Tamoxifen blocks retrograde trafficking of Shiga toxin 1 and 2 and protects against lethal toxicosis.
Shiga toxin 1 (STx1) and 2 (STx2), produced by Shiga toxin-producing Escherichia coli, cause lethal untreatable disease. The toxins invade cells via retrograde trafficking. Direct early endosome-to-Golgi transport allows the toxins to evade degradative late endosomes. Blocking toxin trafficking, particularly at the early endosome-to-Golgi step, is appealing, but transport mechanisms of the more disease-relevant STx2 are unclear. Using data from a genome-wide siRNA screen, we discovered that disruption of the fusion of late endosomes, but not autophagosomes, with lysosomes blocked the early endosome-to-Golgi transport of STx2. A subsequent screen of clinically approved lysosome-targeting drugs identified tamoxifen (TAM) to be a potent inhibitor of the trafficking and toxicity of STx1 and STx2 in cells. The protective effect was independent of estrogen receptors but dependent on the weak base property of TAM, which allowed TAM to increase endolysosomal pH and alter endosomal dynamics. Importantly, TAM treatment enhanced survival of mice injected with a lethal dose of STx1 or STx2. Thus, it may be possible to repurpose TAM for treating Shiga toxin-producing E. coli infections.


Radiologic features of the solitary rectal ulcer syndrome.
A radiologic study of 4 biopsy-proven cases of the solitary rectal ulcer (S.R.U.) syndrome was undertaken. The radiologic findings of S.R.U. were rectal stenosis (one with ulcer), polypoid rectal mass, and multiple sub-mucosal defects with shallow ulcers. The S.R.U., which is benign and requires only dietetic treatment, must be differentiated from other more serious entities such as neoplastic and inflammatory bowel disease.


Calcium Intake among Myanmar Residing in Bago, Kayin, and Yangon Areas.
A cross-sectional survey combined with 24-hour dietary recall and food diary was undertaken to assess the calcium intake of the Myanmar population. The study was conducted from November 2003 to October 2005. A total of 886 subjects of both sexes aged above 2 years from three States and Divisions (Bago, Kayin, and Yangon) of Myanmar were included in the study. The major measures were mean daily calcium intake (mg/day) and major sources of calcium in the diet. Overall mean calcium intake was 197+13mg/day (2-9 years), 421+2mg/day (10-19 years), 399+21 mg/day (20-49 years), and 383+25mg/day (>50 years) for males, while the corresponding values for females were 207+17 mg/day, 366+19 mg/day, 387+16 mg/day, and 327 +19 mg/day. Calcium intake was less than 80% of the recommended dietary allowances (RDA) for Myanmar for ages 2-9 years and 10-29 years in all the study areas, and for the 50 years and above age group in Yangon. Fish paste was found to be the major source of calcium. Milk and milk products contributed very little to total calcium intake, contributing 2.1% for residents in Yangon, 5.1% in Pa-an and none in Bago. Consumption of calcium rich foods, particularly milk and milk products, should be encouraged among the Myanmar people. Towards this end, appropriate nutrition education materials should be developed for promotional purposes.


Neuropeptide Y Expression Defines a Novel Class of GABAergic Projection Neuron in the Inferior Colliculus.
Located in the midbrain, the inferior colliculus (IC) integrates information from numerous auditory nuclei and is an important hub for sound processing. Despite its importance, little is known about the molecular identity and functional roles of defined neuron types in the IC. Using a multifaceted approach in mice of both sexes, we found that neuropeptide Y (NPY) expression identifies a major class of inhibitory neurons, accounting for approximately one-third of GABAergic neurons in the IC. Retrograde tracing showed that NPY neurons are principal neurons that can project to the medial geniculate nucleus. In brain slice recordings, many NPY neurons fired spontaneously, suggesting that NPY neurons may drive tonic inhibition onto postsynaptic targets. Morphologic reconstructions showed that NPY neurons are stellate cells, and the dendrites of NPY neurons in the tonotopically organized central nucleus of the IC cross isofrequency laminae. Immunostaining confirmed that NPY neurons express NPY, and we therefore hypothesized that NPY signaling regulates activity in the IC. In crosses between Npy1rcre and Ai14 Cre-reporter mice, we found that NPY Y1 receptor (Y1R)-expressing neurons are glutamatergic and were broadly distributed throughout the rostrocaudal extent of the IC. In whole-cell recordings, application of a high-affinity Y1R agonist led to hyperpolarization in most Y1R-expressing IC neurons. Thus, NPY neurons represent a novel class of inhibitory principal neurons that are well poised to use GABAergic and NPY signaling to regulate the excitability of circuits in the IC and auditory thalamus.SIGNIFICANCE STATEMENT The identification of neuron types is a fundamental question in neuroscience. In the inferior colliculus (IC), the hub of the central auditory pathway, molecular markers for distinct classes of inhibitory neurons have remained unknown. We found that neuropeptide Y (NPY) expression identifies a class of GABAergic principal neurons that constitute one-third of the inhibitory neurons in the IC. NPY neurons fire spontaneously, have a stellate morphology, and project to the auditory thalamus. Additionally, we found that NPY signaling hyperpolarized the membrane potential of a subset of excitatory IC neurons that express the NPY Y1 receptor. Thus, NPY neurons are a novel class of inhibitory neurons that use GABA and NPY signaling to regulate activity in the IC and auditory thalamus.


Tageted bipolar radiofrequency decompression with vertebroplasty for intractable radicular pain due to spinal metastasis: a case report.
Metastatic spinal tumors are usually quite difficult to treat. In patients with metastatic spinal tumors, conventional radiotherapy fails to relieve pain in 20-30% of cases and open surgery often causes considerable trauma and complications, which delays treatment of the primary disease. Percutaneous vertebroplasty (PVP) is considered to be useful in achieving rapid pain control and preventing further vertebral collapse due to spinal metastasis. However, symptoms of intraspinal neural compression can be contraindications to PVP. To overcome this problem, we performed PVP following targeted bipolar radiofrequency decompression, and examined the effect of the combined treatment in relieving severe radicular pain related to spinal cord compression caused by malignant metastatic tumors.


A Rare Case of Hydrophilic Polymer Embolization After Transcatheter Aortic Valve Replacement.
Endovascular procedures that use a hydrophilic polymer-coated device carry a risk of embolization and ischemic complications when used intravascularly. Because these coatings are increasingly used worldwide, it is important to identify potential adverse effects early. Cutaneous complications of hydrophilic polymer emboli are rare and not commonly described in the literature. Therefore, we report a case of hydrophilic polymer embolization with cutaneous findings in a patient who underwent a recent transcatheter aortic valve replacement.


Ideal Duration of Pretreatment Using a Gelatin Hydrogel Nonwoven Fabric Prior to Subcutaneous Islet Transplantation.
Subcutaneous islet transplantation is a promising treatment for severe diabetes; however, poor engraftment hinders its prevalence. We previously revealed that a gelatin hydrogel nonwoven fabric (GHNF) markedly improved subcutaneous islet engraftment in comparison with intraportal islet transplantation. We herein investigated whether the duration of pretreatment using GHNF affected the outcome of subcutaneous islet transplantation. A silicone spacer with GHNF was implanted into the subcutaneous space of healthy mice at 2, 4, 6, or 8 weeks before transplantation, and then diabetes was induced 7 days before transplantation. Syngeneic islets were transplanted into the pretreated space. Blood glucose, intraperitoneal glucose tolerance, immunohistochemistry, inflammatory mediators, and gene expression were evaluated. The 6-week group showed significantly better blood glucose changes than the other groups (P < 0.05). The cure rate of the 6-week group (60.0%) was the highest among the groups (2-week = 0%, 4-week = 50.0%, 8-week = 15.4%). The number of von Willebrand factor (vWF)-positive vessels in the 6-week group was significantly higher than in the other groups at pre-islet and post-islet transplantation (P < 0.01 [vs 2-and 4-week groups] and P < 0.05 [vs all other groups], respectively). Notably, this beneficial effect was also observed when GHNF was implanted into diabetic mice injected with streptozotocin 7 days before GHNF implantation. The positive rates for laminin, collagen III, and collagen IV increased as the duration of pretreatment became longer and were significantly higher in the 8-week group (P < 0.01). Inflammatory mediators, including interleukin (IL)-1b, granulocyte colony-stimulating factor (G-CSF), and interferon (IFN)-γ, were gradually downregulated according to the duration of GHNF pretreatment and re-elevated in the 8-week group. Taken together, the duration of GHNF pretreatment apparently had an impact on the outcomes of subcutaneous islet transplantation, and 6 weeks appeared to be the ideal duration. Islet graft revascularization, extracellular matrix compensation of the islet capsule, and the inflammatory status at the subcutaneous space would be crucial factors for successful subcutaneous islet transplantation.


Aptamer-Based Chromatographic Methods for Efficient and Economical Separation of Leukocyte Populations.
The manufacturing process of chimeric antigen receptor T cell therapies includes isolation systems that provide pure T cells. Current magnetic-activated cell sorting and immunoaffinity chromatography methods produce desired cells with high purity and yield but require expensive equipment and reagents and involve time-consuming incubation steps. Here, we demonstrate that aptamers can be employed in a continuous-flow resin platform for both depletion of monocytes and selection of CD8+ T cells from peripheral blood mononuclear cells at low cost with high purity and throughput. Aptamer-mediated cell selection could potentially enable fully synthetic, traceless isolations of leukocyte subsets from a single isolation system.


Isolation and characterization of bacterial endophytes of Chelidonium majus L.
The aim of this study was to isolate and identify endophytic bacteria from stems of Chelidonium majus L. (greater celandine) and to evaluate their antifungal properties. In total, 34 bacterial endophyte strains were isolated. The fungistatic effects of these bacteria on the growth of five moulds (Alternaria alternata, Chaetonium sp., Paecilomyces variotti, Byssochlamys fulva, Aureobasidium pullulans) and one species of black yeast (Exophiala mesophila) were tested. The majority of the bacterial isolates were found to inhibit the growth of fungi and those with the strongest antifungal properties were further characterized. Of the twelve isolates examined, 11 were species of Bacillus thuringiensis and one was Bacillus amyloliquefaciens.


[Early recognition of and treatment possibilities in diabetic nephropathies].
Diabetic nephropathy due to glomerulosclerosis develops in 40% of patients with type I diabetes (in type II the incidence is only around 5%). Two mechanisms are of pathogenetic importance: hemodynamic changes with glomerular hyperfiltration leading to glomerulosclerosis and proteinuria, and biochemical alterations of the glomerular basement membrane consisting of an increase and glycosylation of collagen IV as well as a decrease in negatively charged proteoglycans and sialic acid. Diabetic nephropathy runs through several stages, the first being characterized by hyperfunction and hypertrophy. The appearance of microalbuminuria after 10-15 years of diabetes seems to be a good indicator of the later development of clinically overt nephropathy with large urinary protein losses and decreasing renal function. Successful treatment of hypertension may slow the decrease of renal function. For those patients who have reached terminal renal failure, the treatment modalities of hemodialysis, continuous ambulatory peritoneal dialysis (CAPD) and renal transplantation offer a reasonable chance of prolonging life, although the results are generally less good than in non-diabetic renal patients of the same age group. However, the ultimate goal of therapy must remain the successful prevention of the devastating late sequelae of diabetes, including diabetic nephropathy.


Stories of pain and health by elderly Pakistani women in Norway.
This ethnographic study investigates the stories of elderly Pakistani women living in Norway. Migration studies indicate that elderly migrant women are passive, ill victims caught in a marginalized position due to age, ethnicity and gender, and thus have little access to opposition and agency. To broaden the picture it is necessary to develop an innovative approach to understand what is implicated in the process of migration. The importance of considering life conditions that surrounds potential health promotion behaviors of immigrants is stressed by several researchers. However, up to now limited research guided by this perspective has been done in Norway. Therefore, this study explored how elderly Pakistani women in Norway promote their health and well-being through some distinct social interactions. The intention is to bring awareness to how health, even by so-called disadvantaged social groups, may take place. These practices are important to take into consideration when developing health-promoting policies for elderly immigrants. An ethnographic study of 15 Pakistani women, aged 53-75, was carried out in a multisided fieldwork in Oslo using participant observation and ethnographic interviews. The analytical approach was inspired by the constructivist theoretical framework of narrative ethnography. The elderly Pakistani women in Norway construct stories of living in-between cultures and experiences of acculturative stress caused by being elderly, immigrants and women. However, this analysis also suggests that through distinct social relationships, primarily in the context of a voluntary organization, elderly Pakistani women do health by the way they interact and construct a repertoire of social identities. The healing practices taking place among elderly Pakistani women may counteract the negative health outcomes associated with age, migration and gender implications for immigrant health-promoting policy in Norway may be to increase the establishment and allocate funds to sustain voluntary organizations run by and for immigrants.


Widespread distribution of immunoreactive thyroid hormone beta 2 receptor (TR beta 2) in the nuclei of extrapituitary rat tissues.
Messenger RNA for thyroid hormone receptor (TR) isoforms alpha 1 and beta 1 are widely distributed in rat tissues. Until recently, TR beta 2 mRNA was believed to be limited to the pituitary and the assumption was made that TR beta 2 protein was similarly restricted. We determined the distribution of TR beta 2 protein in selected adult and fetal rat tissues using three anti-TR beta 2 antisera directed to different amino acid sequences of the distinctive A/B domain of TR beta 2. The proportion of total nuclear binding capacity cleared by each antiserum was determined by saturation analysis. 10-20% of total binding capacity in adult brain, liver, kidney, and heart was immunoprecipitated by each antiserum. Use of specific antibodies to TR beta 1 and TR alpha 1 showed these isoforms accounted for the remainder of total T3 binding. Fetal liver and brain, however, contained only TR alpha 1. Immunohistochemical analysis of the adult tissues showed TR beta 2 present in nuclei. Reverse transcription polymerase chain reaction detected low levels of TR beta 2 mRNA in the adult tissues. We infer that TR beta 2 accounts for a significant fraction of TR in adult rat tissues despite the low levels of its mRNA.


Power and Sample Size Calculations for the Restricted Mean Time Analysis of Prioritized Composite Endpoints.
As a new way of reporting treatment effect, the restricted mean time in favor (RMT-IF) of treatment measures the net average time the treated have had a less serious outcome than the untreated over a specified time window. With multiple outcomes of differing severity, this offers a more interpretable and data-efficient alternative to the prototypical restricted mean (event-free) survival time. To facilitate its adoption in actual trials, we develop simple approaches to power and sample size calculations and implement them in user-friendly R programs. In doing so we model the bivariate outcomes of death and a nonfatal event using a Gumbel-Hougaard copula with component-wise proportional hazards structures, under which the RMT-IF estimand is derived in closed form. In a standard set-up for censoring, the variance of the nonparametric effect-size estimator is simplified and computed via a hybrid of numerical and Monte Carlo integrations, allowing us to compute the power and sample size as functions of component-wise hazard ratios. Simulation studies show that these formulas provide accurate approximations in realistic settings. To illustrate our methods, we consider designing a new trial to evaluate treatment effect on the composite outcomes of death and cancer relapse in lymph node-positive breast cancer patients, with baseline parameters calculated from a previous study.


Deep Brain Stimulation: Expanding Applications.
For over two decades, deep brain stimulation (DBS) has shown significant efficacy in treatment for refractory cases of dyskinesia, specifically in cases of Parkinson's disease and dystonia. DBS offers potential alleviation from symptoms through a well-tolerated procedure that allows personalized modulation of targeted neuroanatomical regions and related circuitries. For clinicians contending with how to provide patients with meaningful alleviation from often debilitating intractable disorders, DBSs titratability and reversibility make it an attractive treatment option for indications ranging from traumatic brain injury to progressive epileptic supra-synchrony. The expansion of our collective knowledge of pathologic brain circuitries, as well as advances in imaging capabilities, electrophysiology techniques, and material sciences have contributed to the expanding application of DBS. This review will examine the potential efficacy of DBS for neurologic and psychiatric disorders currently under clinical investigation and will summarize findings from recent animal models.


Percutaneous absorption: a new physicochemical predictive model for maximum human in vivo penetration rates.
A diffusion model for stratum corneum-limited percutaneous absorption based on the interaction of the diffusate with the stratum corneum was derived. Two types of interactions were proposed, ion-dipole and lipid-lipid, based on current knowledge of the stratum corneum and on irreversible thermodynamic arguments. The resulting flux equations predict a linear dependence of flux on the dipole moment and ln X of the diffusates , where X is the mole fraction solubility. These flux equations were tested on 21 different diffusates whose human percutaneous absorption rates in vivo had been previously determined. A solubility method was used to classify the interaction pathway for each diffusate . Correlation of the maximum absorption rate for the lipid and polar pathways give correlation coefficients of 0.946 and 0.998, respectively. It is believed that these studies provide a starting point for the ultimate goal of percutaneous absorption research: to be able to bypass in vivo and in vitro studies and to predict absorption solely on the basis of the physicochemical properties of the diffusates .


Electrochemical Sensor Arrays.
The importance of sensor arrays in environmental, food and clinical analysis is discussed. The possible designs of sensor arrays is shown. The most reliable mathematical models for data processing are presented. The importance of different types of electrochemical sensor arrays in analytical chemistry as well as their performances are shown.


Advances in the cytogenetics of Annonaceae, the case of Annona cherimola L.
Annonaceae represent the largest extant family among the early divergent angiosperms. Despite the long-standing interest in its evolutionary and taxonomic aspects, cytogenetic studies on this family remain extremely few even on economically important species. With this study, we realized a detailed characterization of the chromosomes of Annona cherimola (2n = 14) by a combination of in situ hybridization techniques, fluorochrome banding, and karyomorphological analysis. FISH revealed that 45S and 5S rDNA sites are co-localized in correspondence to the secondary constrictions of the SAT-chromosome pair. Some hypotheses on the organization of the linked 45S and 5S rDNA repeats have been made. FISH with Arabidopsis-type telomeric arrays demonstrated that the A. cherimola telomeres are constituted by TTTAGGG sequences and that they are exclusively localized at the extremities of chromosomes. An insight into the chromosome structure of A. cherimola was obtained by the self-GISH procedure which revealed highly repeated DNA sequences localized in the centromeric regions of all chromosomes. The correspondence of s-GISH signals with DAPI banding suggests that these sequences are the principal component of the centromeric heterochromatin of this species. The karyotype of A. cherimola here described is proposed as the basic reference karyotype for successive investigations in Annonaceae.


Optimum inorganic ion concentrations for hematopoiesis cultures.
Current limitations in the ability to culture hematopoietic cells may be due to the use of ion concentrations that reflect those in the general circulation rather than those expected at hematopoietic sites. Expected changes in calcium, phosphate and hydroxyl ion are calculated indirectly using published data. Results indicate doubling of normal concentrations for the first week, followed by 2 weeks of smaller elevations as the osteon undergoes resorption and replacement. The period of 3 weeks fits the expected time of the three stages of differentiation and proliferation of erythrocytes to the maturation phase. Mimicking the high concentrations of these ions in vitro may require the development of dynamic flow cultures because of problems with precipitation of calcium phosphate crystals. After 3 weeks 10% less than normal concentrations is expected as the bone mineral is replaced over a period of months, allowing a static system for maturation.


Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium.
Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.


Opioid rotation in children with cancer.
The purpose of this retrospective study was to determine the therapeutic value of opioid rotation in a large pediatric oncology center. The details for opioid prescriptions, over the course of a year, were obtained from the medical records of children with cancer who had a rotation of opioid during their admission. Twenty-two children or 14% of children on opioid therapy underwent 30 opioid rotations. Mucositis was the cause of pain in 19 (70%) children, bone pain in 3 (11%) children, and postoperative, visceral, or neuropathic pain in the remainder. The opioid was rotated either for excessive side effects with adequate analgesia (70%), excessive side effects with inadequate analgesia (16.7%), or tolerance (6.7%). Five (23%) children required two rotations, 3 during the same admission. The favored rotations were morphine to fentanyl in 20 (67%) children and fentanyl to hydromorphone in 6 (20%). Adverse opioid effects were resolved in 90% of cases, all failures occurred when morphine was rotated to fentanyl. There was no significant loss of pain control or increase in mean morphine equivalent dose requirements. Opioid rotation had a positive impact on managing dose-limiting side effects of, or tolerance to, opioid therapy during cancer pain treatment in children. This was accomplished without loss of pain control or having to significantly increase the dose of opioid therapy.


[Problems and perspectives of psycholinguistics].
A brief historical and critical analysis of psycholinguistics is followed by the assertion that the claim of relevance, which has divided psychologists and linguists for so many years, and the conflicts between the different approaches to research evident in the anthropopsycholinguistic sciences reveal the lack of a single, interdisciplinary approach on the part of psycholinguistic research. Attention is also directed to certain fundamental aspects of psycholinguistics, such as: the psychological problems of translation, linguistic apprenticeship, and the psychological analysis of style.


Detection of occult primary tumors in patients with cervical metastases of unknown primary tumors: comparison of (18)F FDG PET/CT with contrast-enhanced CT or CT/MR imaging-prospective study.
To assess diagnostic accuracy of fluorine 18 ((18)F) fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and computed tomography (CT) in the detection of occult primary tumors and determination of optimal care in patients with cervical metastasis of an unknown primary tumor (CUP) compared with contrast material-enhanced CT alone or combined contrast-enhanced CT and magnetic resonance (MR) imaging (CT/MR imaging). Institutional review board approval and written informed consent were obtained. In total, 56 patients with initially undetected tumors after endoscopic or physical examination were prospectively assessed with (18)F FDG PET/CT and contrast-enhanced CT or contrast-enhanced CT/MR imaging. The contrast-enhanced CT/MR images were read in combination. Results of guided biopsy with general anesthesia served as the reference standard. Diagnostic values of (18)F FDG PET/CT, contrast-enhanced CT, and contrast-enhanced CT/MR imaging were compared with the McNemar test. Primary tumors were detected at 32 sites in 31 (55%) of 56 patients. There were 26 tumors in the palatine tonsil, two in the hypopharynx, two in the base of the tongue, and two in the nasopharynx. PET/CT depicted 22 (69%) of 32 primary tumors, but it failed to depict primary tumors in 10 (31%) of 32 cases. Overall, sensitivity of PET/CT (69%) in detection of primary tumors was higher than that of contrast-enhanced CT (16%) (P < .001) or contrast-enhanced CT/MR imaging (41%) (P = .039), while specificity of these methods did not differ (88%, 76%, and 59% for PET/CT, contrast-enhanced CT, and contrast-enhanced CT/MR imaging, respectively; P > .4). Diagnostic performance (area under the receiver operating characteristics curve [AUC] = 0.759) of PET/CT in tumor detection was significantly better than that of contrast-enhanced CT alone (AUC = 0.531) (P = .001) or contrast-enhanced CT/MR imaging (AUC = 0.537) (P = .036). PET/CT depicted primary tumors in eight (50%) of 16 cases of false-negative CT/MR imaging findings, one distant metastatic case, and two cases of synchronous cancer. (18)F FDG PET/CT is more sensitive in detection of primary tumors than is contrast-enhanced CT or contrast-enhanced CT/MR imaging in patients with CUP; therefore, it may lead to improved therapeutic planning in these patients.


A functional and regulatory map of asthma.
The prevalence and morbidity of asthma, a chronic inflammatory airway disease, is increasing. Animal models provide a meaningful but limited view of the mechanisms of asthma in humans. A systems-level view of asthma that integrates multiple levels of molecular and functional information is needed. For this, we compiled a gene expression compendium from five publicly available mouse microarray datasets and a gene knowledge base of 4,305 gene annotation sets. Using this collection we generated a high-level map of the functional themes that characterize animal models of asthma, dominated by innate and adaptive immune response. We used Module Networks analysis to identify co-regulated gene modules. The resulting modules reflect four distinct responses to treatment, including early response, general induction, repression, and IL-13-dependent response. One module with a persistent induction in response to treatment is mainly composed of genes with suggested roles in asthma, suggesting a similar role for other module members. Analysis of IL-13-dependent response using protein interaction networks highlights a role for TGF-beta1 as a key regulator of asthma. Our analysis demonstrates the discovery potential of systems-level approaches and provides a framework for applying such approaches to asthma.


Protective effects of remifentanil preconditioning on cerebral injury during pump-assisted coronary artery bypass graft.
The protective effects of remifentanil preconditioning on serum superoxide dismutase (SOD) and malondialdehyde (MDA) during pump-assisted coronary artery bypass graft (CABG) were investigated. Forty pump-assisted CABG patients were randomly divided into a remifentanil preconditioning group (R group) and a control group (C group, N = 10; normal saline). The R group was further divided into 3 sub-groups (R1, R2, and R3; N = 10 per group) according to the remifentanil dose (0.6, 1.2, and 1.8 μg·kg(-1)·min(-1), respectively). A venous blood sample was taken at anesthesia induction (T0), before cardiopulmonary bypass (CPB) (T1), CPB 30 min (T2), and after CPB (T3), and protein concentrations were measured. Patients were tested 24 h before and after the operation with the Mini-Mental State Examination (MMSE), and the difference was calculated. The MMSE score difference in the R3 group was lower than those of the other 3 groups (P < 0.05). At T2 and T3, the R3 group showed a significant decrease in S-100β protein and MDA and an increase in SOD (P < 0.05) compared with the other groups, and S-100β was negatively correlated with SOD activity (T2: r = -0.76, -0.80, P < 0.01; T3: r = -0.795, P < 0.01), and was positively correlated with MDA density (T2: r = 0.71, P < 0.01; T3: r = 0.71, P < 0.01). In conclusion, high-dosage remifentanil preconditioning played a protective role on brain damage, possibly through inhibition of the oxidative stress response.


Expression of Nav1.9 channels in human dental pulp and trigeminal ganglion.
There is a higher incidence of local anesthetic failure in endodontic patients experiencing pulpal hyperalgesia. Up-regulation of Nav1.9, a voltage-gated sodium channel isoform, might play a key role in local anesthetic failure because Nav1.9 channels increase neuronal excitability and have low sensitivity to blockade by local anesthetics. Immunocytochemistry was used to examine Nav1.9 channel expression in axons of symptomatic (painful) versus asymptomatic human dental pulp and to determine Nav1.9 expression levels in neuronal somata of the human trigeminal ganglion. Nav1.9 channel immunoreactivity on pulpal axons was significantly increased in painful teeth. Nav1.9 channels were expressed in membranes and cytoplasm of human trigeminal ganglion neurons, with the highest expression in small neuronal somata. Nav1.9 expression in the trigeminal ganglion coupled with increased expression in symptomatic pulp might contribute to hypersensitivity of inflamed pulps and local anesthetic failure. Furthermore, the present study suggests that Nav1.9 channels are potential targets for novel anesthetics.


Colonic small cell undifferentiated carcinoma: a distinct pathological diagnosis with therapeutic implications.
A case of metastatic primary small cell undifferentiated carcinoma of the colon responding to combination chemotherapy is reported. A review of small cell undifferentiated carcinoma of the gastrointestinal tract with attention to the colon is discussed. Recommendations for the management of this rare neoplasm are presented based on its similarity to the more common bronchogenic small cell undifferentiated carcinoma.


Basic physiology of wound healing in the horse.
Wound healing is part of the normal general repair process of the body. Its efficient completion depends on many factors, some physical, eg, pH, oxygen tension and tissue tension, and some biological, eg, cell-cell interaction and feedback of extracellular matrix on to the cells which produce it. The factors which affect healing are discussed and failures and anomalies in the process described. New techniques which may improve the quality of healing in specialised tissues are explained. Recent research on wound healing has concentrated on the role of the different cell types in the process and also on the effects of micro-environment on the enhancement or inhibition of cellular activity. The wound is a situation in which cells are apparently operating at the limits of their powers of survival and very slight modification of the micro-environment can render the tissue either unduly hostile to the cell or can enhance cellular activity. While it is not possible to increase the rate of healing of a clean surgical wound to any useful degree, an understanding of the mechanics of wound healing is essential to a rational treatment of simple or indolent wounds. It is especially important that surgical or medical treatment should complement, rather than compete with, the natural process. Tight bandages, which compress circulation, or excessive washing, which may remove macrophages and dilute bacteriostatic or chemotaxic agents, should be avoided.


Domain architecture of BAF250a reveals the ARID and ARM-repeat domains with implication in function and assembly of the BAF remodeling complex.
BAF250a and BAF250b are subunits of the SWI/SNF chromatin-remodeling complex that recruit the complex to chromatin allowing transcriptional activation of several genes. Despite being the central subunits of the SWI/SNF complex, the structural and functional annotation of BAF250a/b remains poorly understood. BAF250a (nearly 2200 residues protein) harbors an N-terminal DNA binding ARID (~110 residues) and a C-terminal folded region (~250 residues) of unknown structure and function, recently annotated as BAF250_C. Using hydrophobic core analysis, fold prediction and comparative modeling, here we have defined a domain boundary and associate a β-catenin like ARM-repeat fold to the C-terminus of BAF250a that encompass BAF250_C. The N-terminal DNA-binding ARID is found in diverse domain combinations in proteins imparting unique functions. We used a comparative sequence analysis based approach to study the ARIDs from diverse domain contexts and identified conserved residue positions that are important to preserve its core structure. Supporting this, mutation of one such conserved residue valine, at position 1067, to glycine, resulted in destabilization, loss of structural integrity and DNA binding affinity of ARID. Additionally, we identified a set of conserved and surface-exposed residues unique to the ARID when it co-occurs with the ARM repeat containing BAF250_C in BAF250a. Several of these residues are found mutated in somatic cancers. We predict that these residues in BAF250a may play important roles in mediating protein-DNA and protein-protein interactions in the BAF complex.


Epilepsy Mechanisms in Neurocutaneous Disorders: Tuberous Sclerosis Complex, Neurofibromatosis Type 1, and Sturge-Weber Syndrome.
Neurocutaneous disorders are multisystem diseases affecting skin, brain, and other organs. Epilepsy is very common in the neurocutaneous disorders, affecting up to 90% of patients with tuberous sclerosis complex (TSC) and Sturge-Weber syndrome (SWS), for example. The mechanisms underlying the increased predisposition to brain hyperexcitability differ between disorders, yet some molecular pathways overlap. For instance, the mechanistic target of rapamycin (mTOR) signaling cascade plays a central role in seizures and epileptogenesis in numerous acquired and genetic disorders, including several neurocutaneous disorders. Potential routes for target-specific treatments are emerging as the genetic and molecular pathways involved in neurocutaneous disorders become increasingly understood. This review explores the clinical features and mechanisms of epilepsy in three common neurocutaneous disorders-TSC, neurofibromatosis type 1, and SWS.


[Measurement of levels of plasma endothelin-1 and serum nitrate anion in patients with sepsis].
Recently much attention has been paid to the circulatory disturbance and peripheral vascular damage in patients with sepsis and septic shock. We intended to elucidate the interaction between nitric oxide (NO) and endothelin (ET)-1 under various pathological conditions by measuring the concentrations of NO3-, the principal metabolite of NO and immunoreactive ET-1. In cases with good prognosis after the septic shock, ET-1 was significantly higher as compared with these in sepsis without shock. In lethal cases with septic shock, these parameters were abnormally high as compared with the survived case. These levels elevated as the degree of severity progressed. When patients recovered from the septic shock, plasma ET-1 levels rapidly decreased. These results may mean that the level of the concentration of ET-1 plays a key role for prevention of the multiple organ failure even after the recovery from septic shock. The elevated level of NO3- during the initial several days in septic shock will mean that NO is acting to prevent platelet aggregation and to keep blood flow by dilating the arteries during septic shock. On the contrary, it may also be suggested that the elevated level of NO3- and ET-1 leads to the dysfunction of vascular endothelial cells and the apoptosis.


Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial.
Enteral glutamine supplements have been shown to reduce infectious morbidity in trauma patients, but their effect on burn patients is not known. The objective of this study was to measure the impact of enteral glutamine supplementation on infectious morbidity, length of care, and the immune system in burn patients. Double-blinded, randomized clinical trial. Burn center. Forty-five adults with severe burns. Patients were randomized to receive either glutamine or an isonitrogenous control mixture until complete healing occurred. Length of care, incidence of positive blood culture, and mortality were recorded. Phagocytosis by circulating polymorphonuclear cells was measured every 3 days. Patient characteristics were similar in both groups. Four patients were excluded from the analysis, because three of them died within 72 hrs and the fourth could not receive enteral nutrition and amino acid supplements for the first 10 days. Of the remaining 41 patients, length of care in the survivors was not different between groups (0.9 vs. 1.0 days/percent total body surface area for glutamine vs. control, respectively), positive blood culture was three times more frequent in control than in glutamine treatment (4.3 vs. 1.2 days/patient, p <.05), and Pseudomonas aeruginosa was detected in six patients on control and zero on glutamine (p <.05). Phagocytosis by polymorphonuclear cells was not different between groups. Mortality rate was significantly lower in glutamine than in control: intention to treat, two vs. 12 (p <.05); per protocol analysis, zero vs. eight (p <.01). Enteral glutamine supplementation in adult burn patients reduces blood infection by a factor of three, prevents bacteremia with P. aeruginosa, and may decrease mortality rate. It has no effect on level of consciousness and does not appear to influence phagocytosis by circulating polymorphonuclear cells.


High-throughput sequencing identifies HIV-1-replication- and latency-related miRNAs in CD4+ T cell lines.
MicroRNAs are potent gene expression regulators involved in regulating various biological processes, including host-pathogen interactions. In this study, we used high-throughput sequencing to investigate cellular miRNA signatures related to HIV-1 replication and latent infection in CD4+ T cell lines, which included HIV-1-replicating H9/HTLV-IIIB, HIV-1-latently-infected CEM-Bru cells, and their parental uninfected H9 and CEM-SS cells. Relatively few miRNAs were found to be modulated by HIV-1 replication or latent infection, while the cell-lineage-specific miRNA difference was more pronounced, irrespective of HIV-1 infection. In silico analysis showed that some of our HIV-1 infection-regulated miRNA profiles echoed previous studies, while others were novel. In addition, some of the miRNAs that were differentially expressed between the productively and latently infected cells seemed to participate in shaping the differential infection state. Thus, the newly identified miRNA profiles related to HIV-1 replication and latency provide information about the interplay between HIV-1 and its host.


Adaptive evolution and functional innovation of Populus-specific recently evolved microRNAs.
Lineage-specific microRNAs (miRNAs) undergo rapid turnover during evolution; however, their origin and functional importance have remained controversial. Here, we examine the origin, evolution, and potential roles in local adaptation of Populus-specific miRNAs, which originated after the recent salicoid-specific, whole-genome duplication. RNA sequencing was used to generate extensive, comparable miRNA and gene expression data for six tissues. A natural population of Populus trichocarpa and closely related species were used to study the divergence rates, evolution, and adaptive variation of miRNAs. MiRNAs that originated in 5' untranslated regions had higher expression levels and their expression showed high correlation with their host genes. Compared with conserved miRNAs, a significantly higher proportion of Populus-specific miRNAs appear to target genes that were duplicated in salicoids. Examination of single nucleotide polymorphisms in Populus-specific miRNA precursors showed high amounts of population differentiation. We also characterized the newly emerged MIR6445 family, which could trigger the production of phased small interfering RNAs from NAC mRNAs, which encode a transcription factor with primary roles in a variety of plant developmental processes. Together, these observations provide evolutionary insights into the birth and potential roles of Populus-specific miRNAs in genome maintenance, local adaptation, and functional innovation.


Optimization by mass spectrometry of a tryptophan-specific protein cleavage reaction.
Mass spectrometry has been used to define the reaction of BNPS-skatole (3-bromo-3-methyl-2-(o-nitrophenylsulfenyl)indolenine) with selected proteins and peptides, confirming the cleavage of the protein chain at tryptophan residues, characterizing the products, and identifying the side reactions. A short procedure for carrying out the cleavage reaction with minimal side reactions is presented.


Suppressed Kondo effect and Kosterlitz-Thouless-type phase transition induced by level difference in a triple dot device.
Quantum dot system provides an ideal platform for quantum information processing, within which to demonstrate the quantum states is one of the most important issue for quantum simulation and quantum computation. In this paper, we report a peculiar electron state in a parallel triple dot device where the Ruderman-Kittel-Kasuya-Yosida interaction is invalid when the level differences of the dots sweep into appropriate regime. This extraordinary tendency then results in an antiferromagnetic spin coupling between two of the dots and may lead to zero or full conductance, relying deeply on the relation of the two level spacings. e.g. when the level differences are kept equal, the Kondo effect is totally suppressed although the dots are triply occupied, since in this case a local inter-dot transport loop is found to play an important role in the transmission coefficient. By contrast, when the differences are retained symmetric, the Kondo peak reaches nearly to its unitary limit, owing to that the inter-dot transport process is significantly suppressed. To approach these problems, voltage controllable quantum phase transitions of Kosterlitz-Thouless type and first order are shown, and possible pictures related to the many-body effect and the effective Kondo model are given.


Evaluation of systems-oriented public health interventions: alternative research designs.
The need to provide sound evidence of the costs and benefits of real-world public health interventions has driven advances in the development and analysis of designs other than the controlled trial in which individuals are randomized to an experimental condition. Attention to methodological quality is of critical importance to ensure that any evaluation can accurately answer three fundamental questions: (a) Has a change occurred, (b) did the change occur as a result of the intervention, and (c) is the degree of change significant? A range of alternatives to the individual randomized controlled trial (RCT) can be used for evaluating such interventions, including the cluster RCT, stepped wedge design, interrupted time series, multiple baseline, and controlled prepost designs. The key features and complexities associated with each of these designs are explored.


Analysis of antigenic heterogeneity within individual 3-methylcholanthrene-induced mouse sarcomas.
A method of establishing sublines by trocar transplantation in vivo was used to analyze possible cellular heterogeneity with regard to tumor-specific antigens in individual methylcholanthrene-induced sarcomas. Differences in antigenic specificity were found in at least 1 of the 9 pairs of sublines obtained, respectively, from opposite poles of 9 different primary tumors. No evidence suggested such differences among 7 pairs of sublines similarly derived from later transplant generations. The lack of variation in antigenic specificity between members of subline pairs obtained from later transplant generation tumors suggested that antigenic specificity was a stable characteristic. Even when derived from later transplant generations, the sublines of a particular tumor sometimes differed in growth potential, and/or immunizing capacity, and/or responsiveness to immunity. There was little or no correlation between variations in the two parameters: immunizing capacity and responsiveness to immunity. These findings led to the interpretation that immunizing capacity and responsiveness to immunity behaved like partially independent variables, and that variations in these parameters probably depended on factors other than, or in addition to, cellular antigen content per se. The marked, random, spacial heterogeneity revealed within the tumors in cellular growth rate and antigenic properties suggests that changes seen during serial tumor transplantation are probably due to random clonal variation and subsequent selection.


Rapid spread of OXA-244-producing Escherichia coli ST38 in Germany: insights from an integrated molecular surveillance approach; 2017 to January 2020.
Annually, increasing numbers of OXA-244-producing Escherichia coli in 13 German federal states prompted us to initiate an outbreak investigation. Whole genome sequencing revealed that among 148 isolates analysed, most belonged to sequence type 38 with 62 isolates forming a genetically distinct cluster. Although no epidemiological link could be identified between cases, ongoing investigations suggest non-healthcare associated transmission. A screening-PCR was developed facilitating early detection of ST38 cluster isolates to identify the source and transmission route.


Chemogenetics: drug-controlled gene therapies for neural circuit disorders.
Many patients with nervous system disorders have considerable unmet clinical needs or suffer debilitating drug side effects. A major limitation of exiting treatment approaches is that traditional small molecule pharmacotherapy lacks sufficient specificity to effectively treat many neurological diseases. Chemogenetics is a new gene therapy technology that targets an engineered receptor to cell types involved in nervous system dysfunction, enabling highly selective drug-controlled neuromodulation. Here, we discuss chemogenetic platforms and considerations for their potential application as human nervous system therapies.


Functional Na+ channels in cell adhesion probed by transistor recording.
Cell membranes in a tissue are in close contact to each other, embedded in the extracellular matrix. Standard electrophysiological methods are not able to characterize ion channels under these conditions. Here we consider the area of cell adhesion on a solid substrate as a model system. We used HEK 293 cells cultured on fibronectin and studied the activation of Na(V)1.4 sodium channels in the adherent membrane with field-effect transistors in a silicon substrate. Under voltage clamp, we compared the transistor response with the whole-cell current. We observed that the extracellular voltage in the cell-chip contact was proportional to the total membrane current. The relation was calibrated by alternating-current stimulation. We found that Na(+) channels are present in the area of cell adhesion on fibronectin with a functionality and a density that is indistinguishable from the free membrane. The experiment provides a basis for studying selective accumulation and depletion of ion channels in cell adhesion and also for a development of cell-based biosensoric devices and neuroelectronic systems.


Air Compressibility Effect on Bouwer and Rice Seepage Meter.
Measuring a disconnected streambed seepage flux using a seepage meter can give important streambed information and help understanding groundwater-surface water interaction. In this study, we provide a correction for calculating the seepage flux rate with the consideration of air compressibility inside the manometer of the Bouwer and Rice seepage meter. We notice that the effect of air compressibility in the manometer is considerably larger when more air is included in the manometer. We find that the relative error from neglecting air compressibility can be constrained within 5% if the manometer of the Bouwer and Rice seepage meter is shorter than 0.8 m and the experiment is done in a suction mode in which air is pumped out from the manometer before the start of measurement. For manometers longer than 0.8 m, the relative error will be larger than 5%. It may be over 10% if the manometer height is longer than 1.5 m and the experiment is done in a no-suction mode, in which air is not pumped out from the manometer before the start of measurement.


A Capacitive Cochlear Implant Electrode Array Sensing System to Discriminate Fold-Over Pattern.
Purpose During insertion of the cochlear implant electrode array, the tip of the array may fold back on itself and can cause serious complications to patients. This article presents a sensing system for cochlear implantation in a cochlear model. The electrode array fold-over behaviors can be detected by analyzing capacitive information from the array tip. Method Depending on the angle of the array tip against the cochlear inner wall when it enters the cochlear model, different insertion patterns of the electrode array could occur, including smooth insertion, buckling, and fold-over. The insertion force simulating the haptic feedback for surgeons and bipolar capacitance signals during the insertion progress were collected and compared. The Pearson correlation coefficient (PCC) was applied to the collected capacitive signals to discriminate the fold-over pattern. Results Forty-six electrode array insertions were conducted and the deviation of the measured insertion force varies between a range of 20% and 30%. The capacitance values from electrode pair (1, 2) were recorded for analyzing. A threshold for the PCC is set to be 0.94 that can successfully discriminate the fold over insertions from the other two types of insertions, with a success rate of 97.83%. Conclusions Capacitive measurement is an effective method for the detection of faulty insertions and the maximization of the outcome of cochlear implantation. The proposed capacitive sensing system can be used in other tissue implants in vessels, spinal cord, or heart.


Electromyographic and ultrasonographic evaluation of the circum-oral musculature in children.
Muscle activity and thickness of the circum-oral musculature in children with class I molar occlusion having normal anterior relation, anterior deep-bite and anterior open-bite were measured using electromyographic and ultrasonographic techniques. The results demonstrated that the upper lip muscle thickness was least in open-bite subjects and lower lip muscle thickness was maximum in deep-bite subjects. The muscle activity in both the upper and lower lip was high in deep-bite subjects. A significantly negative correlation between muscle activity and thickness was noted only in the middle and left side of the lower lip in subjects having normal anterior relation. The upper lip contributed to the maximum EMG activity in all the three groups observed.


Lumbar curve, trunk muscles, and line of gravity with different heel heights.
The influence of different heel heights on the lumbar curve, pelvic inclination, trunk muscle activity, and the position of the line of gravity was examined in 18 healthy women. They were examined while standing on heel-supports, being 4.5 cm elevated, at the level of and 2.5 cm lower than the support of the forefoot, respectively (Figure 1). Each examination was preceeded by one-hour adaptation to a corresponding shoe type. With increasing heel height, the lumbar lordosis and the pelvis inclination were decreased. The back and abdominal muscles did not alter their activities. The position of the line of gravity kept the distance from the forefoot almost constant, but the ankle joint was shifted towards the line of gravity with increasing heel height.


Alexithymia, depression and social support among Japanese workers.
A number of studies have shown that social support has a direct beneficial effect on well-being and also serves as a buffer to protect people from health problems due to excessive stress. Although preliminary studies report a positive relationship of alexithymia both with depression and reduced social support, there is no study examining whether the beneficial effect of social support on depression differs with the presence of alexithymia. A total of 120 workers aged 19-39 completed the 20-item Toronto Alexithymia Scale (TAS-20) to measure alexithymia, the Beck Depression Inventory-II (BDI-II) to evaluate depressive symptomatology, and the Job Content Questionnaire (JCQ) to assess job strain based on Karasek's demand-control-support model. The interrelationship among TAS-20, BDI-II and 3 subscales of JCQ (job demand, control, and support) were examined. A significant association of depression with low support and high alexithymia was observed. Alexithymia was also associated with reduced support. Further, a statistically significant interaction between alexithymia and support in terms of their effect on depression was observed. Nonalexithymic individuals with low support showed a significantly higher depression score than those who received high support, while alexithymics did not differ in their depression score depending on the degree of support. Consistent results were obtained from the logistic regression analysis examining the odds ratio for depression by support by alexithymia; a significantly increased odds ratio for depression associated with low social support was observed only among nonalexithymics. Alexithymic individuals might be unable to benefit from social support because of their cognitive deficits of emotion.


Reciprocal associations of pain and post-traumatic stress symptoms after whiplash injury: A longitudinal, cross-lagged study.
The objectives of the current study were to investigate (1) the longitudinal, reciprocal associations between pain and post-traumatic stress symptoms as proposed by the mutual maintenance model, and (2) to assess the predictive value of the three clusters of post-traumatic stress, where the model revealed that post-traumatic stress symptoms maintained pain in a consecutive cohort of whiplash-injured. Participants (n = 253; 66.4% women) were people with WAD grades I-III following motor vehicle crashes in Australia. Pain and post-traumatic stress symptoms were assessed by questionnaires over the course of a year (at baseline (<4 weeks), 3, 6 and 12 months post-injury). The objectives were tested using auto-regressive cross-lagged modelling and two additional structural equation models. The analyses revealed that post-traumatic stress symptoms at baseline predicted an increase in pain between baseline and 3 months and that post-traumatic stress symptoms at 6 months predicted an increase in pain between 6 and 12 months, beyond the stability of pain over time. Furthermore, hyperarousal at baseline significantly predicted pain at 3 months and hyperarousal at 6 months significantly predicted pain at 12 months with 16 and 23% explained variance, respectively. [Correction added on 2 March 2018 after first online publication: the explained variance for hyperarousal symptoms at 6 months was previously given incorrectly and has been corrected to 23% in this version.] CONCLUSIONS: The results point to a temporal main effect of post-traumatic stress symptoms on pain over and above the stability of pain itself within the first 3 months post-injury and again in the chronic phase from 6 to 12 months with hyperarousal symptoms driving these effects. From 3 to 6 months, there was a slip in the maintenance patterns with no cross-lagged effects. Investigating mutual maintenance of pain and PTSS in whiplash, the present study found evidence suggesting a maintaining effect of PTSS on pain within the first 3 months post-injury and from 6 to 12 months driven by hyperarousal, highlighting the importance of addressing PTSS.


New trends in rehabilitation of children with ENT disorders.
In the last 20 years, neonatal survival has progressively increased due to the constant amelioration of neonatal medical treatment and surgical techniques. Thus, the number of children with congenital malformations and severe chronic pathologies who need rehabilitative care has progressively increased. Rehabilitation programs for paediatric patients with disorders of voice, speech and language, communication and hearing, deglutition and breathing are not widely available in hospital settings or in long-term care facilities. In most countries, the number of physicians and technicians is still inadequate; moreover, multidisciplinary teams dedicated to paediatric patients are quite rare. The aim of the present study is to present some new trends in ENT paediatric rehabilitation.


A role for pericytes in chronic pain?
The importance of the blood-brain barrier (BBB) and neuroinflammation in neurodegenerative conditions is becoming increasingly apparent, yet very little is known about these neurovascular functions in nonmalignant disease chronic pain. Neural tissue pericytes play critical roles in the formation and maintenance of the BBB. Herein, we review the important roles of neural pericytes and address their potential role in chronic pain. Pericytes are implicated in the function of neural microvasculature, including BBB permeability, neuroimmune factor secretion and leukocyte transmigration. In addition, the multipotent stem cell nature of pericytes affords pericytes the ability to migrate into neural parenchyma and differentiate into pain-associated cell types. These recent findings indicate that pericytes are key players in pathological BBB disruption and neuroinflammation, and as such pericytes may be key players in chronic pain states. Pericytes play key roles in pathological processes associated with chronic pain. We propose that pericytes may be a therapeutic target for painful diseases that have associated neural vascular dysfunction. Given the paucity of new pharmacotherapies for chronic pain conditions, we hope that this review inspires researchers to unearth the potential role(s) of pericytes in chronic pain sowing the seeds for future new chronic pain therapies.


Effects of a 12-Month Complex Proprioceptive-Coordinative Training Program on Soccer Performance in Prepubertal Boys Aged 10-11 Years.
Boraczyński, MT, Sozański, HA, and Boraczyński, TW. Effects of a 12-month complex proprioceptive-coordinative training program on soccer performance in prepubertal boys aged 10-11 years. J Strength Cond Res 33(5): 1380-1393, 2019-The aim was to examine the effects of a series of on-field proprioceptive-coordinative (P-C) exercises on motor performance (MP) in prepubertal soccer players. Fifty-three male soccer players aged 10.1-11.8 years were randomized among 2 experimental programs receiving P-C training (P-CT; n = 26) or regular training (RT; n = 27). A control group (C; n = 22) consisted of age-matched (10.3-11.9 years) cohorts not involved in any regular physical activity. Both experimental groups completed an identical 12-month comprehensive soccer program except training in P-CT was modified to substitute small-sided conditioning games with 24 multimode P-C exercises with modulated exercise intensity (every 8-9 weeks based on predicted maximal heart rate [HRmax]). Pre-, peri-, and posttraining measures included anthropometry and 5 tests assessing soccer-specific MP: movement rhythm (turning the ball backwards-T1), motor adaptation (running with the ball around poles-T2), spatial orientation (running to sequentially numbered balls-T3), balance (single-leg static balance-T4), and kinesthetic differentiation of movement (landing the ball on a 2 × 2 m sector-T5). Repeated-measures analysis of variance revealed no significance between-group differences for age, anthropometry, and body-fat percentage at baseline. Significant main effects for group (P-CT vs. RT) were found in all tests (T1-T5) and main effects for time (group P-CT) in T3-T5, whereas a significant group × time interaction was observed only in T4 (F = 2.98, p = 0.0204). Post hoc tests indicated that P-CT attained significantly better results than RT at peritraining (by 26.4%; p < 0.01) and posttraining (by 31.9%, p < 0.01). Modulated exercise intensity had little effect on soccer performance (T1-T3, T5). Based on the results, it is recommended that the training of young soccer players be supplemented with the bilateral balance exercises and games used in the study. Furthermore, the suitability of monitoring HR in P-C exercises targeting the analyzed MP skills is questionable.


Accuracy of the Modified Somatic Perception Questionnaire and Pain Disability Index in the detection of malingered pain-related disability in chronic pain.
The Modified Somatic Perception Questionnaire (MSPQ) and the Pain Disability Index (PDI) are both popular clinical screening instruments in general orthopedic, rheumatologic, and neurosurgical clinics and are useful for identifying pain patients whose physical symptom presentations and disability may be non-organic. Previous studies found both to accurately detect malingered pain presentations; however, the generalizability of these results is not clear. This study used a criterion groups validation design (retrospective cohort of patients with chronic pain, n = 328) with a simulator group (college students, n = 98) to determine the accuracy of the MSPQ and PDI in detecting Malingered Pain Related Disability. Patients were grouped based on independent psychometric evidence of MPRD. Results showed that MSPQ and PDI scores were not associated with objective medical pathology. However, they accurately differentiated Not-MPRD from MPRD cases. Diagnostic statistics associated with a range of scores are presented for application to individual cases. Data from this study can inform the clinical management of chronic pain patients by screening for psychological overlay and malingering, thus alerting clinicians to the possible presence of psychosocial obstacles to effective treatment and triggering further psychological assessment and/or treatment.


Integrative Analysis of Incongruous Cancer Genomics and Proteomics Datasets.
Cancer is a complex disease characterized by molecular heterogeneity and the involvement of several cellular mechanisms throughout its evolution and pathogenesis. Despite the great efforts made to untangle these mechanisms, cancer pathophysiology remains far from clear. So far, panels of biomarkers have been reported from high-throughput data generated through different platforms. These biomarkers are primarily focused on one type of coding molecules such as transcripts or proteins, mainly due to the apparent heterogeneity of output data resulting from the use of various techniques specific to the molecular type. Hence, there is a major need to understand how these molecules interact and complement each other to be able to explain the deregulated processes involved. The breadth of large-scale data availability as well as the lack of in-depth analysis of publicly available data has raised concerns and enabled opportunities for new strategies to analyze "Big data" more comprehensively. Here, a new protocol to perform integrative analysis based on a systems biology approach is described. The foundation of the approach relies on groups of datasets from published studies compared within the original described groups and organized in a designated format to allow the integration and cross-comparison among different studies and different platforms. This approach follows an unbiased hypothesis-free methodology that will facilitate the identification of commonalities among different data-set sources, and ultimately map and characterize specific molecular pathways using significantly deregulated molecules. This in turn will generate novel insights about the mechanisms deregulated in complex diseases such as cancer.


Evaluation of Posterior Ocular Blood Flow in Diabetic Retinopathy Patients Without Macular Edema Using Optical Coherence Tomography Angiography.
The objective of this study is to investigate and compare the superficial and deep vascular structures of the retina, as well as the changes in the choriocapillaris (CC) and optic disc microvasculature, using optical coherence tomography angiography (OCTA) in patients diagnosed with diabetes mellitus (DM) without diabetic retinopathy (DR), patients with non-proliferative and proliferative DR, and healthy individuals. This prospective study conducted between July 2020 and July 2021 included patients diagnosed with type 2 DM without DR, as well as patients with mild nonproliferative, moderate nonproliferative, and proliferative DR without macular oedema. A control group of 25 age- and gender-matched healthy individuals was also included. OCTA parameters of the patients were examined. In the DR groups, compared to the control group, there was a significant decrease in macular superficial, deep, and CC perfusion areas as the severity of DR increased (p<0.001). The vascular density (VD) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) exhibited a statistically significant decrease in all quadrants of the DR group compared to the control group (p = 0.033 for SCP in the fovea, p<0.001 for all other quadrants). The superficial and deep FAZs showed a significant expansion in the DR group compared to the control group (p = 0.003 for superficial FAZ, p<0.001 for deep FAZ). As the severity of DR increased, there was a statistically significant decrease in the perfusion areas of the optic nerve head (ONH), radial peripapillary capillary (RPC), and vitreous segments (p<0.001 for ONH, p = 0.031 for RPC, p<0.001 for vitreous). There was a statistically significant decrease in RPC VD in all quadrants as the severity of DR increased. Moreover, as the severity of DR increased, a statistically significant decrease in the VD of the ONH was observed in all quadrants except for the inferior nasal (p = 0.094), inferior temporal (p = 0.111), superior temporal (p = 0.18), and temporal (p = 0.284) quadrants. Our study demonstrated the involvement of macular and optic nerve perfusion areas (PA) and VD in diabetic patients. OCTA proved to be a valuable and noninvasive imaging modality, providing an easy and repeatable assessment of posterior segment vascular changes in patients with DR.


[Prognostic significance of p53 and ATM gene deletion in patients with chronic lymphocytic leukemia].
To explore the prognostic significance of p53 and ATM gene deletion in patients with chronic lymphocytic leukemia (CLL). Interphase fluorescence in situ hybridization (FISH) and probes of LSI p53 and LSI ATM were used to detect p53 and ATM gene deletion in 80 patients with CLL. p53 and ATM gene deletion and their association with some prognostic factors were analyzed. The Kaplan-Meier method was used to calculate survivals, and results were compared using the Log-rank test. Multivariate COX regression analysis was used to assess associations between survival and potential risk factors. Out of the 80 CLL patients, p53 gene deletion was found in 14 (17.5%) cases, ATM gene deletion in 9 (11.3% ) cases, and both the two genes deletion in 3 (3.8%) cases. There was no significant differences of p53 and ATM gene deletion rates in sex, age, Binet stages, peripheral lymphocyte count, and the levels of LDH, beta2-MG, and ZAP-70. The p53 and ATM gene deletion rates were higher in the group of CD38 high expression than that in the group of low expression (P=0.025 and P=0.001). Among 41 patients who received fludarabine containing protocol, none of the nine cases with p53 and/or ATM gene deletion achieved complete response (CR), while 12 of 32 (37.5%) cases without the gene deletion achieved CR. The survival time was shorter in patients with p53 gene deletion (P<0.01). There was no association between outcome and ATM gene deletion (P=0.556). On multivariate analysis by COX regression, p53 gene deletion and CD38 expression (P=0.014 and P=0.017, respectively) were found to be independent factors in predicting survival. CLL patients with p53 and/or ATM gene deletion had poor therapeutic effect, and hence poor prognosis.


Synthesis, biological evaluation and molecular modeling studies of imidazo[1,2-a]pyridines derivatives as protein kinase inhibitors.
We report here the synthesis, the biological evaluation and the molecular modeling studies of new imidazo[1,2-a]pyridines derivatives designed as potent kinase inhibitors. This collection was obtained from 2-aminopyridines and 2-bromoacetophenone which afforded final compound in only one step. The bioactivity of this family of new compounds was tested using protein kinase and ATP competition assays. The structure-activity relationship (SAR) revealed that six compounds inhibit DYRK1A and CLK1 at a micromolar range. Docking studies provided possible explanations that correlate with the SAR data. The most active compound 4c inhibits CLK1 (IC50 of 0.7 μM) and DYRK1A (IC50 of 2.6 μM).


Isolated fallopian tube torsion: an unusual cause of acute abdominal pain.
The authors report a rare, unusual case of an isolated fallopian tube torsion in a young woman presenting with acute lower abdominal pain and a negative pregnancy test. The patient who initially presented with clinical and biochemical features suggestive of acute appendicitis was found to have a large necrotic pelvic mass at laparoscopy, discovered to be a torted fallopian tube with no ipsilateral ovarian involvement. The patient had a laparoscopic removal of the necrotic tube and recovered well postoperatively.


Immortalization and characterization of human myometrial cells from term-pregnant patients using a telomerase expression vector.
An examination of cellular processes involved in myometrial function has been greatly assisted by the use of human myometrial cells in primary culture. However, these cells can be used only for several passages before they senesce, and responses to various agents change with time in culture. The use of transformed cells is limited, as they can be polynucleated and can lose or gain chromosomes. We have developed three telomerase-immortalized cell lines from term-pregnant human myometrium to eliminate variability between passage numbers and allow genetic manipulations of myometrial cells to fully characterize signal pathways. These cells have a normal karyotype and were verified to be uterine smooth muscle by immunocytochemical staining for smooth muscle cell-specific alpha-actin and high affinity oxytocin antagonist binding sites. The three cell lines and the cells in primary culture from which they were derived were examined by cDNA microarray analysis. Of >10 000 expressed genes, there were consistent changes in the expression of approximately 1% in the three immortalized cell lines. We were unable to detect any significant differences between primary and immortalized cells in signal pathways such as epidermal growth factor-stimulated epidermal growth factor receptor phosphorylation, insulin-stimulated Akt phosphorylation, oxytocin and lysophosphatidic acid-stimulated extracellular signal-regulated kinase 1 and 2 phosphorylation, myosin light chain phosphorylation, and interleukin-1 induction of IkappaBalpha degradation. The immortalized cells should be useful for a range of studies, including high throughput analyses of the effects of environmental agents on the human myometrium.


Photosubstitution of cymantrenylalanine as a tool in peptide chemistry. Synthesis and biological activity of new GnRH analogs.
Beyond its aromatic character and important hydrophobicity, cymantrenylalanine, a metallocenic amino-acid, can be easily photosubstituted with phosphine and phosphite ligands to readily yield new analogs with different hydrophobicity and steric hindrance. The incorporation of phosphine and phosphite ligands is described. As an illustration of the offered possibilities, the synthesis and the biological activity of two new GnRH analogs modified in position 6 are reported.


Charge localization in stacked radical cation DNA base pairs and the benzene dimer studied by self-interaction corrected density-functional theory.
The incomplete cancellation of the electron self-interaction can be a serious shortcoming of density-functional theory especially when treating odd-electron systems. In this work, several popular and potentially viable correction schemes are applied in order to characterize the electronic structure of stacked molecular pairs, consisting of a neutral molecule and adjacent radical cation, as a function of separation distance. The unphysical sharing of the positive charge between adjacent molecules separated by 6-7 A is corrected for by applying a new empirical scheme proposed by VandeVondele and Sprik [Phys. Chem. Chem. Phys. 2005, 7, 1363] with a unique choice of parameters. This method is subsequently applied to characterize the electronic structure of two neighboring guanines excised from a canonical Arnott B-DNA structure and will be used in future investigations of certain model DNA fibers.


Principles, protocols and patients: the practical management of a limit in ICU.
The definition and management of a limit is a common but sometimes extremely complex problem in the Intensive Care Unit (ICU). Guidelines and consensus documents have been published in order to help clinicians. Yet, many controversial issues are brought into question. Legal rules are sometimes vague and derive more from the interpretation of various and unrelated principles (which vary from country to country) than from a clear ad hoc law. In this sense, the practical management of a limit in ICU is usually run by a dual normativity: an external one, which derives from the cultural, moral and legal values of the society, and an internal one, which depends on the particular clinical and human situation, namely the values of everybody involved in (the patient, his/her relatives, the health staff) and the relationships among these people. The considerable freedom left for the decision by an open communication is a great and favourable potential which must be used in the interest of the patient's and of his/her family.


A Simple Tetraminocalix[4]arene as a Highly Efficient Catalyst under "On-Water" Conditions through Hydrophobic Amplification of Weak Hydrogen Bonds.
The simple tetraminocalix[4]arene 1, which contains weak H-bond-donor NH2 groups, is reported to be a highly efficient organocatalyst for the Vinylogous Mukaiyama Aldol Reaction (VMAR) of 2-(trimethylsilyloxy)furan 5 with α-ketoesters 6 a-l under "on-water" conditions owing to the hydrophobic amplification of weak H-bond interactions. The catalytic efficiency of calixarene catalyst 1 was shown to be closely related to its recognition abilities towards the reactants 5 and 6 through a multipoint recognition model. The proposed model provided good explanations for the differences on the reaction rate acceleration and on the stereoselectivity observed with different substrates.


Randomized controlled trial of the tolerability and completion of maraviroc compared with Kaletra® in combination with Truvada® for HIV post-exposure prophylaxis (MiPEP Trial).
Post-exposure prophylaxis (PEP) for HIV is often poorly tolerated and not completed. Alternative PEP regimens may improve adherence and completion, aiding HIV prevention. We conducted a randomized controlled trial of a maraviroc-based PEP regimen compared with a standard-of-care regimen using ritonavir-boosted lopinavir. Patients meeting criteria for PEP were randomized to tenofovir disoproxil/emtricitabine (200/245 mg) once daily plus ritonavir-boosted lopinavir (Kaletra ® 400/100 mg) or maraviroc 300 mg twice daily. The composite primary endpoint was completion of 28 days of the allocated PEP regimen without grade 3 or 4 clinical or laboratory adverse events (AEs) related to the PEP medication. Two hundred and thirteen individuals were randomized (107 to maraviroc; 106 to Kaletra ® arm). Follow-up rates were high in both groups. There was no difference in the primary endpoint; 70 (71%) in the maraviroc and 64 (65%) in the Kaletra ® arm ( P = 0.36) completed PEP without grade 3 or 4 AEs. Discontinuation of PEP was the same (18%) in both groups. There were no grade 3 or 4 clinical AEs in either arm, but more grade 1 or 2 clinical AEs in the Kaletra ® arm (91% versus 70%; P < 0.001). Antidiarrhoeal medication use was higher in the Kaletra ® arm (67% versus 25%; P < 0.001). There were no HIV seroconversions in the study period. The completion rate in the absence of grade 3 or 4 AEs was similar with both regimens. Maraviroc-based PEP was better tolerated, supporting its use as an option for non-occupational PEP.


Promoting problem-based learning (PBL) in nursing education: A Malaysian experience.
Since the introduction of problem-based learning (PBL) into medical education in the late 1960s, several new and old medical schools have adopted this approach the main attraction of which includes the promotion of student-centered and life-long learning, team spirit, communication skills and enquiry. With an ever-increasing information base and changing attitudes in the health sciences, these are highly desirable characteristics of the health worker of the future, who will be required to grapple with these phenomenal changes. From medical education, the PBL approach has inevitably spread to other disciplines, especially the health-related disciplines. In the Asia-pacific region (Malaysia in particular), PBL was introduced into medical education in the early 1970s, but the growth has been slow; the reasons are discussed. Only recently (in the 1990s) have more medical and non-medical schools started to adopt PBL. The management of the Pantai Institute of Health Science and Nursing decided to adopt PBL for the Nursing curriculum. A one-day introductory workshop was, therefore, organized to expedite the process. Post-workshop feedback obtained through a five-point Likert scale questionnaire indicated a successful outcome. The workshop process is, therefore, documented as reference especially for Nursing colleges in places where PBL expertise is in short supply.


Pharmacotherapy of schizophrenia patients with comorbid substance abuse.
Substance abuse worsens the course of schizophrenia and significantly impairs the relationship between the patient and the health care team. Recent advances in laboratory studies of substance abuse and the pharmacology of schizophrenia open up new possibilities for pharmacotherapy of substance abuse in schizophrenia patients. D1 dopaminergic receptor agonists may directly block the drive for stimulant use. D2 dopaminergic receptor antagonists may indirectly block the drive for stimulant and nicotine use, while opioid antagonists appear to reduce the drive to use alcohol. New generations of neuroleptics with serotonin (5-HT2) receptor antagonism and/or 5-HT1A agonist activity may reduce substance abuse in schizophrenia patients who self-medicate negative symptoms or neuroleptic side effects. Pharmacotherapy efficacy may be enhanced by adding contingency management, social skills training, and other manualized programs. Tables are provided of potentially useful medications. Preliminary results are presented of cocaine-abusing schizophrenia patient treated with desipramine and traditional neuroleptics.


[Etiologic and epidemiologic aspects of neural tube defects].
A case-control study of neural tube defects (NTD) was undertaken from 1979 to 1986 in the department of Bas-Rhin in Northeastern France. For 105,374 consecutive births the incidence of spina bifida was 0.62 in 1,000, the incidence of anencephaly was 0.33 in 1,000 and that of encephalocele was 0.14 in 1,000. Sex ratios were respectively 1.06, 0.64 and 0.75. Among the numerous etiological factors which were studied we observed a seasonal factor (more conceptions in April, less in September). Birth weight and length were lower in children with spina bifida than in controls. Metrorrhagia was more frequent during pregnancies with anencephaly as was oligoamnios in pregnancies with encephalocele. Routine US prenatal diagnosis, which was performed in 90% of the pregnant women, allowed diagnoses in 88% of the fetuses with anencephaly but only in 53% of the fetuses with spina bifida and in 64% of the fetuses with encephalocele. For these last two anomalies diagnosis could often be performed because a malformation was associated with a NTD.


Properties and Antioxidant Capacity of Anchovy (Engraulis encrasicholus) By-Product Protein Films Containing Thyme Essential Oil.
In this study, some properties and antioxidant capacity of anchovy (Engraulis encrasicholus) by-product protein films with added 0.5, 1.0 and 1.5% of thyme essential oil were investigated. The films with thyme essential oil had higher elongation at break, water vapour permeability and oxygen permeability, lower solubility and tensile strength than control film (p<0.05). The incorporation of thyme essential oil affected transparency values of the films, but only the addition of 1.5% of thyme essential oil significantly reduced the transparency (p<0.05). In the film matrix, molecular organisation and intermolecular interaction were changed by thyme essential oil addition. The films with thyme essential oil had a heterogeneous surface and a relatively smooth cross-section structure. Slightly higher phase transition and lower glass transition temperatures were observed in films with thyme essential oil. The antioxidant capacity of the films was improved by incorporating thyme essential oil depending on its volume fraction.


Sub-kilohertz linewidth narrowing of a mid-infrared optical parametric oscillator idler frequency by direct cavity stabilization.
We stabilize the idler frequency of a singly resonant optical parametric oscillator directly to the resonance of a mid-infrared Fabry-Perot reference cavity. This is accomplished by the Pound-Drever-Hall locking scheme, controlling either the pump laser or the resonant signal frequency. A residual relative frequency noise power spectral density below 10(3) Hz(2)/Hz is reached on average, with a Gaussian linewidth of 920 Hz over 100 ms, which reveals the potential for reaching spectral purity down to the hertz level by locking the optical parametric oscillator against a mid-infrared cavity with state-of-the-art superior performance.


Managing premedications and the risk for reactions to infusional monoclonal antibody therapy.
Monoclonal antibodies-including rituximab, alemtuzumab, trastuzumab, bevacizumab, cetuximab, and panitumumab-have improved the treatment of various malignancies. Although generally better tolerated with less toxicity than conventional anticancer agents, monoclonal antibodies may cause infusion-related reactions like other infusional agents. The incidence of infusion reactions varies by agent, but severe events occur only occasionally, mostly with the first or second infusion. Although the exact etiology of infusion reactions remains unclear, they may arise via either IgE- or non-IgE-dependent mechanisms. There is a compelling clinical need to improve the risk assessment for severe infusion reactions. The recent identification of pre-existing IgE crossreacting with cetuximab, its association with severe reactions, and regional variation in the prevalence may provide a marker for high-risk assessment. Premedication with antihistamines, acetaminophen, and/or corticosteroids is a common practice to prevent infusion reactions with all monoclonal antibodies. However, a recent observational study suggests that premedication may no longer be necessary after the second infusion of cetuximab if patients did not develop any symptoms with the first two infusions. Considering the heterogeneity of infusion reactions, clinicians need to recognize the underlying nature of these events in order to identify patients at risk as well as provide optimal prophylactic measures and management of symptoms.


Development of an in-vacuum minipole undulator.
An in-vacuum minipole (short-period) insertion device has been developed in a collaboration between SPring-8 and the National Synchrotron Light Source (NSLS). The magnetic arrays were constructed by SPring-8 and were installed in a chamber with mechanical parts in the X-ray ring (E = 2.584 GeV) at the NSLS in May 1997. The device is made of permanent magnets with 30.5 periods and a period length of 11 mm. It is designed to produce fundamental radiation at 4.6 keV, and, with a modest value of deflection parameter (K = 0.7 at 3.3 mm gap), enables higher harmonics to be used for a variety of experiments.


Mutual information of local field potentials distinguishes area-V2 stripe compartments.
Determining how information is represented by populations of neurons in different cortical areas is critical to our understanding of the brain mechanisms of visual perception. Recently, information-theoretical approaches have been applied to the analysis of spike trains of multiple neurons. However, other neurophysiological signals, such as local field potentials (LFPs), offer a different source of information worthy of investigating in this way. In this study, we investigate how the modular organization of area V2 of macaque monkeys impacts the information represented in LFPs. LFPs were recorded from a 32-channel microelectrode array implanted in area V2 of an anesthetized macaque monkey. The electrode positions were recovered in histological tissue stained for cytochrome oxidase (CO) to reveal the modular organization of V2. Visual stimuli consisted of a variety of moving gratings that differed in orientation, direction, spatial frequency, and chromatic content. LFPs were separated into different frequency bands for analysis of mutual information as a function of stimulus type and CO-stripe location. High-γ-band LFPs revealed the highest information content across the electrode array. The distributions of total mutual information as well as mutual information due to correlations varied greatly by CO stripe. This analysis indicates that local correlations within each CO stripe generally reduce mutual information, whereas correlations between stripes greatly increase mutual information. The decomposition mutual information based on the power of different frequency bands of LFPs provides new insight into the impact of modular architecture on population coding in area V2. Unlike other cortical areas, such as V1, where mutual information based on LFP correlations is largely determined by cortical separation, mutual information in V2 is also fundamentally determined by the CO-stripe architecture.


Intra-articular injuries of the elbow: pitfalls of diagnosis and treatment.
Poor results in treating fractures and dislocations about the elbow may be avoided if the surgeon is aware of the possible injuries, examines good radiographs of both elbows, and treats the injury promptly and appropriately. A displaced fracture of the lateral or medial condyle of the humerus should be suspected if there is a flake fracture of the adjoining metaphysis; open reduction and internal fixation give better results than closed reduction. A shear fracture of the capitulum humeri can only be seen on a lateral radiograph; excision of the fragment, followed by mobilization, is sufficient for a good functional result. Dislocation of the elbow in a child may avulse the medial epicondyle, which sometimes lodges in the joint; it is essential to recognize this and remove the fragment without delay to avoid early degenerative arthritis. An apparently isolated fracture of the ulna should alert the surgeon to the possibility of a dislocation of the radial head; the dislocation and the fracture must be reduced and stabilized to conserve elbow function.


Patient-centered drug development and the Learning Health System.
Patient-centered drug development (PCDD) is a shift in the way that drugs are developed, systematically incorporating patient participation in all stages of medicines development. The more the research sector understands the needs and values of patients, the more effective and efficient it can be in bringing meaningful drugs and evidence to patients and providers. In this paper, we describe PCDD, provide examples of PCDD work across the phases of drug development, and discuss the challenges to making PCDD systematic. We describe how the developing Learning Health System will enable PCCD: we believe that the Learning Health System will address PCDD barriers by connecting stakeholders, enabling the more efficient flow of data, information, and evidence in the health ecosystem, and by providing governance for the connected ecosystem.


Treatment of Pediatric Anogenital Warts in the Era of HPV-Vaccine: A Literature Review.
Anogenital warts (AWs) represent a therapeutic challenge, especially in infants, due to sensitive skin and frequent disease recurrence. Though the initial wait-and-see approach is often adopted in asymptomatic immunocompetent children, with spontaneous clearing in almost 90% of cases within two years, persistent or symptomatic lesions can be reasonably treated. However, few studies have been conducted on children. Consequently, most treatments on patients under age 12 are not approved by the Food and Drug Administration. Herein, we review possible therapies for pediatric use in AW and report an illustrative case of a two-year-old boy with atopic skin and symptomatic, persistent AWs who was successfully treated with topical podophyllotoxin, without adverse effects or recurrence. Among available therapies for AWs, topical therapies, such as immunomodulating-agents (topical imiquimod 5% and 3.75% cream, sinecatechins 15% ointment) and cytotoxic agents (podophyllotoxin and cidofovir) are considered manageable in children because of their low aggressiveness. In particular, podofillotoxin gel 5% and imiquimod 5% cream have been reported to be safe and efficacious in children. Currently, HPV vaccination is not recommended as a treatment for established HPV infection and AWs, yet a possible therapeutic role of HPV vaccination was recently suggested in the literature and deserves mention.


Malaria prophylaxis.
A trial of malaria prophylaxis was carried out on 744 army personnel who were camping in an endemic area over a 3-month period. Three antimalarial drugs were used under strict control and the local population was used as a control, to prove that malaria was present during this time. No cases of malaria occurred in the trial group during this period.


Hybrid molecular systems containing tetrathiafulvalene and iron-alkynyl electrophores: five-component functional molecules obtained from C-H bond activation.
Treatment of [Cp*(dppe)Fe-C≡C-TTFMe3] (1) with Ag[PF6] (3 equiv) in DMF provides the binuclear complex [Cp*(dppe)Fe=C=C=TTFMe2 =CH-CH=TTFMe2 =C=C=Fe(dppe)Cp*][PF6]2 (2[PF6 ]2) isolated as a deep-blue powder in 69 % yield. EPR monitoring of the reaction and comparison of the experimental and calculated EPR spectra allowed the identification of the radical salt [Cp*(dppe)Fe=C=C=TTFMe2 =CH][PF6]2 ([1-CH][PF6]) an intermediate of the reaction, which results from the activation of the methyl group attached in vicinal position with respect to the alkynyl-iron on the TTF ligand by the triple oxidation of 1 leading to its deprotonation by the solvent. The dimerization of [1-CH][PF6] through carbon-carbon bond formation provides 2[PF6]2. The cyclic voltammetry (CV) experiments show that 2[PF6]2 is subject to two sequential well-reversible one-electron reductions yielding the complexes 2[PF6] and 2. The CV also shows that further oxidation of 2[PF6]2 generates 2[PF6]n (n=3-6) at the electrode. Treatment of 2[PF6]2 with KOtBu provides 2[PF6] and 2 as stable powders. The salts 2[PF6] and 2[PF6]2 were characterized by XRD. The electronic structures of 2(n+) (n=0-2) were computed. The new complexes were also characterized by NMR, IR, Mössbauer, EPR, UV/Vis and NIR spectroscopies. The data show that the three complexes 2[PF6]n are iron(II) derivatives in the ground state. In the solid state, the dication 2(2+) is diamagnetic and has a bis(allenylidene-iron) structure with one positive charge on each iron building block. In solution, as a result of the thermal motion of the metal-carbon backbone, the triplet excited state becomes thermally accessible and equilibrium takes place between singlet and triplet states. In 2[PF6], the charge and the spin are both symmetrically distributed on the carbon bridge and only moderately on the iron and TTFMe2 electroactive centers.


PARS PLANA VITRECTOMY FOR THE TREATMENT OF TRACTIONAL AND DEGENERATIVE LAMELLAR MACULAR HOLES: Functional and Anatomical Results.
Functional and anatomical outcomes of vitrectomy with membrane peeling were compared in tractional lamellar macular holes (LMH)/macular pseudoholes (MPH) versus degenerative LMH. This multicenter retrospective study enrolled patients with a minimum follow-up of 6 months. The association of spectral domain optical coherence tomography parameters with preoperative and postoperative best-corrected visual acuity was analyzed. Seventy-seven (74.8%) tractional LMH/MPH and 26 (25.2%) degenerative LMH were included. Preoperative best-corrected visual acuity was better in tractional LMH/MPH (0.39 ± 0.2 logarithm of the minimal angle of resolution, 20/50 Snellen equivalent) than degenerative LMH (0.56 ± 0.2 logarithm of the minimal angle of resolution, 20/66 Snellen equivalent; P < 0.001). Premacular membranes were found in all tractional LMH/MPH, whereas LMH-associated epiretinal proliferation (LHEP) was present in all degenerative LMH. Primary anatomical success was achieved in 97/103 eyes (94.2%), with foveal restoration occurring earlier in degenerative LMH (1.6 ± 2.3 vs. 3.3 ± 3.6 months; P = 0.025). Best-corrected visual acuity improved in both tractional LMH/MPH and degenerative LMH (P < 0.001 and P = 0.012, respectively) but was better in tractional LMH/MPH (P = 0.001). The presence of premacular membranes and absence of LMH-associated epiretinal proliferation in all tractional LMH/MPH further distinguishes this from degenerative LMH. Best-corrected visual acuity improved in both subgroups but more so in tractional LMH/MPH. Complete anatomical restoration of foveal microanatomy was rare in degenerative LMH, reflecting significant morphological and pathophysiological differences between the two lesions.