanced BTC. Patients with advanced BTC treated with palliative chemotherapy between April 2000 and October 2005 at Regensburg University Hospital were reviewed retrospectively. We analyzed the efficacy and safety of an institutional standard 3-drug regimen consisting of irinotecan, gemcitabine and 5-FU (IGF). One cycle, lasting 21 days, included applications on days 1 and 8 consisting of 75 mg/m2 irinotecan i.v. for 90 min, 1,000 mg/m2 gemcitabine i.v. for 30 min and 2,000 mg/m2 fluorouracil (5-FU) for 24 h. A total of 12 histologically confirmed cases with gallbladder cancer and intrahepatic BTC were reviewed. Fifty percent of the patients (6/12) had been pretreated with other chemotherapies. Median progression-free survival was 9.4 months (1.5-21.5) and median overall survival was 17.2 months (2.5-24.3). Only neutropenia (8%) was observed as an NCI-CTC grade 3 toxicity. Anemia and leucopenia grades 1 and 2 were the most common side effects. The combination of IGF shows a promising survival benefit with manageable toxicity in patients with advanced BTC. Therefore, this regimen seems to be a feasible second-line treatment option for patients with rapid progression under first-line therapy with gemcitabine and cisplatin and with a good performance status.


Candidemia in non-ICU surgical wards: Comparison with medical wards.
Candidemia acquired outside critical care or hematological areas has received much attention in recent years; however, data on candidemia in surgical departments are very scarce. Our objectives were to describe episodes of candidemia diagnosed in surgical wards and to compare them with episodes occurring in medical wards. We performed a post hoc analysis of a prospective, multicenter study implemented in Spain during 2010-2011 (CANDIPOP project). Of the 752 episodes of candidemia, 369 (49.1%) occurred in patients admitted to surgical wards (165, 21.9%) or medical wards (204, 27.2%). Clinical characteristics associated with surgical patients were solid tumor as underlying disease, recent surgery, indwelling CVC, and parenteral nutrition. Candidemia was more commonly related to a CVC in the surgical than in the medical wards. The CVC was removed more frequently and early management was more appropriate within 48 hours of blood sampling in the surgical patients. Overall, 30-day mortality in the surgical departments was significantly lower than in medical wards (37.7% vs. 15.8%, p<0.001). Multivariate analysis revealed admission to a surgical ward and appropriate early management of candidemia as factors independently associated with a better outcome. We found that approximately 50% of episodes of candidemia occurred in non-hematological patients outside the ICU and that clinical outcome was better in patients admitted to surgical wards than in those hospitalized in medical wards. These findings can be explained by the lower severity of underlying disease, prompt administration of antifungal therapy, and central venous catheter removal.


Caspase-1 activation by NLRP3 inflammasome dampens IL-33-dependent house dust mite-induced allergic lung inflammation.
The cysteine protease caspase-1 (Casp-1) contributes to innate immunity through the assembly of NLRP3, NLRC4, AIM2, and NLRP6 inflammasomes. Here we ask whether caspase-1 activation plays a regulatory role in house dust mite (HDM)-induced experimental allergic airway inflammation. We report enhanced airway inflammation in caspase-1-deficient mice exposed to HDM with a marked eosinophil recruitment, increased expression of IL-4, IL-5, IL-13, as well as full-length and bioactive IL-33. Furthermore, mice deficient for NLRP3 failed to control eosinophil influx in the airways and displayed augmented Th2 cytokine and chemokine levels, suggesting that the NLPR3 inflammasome complex controls HDM-induced inflammation. IL-33 neutralization by administration of soluble ST2 receptor inhibited the enhanced allergic inflammation, while administration of recombinant IL-33 during challenge phase enhanced allergic inflammation in caspase-1-deficient mice. Therefore, we show that caspase-1, NLRP3, and ASC, but not NLRC4, contribute to the upregulation of allergic lung inflammation. Moreover, we cannot exclude an effect of caspase-11, because caspase-1-deficient mice are deficient for both caspases. Mechanistically, absence of caspase-1 is associated with increased expression of IL-33, uric acid, and spleen tyrosine kinase (Syk) production. This study highlights a critical role of caspase-1 activation and NLPR3/ASC inflammasome complex in the down-modulation of IL-33 in vivo and in vitro, thereby regulating Th2 response in HDM-induced allergic lung inflammation.


annotatr: genomic regions in context.
Analysis of next-generation sequencing data often results in a list of genomic regions. These may include differentially methylated CpGs/regions, transcription factor binding sites, interacting chromatin regions, or GWAS-associated SNPs, among others. A common analysis step is to annotate such genomic regions to genomic annotations (promoters, exons, enhancers, etc.). Existing tools are limited by a lack of annotation sources and flexible options, the time it takes to annotate regions, an artificial one-to-one region-to-annotation mapping, a lack of visualization options to easily summarize data, or some combination thereof. We developed the annotatr Bioconductor package to flexibly and quickly summarize and plot annotations of genomic regions. The annotatr package reports all intersections of regions and annotations, giving a better understanding of the genomic context of the regions. A variety of graphics functions are implemented to easily plot numerical or categorical data associated with the regions across the annotations, and across annotation intersections, providing insight into how characteristics of the regions differ across the annotations. We demonstrate that annotatr is up to 27× faster than comparable R packages. Overall, annotatr enables a richer biological interpretation of experiments. http://bioconductor.org/packages/annotatr/ and https://github.com/rcavalcante/annotatr. email@example.com. Supplementary data are available at Bioinformatics online.


Greenland Ice Core Record of Last Glacial Dust Sources and Atmospheric Circulation.
Abrupt and large-scale climate changes have occurred repeatedly and within decades during the last glaciation. These events, where dramatic warming occurs over decades, are well represented in both Greenland ice core mineral dust and temperature records, suggesting a causal link. However, the feedbacks between atmospheric dust and climate change during these Dansgaard-Oeschger events are poorly known and the processes driving changes in atmospheric dust emission and transport remain elusive. Constraining dust provenance is key to resolving these gaps. Here, we present a multi-technique analysis of Greenland dust provenance using novel and established, source diagnostic isotopic tracers as well as results from a regional climate model including dust cycle simulations. We show that the existing dominant model for the provenance of Greenland dust as sourced from combined East Asian dust and Pacific volcanics is not supported. Rather, our clay mineralogical and Hf-Sr-Nd and D/H isotopic analyses from last glacial Greenland dust and an extensive range of Northern Hemisphere potential dust sources reveal three most likely scenarios (in order of probability): direct dust sourcing from the Taklimakan Desert in western China, direct sourcing from European glacial sources, or a mix of dust originating from Europe and North Africa. Furthermore, our regional climate modeling demonstrates the plausibility of European or mixed European/North African sources for the first time. We suggest that the origin of dust to Greenland is potentially more complex than previously recognized, demonstrating more uncertainty in our understanding dust climate feedbacks during abrupt events than previously understood.


Adhesive Carbon Paste Electrode for Convenient and Long-term Electrocardiogram Monitoring: A Pilot Study.
Long-term electrocardiogram (ECG) monitoring is an important and widely-used technique in the clinic that helps with the diagnosis of possible diseases that cannot be detected in a short time monitoring. However, the clinically used electrode needs conductive gel to reduce the impedance between the skin and the electrodes, which easily causes the possibility of allergy. Moreover, as the conductive gel becomes dry, the signal's quality will decrease accordingly. In this paper, we proposed a novel adhesive Carbon Paste Electrode (CPE) to achieve convenient and long-term ECG monitoring. By comparing the time-domain waveforms, the R-R peak intervals difference, and the Signal-to-Noise Ratio (SNR) of ECG with the traditional conductive gel-based electrode (Gel) in fixed and unfixed conditions, the performance of the proposed CPE was investigated. The results showed that the CPE could achieve similar ECG monitoring both in fixed and unfixed conditions. When on Day 2, the quality acquired by Gel began to decrease while CPE was still stable, which was obvious especially in unfixed condition. The R-R peak intervals showed that on Day 2, the Gel was unreliable with some abnormal points occurring. Besides, the results of SNR and average heart rate (AHR) also confirmed that the CPE could achieve similar results as Gel on Day 1 and outperformed Gel on Day 2. It is believed that the proposed CPE opens a window of high-quality long-term ECG monitoring with more convenience.


Three-dimensional CT angiography assessment of the impact of the dermis and the subdermal plexus in DIEP flap perfusion.
Single-stage breast reconstruction following skin-sparing or nipple-sparing mastectomy with free deep inferior epigastric perforator (DIEP) flap usually does not require a large skin paddle. Most of the flap skin paddle is removed, and the flap is placed under native, conserved skin to provide adequate volume to the reconstructed breast mound. We hypothesized that conservation of intact dermis and its subdermal plexus has a critical role in overall flap perfusion through recruitment of indirect linking vessels. The study goal was to investigate and compare the vascularity of DIEP flaps with intact dermis versus DIEP flaps with the dermis removed. Twelve hemi-DIEP flaps were harvested from fresh cadavers. The largest dominant perforator was cannulated using a 24-gauge butterfly catheter. Flaps were imaged with computed tomography (CT) after injection of a contrast agent. After scanning, the contrast agent was flushed out of the flap. The flap skin was removed with cautery at the subdermal dissection plane. The flaps were reimaged with CT after injection of the contrast agent. Three-dimensional (3-D) CT angiographic reconstructions were obtained for each protocol stage, and the percentage of flap perfusion was calculated. Flap vascularity with and without dermis was compared. A mean difference of 25.9% in flap perfusion occurred when the dermis was removed (P < 0.001). The 3-D CT angiographic images showed that the impact of dermis excision was caused by interrupting the recurrent flow through the dermis and subdermal plexus via indirect linking vessels. The dermis has a significant role in enhancing overall DIEP flap perfusion through preservation of indirect linking vessels organized in the subdermal plexus. Despite being time consuming, a cautious de-epithelialization of the DIEP flap should be performed to retain dermis integrity. Enhancement of flap vascularity ultimately leads to a decrease in such complications as partial or total flap necrosis, as well as fat necrosis.


Langasite surface acoustic wave gas sensors: modeling and verification.
We report finite element simulations of the effect of conductive sensing layers on the surface wave velocity of langasite substrates. The simulations include both the mechanical and electrical influences of the conducting sensing layer. We show that three-dimensional simulations are necessary because of the out-of-plane displacements of the commonly used (0, 138.5, 26.7) Euler angle. Measurements of the transducer input admittance in reflective delay-line devices yield a value for the electromechanical coupling coefficient that is in good agreement with the three-dimensional simulations on bare langasite substrate. The input admittance measurements also show evidence of excitation of an additional wave mode and excess loss resulting from the finger resistance. The results of these simulations and measurements will be useful in the design of surface acoustic wave gas sensors.


Next-generation sequencing for endocrine cancers: Recent advances and challenges.
Contemporary molecular biology research tools have enriched numerous areas of biomedical research that address challenging diseases, including endocrine cancers (pituitary, thyroid, parathyroid, adrenal, testicular, ovarian, and neuroendocrine cancers). These tools have placed several intriguing clues before the scientific community. Endocrine cancers pose a major challenge in health care and research despite considerable attempts by researchers to understand their etiology. Microarray analyses have provided gene signatures from many cells, tissues, and organs that can differentiate healthy states from diseased ones, and even show patterns that correlate with stages of a disease. Microarray data can also elucidate the responses of endocrine tumors to therapeutic treatments. The rapid progress in next-generation sequencing methods has overcome many of the initial challenges of these technologies, and their advantages over microarray techniques have enabled them to emerge as valuable aids for clinical research applications (prognosis, identification of drug targets, etc.). A comprehensive review describing the recent advances in next-generation sequencing methods and their application in the evaluation of endocrine and endocrine-related cancers is lacking. The main purpose of this review is to illustrate the concepts that collectively constitute our current view of the possibilities offered by next-generation sequencing technological platforms, challenges to relevant applications, and perspectives on the future of clinical genetic testing of patients with endocrine tumors. We focus on recent discoveries in the use of next-generation sequencing methods for clinical diagnosis of endocrine tumors in patients and conclude with a discussion on persisting challenges and future objectives.


NIH Funds Pediatric Data Resource Center.
Children's Hospital of Philadelphia will lead a collaborative effort-funded with $14.8 million from the NIH-to pool genomic and phenotypic data from tens of thousands of patients to study the causes of pediatric cancer and structural birth defects.


Dexamethasone receptor levels in palatal and lung fibroblasts of adult A/J and C57BL/6J mice: relationship to glucocorticoid-induced cleft palate.
Glucocorticoid-induced cleft palate (CP) has been used as an animal model for hormonal teratogenesis. In mice, the susceptibility to glucocorticoid-induced CP varies with the strain, A/J being very sensitive and C57/BL6J relatively resistant. Studies in adult and embryonic murine tissues have attempted to correlate the number of glucocorticoid receptors and CP susceptibility, with conflicting results. The relative quantities of dexamethasone receptors were now studied in established palatal and lung fibroblast cell cultures obtained from adult C57 and A/J mice. A rapidly saturable, stable binding system was demonstrated. Scatchard plots were linear indicating a single class of high affinity receptors. The glucocorticoid receptor number ranged from 6.2 x 10(-16) mole/microgram prot to 8.6 x 10(-16) mole/microgram prot, while the KD varied from 1.0 x 10(-8) M to 2.8 x 10(-8) M. The differences in receptor characteristics between murine strains were not significant (p greater than 0.05). The absence of a difference in receptor number between the two strains may reflect the limitation of fibroblast cell culture in assessing glucocorticoid binding in vivo. Alternatively, if a difference in palatal dexamethasone receptor levels between mice strains exists, it may occur only in the embryo.


Induction of oral tolerance to prevent diabetes with transgenic plants requires glutamic acid decarboxylase (GAD) and IL-4.
Induction of specific immunological unresponsiveness by feeding protein antigens is termed oral tolerance and may be a potential therapy for autoimmune diseases. Whereas oral tolerance therapy may be both simple and effective, the requirement for large amounts of protein will limit clinical testing of autoantigens, which are difficult to produce. We have previously demonstrated transgenic plant production and direct oral delivery of a beta cell autoantigen murine GAD67 to prevent autoimmune diabetes in nonobese diabetic mice. Mucosal adjuvants such as cholera toxin B subunit may lower the level of autoantigen required, but the development of neutralizing mucosal antibody responses may limit usefulness in enhancing long-term oral tolerance. IL-4, being an endogenous protein, would avoid this result and possibly enhance oral tolerance but has not been tested as a mucosal adjuvant. In this study, human GAD65 (hGAD65), as well as murine IL-4, was expressed in transgenic plants for feeding trials. Both IL-4 and hGAD65 plant tissue were required to protect nonobese diabetic mice from diabetes, and no benefit was found if either was used alone. Combined therapy enhanced levels of IgG1 anti-GAD antibodies, increased splenocyte IL-4/IFN-gamma cytokine responses, and produced protective regulatory T cells. These results demonstrate that orally administered plant IL-4 remains biologically active and is synergistic when given with hGAD65 in inducing robust oral immune tolerance. Using transgenic plants expressing IL-4 and GAD65 may be a novel clinical approach to the prevention of human type 1 diabetes by oral tolerance.


Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective, randomized phase III trial of the Italian Society for Integrated Locoregional Therapy in Oncology.
Gemcitabine is considered the gold standard treatment for unresectable pancreatic adenocarcinoma. Intra-arterial drug administration had shown some interesting results in small phase II studies. In this study, patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or FLEC: 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluorouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles. The primary endpoint was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=0.036). Survival at 1 year increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=0.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both groups (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma.


Presynaptic membrane of inhibitory crayfish axon terminals is stained by antibodies raised against mammalian GABA(A) receptor subunits alpha3 and beta(2/3).
The opener muscle of the dactyl of the walking leg of crayfish is innervated by one excitatory axon releasing glutamate and one inhibitory axon releasing GABA. Functional GABA(A) receptors are present postsynaptically on the muscle and presynaptically on terminals and release boutons of the excitatory axon, whereas presynaptic GABA(A) autoreceptors have not been reported on terminals or release boutons of the inhibitory axon. Using antibodies raised against mammalian GABA(A) receptor subunits alpha3 and beta(2/3), we obtained highly specific staining of the presynaptic membrane of the inhibitory bouton and of the postsynaptic membrane of the muscle. Using pre- and postembedding techniques, staining was localized to only presynaptic and postsynaptic membranes of synaptic active zones. We also found extrasynaptic receptor subunit immunoreactivity near (up to 100 nm) to the active zones. Staining with antibodies for the alpha3 and beta(2/3) subunits showed colocalization of particles of the two subunits. We suggest that presynaptic inhibitory boutons of the crayfish possess GABA(A)-like autoreceptors composed of at least the alpha3 and beta(2/3) subunits.


Moderate hypothermia induces a preferential increase in pancreatic islet blood flow in anesthetized rats.
The aim of the study was to characterize the effects of induced moderate hypothermia on splanchnic blood flow, with particular reference to that of the pancreas and the islets of Langerhans. We also investigated how interference with the autonomic nervous system at different levels influenced the blood perfusion during hypothermia. For this purpose, hypothermia (body temperature of 28 degrees C) was induced by external cooling, whereas normothermic (37.5 degrees C) anesthetized Sprague-Dawley rats were used as controls. Some rats were pretreated with either propranolol, yohimbine, atropine, hexamethonium, or a bilateral abdominal vagotomy. Our findings suggest that moderate hypothermia elicits complex, organ-specific circulatory changes, with increased perfusion noted in the pylorus, as well as the whole pancreas and the pancreatic islets. The pancreatic islets maintain their high blood perfusion through mechanisms involving both sympathetic and parasympathetic mediators, whereas the increased pyloric blood flow is mediated through parasympathetic mechanisms. Renal blood flow was decreased, and this can be prevented by ganglionic blockade and is also influenced by beta-adrenoceptors.


Continuous stimulation of the plant immune system by the peptide elicitor PIP-1 is required for phytoalexin biosynthesis in tobacco cells.
The peptide elicitor PIP-1 (YGIHTH-nh2) induced various defense responses in tobacco cells. Types of defense responses induced by PIP-1 were different based on its concentration range: oxidative burst (an early response) was induced at low micromolar levels, but phytoalexin production (a late response) required about 10-50-fold higher concentrations than those required for oxidative burst. We assumed that rapid decreases in the PIP-1 concentration due to enzymatic hydrolysis in the culture media could cause this difference. To examine the potential impact of such degradation particularly on induction of phytoalexin biosynthesis, we designed a degradation-resistant analogue, MePIP-1, in which the amide bond between the fifth and sixth residues was N-methylated. MePIP-1 was considerably more stable than PIP-1 and induced significant phytoalexin production upon treatment at low micromolar levels. Further investigation of the mechanism of action of MePIP-1 showed a requirement of continuous elicitor stimulation for 3-6 h for the phytoalexin production, which is likely to be regulated by long-lasting MAP kinase activation.


Comparing cold and warm tumescent anesthesia for pain perception during and after the endovenous laser ablation procedure with 1470 nm diode laser.
The aim of this study was to compare the pain perception and side effects during and after endovenous laser ablation with a 1470 nm diode laser using cold or room temperature tumescence anesthesia. One hundred and one patients were randomly assigned in two groups. Group A received room temperature (+24℃) and Group B received cold (+4℃) tumescence fluid, which was used for local anesthesia in the track of great saphenous vein. A visual analog score was recorded immediately after the procedure. Patients were asked to register pain scores and the amount of pain medication consumed during the week. There was no significant difference concerning gender, age, Clinical Etiological Anatomical Pathological Classification, body mass index, or diameter of the treated vein. In Group A, the mean linear endovenous energy density was 59.5 J/cm and in Group B, it was 60.4 J/cm. The average visual analog score after the endovenous laser ablation procedure in Group A was 5 and in Group B was 2. Third day after the procedure, the average visual analog score in Group A was 3 and in Group B was 1. Patients in Group B needed significantly less analgesics compared with patients in Group A (p<0.05). The most frequent side effects in both groups were ecchymosis, induration, and minor paraesthesia, all of which were more common in Group A (p < 0.001). To date, most published endovenous laser ablation series describe the use of room temperature tumescence fluid infiltration of the perivenous stroma for tumescent analgesia and protection against thermal injury to the nearby structures. We describe an alternative technique using cold tumescence fluid infiltration, which is equally effective as, but safer than, room temperature tumescence fluid infiltration, and which yields better visual analog scores.


High-Velocity Impacts of Pyrophoric Alloy Fragments on Thin Armour Steel Plates.
The terminal ballistics effects of Intermetallic Reactive Materials (IRM) fragments have been the object of intense research in recent years. IRM fragments flying at velocities up to 2000 m/s represent a realistic threat in modern warfare scenarios as these materials are substituting conventional solutions in defense applications. The IRM add Impact Induced Energy Release (IIER) to the mechanical interaction with a target. Therefore, the necessity of investigations on IIER to quantify potential threats to existing protection systems. In this study, Mixed Rare Earths (MRE) fragments were used due to the mechanical and pyrophoric affinity with IRM, the commercial availability and cost-effectiveness. High-Velocity Impacts (HVI) of MRE were performed at velocities ranging from 800 to 1600 m/s and recorded using a high-speed camera. 70 MREs cylindrical fragments and 24 steel fragments were shot on armour steel plates with thicknesses ranging from 2 mm to 3 mm. The influence of the impact pitch angle (α) on HVI outcomes was assessed, defining a threshold value at α of 20°. The influence of the failure modes of MRE and steel fragments on the critical impact velocities (CIV) and critical kinetic energy (Ekin crit) was evaluated. An energy-based model was developed and fitted with sufficient accuracy the Normalised EKin crit (E˜kincrit) determined from the experiments. IIER was observed in all the experiments involving MRE. From the analyses, it was observed that the IIER spreads behind the targets with velocities comparable to the residual velocities of plugs and shattered fragment.


Turning Away From Industrial Health Care Toward Careful and Kind Care.
The health care industry is increasingly driven by the pursuit of value. The author of this Invited Commentary believes this value is nothing more than a business rebranding of efficiency with little connection to care. Overclocked clinicians, increasingly impaired by symptoms of burnout and too focused on documenting, cannot see patients in high definition. The author shows that treatment which is blind to patients' contexts often overwhelms patients with medical errands, a topic absent from medical curricula. Care must not be the means by which health care satisfies its industrial mission but, rather, the end for which it mobilizes its means. In unhurried consultations, clinicians must appreciate and respond sensibly to patients' problematic situation, and care for and about them. Medical training must cultivate future clinicians who value caring over caring for value. Medical educators and trainees at all levels must turn away from industrial health care, toward careful and kind care for all.


Let-7b expression determines response to chemotherapy through the regulation of cyclin D1 in glioblastoma.
Glioblastoma is the most common type of primary brain tumors. Cisplatin is a commonly used chemotherapeutic agent for Glioblastoma patients. Despite a consistent rate of initial responses, cisplatin treatment often develops chemoresistance, leading to therapeutic failure. Cellular resistance to cisplatin is of great concern and understanding the molecular mechanisms is an utter need. Glioblastoma cell line U251 cells were exposed to increasing doses of cisplatin for 6 months to establish cisplatin-resistant cell line U251R. The differential miRNA expression profiles in U251 and U251R cell lines were identified by microarray analysis and confirmed by Q-PCR. MiRNA mimics were transfected into U251R cells, and cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. U251R cells showed 3.1-fold increase in cisplatin resistance compared to its parental U251 cells. Microarray analysis identified Let-7b and other miRNAs significantly down-regulated in U251R cells compared to U251 cells. Transfection of Let-7b mimics greatly re-sensitized U251R cells to cisplatin, while transfection of other miRNAs has no effect or slightly effect. Cyclin D1 is predicted as a target of Let-7b through bioinformatics analysis. Over-expression of Let-7b mimics suppressed cyclin D1 protein expression and inhibited cyclin D1-3'-UTR luciferase activity. Knockdown of cyclin D1 expression significantly increased cisplatin-induced G1 arrest and apoptosis. Collectively, our results indicated that cisplatin treatment leads to Let-7b suppression, which in turn up-regulates cyclin D1 expression. Let-7b may serve as a marker of cisplatin resistance, and can enhance the therapeutic benefit of cisplatin in glioblastoma cells.


Immuno-Metabolic Modulation of Liver Oncogenesis by the Tryptophan Metabolism.
Metabolic rewiring in tumor cells is a major hallmark of oncogenesis. Some of the oncometabolites drive suppressive and tolerogenic signals from the immune system, which becomes complicit to the advent and the survival of neoplasia. Tryptophan (TRP) catabolism through the kynurenine (KYN) pathway was reported to play immunosuppressive actions across many types of cancer. Extensive debate of whether the culprit of immunosuppression was the depletion of TRP or rather KYN accumulation in the tumor microenvironment has been ongoing for years. Results from clinical trials assessing the benefit of inhibiting key limiting enzymes of this pathway such as indoleamine 2,3-dioxygenase (IDO1) or tryptophan 2,3-dioxygenase (TDO2) failed to meet the expectations. Bearing in mind the complexity of the tumoral terrain and the existence of different cancers with IDO1/TDO2 expressing and non-expressing tumoral cells, here we present a comprehensive analysis of the TRP global metabolic hub and the driving potential of the process of oncogenesis with the main focus on liver cancers.


Cost-effectiveness of strategies to prevent methicillin-resistant Staphylococcus aureus transmission and infection in an intensive care unit.
OBJECTIVE To create a national policy model to evaluate the projected cost-effectiveness of multiple hospital-based strategies to prevent methicillin-resistant Staphylococcus aureus (MRSA) transmission and infection. DESIGN Cost-effectiveness analysis using a Markov microsimulation model that simulates the natural history of MRSA acquisition and infection. PATIENTS AND SETTING Hypothetical cohort of 10,000 adult patients admitted to a US intensive care unit. METHODS We compared 7 strategies to standard precautions using a hospital perspective: (1) active surveillance cultures; (2) active surveillance cultures plus selective decolonization; (3) universal contact precautions (UCP); (4) universal chlorhexidine gluconate baths; (5) universal decolonization; (6) UCP + chlorhexidine gluconate baths; and (7) UCP+decolonization. For each strategy, both efficacy and compliance were considered. Outcomes of interest were: (1) MRSA colonization averted; (2) MRSA infection averted; (3) incremental cost per colonization averted; (4) incremental cost per infection averted. RESULTS A total of 1989 cases of colonization and 544 MRSA invasive infections occurred under standard precautions per 10,000 patients. Universal decolonization was the least expensive strategy and was more effective compared with all strategies except UCP+decolonization and UCP+chlorhexidine gluconate. UCP+decolonization was more effective than universal decolonization but would cost $2469 per colonization averted and $9007 per infection averted. If MRSA colonization prevalence decreases from 12% to 5%, active surveillance cultures plus selective decolonization becomes the least expensive strategy. CONCLUSIONS Universal decolonization is cost-saving, preventing 44% of cases of MRSA colonization and 45% of cases of MRSA infection. Our model provides useful guidance for decision makers choosing between multiple available hospital-based strategies to prevent MRSA transmission.


[Safety and efficacy of movalis injected into trigger points in lumbago-ischialgia syndrome].
Efficacy and safety of movalis (meloxicam) injected into trigger points of 94 patients with vertebrogenic lumbago-ischialgia syndrome have been assessed. Patients have been stratified into 3 randomized groups: the first group received 3 injections of movalis into trigger points with the following administration of tablets (15 mg per day); 2nd group received - 3 intramuscular injection movalis with the following administration of tablets (15 mg per day); 3nd - was control. Treatment efficacy has been assessed with the Visual-Analogous scale, a five-point scale for assessment of vertebroneurological symptoms, the Oswestry Disability Index, the McGill Pain Questionnaire, stimulating ENMG. Patients treated with movalis injections into trigger points and intramuscular had no local side-effects. The analgesic effect was more pronounced after three injections into trigger points compared to the intramuscular injection. The efficacy of treatment was the highest in the first group (75,6%) comparing to the 2nd (64,3%) and the 3rd (33,3%) ones.


Maternal deprivation alters epithelial secretory cell lineages in rat duodenum: role of CRF-related peptides.
Chronic psychological stress is associated with development of intestinal barrier dysfunction and impairs host defence mechanisms. The intestinal epithelium, consisting of enterocytes, endocrine cells, goblet cells and Paneth cells, is an important component of this barrier. In the present study, the impact of maternal deprivation (MD) on secretory lineages of duodenal epithelium and the involvement of the peripheral corticotropin-releasing factor (CRF) pathway were investigated. Rat pups were deprived of their dam for 3 h/day (days 5-20). Non-deprived pups served as controls. On days 8, 13, 20, 24, 34, 44 and 84, duodenal tissues were collected for quantitative real-time PCR and immunohistochemistry studies. MD induced a sustained decrease in the number of Paneth and goblet cells but hyperplasia of endocrine cells. These alterations were associated with a duodenal increase of CRF, urocortin 2 and CRF receptor subtype 2 (CRFR(2)) mRNA, whereas CRFR(1) expression was decreased. The effects of MD on intestinal epithelium were inhibited by the CRFR(1)/R(2) antagonist astressin injected daily before MD. Studies using specific receptor antagonists in rats subjected to MD revealed that CRFR(1) was involved in the hyperplasia of endocrine cells and CRFR(2) in the depletion of Paneth cells. Conversely, daily injection of CRF and of the CRFR(2) agonist urocortin 2 in control rats resulted in changes in epithelial differentiation similar to MD. The activation of CRFR(1) and CRFR(2) induced by MD markedly altered the quantitative distribution of secretory cells of the intestinal epithelium. These alterations, in particular the depletion of Paneth and goblet cells, may create conditions leading to the development of an epithelial barrier defect.


ENT involvement and orobuccal movements' disorders in Pandas patients: assessment and rehabilitations tools.
PANDAS are known as the spectrum of autoimmune pathologies related to a previous or current infection by group A beta-hemolytic streptococcus (SBEGA), dealing with several neuropsychiatric manifestations that mainly affect pediatric age. The main features consist of behavioral disease or movement disease characterized by acute-onset, presenting especially through infant period or adolescence. Specific manifestations, occurring during the progression of the disease, are the presence of otorhinolaryngologic symptoms (ENT) and orofacial movement disorders associated with temporomandibular joint pain. We enrolled 130 children (5-15 years) with a clinical diagnosis of PANDAS between 2012 and 2018. Participants were assessed using ENT specific parameters, PSG to examine respiratory disorders and conventional audiological evaluation. Descriptive and comparative statistical analyses were performed with a control group of 51 healthy patients. The prevalence of ENT symptoms associated was significantly detected in 88 patients of 130 in Group A (relative frequency (%) 67.6; p=0.041) and in 51 patients of 130 in the control Group B (relative frequency (%) 39.2; p=0.063). In relation to prevalence of SDB, 54 subjects have presented nocturnal respiratory obstructive symptoms from mild to severe (relative frequency (%) 61.3; p=0.033) vs. 20 patients of Group B (relative frequency (%) 39.2; p=0.055). The obstructive severity average type was correlated to the consensual adenotonsillar development (size 3-4), (relative frequency (%) 45.4; p=0.047). The audiological deficits found were mostly of transmissive type with OME correlated and linked to the presence of occasional episodes of AOM. The four PANDAS patients who presented orobuccal dystonia (relative frequency (%) 4.54; p=0.091) achieved an improvement of the algic symptoms through the exercises of self-rehabilitation. Findings from our study show that respiratory diseases, characterizing a group of patients with pandas, are the direct consequences of the malformed or hypertrophic condition and suggesting in these conditions surgical therapy as an approaching tool.


A study of hand injury and emergency management in a developing country.
Injury to the underlying structures of the hand carries the potential for serious handicap. To reduce this risk, even the smallest hand injuries require proper medical care. To assess wound healing, mobility, and the ability to perform normal essential function post-operatively in open hand injuries associated with fracture. Thirty patients with 45 metacarpal and phalangeal fractures of the hand were divided into three groups: Group 1 (n = 13) cases with single fractures of hand, excluding thumb; Group 2 (n = 9) cases with multiple fracture of hand, excluding thumb; Group 3 (n = 8) cases with fractures involving thumb and first metacarpal. Tendon injuries were repaired. For fractures, Kirschner wire fixation was done. In two cases with multiple fractures, Joshi's external support system (JESS) fixator was applied. Patients were followed up for 12 weeks. One patient with proximal phalangeal fracture developed extension lag. No stiffness was observed in any of the cases treated by intramedullary Kirschner wire fixation. No non-union or delayed union was observed following cross-wire fixation with two Kirschner wires. Two case of open fracture developed superficial infection. Two patients with multiple fractures developed angulation at fracture site after the Kirschner wires were removed 4 weeks postoperatively, and two cases of multiple fractures developed hypertrophic non-union. Delicate handling of tissues, preservation of gliding planes for tendons, prevention of infection, accurate reduction and fixation, and early and appropriate physiotherapy affect prognosis in case of hand injuries.


The neural networks of inhibitory control in posttraumatic stress disorder.
Posttraumatic stress disorder (PTSD) involves deficits in information processing that may reflect hypervigilence and deficient inhibitory control. To date, however, no PTSD neuroimaging study has directly examined PTSD-related changes in executive inhibition. Our objective was to investigate the hypothesis that executive inhibitory control networks are compromised in PTSD. Functional magnetic resonance imaging (fMRI) was used during a Go/No-Go inhibition task completed by a sample of patients with PTSD (n = 23), a matched sample of healthy (i.e. without trauma exposure) control participants (n = 23) and a sample of control participants with trauma exposure who did not meet criteria for PTSD (n = 17). Participants with PTSD showed more inhibition-related errors than did individuals without trauma exposure. During inhibition, control participants activated a right-lateralized cortical inhibitory network, whereas patients with PTSD activated only the left lateral frontal cortex. PTSD was associated with a reduction in right cortical activation and increased activation of striatal and somatosensory regions. The increased inhibitory error and reduced right frontal cortical activation are consistent with compromised inhibitory control in PTSD, while the increased activation of brain regions associated with sensory processing and a greater demand on inhibitory control may reflect enhanced stimulus processing in PTSD, which may undermine cortical control mechanisms.


Genetic variation in spontaneous ovulation rate and LH receptor induction in mice.
Selection for litter size (Line S1) and for post-weaning body weight gain (Line G) increased spontaneous ovulation rate in mature females by 69 and 73%, respectively, over that of randomly bred control mice (Line C). Inbreeding from S1 mice with selection for litter size produced highly inbred lines with elevated ovulation rates. Inbreeding from Line C mice produced a 21% divergence among lines, but did not depress the mean ovulation rate. Crosses of these lines revealed little heterosis in ovulation rate. LH receptors were induced by treating females from 22 days of age with diethylstilboestrol for 4 days and FSH for 2 days. The in-vitro binding of 125I-labelled hCG per microgram DNA decreased 56% in response to selection for litter size and increased 57% in response to selection for body weight gain, indicating high susceptibility of this trait to genetic change. Inbreeding from Line C mice produced a 135% divergence amongst lines, but did not depress the mean LH receptor induction. Body weight had significant effects on ovulation rate and LH receptor induction. These results show that selection for litter size and for rapid post-weaning body weight gain increases ovulation rate, but we suggest that different mechanisms are involved in these responses.


Listening with a narrative ear: Insights from a study of fall stories in older adults.
To determine the value of adding a patient narrative to the clinical assessment of falls in the elderly. Qualitative study of interviews. A fall prevention clinic in Calgary, Alta. Fifteen older adults on a wait list for assessment by the fall clinic and the physiotherapists who assessed them. Participants' stories were audiorecorded and later transcribed and summarized. Stories were collected using open-ended questions, first inviting participants to tell the interviewer about themselves, and then the circumstances of their falls and their reflections on them. In a subsequent visit, transcriptions or summaries were returned to patients for member checking. Narratives were read and analyzed by all 4 investigators using a narrative approach and a close-reading technique. With the patients' additional consent, stories were shared with the fall prevention team for their insights and reactions. Interviews with physiotherapists were audiorecorded and transcribed. The narrative analysis provided new insights into the attitudes about and perceptions of the causes of falls, their effects, and rehabilitation. Close reading exposed presentation of self, locus of control, and underlying social and emotional issues. The addition of patient narratives to clinical assessments offers clinicians an understanding of patients' perspectives, which can be used to better engage patients in rehabilitation.