Candida albicans-epithelial interactions and induction of mucosal innate immunity.
Candida albicans is a human fungal pathogen that causes millions of mucosal and life-threatening infections annually. C. albicans initially interacts with epithelial cells, resulting in fungal recognition and the formation of hyphae. Hypha formation is critical for host cell damage and immune activation, which are both driven by the secretion of Candidalysin, a recently discovered peptide toxin. Epithelial activation leads to the production of inflammatory mediators that recruit innate immune cells including neutrophils, macrophages and innate Type 17 cells, which together work with epithelial cells to clear the fungal infection. This review will focus on the recent discoveries that have advanced our understanding of C. albicans-epithelial interactions and the induction of mucosal innate immunity.


Cytoplasmic structure in rapid-frozen axons.
Turtle optic nerves were rapid-frozen from the living state, fractured, etched, and rotary shadowed. Stereo views of fractured axons show that axoplasm consists of three types of longitudinally oriented domains. One type consists of neurofilament bundles in which individual filaments are interconnected by a cross-bridging network. Contiguous to neurofilament domains are domains containing microtubules suspended in a loose, granular matrix. A third domain is confined to a zone, 80-100 nm wide, next to the axonal membrane and consists of a dense filamentous network connecting the longitudinal elements of the axonal cytoskeleton to particles on the inner surface of the axolemma. Three classes of membrane-limited organelles are distinguished: axoplasmic reticulum, mitochondria, and discrete vesicular organelles. The vesicular organelles must include lysosomes, multivesicular bodies, and vesicles which are retrogradely transported in axons, though some vesicular organelles may be components of the axoplasmic reticulum. Organelles in each class have a characteristic relationship to the axonal cytoskeleton. The axoplasmic reticulum enters all three domains of axoplasm, but mitochondria and vesicular organelles are excluded from the neurofilament bundles, a distribution confirmed in thin sections of cryoembedded axons. Vesicular organelles differ from mitochondria in at least three ways with respect to their relationships to adjacent axoplasm: (a) one, or sometimes both, of their ends are associated with a gap in the surrounding granular axoplasm; (b) an appendage is typically associated with one of their ends; and (c) they are not attached or closely apposed to microtubules. Mitochondria, on the other hand, are only rarely associated with gaps in the axoplasm, do not have an appendage, and are virtually always attached to one or more microtubules by an irregular array of side-arms. We propose that the longitudinally oriented microtubule domains are channels within which organelles are transported. We also propose that the granular material in these channels may constitute the myriad enzymes and other nonfibrous components that slowly move down the axon.


Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia.
The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regard to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) became of special interest in this setting as they are associated with unfavorable prognosis. Because of sequence-dependent protein conformational changes FLT3-ITD tends to autophosphorylate and displays a constitutive intracellular localization. Here, we analyzed the effect of tyrosine kinase inhibitors (TKIs) on the localization of the FLT3 receptor and its mutants. TKI treatment increased the surface expression through upregulation of FLT3 and glycosylation of FLT3-ITD and FLT3-D835Y mutants. In T cell-mediated cytotoxicity (TCMC) assays, using a bispecific FLT3 × CD3 antibody construct, the combination with TKI treatment increased TCMC in the FLT3-ITD-positive AML cell lines MOLM-13 and MV4-11, patient-derived xenograft cells and primary patient samples. Our findings provide the basis for rational combination of TKI and FLT3-directed immunotherapy with potential benefit for FLT3-ITD-positive AML patients.


[Chronic hepatitis C virus infection: clinical picture and treatment possibilities].
It has been estimated that between 1.5 and 2 million people in Italy have anti-HCV antibodies. The vast majority are chronically infected with HCV and are unaware of the infection. Chronic hepatitis C is asymptomatic during most of its course, which lasts decades. The diagnosis is based on anti-HCV antibodies and, subsequently, an HCV-RNA test, to be performed in all subjects with persistently elevated ALT and in those who are at risk of HCV infection. The identification of infected subjects allows prophylaxis of advanced liver disease, cirrhosis and hepatocellular carcinoma by antiviral treatment, which is effective in about 50% of patients. The current standard of care for chronic HCV infection is the combination of pegylated interferon and ribavirin. Their dosage and the duration of therapy are tailored to the HCV genotype and the time to viral response. The frequent occurrence of adverse events, mainly hematological, requires careful monitoring, dose reduction in some cases, and, rarely, the use of erythrocyte or leukocyte growth factors. A new class of drugs for HCV treatment, the direct acting antivirals, is currently under development. Two of these drugs, the viral protease inhibitors boceprevir and telaprevir, are awaiting registration in Europe for use in association with pegylated interferon and ribavirin. These drugs are expected to ameliorate the virus eradication rates in patients who have not received previous antiviral treatment and, more importantly, to accomplish effective treatment in those patients who are partial responders to the current standard of care.


Fusiform gyrus volume reduction in first-episode schizophrenia: a magnetic resonance imaging study.
The fusiform gyrus (occipitotemporal gyrus) is thought to be critical for face recognition and may possibly be associated with impaired facial recognition and interpretation of facial expression in schizophrenia. of postmortem studies have suggested that fusiform gyrus volume is reduced in schizophrenia, but there have been no in vivo structural studies of the fusiform gyrus in schizophrenia using magnetic resonance imaging. High-spatial resolution magnetic resonance images were used to measure the gray matter volume of the fusiform gyrus in 22 patients with first-episode schizophrenia (first hospitalization), 20 with first-episode affective psychosis (mainly manic), and 24 control subjects. Patients with first-episode schizophrenia had overall smaller relative volumes (absolute volume/intracranial contents) of fusiform gyrus gray matter compared with controls (9%) and patients with affective psychosis (7%). For the left fusiform gyrus, patients with schizophrenia showed an 11% reduction compared with controls and patients with affective psychosis. Right fusiform gyrus volume differed in patients with schizophrenia only compared with controls (8%). Schizophrenia is associated with a bilateral reduction in fusiform gyrus gray matter volume that is evident at the time of first hospitalization and is different from the presentation of affective psychosis.


Impact of partial versus whole breast radiation therapy on fatigue, perceived stress, quality of life and natural killer cell activity in women with breast cancer.
This pilot study used a prospective longitudinal design to compare the effect of adjuvant whole breast radiation therapy (WBRT) versus partial breast radiation therapy (PBRT) on fatigue, perceived stress, quality of life and natural killer cell activity (NKCA) in women receiving radiation after breast cancer surgery. Women (N = 30) with early-stage breast cancer received either PBRT, Mammosite brachytherapy at dose of 34 Gy 10 fractions/5 days, (N = 15) or WBRT, 3-D conformal techniques at dose of 50 Gy +10 Gy Boost/30 fractions, (N = 15). Treatment was determined by the attending oncologist after discussion with the patient and the choice was based on tumor stage and clinical need. Women were assessed prior to initiation of radiation therapy and twice after completion of radiation therapy. At each assessment, blood was obtained for determination of NKCA and the following instruments were administered: Perceived Stress Scale (PSS), Functional Assessment of Cancer Therapy-Fatigue (FACT-F), and Functional Assessment of Cancer Therapy-General (FACT-G). Hierarchical linear modeling (HLM) was used to evaluate group differences in initial outcomes and change in outcomes over time. Fatigue (FACT-F) levels, which were similar prior to radiation therapy, demonstrated a significant difference in trajectory. Women who received PBRT reported progressively lower fatigue; conversely fatigue worsened over time for women who received WBRT. No difference in perceived stress was observed between women who received PBRT or WBRT. Both groups of women reported similar levels of quality of life (FACT-G) prior to initiation of radiation therapy. However, HLM analysis revealed significant group differences in the trajectory of quality of life, such that women receiving PBRT exhibited a linear increase in quality of life over time after completion of radiation therapy; whereas women receiving WBRT showed a decreasing trajectory. NKCA was also similar between therapy groups but additional post hoc analysis revealed that better quality of life significantly predicted higher NKCA regardless of therapy. Compared to WBRT, PBRT results in more rapid recovery from cancer-related fatigue with improved restoration of quality of life after radiation therapy. Additionally, better quality of life predicts higher NKCA against tumor targets, emphasizing the importance of fostering quality of life for women undergoing adjuvant radiation therapy.


Blastoid Variant of Mantle Cell Lymphoma with Leukemic Presentation - A Rare Case Report.
Mantle Cell Lymphoma (MCL) is a type of Non-Hodgkin's lymphoma and has a wide spectrum of histopathological subtypes of which the blastoid or the blastic variant constitutes 10-15% of all cases. It is difficult to diagnose blastoid variant of MCL on the basis of morphology alone as it mimics lymphoblastic lymphoma and centroblastic large cell lymphoma, hence additional analysis like immunophenotyping and molecular studies aid in its diagnosis. We present a case of 45-year-old male who presented to medicine OPD with chief complaints of fever, fatigability and inguinal swelling. Complete blood count, peripheral smear and bone marrow examination was performed. Peripheral smear showed thrombocytopenia along with 53% abnormal cells. On bone marrow examination 43% abnormal lymphoid cells were seen. This case was diagnosed as blastoid variant of MCL on the basis of routine morphology and immunohistochemistry on bone marrow biopsy and flow cytometric immunophenotyping on peripheral blood.


Long-Term Survival of Patients with Tracheostomy Having Different Diseases Followed up in the Respiratory Intensive Care Unit Outpatient Clinic: Which Patients are Lucky?
Tracheostomy is a method of separating a patient from the mechanical ventilator in the intensive care unit (ICU). The long-term survivors among patients followed up with tracheostomy and ventilator in the respiratory ICU (RICU) outpatient clinic due to different diseases were investigated. This was a retrospectively designed cohort study between January 2004 and July 2018. Patients with chronic respiratory failure followed up with tracheostomy and/or ventilator at the RICU outpatient clinic were included in the study. Age, gender, indications and date of tracheostomy, use of domestic mechanical ventilation, and mortality were recorded. The groups were compared according to age, gender, and tracheostomy indication diseases, and the 1-3-year long-term mortality rates were analyzed by the Kaplan-Meier survival analysis, and the Cox regression test was performed. A total of 134 (64% male) patients with a median age of 66 (54-73) years were included in the study. The indications for tracheostomy were heart failure (HF) and cerebrovascular diseases (38.1%), chronic obstructive pulmonary disease (COPD) (23.1%), neuromuscular diseases (22.4%), obesity hypoventilation (9.7%), and kyphoscoliosis (6.7%). Mortality was higher in patients >75 years old in the 3-year follow-up (p=0.022). The 3-year mortality hazard ratio (HR) factors and 95% confidence interval (CI) were as follows: age >75 years HR=1.71 (95% CI, 1.03-2.82; p<0.036) and HF and cerebrovascular disease diseases sequela HR=1.84 (95% CI, 1.03-3.29; p<0.041) significantly increased the 3-year mortality, and having COPD decreased mortality in 46% (p<0.041). Patients with neuromuscular disorders, kyphoscoliosis, and COPD who have undergone tracheostomy were the luckiest group according to the 3-year survival rates, whereas patients with HF and cerebrovascular diseases were the unluckiest ones. The most important decision triangle is the patient's acceptance (A), family support (B), and tracheostomy indication (C), and this may vary from country to country depending on the beliefs of subjects.


Confinement effects on monosaccharide transport in nanochannels.
Transport theories based on the continuum hypothesis may not be appropriate at the nanoscale in view of surface effects. We employed molecular dynamics simulations to study the effects of confinement and concentration on diffusive transport of glucose in silica nanochannels (10 nm or smaller). We found that glucose modifies the electrical properties of nanochannels and that, below 5 nm in channel height, glucose adsorption and diffusivity are significantly reduced. With increasing concentration, the diffusivity is reduced linearly in the bulk, while it is reduced nonlinearly at the interface. The effective diffusivity reduction is related to the interface thickness, which can be 2-4 nm depending on concentration, and has an unexpected reduction at low concentrations. Results suggest that nanochannels present a one-dimensional cage environment that affects diffusivity in a fashion similar to cage-breaking diffusion. Our simulation results, consistent with the experimental observations presented here, suggest that nanoconfinement is the essential cause of the observed altered fluid diffusive transport, not accounted for by classical theories, because of coupling of confinement and concentration effects.


Associations between Urinary, Dietary, and Water Fluoride Concentrations among Children in Mexico and Canada.
Fluoride, which may be toxic to the developing brain, is added to salt in Mexico and drinking water in Canada to prevent dental caries. We compared childhood urinary fluoride (CUF) concentrations in Mexico City and Canada to characterize patterns of fluoride exposure in these two populations. We also examined associations of CUF with dietary and water fluoride levels in Mexico City and Canada respectively. We included 561 children (ages 4–6; mean age 4.8 years) from the Programming Research in Obesity, Growth, Environment, and Social Stress (PROGRESS) cohort in Mexico City, and 645 children (ages 2–6; mean age 3.7 years) from the Maternal–Infant Research on Environmental Chemicals (MIREC) cohort in Canada. We applied Spearman correlations, T-tests, ANOVA or covariate-adjusted linear regression to examine associations of CUF (mg/L; adjusted for specific gravity) with demographics and dietary or water fluoride concentrations. We used Welch equivalence testing to compare means across cohorts. Mean (SD) CUF was equivalent (t = 4.26, p < 0.001) in PROGRESS: 0.74 (0.42) and fluoridated Canadian communities: 0.66 (0.47), but lower in non-fluoridated Canadian communities: 0.42 (0.31) (t = −6.37, p < 0.001). Water fluoride concentrations were significantly associated with CUF after covariate adjustment for age and sex in MIREC (B = 0.44, 95% CI: 0.30, 0.59, p < 0.001). In contrast, daily food and beverage fluoride intake was not associated with CUF in PROGRESS (p = 0.82). We found that CUF levels are comparable among children in Mexico City and fluoridated Canadian communities, despite distinct sources of exposure. Community water fluoridation is a major source of fluoride exposure for Canadian children.


Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung.
For gene therapy to improve lung function in cystic fibrosis (CF) subjects, repeated administration of the gene transfer agent over the lifetime of patients is likely to be necessary. This requirement limits the utility of adenoviral and adeno-associated viral vectors (both previously evaluated in CF gene therapy trials) because of induced adaptive immune responses that render repeated dosing ineffective. For CF gene therapy trials, non-viral vectors are currently the only viable option. We previously showed that the cationic lipid formulation GL67A is the most efficient of several non-viral vectors analysed for airway gene transfer. Here, we assessed the efficacy and safety of administering 12 inhaled doses of GL67A complexed with pGM169, a CpG-free plasmid encoding human CFTR complementary DNA, into mice. We show that repeated administration of pGM169/GL67A to murine lungs is feasible, safe and achieves reproducible, dose-related and persistent gene expression (>140 days after each dose) using an aerosol generated by a clinically relevant nebuliser. This study supports progression into the first non-viral multidose lung trial in CF patients.


Linking agroecosystems producing farmed seafood with food security and health status to better address the nutritional challenges in Bangladesh.
Aquaculture is one of the fastest-growing food production sectors in many low-income and food-deficit countries with aquatic ecozones. Yet its specific impact on nutrition and livelihood in local communities, where commercial and/or export-orientated aquaculture activities are developed, is largely unknown. The present narrative and argumentative review aims to provide an overview of our current understanding of the connections between aquaculture agroecosystems, local and national fish production, fish consumption patterns and nutrition and health outcomes. The agroecological dynamic in a coastal-estuarine zone, where the aquatic environment ranges from fully saline to freshwater, is complex, with seasonal and annual fluctuations in freshwater supply creating a variable salinity gradient which impacts on aquatic food production and on food production more generally. The local communities living in these dynamic aquatic ecozones are vulnerable to poverty, poor diet and health, while these ecosystems produce highly valuable and nutritious aquatic foods. Policies addressing the specific challenges of risk management of these communities are limited by the sectoral separation of aquatic food production - the fisheries and aquaculture sector, the broader food sector - and public health institutions. Here we provide an argument for the integration of these factors to improve aquaculture value chains to better address the nutritional challenges in Bangladesh.


Perinatal maternal depression and cortisol function in pregnancy and the postpartum period: a systematic literature review.
Perinatal depression has a significant impact on both mother and child. However, the influence of hormonal changes during pregnancy and the postpartum period remains unclear. This article provides a systematic review of studies examining the effects of maternal cortisol function on perinatal depression. A systematic search was conducted of six electronic databases for published research on the relationship between cortisol and perinatal depression. The databases included; MEDLINE complete, PsychINFO, SCOPUS, Psychology and Behavioural Sciences, Science Direct and EBSCO, for the years 1960 to May 2015. Risk of bias was assessed and data extraction verified by two investigators. In total, 47 studies met criteria and studies showed considerable variation in terms of methodology including sample size, cortisol assays, cortisol substrates, sampling processes and outcome measures. Those studies identified as higher quality found that the cortisol awakening response is positively associated with momentary mood states but is blunted in cases of major maternal depression. Furthermore, results indicate that hypercortisolemia is linked to transient depressive states while hypocortisolemia is related to chronic postpartum depression. Future research should aim to improve the accuracy of cortisol measurement over time, obtain multiple cortisol samples in a day and utilise diagnostic measures of depression. Future studies should also consider both antenatal and postnatal depression and the differential impact of atypical versus melancholic depression on cortisol levels, as this can help to further clarify the relationship between perinatal depression and maternal cortisol function across pregnancy and the postpartum period.


Emergent management of postpartum hemorrhage for the general and acute care surgeon.
Postpartum hemorrhage is one of the rare occasions when a general or acute care surgeon may be emergently called to labor and delivery, a situation in which time is limited and the stakes high. Unfortunately, there is generally a paucity of exposure and information available to surgeons regarding this topic: obstetric training is rarely found in contemporary surgical residency curricula and is omitted nearly completely from general and acute care surgery literature and continuing medical education. The purpose of this manuscript is to serve as a topic specific review for surgeons and to present a surgeon oriented management algorithm. Medline and Ovid databases were utilized in a comprehensive literature review regarding the management of postpartum hemorrhage and a management algorithm for surgeons developed based upon a collaborative panel of general, acute care, trauma and obstetrical surgeons' review of the literature and expert opinion. A stepwise approach for surgeons of the medical and surgical interventions utilized to manage and treat postpartum hemorrhage is presented and organized into a basic algorithm. The manuscript should promote and facilitate a more educated, systematic and effective surgeon response and participation in the management of postpartum hemorrhage.


Microcirculation of the pancreas in the rat and rabbit with special reference to the insulo-acinar portal system and emissary vein of the islet.
Microcirculation of the pancreas in the rat and rabbit with special reference to the islets was studied by scanning electron microscopy (SEM) of vascular corrosion casts, light microscopy (LM) of India ink-injected/cleared tissues, and intravital microscopy of in situ organs. The following observations were made: Approximately 10-20% of the total terminal arterioles supplied the islets, while the remainder directly supplied the exocrine pancreas. The vas afferens of the islets divided into sinusoidal capillaries with frequent U-shaped turns in the cortical A and D cell area of the islets, and their secondary branches supplied the core B cell area. Intravital microscopy confirmed that blood irrigated the cortex of the islets first and the core portion second. All islets observed possessed insulo-acinar portal vessels. About 60% of the islets in the rat possessed emissary veins leading directly into the systemic circulation, while in the rabbit, less than 5% of islets possessed emissary venules of small diameter. Thus, the well-developed emissary veins of the islets seemed characteristic of the rat, as compared with the rabbit and several other mammals examined previously. The insulo-acinar portal system seems to represent a short vascular route through which islet secretions are transported in high concentrations to the exocrine pancreas, there to exert their actions. The emissary veins of the islet seem to serve for the quick conveyance of insular secretions into general circulation. It is suggested that the pancreatic lobule is made up of subdivisions or microcirculatory units, each of which is supplied centrally by the insulo-acinar portal system, while peripherally the unit also receives direct branches of intralobular arterioles. The veins run the periphery of the unit. The occurrence of sphincters in the vas afferens and the emissary veins of the islets is suggested as being involved in the regulation of the islet blood flow.


Reliability of journal impact factor rankings.
Journal impact factors and their ranks are used widely by journals, researchers, and research assessment exercises. Based on citations to journals in research and experimental medicine in 2005, Bayesian Markov chain Monte Carlo methods were used to estimate the uncertainty associated with these journal performance indicators. Intervals representing plausible ranges of values for journal impact factor ranks indicated that most journals cannot be ranked with great precision. Only the top and bottom few journals could place any confidence in their rank position. Intervals were wider and overlapping for most journals. Decisions placed on journal impact factors are potentially misleading where the uncertainty associated with the measure is ignored. This article proposes that caution should be exercised in the interpretation of journal impact factors and their ranks, and specifically that a measure of uncertainty should be routinely presented alongside the point estimate.


Characterization of the promoter and the transcriptional regulation of the lipoxin A4 receptor (FPR2/ALX) gene in human monocytes and macrophages.
The lipoxin A4 receptor FPR2/ALX plays an important part in host defense and inflammation. The receptor binds structurally diverse agonistic ligands, which mainly regulate chemotaxis and activation of leukocytes. However, little is known about the promoter region of the FPR2/ALX gene and its transcriptional regulation in leukocytes. We identified two TATA-less promoter regions, separated by 224 bp, that drive the expression of FPR2/ALX in macrophages. Both promoter regions increased transcription in a reporter assay, and the basal transcription factors OCT1 and SP1 were shown to bind the first and the second promoter, respectively, and to transactivate transcription. Although monocytes expressed high levels of FPR2/ALX mRNA from the second promoter region, differentiation into macrophages abrogated FPR2/ALX expression. Stimulation of macrophages with a set of cytokines revealed that only IFN-γ and LPS increased FPR2/ALX expression from the first promoter to levels similar to those detected in monocytes. The upregulation by IFN-γ is in part mediated by the interaction of IFN regulatory factor 1 with an IFN-responsive sequence element transcription factor binding site located in the first promoter region of the FPR2/ALX gene. However, this upregulation on the mRNA level did not translate into FPR2/ALX protein expression in macrophages owing to reduced translation of the longer mRNA from the first promoter. In contrast, FPR2/ALX mRNA transcribed from the second promoter was translated into surface expression of FPR2/ALX in monocytes. These data support a model in which FPR2/ALX plays a role in chemotaxis and activation of monocytes; however, they also suggest that its function in resident tissue macrophages is limited.


[Cloning and expression analysis of two salt and Fusarium graminearum stress associated UDP-glucosyltransferases genes in wheat].
Glycosyltransferases (GTs) play important roles in stress responses of plants by glycosylating hormones and secondary metabolites. UDP-glucosyltransferases (UGTs), which use UDP-glucuronic acid in animals, UDP-glucose, UDP-galactose, and UDP- rhamnose in plant as sugar donors, belong to family 1 of GTs. As a secondary metabolite produced by Fusarium graminearum during infection of grains, deoxynivalenol (DON) is not only harmful to human and animal's health by inhibiting protein synthesis, but also acts as a virulence factor during fungal pathogenesis. In order to study expression profile of UGT genes in wheat, two UGTs, designated TaUGT1 and TaUGT2, were isolated from bread wheat (Triticum aestivum L.) by reverse transcriptase-polymerase chain reaction. The genomic sequences of both genes had one intron. Their coding sequences shared 91% and 90% similarities at nucleic acid level and the deduced protein sequence level. The analysis of conserved domain revealed that these two cDNAs encoded UDP-glucoronosyl and UDP-glucosyl transferase with PSPG (Putative secondary plant glycosyltransferase) domain. Real-time PCR was carried out to detect the expression profiles of the two UGTs in wheat under various stress conditions. In young spikes infected by Fusarium graminearum, TaUGT2 was induced but TaUGT1 was repressed. These two genes were upregulated under higher NaCl concentration. In conclusion, TaUGT2 may participate in wheat resistance to Fusarium head blight in which mycotoxin DON plays a role, and these two genes might be involved in responses of wheat to salt stress.


Improved outcomes with quality improvement interventions in pediatric inflammatory bowel disease.
Variations in chronic illness care are common in our health care system and may lead to suboptimal outcomes. Specifically, inconsistent use and suboptimal medication dosing have been demonstrated in the care of patients with inflammatory bowel disease (IBD). Quality improvement (QI) efforts have improved outcomes in conditions such as asthma and diabetes mellitus, but have not been well studied in IBD. We hypothesized that QI efforts would lead to improved outcomes in our pediatric IBD population. A QI team was formed within our IBD center in 2005. By 2007, we began prospectively capturing physician global assessment (PGA) and patient-reported global assessment. Significant QI interventions included creating evidence-based medication guidelines, joining a national QI collaborative, initiation of preclinic planning, and monitoring serum 25-hydroxyvitamin D. From 2007 to 2010, 505 patients have been followed at our IBD center. During this time, the frequency of patients in clinical remission increased from 59% to 76% (P < 0.05), the frequency of patients who report that their global assessment is >7 increased from 69% to 80% (P < 0.05), and the frequency of patients with a Short Pediatric Crohn's Disease Activity Index (sPCDAI) <15 increased from 60% to 77% (P < 0.05). The frequency of repeat steroid use decreased from 17% to 10% (P < 0.05). We observed an association between the use of a vitamin D supplement (P = 0.02), serum 25-hydroxyvitamin D (P < 0.05), and quiescent disease activity. Our results show that significant improvements in patient outcomes are associated with QI efforts that do not rely on new medication or therapies.


Mesenchymal Stem/Stromal Cells for Rheumatoid Arthritis Treatment: An Update on Clinical Applications.
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects the lining of the synovial joints leading to stiffness, pain, inflammation, loss of mobility, and erosion of joints. Its pathogenesis is related to aberrant immune responses against the synovium. Dysfunction of innate and adaptive immunity, including dysregulated cytokine networks and immune complex-mediated complement activation, are involved in the progression of RA. At present, drug treatments, including corticosteroids, antirheumatic drugs, and biological agents, are used in order to modulate the altered immune responses. Chronic use of these drugs may cause adverse effects to a significant number of RA patients. Additionally, some RA patients are resistant to these therapies. In recent years, mesenchymal stem/stromal cell (MSCs)-based therapies have been largely proposed as a novel and promising stem cell therapeutic approach in the treatment of RA. MSCs are multipotent progenitor cells that have immunomodulatory properties and can be obtained and expanded easily. Today, nearly one hundred studies in preclinical models of RA have shown promising trends for clinical application. Proof-of-concept clinical studies have demonstrated satisfactory safety profile of MSC therapy in RA patients. The present review discusses MSC-based therapy approaches with a focus on published clinical data, as well as on clinical trials, for treatment of RA that are currently underway.


The changing pattern of fever of unknown origin in the Republic of North Macedonia.
The study aimed to compare the etiologic spectrum of diseases causing fever of unknown origin (FUO) and methods for definitive diagnosis in a tertiary care hospital in the Republic of North Macedonia during two different time periods. There were analysed retrospectively the causes for FUO and final diagnostic approaches in 185 patients with classic FUO that were treated at the University Hospital for Infectious Diseases in Skopje during two time periods. Seventy nine patients were treated during 1991 to 1995 and 106 patients during 2011 to 2015. When comparing these two periods, infections were present in 46.8% and 29.2% (p = 0.014), non-infective inflammatory disorders in 22.8% and 25.5% (p = 0.674), neoplasms in 10.1% and 13.2% (p = 0.522), miscellaneous in 8.9% and 12.3% (p = 0.461) and undiagnosed cases in 11.4% and 19.8% (p = 0.124), respectively. The most common causes for FUO during the first period were abscesses (8.9%), tuberculosis and systemic lupus erythematosus (7.6% each), whereas in the second period the commonest causes were adult onset Still disease and solid organ neoplasm (7.6% each), polymyalgia rheumatica, abscesses and visceral leishmaniasis (5.7% each). The newer imaging techniques and clinical course evaluation had superior diagnostic significance during the second period. A changing pattern of diseases causing FUO during the examined periods was evident. Infections continue to be the most common cause but with decreasing incidence when compared to 20 years ago. Even nowadays clinical evaluation and follow-up still remain the vital diagnostic tools in determining the etiology of FUO.


The Virtual Multifrequency Spectrometer: a new paradigm for spectroscopy.
On going developments of hardware and software are changing computational spectroscopy from a strongly specialized research area to a general tool in the inventory of most researchers. Increased interactions between experimentally-oriented users and theoretically-oriented developers of new methods and models would result in more robust, flexible and reliable tools and studies for the systems of increasing complexity, which are of current scientific and technological interest. This is the philosophy behind this review, which presents the development of a so-called virtual multi-frequency spectrometer (VMS) including state-of-the-art approaches in a user-friendly frame. The current status of the VMS tool will be illustrated by a number of case studies with special reference to infrared and UV-vis regions of the electro-magnetic spectrum including also chiral spectroscopies. Only the basic theoretical background will be provided avoiding explicit equations as far as possible, and pointing out the most recent advancements beyond the standard rigid-rotor harmonic-oscillator model coupled to vertical electronic excitation energies.


Mapping the contribution of beta3-containing GABAA receptors to volatile and intravenous general anesthetic actions.
Agents belonging to diverse chemical classes are used clinically as general anesthetics. The molecular targets mediating their actions are however still only poorly defined. Both chemical diversity and substantial differences in the clinical actions of general anesthetics suggest that general anesthetic agents may have distinct pharmacological targets. It was demonstrated previously that the immobilizing action of etomidate and propofol is completely, and the immobilizing action of isoflurane partly mediated, by beta3-containing GABAA receptors. This was determined by using the beta3(N265M) mice, which carry a point mutation known to decrease the actions of general anesthetics at recombinant GABAA receptors. In this communication, we analyzed the contribution of beta3-containing GABAA receptors to the pharmacological actions of isoflurane, etomidate and propofol by means of beta3(N265M) mice. Isoflurane decreased core body temperature and heart rate to a smaller degree in beta3(N265M) mice than in wild type mice, indicating a minor but significant role of beta3-containing GABAA receptors in these actions. Prolonged time intervals in the ECG and increased heart rate variability were indistinguishable between genotypes, suggesting no involvement of beta3-containing GABAA receptors. The anterograde amnesic action of propofol was indistinguishable in beta3(N265M) and wild type mice, suggesting that it is independent of beta3-containing GABAA receptors. The increase of heart rate variability and prolongation of ECG intervals by etomidate and propofol were also less pronounced in beta3(N265M) mice than in wild type mice, pointing to a limited involvement of beta3-containing GABAA receptors in these actions. The lack of etomidate- and propofol-induced immobilization in beta3(N265M) mice was also observed in congenic 129X1/SvJ and C57BL/6J backgrounds, indicating that this phenotype is stable across different backgrounds. Our results provide evidence for a defined role of beta3-containing GABAA receptors in mediating some, but not all, of the actions of general anesthetics, and confirm the multisite model of general anesthetic action. This pharmacological separation of anesthetic endpoints also suggests that subtype-selective substances with an improved side-effect profile may be developed.


Economic benefits of the Mediterranean-style diet consumption in Canada and the United States.
The Mediterranean-style diet (MedDiet) is an established healthy-eating behavior that has consistently been shown to favorably impact cardiovascular health, thus likely improving quality of life and reducing costs associated with cardiovascular disease (CVD). Data on the economic benefits of MedDiet intakes are, however, scarce. The objective of this study was to estimate the annual healthcare and societal cost savings that would accrue to the Canadian and American public, independently, as a result of a reduction in the incidence of CVD following adherence to a MedDiet. A variation in cost-of-illness analysis entailing three stages of estimations was developed to 1) identify the proportion of individuals who are likely to adopt a MedDiet in North America, 2) assess the impact of the MedDiet intake on CVD incidence reduction, and 3) impute the potential savings in costs associated with healthcare and productivity following the estimated CVD reduction. To account for the uncertainty factor, a sensitivity analysis of four scenarios, including ideal, optimistic, pessimistic, and very-pessimistic assumptions, was implemented within each of these stages. Significant improvements in CVD-related costs were evident with varying MedDiet adoption and CVD reduction rates. Specifically, CAD $41.9 million to 2.5 billion in Canada and US $1.0-62.8 billion in the United States were estimated to accrue as total annual savings in economic costs, given the 'very-pessimistic' through 'ideal' scenarios. Closer adherence to dietary behaviors that are consistent with the principles of the MedDiet is expected to contribute to a reduction in the monetary burdens of CVD in Canada, the United States, and possibly other parts of the world.


The influence of urbanisation on measures of Plasmodium falciparum infection prevalence in East Africa.
There is a growing interest in the effects of urbanisation in Africa on Plasmodium falciparum risks and disease outcomes. We undertook a review of published and unpublished literature to identify parasite survey data from communities in East Africa. Data were selected to represent the most reliable and contemporary estimates of infection prevalence and were categorised by urban or rural status using a number of approaches. We identified 329 spatially distinct surveys undertaken since 1980 in the sub-region of which 37 were undertaken in urban settlements and 292 in rural settlements. Overall rural settlements reported significantly higher parasite prevalence among children aged 0-14 than urban settlements (on average 10% higher infection rates; p<0.05). No urban settlements recorded parasite prevalence in excess of 75%. In areas of East Africa where climatic conditions are likely to support higher parasite transmission, the rural-urban difference was most marked. There was a significant trend towards documenting higher classes of parasite prevalence in rural compared to urban settlements (p<0.05) and the mean difference between rural and urban samples was 18% (p<0.001). These results further highlight the need to better define urban extents in Africa in order to capture the non-climatic determinants of infection and disease risk and provide a more informed approach to describing the burden of disease across the continent.


Heavy maternal alcohol consumption and cerebral palsy in the offspring.
The aim of this study was to investigate the association between heavy maternal alcohol consumption and pre- peri- and postneonatally acquired cerebral palsy (CP). The records of all mothers with an International Classification of Diseases, revision 9 or 10 (ICD-9/-10) alcohol-related diagnostic code, indicating heavy alcohol consumption, recorded on population-based health, mental health, and drug and alcohol data sets from 1983 to 2007, and their children were identified through the Western Australian Data-linkage System. This 'exposed' cohort was frequency matched with mothers without an alcohol-related diagnosis and their offspring (comparison group). Cases of CP were identified through linkage with the Western Australia CP Register. Analyses were undertaken using multivariate logistic regression. There were 23 573 live births in the exposed group (58.6% non-Aboriginal; 41.4% Aboriginal) and 292 cases of CP. The odds of pre/perinatally acquired CP were elevated for children of non-Aboriginal mothers with an alcohol-related diagnosis recorded during pregnancy (adjusted odds ratio 3.32; 95% confidence interval [CI] 1.30-8.48) and for Aboriginal children when an alcohol-related diagnosis was recorded up to 12 months before the mother's pregnancy (adjusted odds ratio 2.49; 95% CI 0.99-6.25). Increased odds of postneonatally acquired CP following any alcohol-related diagnosis were found for non-Aboriginal children (adjusted odds ratio 7.92; 95% CI 2.23-28.14). These results suggest that heavy maternal alcohol consumption is a direct cause of pre/perinatally acquired CP, and an indirect cause of postneonatally acquired CP, in non-Aboriginal children. The lack of an association for Aboriginal children requires further investigation but may be due to under ascertainment of alcohol use disorders during pregnancy and other aetiological pathways.


Terahertz single-shot quadrature phase-shifting interferometry.
A single-shot quadrature phase-shifting interferometry architecture is presented that is applicable to antenna coupled detector technologies. The method is based on orthogonally polarized object and reference beams and on linear and circular polarization sensitive antennas in space-division multiplexing. The technique can be adapted to two-, three-, and four-step and Gabor holography recordings. It is also demonstrated that the space-division multiplexing does not necessarily cause sparse sampling. A sub-THz detector array is presented containing multiple on-chip antennas and FET plasma wave detectors implemented in a 90 nm complementary metal-oxide semiconductor technology. As an example, two-step phase-shifting reconstruction results are given at 360 GHz.


Eating Disorder Symptoms and Proneness in Gay Men, Lesbian Women, and Transgender and Non-conforming Adults: Comparative Levels and a Proposed Mediational Model.
In this study we sought to compare eating disorder attitudes and behaviors, and proneness to an eating disorder ("ED proneness"), between gay men, lesbian women, and transgender and non-conforming (TGNC) adults. A further aim was to identify and compare risk and protective factors, and examine a mediational model based on the interpersonal theory of eating disorders (IPT-ED), whereby the association between interpersonal factors and ED proneness would be mediated by psychological constructs pertaining to the self and negative affect. Data was obtained from a larger national study of health risk and protective factors among sexual minority and gender diverse populations. The sample included 97 gay men, 82 lesbian women, and 138 TGNC adults. Participants completed the National College Health Assessment, Eating Disorders Screen for Primary Care, Patient Health Questionnaire Depression scale, Generalized Anxiety Disorder 7 scale, Self-Compassion Scale-Short Form, Negative Social Exchange subscale of the Multidimensional Health Profile, Interpersonal Needs Questionnaire, and Perceived Stigma Scale. There was a significant difference between groups in ED proneness, with lesbian women (66.7%) having a significantly higher percentage than gay men (47.6%). There was also a significant difference between groups in weight-based self-worth, with the lowest percentage in gay men (63%) and the highest percentage in lesbian women (82%), as well as dissatisfaction with eating patterns, with the highest percentage in TGNC adults (69.8%) and the lowest percentage in gay men (47.7%). There was a low percentage of inappropriate compensatory behaviors, with no significant difference between groups. Logistic regression analyses showed that the predictor variables of ED proneness were depression, perceived stigma, and self-compassion in gay men; depression in lesbian women; and self-compassion in the TGNC adults. Mediation analyses showed that thwarted belongingness (i.e., an unmet to belong) and perceived stigma had an indirect association with ED proneness that was mediated by self-compassion and depression (for perceived stigma alone) in gay men, depression in lesbian women, and self-compassion in TGNC adults. The interpersonal theory of eating disorders therefore extends to sexual minority and gender diverse populations; however, the results suggest a broadening of theoretical models and intervention programs to include the role of stigma and self-compassion.


[Neprilysin inhibition and chronic kidney disease].
Patients with chronic kidney disease (CKD) have a higher incidence of cardiovascular (acute and chronic) events, which in turn have an increased risk of progression to end-stage renal disease (ESRD) Inhibition of neprilysin, in addition to offering a new therapeutic target in patients with heart failure, could represent a potential improvement strategy in cardiovascular and renal outcome of patients with CKD. Inhibition of neprilysin by inhibiting the breakdown of natriuretic peptides, increases their bioavailability resulting in an increase in diuresis and sodium excretion and, in addition to exerting an inhibition of the renin-angiotensin-aldosterone (RAAS) system. Inhibition of RAAS, in turn, generates a series of counter-regulations that can balance the adverse effects present in CKD and heart failure (HF). The idea of blocking neprilysin is not very recent, but the first drugs used as inhibitors had an inadmissible incidence of angioedema. Among the latest generation molecules that can perform a specific inhibitory action on the neprilysin receptor and, at the same time, on the angiotensin II receptor thanks to the association with valsartan there is the LCZ696 (sacubitril / valsartan). This drug has shown promising benefits both in the treatment arterial hypertension and heart failure. It is hoped that equally positive effects may occur in CKD patients, particularly those with macroproteinuria.


Adaptation, allometry, and hypertension.
Essential hypertension is a "disease of civilization" but has a clear genetic component. From an evolutionary perspective, persistence in the human genome of elements capable of raising blood pressure presupposes their adaptive significance. Recently, two hypotheses that explicitly appeal to selectionist arguments, the "slavery" and "thrifty gene" theories, have been forwarded. We find neither completely successful, and we advance an alternative explanation of the adaptive importance of genes responsible for hypertension. We propose that blood pressure rises during childhood and adolescence to subserve homeostatic needs of the organism. Specifically, we contend that blood pressure is a flexible element in the repertoire of renal homeostatic mechanisms serving to match renal function to growth. The effect of modern diet and lifestyle on human growth stimulates earlier and more vigorous development, straining biologically necessary relationships between renal and general somatic growth and requiring compensation via homeostatic mechanisms preserved during evolution. Prime among such mechanisms is blood pressure, which rises as a compensation to maintain renal function in the face of greater growth. Since virtually all members of acculturated societies share in the modern lifestyle, the demands imposed by accelerated growth and development result in a populational shift to higher blood pressures, with a consequent increase in the prevalence of hypertension. We propose that hypertension is the product of maladaptation of highly genetically conserved mechanisms subserving important biological homeostatic needs. Elucidation of the mechanisms underlying hypertension will require approaches that examine the developmental processes linking growth to blood pressure.


Physicians' attitudes toward patients' use of alternative cancer therapies.
To determine physicians' attitudes and reactions to their patients' use of alternative cancer therapies, factors that affect these reactions and physicians' views of how the use of such therapies affects the physician-patient relationship. Qualitative study involving in-depth semistructured interviews. Toronto. Nineteen oncologists and 35 general practitioners (GPs) were selected by means of purposive sampling; 18 oncologists and 12 GPs agreed to participate. Attitudes and reactions to patients' use of alternative cancer therapies; factors affecting physicians' reactions to such use; and physicians' views of how the use of such therapies affects the physician-patient relationship. Many physicians perceived themselves to be unfamiliar with available alternative cancer therapies and indicated that their main sources of information were their patients and the lay press. Although most of the physicians viewed the efficacy of such therapies as scientifically unproven, they would respect their patients' decision to use them and encourage them to continue with standard treatment. Factors found to influence the physicians' reactions included the prognosis with standard treatments, the exclusivity of the use of alternative therapies and whether the alternative therapies were harmful. Although many of the participants felt that a patient's use of alternative cancer therapies did not affect the physician-patient relationship, a few indicated that it did cause some tension. Because many physicians lack information on alternative cancer therapies and most of these therapies have not been scientifically proven, physicians' attitudes and reactions to their use by patients are influenced to a greater degree by the efficacy or inefficacy of standard treatment and the invasiveness of the alternative therapy than by the efficacy of the alternative therapy used.


Antimicrobial action of chelating agents: repercussions on the microorganism development, virulence and pathogenesis.
Infections caused by resistant microorganisms often fail to respond to conventional therapy, resulting in prolonged illness, increased treatment costs and greater risk of death. Consequently, the development of novel antimicrobial drugs is becoming more demanding every day since the existing drugs either have too many side-effects or they tend to lose effectiveness due to the selection of resistant strains. In view of these facts, a number of new strategies to obstruct vital biological processes of a microbial cell have emerged; one of these is focused on the use of metal-chelating agents, which are able to selectively disturb the essential metal metabolism of the microorganism by interfering with metal acquisition and bioavailability for crucial reactions. The chelation activity is able to inhibit the biological role of metal-dependent proteins (e.g., metalloproteases and transcription factors), disturbing the microbial cell homeostasis and culminating in the blockage of microbial nutrition, growth and development, cellular differentiation, adhesion to biotic (e.g., extracellular matrix components, cell and/or tissue) and abiotic (e.g., plastic, silicone and acrylic) structures as well as controlling the in vivo infection progression. Interestingly, chelating agents also potentiate the activity of classical antimicrobial compounds. The differences between the microorganism and host in terms of the behavior displayed in the presence of chelating agents could provide exploitable targets for the development of an effective chemotherapy for these diseases. Consequently, metal chelators represent a novel group of antimicrobial agents with potential therapeutic applications. This review will focus on the anti-fungal and anti-protozoan action of the most common chelating agents, deciphering and discussing their mode of action.


Antigen-specific T lymphocyte clones. I. Characterization of a T lymphocyte clone expressing antigen-specific suppressive activity.
We have generated continuously propagatable T lymphocyte clones to study antigen-specific T cell functions. All Ly-2+ clones mediate suppressive activity and secrete a characteristic pattern of polypeptides that differs from Ly-2- T cell clones. Cells of one clone, Cl.Ly23/4, specifically bind glycophorin from sheep erythrocytes (SRBC). After incubation with [35S]methionine, supernate material from this clone also contains biosynthetically labeled 70,000-mol wt proteins that specifically bind to SRBC and this binding is inhibited by glycophorin from sheep but not other erythrocytes. These antigen-binding 70,000-mol wt peptides specifically and completely suppress primary anti-SRBC responses generated by mixtures of primed Ly-1+2- cells and B cells. Suppression by these antigen-binding peptides reflects direct inhibition of T-helper activity.


Challenges to Implementing a National Health Information System in Cameroon: Perspectives of Stakeholders.
In the early 90s, the Cameroon Ministry of Health implemented a National Health Information System (NHIS) based on a bottom-up approach of manually collecting and reporting health data. Little is known about the implementation and functioning of the NHIS. The purpose of this study was to assess the implementation of the NHIS by documenting experiences of individual stakeholders, and to suggest recommendations for improvement. We reviewed relevant documents and conducted face-to-face interviews (N=4) with individuals directly involved with data gathering, reporting and storage. Content analysis was used to analyze textual data. We found a stalled and inefficient NHIS characterized by general lack of personnel, a labor-intensive process, delay in reporting data, much reliance on field staff, and lack of incentives. A move to an electronic health information system without involving all stakeholders and adequately addressing the issues plaguing the current system is premature.


Implementing the Institute of Medicine definition of disparities: an application to mental health care.
In a recent report, the Institute of Medicine (IOM) defines a health service disparity between population groups to be the difference in treatment or access not justified by the differences in health status or preferences of the groups. This paper proposes an implementation of this definition, and applies it to disparities in outpatient mental health care. Health Care for Communities (HCC) reinterviewed 9,585 respondents from the Community Tracking Study in 1997-1998, oversampling individuals with psychological distress, alcohol abuse, drug abuse, or mental health treatment. The HCC is designed to make national estimates of service use. Expenditures are modeled using generalized linear models with a log link for quantity and a probit model for any utilization. We adjust for group differences in health status by transforming the entire distribution of health status for minority populations to approximate the white distribution. We compare disparities according to the IOM definition to other methods commonly used to assess health services disparities. Our method finds significant service disparities between whites and both blacks and Latinos. Estimated disparities from this method exceed those for competing approaches, because of the inclusion of effects of mediating factors (such as income) in the IOM approach. A rigorous definition of disparities is needed to monitor progress against disparities and to compare their magnitude across studies. With such a definition, disparities can be estimated by adjusting for group differences in models for expenditures and access to mental health services.


Psychosocial factors associated with mouth and throat cancer examinations in rural Florida.
We examined the knowledge and prevalence of mouth and throat cancer examinations in a sample drawn from rural populations in north Florida. Telephone interviews were conducted across rural census tracts throughout north Florida in 2009 and 2010, in a survey that had been adapted for cultural appropriateness using cognitive interviews. The sample consisted of 2526 respondents (1132 men and 1394 women; 1797 Whites and 729 African Americans). Awareness of mouth and throat cancer examination (46%) and lifetime receipt (46%) were higher than reported in statewide studies performed over the past 15 years. Only 19% of the respondents were aware of their examination, whereas an additional 27% reported having the examination when a description was provided, suggesting a lack of communication between many caregivers and rural patients. Surprisingly, anticipated racial/ethnic differences were diminished when adjustments were made for health literacy and several measures of socioeconomic status. These findings support the notion that health disparities are multifactorial and include characteristics such as low health literacy, lack of access to care, and poor communication between patient and provider.


Behavioral Indices of Multisensory Integration: Orientation to Visual Cues is Affected by Auditory Stimuli.
Physiological studies have demonstrated that inputs from different sensory modalities converge on, and are integrated by, individual superior colliculus neurons and that this integration is governed by specific spatial rules. The present experiments were an attempt to relate these neural processes to overt behavior by determining if behaviors believed to involve the circuitry of the superior colliculus would show similar multisensory dependencies and be subject to the same rules of integration. The neurophysiological-behavioral parallels proved to be striking. The effectiveness of a stimulus of one modality in eliciting attentive and orientation behaviors was dramatically affected by the presence of a stimulus from another modality in each of the three behavioral paradigms used here. Animals trained to approach a low intensity visual cue had their performance significantly enhanced when a brief, low intensity auditory stimulus was presented at the same location as the visual cue, but their performance was significantly depressed when the auditory stimulus was disparate to it. These effects were independent of the animals' experience with the modifying (i.e. auditory) stimulus and exceeded what might have been predicted statistically based on the animals' performance with each single-modality cue. The multiplicative nature of these multisensory interactions and their dependence on the relative positions and intensities of the two stimuli were all very similar to those observed physiologically for single cells. The few differences that were observed appeared to reflect the fact that understanding integration at the level of the single cell requires reference to the individual cell's multisensory receptive field properties, while at the behavioral level populations of receptive fields must be evaluated. These data illustrate that the rules governing multisensory integration at the level of the single cell also predict responses to these stimuli in the intact behaving organism.


A two-phase innate host response to alphavirus infection identified by mRNP-tagging in vivo.
A concept fundamental to viral pathogenesis is that infection induces specific changes within the host cell, within specific tissues, or within the entire animal. These changes are reflected in a cascade of altered transcription patterns evident during infection. However, elucidation of this cascade in vivo has been limited by a general inability to distinguish changes occurring in the minority of infected cells from those in surrounding uninfected cells. To circumvent this inherent limitation of traditional gene expression profiling methods, an innovative mRNP-tagging technique was implemented to isolate host mRNA specifically from infected cells in vitro as well as in vivo following Venezuelan equine encephalitis virus (VEE) infection. This technique facilitated a direct characterization of the host defense response specifically within the first cells infected with VEE, while simultaneous total RNA analysis assessed the collective response of both the infected and uninfected cells. The result was a unique, multifaceted profile of the early response to VEE infection in primary dendritic cells, as well as in the draining lymph node, the initially targeted tissue in the mouse model. A dynamic environment of complex interactions was revealed, and suggested a two-step innate response in which activation of a subset of host genes in infected cells subsequently leads to activation of the surrounding uninfected cells. Our findings suggest that the application of viral mRNP-tagging systems, as introduced here, will facilitate a much more detailed understanding of the highly coordinated host response to infectious agents.


Pillbox: a solid dosage medication identification tool.
Pillbox is a tool that can be used to rapidly identify solid dosage medications. The database, created and maintained by the National Library of Medicine with the support of the Food and Drug Administration, seeks to enhance patient safety through the identification of solid dosage medication. Users enter physical characteristics of a medication, possible matches are provided, and links to additional resources are offered. A comparison with comparable resources was conducted, and future enhancements to Pillbox are discussed.


MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, whereas acute myeloid leukemia (AML) is the most common acute leukemia in adults. In general, ALL has a better prognosis than AML. To understand the distinct mechanisms in leukemogenesis between ALL and AML and to identify markers for diagnosis and treatment, we performed a large-scale genome-wide microRNA (miRNA, miR) expression profiling assay and identified 27 miRNAs that are differentially expressed between ALL and AML. Among them, miR-128a and -128b are significantly overexpressed, whereas let-7b and miR-223 are significantly down-regulated in ALL compared with AML. They are the most discriminatory miRNAs between ALL and AML. Using the expression signatures of a minimum of two of these miRNAs resulted in an accuracy rate of >95% in the diagnosis of ALL and AML. The differential expression patterns of these four miRNAs were validated further through large-scale real-time PCR on 98 acute leukemia samples covering most of the common cytogenetic subtypes, along with 10 normal control samples. Furthermore, we found that overexpression of miR-128 in ALL was at least partly associated with promoter hypomethylation and not with an amplification of its genomic locus. Taken together, we showed that expression signatures of as few as two miRNAs could accurately discriminate ALL from AML, and that epigenetic regulation might play an important role in the regulation of expression of miRNAs in acute leukemias.


Information Dynamics Analysis: A new approach based on Sparse Identification of Linear Parametric Models.
The framework of information dynamics allows to quantify different aspects of the statistical structure of multivariate processes reflecting the temporal dynamics of a complex network. The information transfer from one process to another can be quantified through Transfer Entropy, and under the assumption of joint Gaussian variables it is strictly related to the concept of Granger Causality (GC). According to the most recent developments in the field, the computation of GC entails representing the processes through a Vector Autoregressive (VAR) model and a state space (SS) model typically identified by means of the Ordinary Least Squares (OLS). In this work, we propose a new identification approach for the VAR and SS models, based on Least Absolute Shrinkage and Selection Operator (LASSO), that has the advantages of maintaining good accuracy even when few data samples are available and yielding as output a sparse matrix of estimated information transfer. The performances of LASSO identification were first tested and compared to those of OLS by a simulation study and then validated on real electroencephalographic (EEG) signals recorded during a motor imagery task. Both studies indicated that LASSO, under conditions of data paucity, provides better performances in terms of network structure. Given the general nature of the model, this work opens the way to the use of LASSO regression for the computation of several measures of information dynamics currently in use in computational neuroscience.


Separating memoranda in depth increases visual working memory performance.
Visual working memory is the mechanism supporting the continued maintenance of information after sensory inputs are removed. Although the capacity of visual working memory is limited, memoranda that are spaced farther apart on a 2-D display are easier to remember, potentially because neural representations are more distinct within retinotopically organized areas of visual cortex during memory encoding, maintenance, or retrieval. The impact on memory of spatial separability in depth is less clear, even though depth information is essential to guiding interactions with objects in the environment. On one account, separating memoranda in depth may facilitate performance if interference between items is reduced. However, depth information must be inferred indirectly from the 2-D retinal image, and less is known about how visual cortex represents depth. Thus, an alternative possibility is that separation in depth does not attenuate between-items interference; it may even impair performance, as attention must be distributed across a larger volume of 3-D space. We tested these alternatives using a stereo display while participants remembered the colors of stimuli presented either near or far in the 2-D plane or in depth. Increasing separation in-plane and in depth both enhanced performance. Furthermore, participants who were better able to utilize stereo depth cues showed larger benefits when memoranda were separated in depth, particularly for large memory arrays. The observation that spatial separation in the inferred 3-D structure of the environment improves memory performance, as is the case in 2-D environments, suggests that separating memoranda in depth might reduce neural competition by utilizing cortically separable resources.


The experienced temperature sensitivity and regulation survey.
Individuals differ in thermosensitivity, thermoregulation, and zones of thermoneutrality and thermal comfort. Whereas temperature sensing and -effectuating processes occur in part unconsciously and autonomic, awareness of temperature and thermal preferences can affect thermoregulatory behavior as well. Quantification of trait-like individual differences of thermal preferences and experienced temperature sensitivity and regulation is therefore relevant to obtain a complete understanding of human thermophysiology. Whereas several scales have been developed to assess instantaneous appreciation of heat and cold exposure, a comprehensive scale dedicated to assess subjectively experienced autonomic or behavioral thermoregulatory activity has been lacking so far. We constructed a survey that specifically approaches these domains from a trait-like perspective, sampled 240 volunteers across a wide age range, and analyzed the emergent component structure. Participants were asked to report their thermal experiences, captured in 102 questions, on a 7-point bi-directional Likert scale. In a second set of 32 questions, participants were asked to indicate the relative strength of experiences across different body locations. Principal component analyses extracted 21 meaningful dimensions, which were sensitive to sex-differences and age-related changes. The questions were also assessed in a matched sample of 240 people with probable insomnia to evaluate the sensitivity of these dimensions to detect group differences in a case-control design. The dimensions showed marked mean differences between cases and controls. The survey thus has discriminatory value. It can freely be used by anyone interested in studying individual or group differences in thermosensitivity and thermoregulation.


Non-perfusion severity correlates with central macular thickness and microvascular impairment in branch retinal vein occlusions.
To study peripheral capillary non-perfusion (PCN-P) in branch retinal vein occlusion (BRVO) by means of ultra wide-field fluorescein angiography (UWFFA), and to correlate its extent and severity with optical coherence tomography (OCT) and OCT-angiography (OCTA) parameters and best corrected visual acuity (BCVA). Prospective case series with 2 years of planned follow-up. We recruited patients from June 2019 to December 2019. Ophthalmologic examination included BCVA, UWFFA, OCT and OCTA. Partial (p) and complete (c) ischemic index (ISI) were evaluated on UWFFA images. Vessel density (VD) in both the macular region and the optic nerve head (ONH) was calculated. Twelve BRVO subjects and 12 healthy controls were recruited. Mean age was 63.8 ± 8.74 years. Mean BCVA improved from 0.43 ± 0.25 logMAR to 0.15 ± 0.18 after two years (p < 0.01), while mean central macular thickness (CMT) decreased from 463.83 ± 200.85 µm to 353.17 ± 108.85 µm (p > 0.05). Mean cISI, pISI and total ISI were 25.2 ± 13.0%, 6.3 ± 5.0% and 31.5 ± 12.0%, respectively. Except for VDs of the superficial capillary plexus and choriocapillaris in the macular region, all VDs were lower in the BRVO group (p < 0.01). cISI and tISI negatively correlated with mDCP (p < 0.01), whereas only pISI correlated with CMT at baseline (p < 0.05). Additionally, cISI also negatively correlated with VD at the ONH (p < 0.05). The amount of complete and partial ischemia may have different implications in BRVO, with the former being more associated with microvascular impairment and the latter with macular edema.


Effects of a forgiveness intervention for older adults.
The authors' aim in the present study was to examine the effects of a brief forgiveness intervention for older adults. The psychoeducational group intervention consists of (a) established core components of previous forgiveness interventions and (b) additional components considering specific needs of older adults. Seventy-eight older adults (mean age 70.1 years) were randomized to a treatment condition or a waiting-list control condition. The intervention reduced the levels of perceived actual transgression painfulness, transgression-related emotions and cognitions, and negative affect. These findings suggest the promise of forgiveness interventions for older adults that help participants clarify and deal with past, present, and future interpersonal transgressions.


Utilization of screening mammography among middle-aged and older women.
This study examines patterns of screening mammogram use, investigating the relationship of screening with demographic, health status, and healthcare factors. Data from 1242 women aged ?41 were obtained from a random sample of mailed surveys to community households in an eight-county region in Central Texas in 2010. The dependent variable was the timing of the participants' most recent screening mammography (in the past 12 months, between 1 and 2 years, or >2 years). Predictor variables included demographic, health status, and healthcare access factors. Multinomial logistic regression identified variables associated with screening mammography practices. The majority of women reported having at least one mammogram during their lifetime (93.0%) and having a mammography within the past 2 years (76.2%). Participants who reported not having a routine checkup in the past 12 months (odds ratio [OR] 0.12, p<0.001), having a lapse of insurance in the past 3 years (OR 2.95, p<0.05), and living in a health provider shortage area (OR 1.42, p<0.05) were less likely to be screened within the past 2 years. Routine healthcare plays a major role in preventive screening, which indicates screening mammography practices can be enhanced by improving participation in routine checkups with medical providers, continuity of insurance coverage, and women's access to healthcare. Interventions to encourage screening mammography may be particularly needed for women who have experienced a lapse in insurance or have not had a checkup in the past year.


Oral Mineralocorticoid-Receptor Antagonists: Real-Life Experience in Clinical Subtypes of Nonresolving Central Serous Chorioretinopathy With Chronic Epitheliopathy.
To evaluate the efficacy and safety of oral mineralocorticoid-receptor antagonist (MRa) therapy in three clinical presentations of nonresolving central serous chorioretinopathy (CSCR) with chronic epitheliopathy. Retrospective case series of consecutive patients with nonresolving CSCR treated with oral eplerenone or spironolactone. Treatment criteria were: persistent CSCR with subretinal fluid (SRF) lasting longer than 4 months; recurrent CSCR with SRF lasting longer than 2 months; persistent CSCR (SRF ≥ 4 months) with fundus autofluorescence gravitational tracks. Outcomes at 1, 3, and 6 months were: foveal SRF height, central macular thickness (CMT), subfoveal choroidal thickness (SFCT), best-corrected visual acuity (BCVA), and occurrence of side effects. Among 54 eyes from 42 patients (mean age: 53 years), mean foveal SRF, CMT, and SFCT decreased significantly at 1, 3, and 6 months after treatment initiation. Mean BCVA improved significantly at 6 months. In the subgroup analysis, mean foveal SRF, CMT, and SFCT decreased significantly at 3 and 6 months in the persistent and recurrent groups. In persistent cases with tracks, a significant diminution of mean CMT and SFCT was achieved at 6 months. Treatment-related side effects were observed in 6 patients, prompting treatment discontinuation in one case. Response to treatment was observed in the three subgroups. In persistent CSCR with tracks the response was delayed compared with persistent and recurrent cases, suggesting that longer treatment durations would be beneficial in patients with gravitational tracks of RPE alteration. The clinical response to oral MRa is consistent with the involvement of the mineralocorticoid pathway in CSCR pathogenesis.


Cadralazine for the treatment of preeclampsia. An open, noncomparative, dose-finding pilot study.
The antihypertensive effect, tolerability, and influence on placental and fetal circulation of cadralazine, a 6-substituted derivative of 3-hydrazinopyridoxine structurally related to hydralazine, was assessed in 46 preeclamptic patients in the third trimester of pregnancy and with diastolic blood pressure of 100-120 mm Hg after 24 hours of bed rest. Patients who fulfilled the inclusion criteria at the initial report (24-48-hour run-in period after hospitalization) entered the titration period. During titration, cadralazine was administered at an initial dose of 5 mg once a day; if after 3 days diastolic blood pressure was still above 90 mm Hg, 5 mg more was added for another 3 days, and so forth, until the maximum dose (20 mg once a day) was reached. Patients who did not lower diastolic blood pressure below 90 mm Hg were considered nonresponders; those who achieved the desired diastolic level (responders) entered the maintenance period, which lasted until delivery. Eight patients delivered during the titration period (premature discontinuation group). A significant decrease in systolic and diastolic blood pressures was observed between the initial report and the titration period. During titration, there were 27 responders (71%) and 11 nonresponders. One of the responders was lost to follow-up. Cadralazine proved to be effective in lowering blood pressure levels; in the group of responders, a mean diastolic reduction of 20% was observed. This significant decrease was not affected by the diastolic blood pressure increase observed at the end of gestation. No adverse effects from the drug were observed on fetal development or immediate postnatal adaptation to stress during labor, and only mild maternal side effects were detected (headache).


Laboratory tests of antifungal agents to treat tadpoles against the pathogen Batrachochytrium dendrobatidis .
The fungus Batrachochytrium dendrobatidis (Bd), which is the etiological agent of the disease chytridiomycosis, is threatening both wild and captive amphibians. While there are some methods of treating amphibians in captivity, no method has yet been shown to be a promising treatment for amphibian populations in natural habitats. Here we present the results of a laboratory experiment in which we tested 2 antifungal agents that might be used to treat amphibians in the field. As a first step towards the goal of developing mitigation methods, we tested the efficiency of these agents in reducing Bd prevalence and loads (zoospore counts) in the laboratory. We exposed naturally infected tadpoles of the midwife toad Alytes obstetricans to different concentrations of the antifungal agents for 7 d. We found that Virkon Aquatic® affected neither Bd prevalence nor loads. At 0.625 ml l-1 of General Tonic®, prevalence was reduced to 60%, and infected animals had greatly reduced burdens. However, tadpole length was reduced by 19% and mass by 32% on average compared to the control group, suggesting a negative effect on fitness. Tadpole survival was not affected at 0.625 ml l-1 or 1.25 ml l-1, but was reduced to 60% at 2.5 ml l-1. Keeping animals in a dilution of General Tonic® for 7 d at a concentration of 0.625 ml l-1 might be an easy way to reduce zoospore counts in large numbers of animals at relatively low cost.


Breaking colinearity in the mouse HoxD complex.
Vertebrate Hox genes are activated in a spatiotemporal sequence that reflects their clustered organization. While this colinear relationship is a property of most metazoans with an anterior to posterior polarity, the underlying molecular mechanisms are unknown. Previous work suggested that Hox genes were made progressively available for transcription in the course of gastrulation, implying the existence of an element capable of initiating a repressive conformation, subsequently relieved from the clusters sequentially. We searched for this element by combining a genomic walk with successive transgene insertions upstream of the HoxD complex followed by a series of deletions. The largest deficiency induced posterior homeotic transformations coincidentally with an earlier activation of Hoxd genes. These data suggest that a regulatory element located upstream of the complex is necessary for setting up the early pattern of Hox gene colinear activation.


Subconjunctival injection of mesenchymal stem cells for corneal failure due to limbal stem cell deficiency: state of the art.
Mesenchymal stem cells (MSCs) have unique and beneficial properties and are currently used to treat a broad variety of diseases. These properties include the potential for differentiation into other cell types, secretion of different trophic factors that promote a regenerative microenvironment, anti-inflammatory actions, selective migration to damaged tissues, and non-immunogenicity. MSCs are effective for the treatment of ocular surface diseases such as dry eye, corneal burns, and limbal stem cell deficiency (LSCD), both in experimental models and in humans. LSCD is a pathological condition in which damage occurs to the limbal epithelial stem cells, or their niche, that are responsible for the continuous regeneration of the corneal epithelium. If LSCD is extensive and/or severe, it usually causes corneal epithelial defects, ulceration, and conjunctival overgrowth of the cornea. These changes can result in neovascularization and corneal opacity, severe inflammation, pain, and visual loss. The effectiveness of MSCs to reduce corneal opacity, neovascularization, and inflammation has been widely studied in different experimental models of LSCD and in some clinical trials; however, the methodological disparity used in the different studies makes it hard to compare outcomes among them. In this regard, the MSC route of administration used to treat LSCD and other ocular surface diseases is an important factor. It should be efficient, minimally invasive, and safe. So far, intravenous and intraperitoneal injections, topical administration, and MSC transplantation using carrier substrata like amniotic membrane (AM), fibrin, or synthetic biopolymers have been the most commonly used administration routes in experimental models. However, systemic administration carries the risk of potential side effects and transplantation requires surgical procedures that could complicate the process. Alternatively, subconjunctival injection is a minimally invasive and straightforward technique frequently used in ophthalmology. It enables performance of local treatments using high cell doses. In this review, we provide an overview of the current status of MSC administration by subconjunctival injection, analyzing the convenience, safety, and efficacy for treatment of corneal failure due to LSCD in different experimental models. We also provide a summary of the clinical trials that have been completed, are in progress, or being planned.


Physical Exercise and Spatial Training: A Longitudinal Study of Effects on Cognition, Growth Factors, and Hippocampal Plasticity.
Physical exercise has been suggested to improve cognitive performance through various neurobiological mechanisms, mediated by growth factors such as BDNF, IGF-I, and VEGF. Moreover, animal research has demonstrated that combined physical and cognitive stimulation leads to increased adult neurogenesis as compared to either experimental condition alone. In the present study, we therefore investigated whether a sequential combination of physical and spatial training in young, healthy adults elicits an additive effect on training and transfer gains. To this end, we compared the effects of (i) eight 20-minute sessions of cycling, (ii) sixteen 30-minute sessions of spatial training, (iii) a combination of both, and included (iv) a passive control cohort. We assessed longitudinal changes in cognitive performance, growth factor levels, and T1 relaxation of hippocampal subfields (acquired with 7 T MRI). While substantial physical and spatial training gains were elicited in all trained groups, longitudinal transfer changes did not differ between these groups. Notably, we found no evidence for an additive effect of sequential physical and spatial training. These results challenge the extrapolation from the findings reported in animals to young, healthy adults.


Influence of preoperative hydronephrosis and ureteral orifice involvement in the survival of patients undergoing radical cystectomy: A retrospective comparative study.
The aim of the present study was to evaluate the influence of preoperative hydronephrosis and ureteral orifice involvement (UOI) on survival of patients undergoing radical cystectomy (RC) for bladder cancer (BC). A total of 162 patients with BC underwent RC between January 2006 and March 2017. Patients were divided into two groups for both presences of preoperative hydronephrosis and orifice involvement at final pathology. Additionally, tumors with orifice involvement were subgrouped histopathologically after RC as those with only UOI and those with invasive to the ureter with an additional concurrent site at final pathology. Preoperative hydronephrosis was detected in 57 patients. Preoperative and postoperative creatinine on month 3 were higher in the preoperative hydronephrosis (+) group (p<0.001). In addition, postoperative T stage, surgical margin positivity, invasion of urethra, and pathological upstaging were higher in this group. Cancer-specific survival (CSS) and overall survival (OS) were better in the hydronephrosis (-) group than in the hydronephrosis (+) group (p=0.001 and p=0.001, respectively). Preoperative hydronephrosis was found to be an independent factor in pathological upstaging. Patients were divided into two groups according to the presence of UOI. Group 1 consisted of patients without UOI, and group 2 with UOI. Preoperative hydronephrosis, hydronephrosis grade, and T stage were statistically higher in tumors with UOI. Moreover, CSS and OS were lower in group 2 than in group 1. Preoperative hydronephrosis and UOI are predicting factors on survival of patients undergoing RC for BC. Preoperative hydronephrosis was found to be an independent factor in pathological upstaging.


Trastuzumab-related cardiotoxicity in patients with nonlimiting cardiac comorbidity.
Significant and symptomatic cardiac comorbidity is a contraindication to adjuvant trastuzumab in breast cancer patients. However, some patients with asymptomatic, nonlimiting cardiac comorbidity and normal baseline left ventricular ejection fraction (LVEF) receive adjuvant trastuzumab in the clinical practice. We sought to describe the tolerability of trastuzumab in these patients. Retrospective analysis of patients with baseline asymptomatic, nonlimiting cardiac comorbidity receiving adjuvant trastuzumab at six Institutions between July 2007 and January 2016. Thirty-seven patients with HER2-positive, surgery treated breast cancer at high risk of relapse were studied. Median age was 64 years (range 36-82), median baseline LVEF 61% (range 50%-85%). Thirteen patients (35%) received trastuzumab with adjuvant anthracycline and taxane-based regimens, 19 (51%) with taxane-based, three (8%) with off-label vinorelbine and two (5%) with off-label endocrine therapy. Most frequent cardiac comorbidities were ischemic heart disease (35%), valvular disease (30%), atrial fibrillation (19%), and conduction disorders (14%). Nine patients (24.3%) experienced a cardiac event: congestive heart failure (one patient, 3%), asymptomatic LVEF reduction (six patients, 16%), and rhythm disturbances (two patients, 5%). Trastuzumab had to be discontinued either permanently (five patients, 14%) or temporarily (two patients, 5%). At the time of last follow-up visit, all patients showed LVEF within normal limits, except one who had experienced a symptomatic cardiac event (LVEF value at last follow-up 46%). Caution is needed in patients with significant ongoing cardiovascular risk factors, but when adjuvant trastuzumab is deemed beneficial on breast cancer outcomes, nonlimiting cardiac comorbidity should not preclude treatment.


Performance of Interferon-Gamma and IP-10 Release Assays for Diagnosing Latent Tuberculosis Infections in Patients with Concurrent Malaria in Tanzania.
Interferon-gamma (IFN-γ) release assays (IGRAs) are used to detect cellular immune recognition of Mycobacterium tuberculosis The chemokine IFN-γ-inducible protein 10 (IP-10) is an alternative diagnostic biomarker to IFN-γ. Several conditions interfere with IGRA test performance. We aimed to assess the possible influence of Plasmodium falciparum infection on the IGRA test QuantiFERON-TB GOLD® In-Tube (QFT) test and an in-house IP-10 release assay. In total, 241 Tanzanian adults were included; 184 patients with uncomplicated malaria (88 human immunodeficiency virus [HIV] coinfected) and 57 HIV-infected patients without malaria infection. Malaria was treated with artemether-lumefantrine (Coartem®). QFT testing was performed before initiation of malaria treatment and at days 7 and 42. In total, 172 patients completed follow-up. IFN-γ and IP-10 was measured in QFT supernatants. We found that during malaria infection IFN-γ and IP-10 levels in the unstimulated samples were elevated, mitogen responsiveness was impaired, and CD4 cell counts were decreased. These alterations reverted after malaria treatment. Concurrent malaria infection did not affect QFT test results, whereas there were more indeterminate IP-10 results during acute malaria infection. We suggest that IGRA and IP-10 release assay results of malaria patients should be interpreted with caution and that testing preferably should be postponed until after malaria treatment.


Analysis of neomycin, kanamycin, tobramycin and amikacin resistance mechanisms in gentamicin-resistant isolates of Enterobacteriaceae.
Twenty-four gentamicin-resistant isolates of Enterobacteriaceae, obtained from the clinical laboratories of three health centres in Nablus, Palestine, were tested for susceptibility to neomycin, kanamycin, tobramycin and amikacin. Resistance rates were 29.2% for neomycin, 58.3% for kanamycin, 45.8% for tobramycin and 8.3% for amikacin. Fourteen (58.3%) isolates were noted to be multiresistant, i.e., resistant to gentamicin and two or more other aminoglycosides; resistance to gentamicin, kanamycin and tobramycin was the most common pattern of multiple resistance. This pattern implies the involvement of adenyltransferase ANT(")-I activity. Plasmid profiles and curing experiments suggested a plasmid localisation of gentamicin, neomycin, kanamycin and tobramycin resistance genes. However, a chromosomal location is proposed for plasmid-deficient strains. Cross-resistance in two isolates to all aminoglycosides tested suggested membrane impermeability to aminoglycosides as the mechanism of resistance.


Functional respiratory imaging provides novel insights into the long-term respiratory sequelae of bronchopulmonary dysplasia.
Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Lung function and imaging are classically used to assess BPD. Functional respiratory imaging (FRI) combines a structural and functional assessment of the airways and their vasculature. We aimed to assess BPD using FRI and to correlate these findings with the clinical presentation. We included 37 adolescents with a history of preterm birth (22 BPD cases and 15 preterm controls). The study protocol included a detailed history, lung function testing and computed tomography (CT) (at total lung capacity (TLC) and functional residual capacity (FRC)) with FRI. CT images were also assessed using the Aukland scoring system. BPD patients had lower forced expiratory volume in 1 s to forced vital capacity ratio (p=0.02) and impaired diffusion capacity (p=0.02). Aukland CT scores were not different between the two groups. FRI analysis showed higher lobar volumes in BPD patients at FRC (p<0.01), but not at TLC. Airway resistance was significantly higher in the BPD group, especially in the distal airways. Additionally, FRI showed more air trapping in BPD patients, in contrast to findings on conventional CT images. This study is the first to use FRI in research for BPD. FRI analysis showed higher lobar volumes in BPD patients, indicating air trapping and reduced inspiratory capacity. In contrast to Aukland CT scores, FRI showed more air trapping in the BPD group, suggesting that FRI might be a more sensitive detection method. Importantly, we also showed increased distal airway resistance in BPD patients. By combining structural and functional assessment, FRI may help to better understand the long-term sequelae of BPD.


Metal extent in blood of livestock from Dandora dumping site, Kenya: Source identification of Pb exposure by stable isotope analysis.
Nairobi city in Kenya produces 2000 tons/day of garbage, and most of it is dumped onto the Dandora dumping site, home to a quarter-million residents. This study was conducted (1) to assess the contamination levels of nine metals and a metalloid (arsenic) in the blood of pigs, goats, sheep and cattle from Dandora, and (2) to identify a possible source of lead (Pb) pollution. Cadmium (Cd, 0.17-4.35 μg/kg, dry-wt) and Pb (90-2710 μg/kg) levels in blood were generally high, suggesting human exposure to Cd through livestock consumption and Pb poisoning among pigs (2600 μg/kg) and cattle (354 μg/kg). Results of Pb isotope ratios indicated that the major exposure route might differ among species. Our results also suggested a possibility that the residents in Dandora have been exposed to the metals through livestock consumption.


A two-step model for senescence triggered by a single critically short telomere.
Telomeres protect chromosome ends from fusion and degradation. In the absence of a specific telomere elongation mechanism, their DNA shortens progressively with every round of replication, leading to replicative senescence. Here, we show that telomerase-deficient cells bearing a single, very short telomere senesce earlier, demonstrating that the length of the shortest telomere is a major determinant of the onset of senescence. We further show that Mec1p-ATR specifically recognizes the single, very short telomere causing the accelerated senescence. Strikingly, before entering senescence, cells divide for several generations despite complete erosion of their shortened telomeres. This pre-senescence growth requires RAD52 (radiation sensitive) and MMS1 (methyl methane sulfonate sensitive), and there is no evidence for major inter-telomeric recombination. We propose that, in the absence of telomerase, a very short telomere is first maintained in a pre-signalling state by a RAD52-MMS1-dependent pathway and then switches to a signalling state leading to senescence through a Mec1p-dependent checkpoint.


Does Implicit Voice Learning Improve Spoken Language Processing? Implications for Clinical Practice.
In typical interactions with other speakers, including a clinical environment, listeners become familiar with voices through implicit learning. Previous studies have found evidence for a Familiar Talker Advantage (better speech perception and spoken language processing for familiar voices) following explicit voice learning. The current study examined whether a Familiar Talker Advantage would result from implicit voice learning. Thirty-three adults and 16 second graders were familiarized with 1 of 2 talkers' voices over 2 days through live interactions as 1 of 2 experimenters administered standardized tests and interacted with the listeners. To assess whether this implicit voice learning would generate a Familiar Talker Advantage, listeners completed a baseline sentence recognition task and a post-learning sentence recognition task with both the familiar talker and the unfamiliar talker. No significant effect of voice familiarity was found for either the children or the adults following implicit voice learning. Effect size estimates suggest that familiarity with the voice may benefit some listeners, despite the lack of an overall effect of familiarity. We discuss possible clinical implications of this finding and directions for future research.


Microsurgical resection of medullary cavernoma via the olivary zone by the retrosigmoid supracondylar approach.
Microsurgical resection of the medullary cavernoma is rare, comprising less than 15% of more than 250 surgeries of brainstem cavernoma performed by the senior author (H.B.).1 This video demonstrates a case of a cavernous malformation inside the lateral part of the medulla, which was surgically treated via the olivary zone by the retrosigmoid supracondylar approach in a half-sitting position. Osseous drilling of the lateral foramen magnum provided wide exposure of the cerebellomedullary cistern around the olive.2,3 The lesion was completely dissected at the appropriate cleavage plane from the normal parenchyma. The patient developed no new neurological deficits and had no recurrence during 3 years of follow-up after the operation. The video can be found here: https://youtu.be/7i7SccS5HmU.


The polyuria of solute diuresis.
Polyuria is an important symptom or sign because of its potential severity, diverse causes, and interesting pathophysiology. Whereas polyuria induced by water diuresis is reasonably well understood and easily recognized by clinicians, that produced by solute diuresis is more likely to cause confusion. In this article, we focus on solute diuresis as a cause of polyuria, review the classification and pathophysiology of polyuria, and describe the clinical and laboratory studies useful for the evaluation of the polyuric patient. A stepwise, logical approach is provided (1) to determine whether a patient has a water diuresis, a solute diuresis, or both (concurrently), and (2) if a solute diuresis is present, to determine if it is caused by electrolytes (eg, sodium chloride sodium bicarbonate), by nonelectrolytes (eg, glucose, urea), or by both. How to assess these possibilities and to determine the specific cause of the diuresis is discussed in detail. Three representative case examples are provided. Selected causes of a solute diuresis also are reviewed.