Responses to Ang II (Angiotensin II), Salt Intake, and Lipopolysaccharide Reveal the Diverse Actions of TNF-α (Tumor Necrosis Factor-α) on Blood Pressure and Renal Function.
TNF-α (tumor necrosis factor-alpha) is the best known as a proinflammatory cytokine; yet, this cytokine also has important immunomodulatory and regulatory functions. As the effects of TNF-α on immune system function were being revealed, the spectrum of its activities appeared in conflict with each other before investigators defined the settings and mechanisms by which TNF-α contributed to both host defense and chronic inflammation. These effects reflect self-protective mechanisms that may become harmful when dysregulated. The paradigm of physiological and pathophysiological effects of TNF-α has since been uncovered in the lung, colon, and kidney where its role has been identified in pulmonary edema, electrolyte reabsorption, and blood pressure regulation, respectively. Recent studies on the prohypertensive and inflammatory effects of TNF-α in the cardiovascular system juxtaposed to those related to NaCl and blood pressure homeostasis, the response of the kidney to lipopolysaccharide, and protection against bacterial infections are helping define the mechanisms by which TNF-α modulates distinct functions within the kidney. This review discusses how production of TNF-α by renal epithelial cells may contribute to regulatory mechanisms that not only govern electrolyte excretion and blood pressure homeostasis but also maintain the appropriate local hypersalinity environment needed for optimizing the innate immune response to bacterial infections in the kidney. It is possible that the wide range of effects mediated by TNF-α may be related to severity of disease, amount of inflammation and TNF-α levels, and the specific cell types that produce this cytokine, areas that remain to be investigated further.


A rare case of Interferon-alpha-Induced Hyperthyroidism in patients with a chronic hepatitis C with granulocytopenia and transaminasemia treated successfully with radioiodine.
Conventional management of Interferon-α-Induced Hyperthyroidism (IIH) with radioactive iodine (RAI) may be used when treatment with beta blockers or antithyroid drugs (ATD), proves ineffective or is contraindicated. We present a 38-year-old woman who has been treated with combined pegylated interferon alpha (INF-α) and Ribavirin for chronic hepatitis C. Destructive thyrotoxicosis appeared after four months of continuous IFN-α therapy and a beta blocker was prescribed. Initially, the patient presented normal TSH 2.4 µIU/mL, however during therapy with INF-α, TSH diminished to 0.05 and thyroid hormones were elevated: fT4 23.1 pmol/L, fT3 7.2 pmol/L. Ultrasound examination showed completely irregular and greatly decreased echogenicity of the thyroid gland. The radioiodine uptake (RAIU) was deeply decreased to 2 and 3% at 5 h and 24 h, respectively. The thyroid scintiscan showed lack of isotope accumulation. Hypothyroidism developed and L-thyroxine was prescribed. The following year, hyperthyroidism reoccurred with TSH 0.08 µIU/mL, fT4 26.4 pmol/L, fT3 8.2 pmol/L, positive TSHR-Abs 6.2 (normal <2 IU/L) and mild Graves' Ophthalmopathy (GO). RAIU values were 23% at 5 h and 46% at 24 h. Thyroid scintiscan showed diffuse goiter. At this point beta blocker was introduced and ATD was started. After three months of therapy an increased level of aminotransferases and granulocytopaenia were observed. Hence, the patient received RAI and glucocorticosteroid, while INF-α therapy was continued. After approximately 4 months, hypothyroidism reappeared with insignificantly raised TSH level. One year later the patient was euthyroid and required no further treatment. Our report suggests that: 1. Radioiodine therapy might be an effective and safe method of treatment in cases of IIH with mild GO. 2. IFN-α therapy need not be discontinued in patients with IIH.


[Characteristics of patient contingents at G.A.Zakhar'in tuberculosis Moscow clinical hospital No.3].
The paper analyzes patient contingents at one of the largest tuberculosis hospitals in Russia in 1995 to 1998. Ti has been ascertained that there has been an increase in the number of patients transferred from general hospitals from 9.7 to 27.4%. Patients with caseous pneumonia and intrathoracic lymph node tuberculosis have doubled.


Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling.
Cell identity is governed by gene expression, regulated by transcription factor (TF) binding at cis-regulatory modules. Decoding the relationship between TF binding patterns and gene regulation is nontrivial, remaining a fundamental limitation in understanding cell decision-making. We developed the NetNC software to predict functionally active regulation of TF targets; demonstrated on nine datasets for the TFs Snail, Twist, and modENCODE Highly Occupied Target (HOT) regions. Snail and Twist are canonical drivers of epithelial to mesenchymal transition (EMT), a cell programme important in development, tumour progression and fibrosis. Predicted "neutral" (non-functional) TF binding always accounted for the majority (50% to 95%) of candidate target genes from statistically significant peaks and HOT regions had higher functional binding than most of the Snail and Twist datasets examined. Our results illuminated conserved gene networks that control epithelial plasticity in development and disease. We identified new gene functions and network modules including crosstalk with notch signalling and regulation of chromatin organisation, evidencing networks that reshape Waddington's epigenetic landscape during epithelial remodelling. Expression of orthologous functional TF targets discriminated breast cancer molecular subtypes and predicted novel tumour biology, with implications for precision medicine. Predicted invasion roles were validated using a tractable cell model, supporting our approach.


Mechanical pain hypersensitivity after incisional surgery is enhanced in rats subjected to neonatal peripheral inflammation: effects of N-methyl-D-aspartate receptor antagonists.
Neonatal pain and inflammation may lead to a long-term effect on nociceptive processing in adults. The current study examined the characteristics of postoperative incisional pain behaviors in adult rats that were subjected to neonatal peripheral inflammation. Rat pups received a subcutaneous injection of saline or carrageenan into the plantar surface of the left hind paw at postnatal day 1. Naive pups were used as the control. Paw withdrawal thresholds to punctuate mechanical stimuli were examined at postnatal days 35, 42, and 49. After rats received a plantar incision on the left or right hind paw at postnatal day 50, paw withdrawal thresholds were measured at 4 h, 1 day, 2 days, 3 days, 5 days, and 7 days after incision. In addition, spinal cord Fos expression was detected at 2 h after incision. Finally, the effects of intrathecal N-methyl-D-aspartate receptor antagonists DL-2-amino-5-phosphonovaleric acid and dizocilpine and the nitric oxide synthase inhibitor L-N-nitro-arginine methylester on incisional pain were examined at 4 h after incision. Although the rats subjected to neonatal peripheral carrageenan injection developed mechanical hypoalgesia in bilateral hind paws at baseline, they displayed increased spinal cord Fos expression at 2 h and exaggerated mechanical pain hypersensitivity at 4 h (but not at other time points) after plantar incision. Intrathecal DL-2-amino-5-phosphonovaleric acid, dizocilpine, and L-N-nitro-arginine methylester significantly attenuated incision-induced mechanical pain hypersensitivity at 4 h after incision in the neonatally carrageenan-treated rats, but not in the naive or neonatally saline-treated rats. The authors' results suggest that early inflammatory insults during the neonatal period could produce excessive incision-associated mechanical pain hypersensitivity in adult rats. Spinal cord N-methyl-D-aspartate receptors and downstream nitric oxide signaling might contribute to this abnormal pain hypersensitivity, although the mechanisms underlying the long-term effect of neonatal inflammation are still unclear.


Serotonin induces or inhibits neuritic regeneration of leech CNS neurons depending on neuronal identity.
Recovery of motor function after central nervous system (CNS) injury is dependent on the regeneration capacity of the nervous system, which is a multifactorial process influenced, among other things, by the role of neuromodulators such as serotonin. The neurotransmitter serotonin can promote neuronal regeneration but there are also reports of it causing restriction, so it is important to clarify these divergent findings in order to understand the direct scope and side effects of potential pharmacological treatments. We evaluated the effect of serotonin on the extent of neuritic outgrowth and morphology of three different neuronal types in the leech Haementeria officinalis during their regeneration in vitro: Retzius interneurons (Rz), annulus erector (AE) motoneurons, and anterolateral number 1 (AL1) CNS neurons. Neurons were isolated and cultured in L15 medium, with or without serotonin. Growth parameters were registered and quantified, and observed differences were analyzed. The addition of serotonin was found to induce AL1 neurons to increase their average growth dramatically by 8.3-fold (P=0.02; n=5), and to have no clear effect on AE motoneurons (P=0.44; n=5). For Rz interneurons, which normally do not regenerate their neurites, the addition of concanavaline-A causes substantial growth, which serotonin was found to inhibit on average by 98% (P=0.02; n=5). The number of primary neurites and their branches were also affected. These results reveal that depending on the neuronal type, serotonin can promote, inhibit, or have no effect on neuronal regeneration. This suggests that after CNS injury, non-specific pharmacological treatments affecting serotonin may have different effects on different neuronal populations.


The efficacy of psychotherapy: focus on psychodynamic psychotherapy as an example.
The growing number of individuals seeking treatment for mental disorders calls for intelligent and responsible decisions in health care politics. However, the current relative decrease in reimbursement of effective psychotherapy approaches occurring in the context of an increase in prescription of psychotropic medication lacks a scientific base. Using psychodynamic psychotherapy as an example, we review the literature on meta-analyses and recent outcome studies of effective treatment approaches. Psychodynamic psychotherapy is an effective treatment for a wide variety of mental disorders. Adding to the known effectiveness of other shorter treatments, the results indicate lasting change in many cases, especially for complex and difficult to treat patients, ultimately reducing health-care utilization. Research-informed health care decisions that take into account the solid evidence for the effectiveness of psychotherapy, including psychodynamic psychotherapy, have the potential to promote choice, increase mental health, and reduce society's burden of disease in the long run.


Factors Associated With Incidental Retinal Emboli in the U.S. Adult Population.
We sought to estimate the prevalence of incidental retinal emboli and identify associated factors using a nationally representative sample of the U.S. Cross-sectional study. We included adult (age ≥40 years) participants of the 2005-2008 National Health and Nutrition Examination Survey (NHANES). Incidental retinal emboli were identified through retinal fundus photography. Multivariable logistic regression was used to determine the association between the presence of retinal emboli and sociodemographic, lifestyle, and clinical factors (age, sex, race/ethnicity, education, income, smoking, alcohol use, body mass index [BMI], hypertension, diabetes, hypercholesterolemia, and history of cardiovascular disease). This study included 5,764 adults (53% female). Incidental retinal emboli were identified in 0.7% (39/5764) of individuals. The survey-weighted prevalence of retinal emboli increased with age, from 0.1% in participants 40-49 years of age to 1.4% in participants≥70 years of age. The prevalence did not differ by sex or race/ethnicity. Factors associated with retinal emboli after adjusting for age and sex included underweight BMI (odds ratio [OR] 7.24 [95% confidence interval {CI} 1.06-49.3]), current smoking (OR 6.16 [95% CI 1.49-25.5]), low household income (OR 4.41 [95% CI 1.3-15.0]), and hypertension (OR 2.67 [95% CI 1.31-5.44]). In a cohort representative of the U.S. adult population, the prevalence of incidental retinal emboli increased with age but did not differ by sex, race, or ethnicity. Further investigation into the potential association of socioeconomic and nutritional status with retinal emboli may enable opportunities to identify individuals with underlying cardiovascular risk.


Neonatal metabolic effects of oral ritodrine hydrochloride administration.
Neonatal hypoglycemia and hyperinsulinemia have been reported following maternal ritodrine administration, but no prospective controlled study of the neonatal metabolic and cardiovascular effects of maternal ritodrine is available. We conducted a double-blind prospective study in 35 patients with preterm labor and/or ruptured membranes. Patients in premature labor received ritodrine (max dose, 350 mcg/min) or a placebo intravenously for 12 hours, and then orally (20 mg every 4 hours) until labor ensued. Patients with ruptured membranes received only oral therapy. Only patients who were maintained on oral therapy for a minimum of 12 hours and who were within 6 hours of their last dose of oral therapy were included in the analysis. Glucose and insulin values in cord blood at 6 and 12 hours of age were not significantly different between the ritodrine and placebo groups. There were no hypoglycemic infants in the ritodrine group. Mean systolic and diastolic blood pressure, heart rate and blood volume were similar for ritodrine and control infants. Although premature infants are at high risk for hypoglycemia it appears from this study that chronic oral ritodrine therapy does not significantly affect neonatal glucose homeostasis.


Alcohol and the risk of prostate cancer and benign prostatic hyperplasia.
To examine the association between alcohol and the risk of prostate cancer/benign prostatic hyperplasia (BPH) in a population with a wide range of alcohol consumption, using a hospital-based, case-control study. Data from several epidemiologic studies have allowed us to exclude a strong association between alcohol drinking and prostate cancer risk. However, limited information is available for BPH. Also, it is unclear whether various types of alcoholic beverages may have a different impact on risk. We conducted this hospital-based case-control study in Italy between 1991 and 2002. A total of 2663 men younger than 75 years had incident, histologically confirmed prostate carcinoma (1294 cases) or symptomatic obstructive BPH (1369 cases) (maximal flow rate less than 15 mL/s) refractory to medical treatment. A total of 1451 patients younger than 75 years were used as controls. Odds ratios and corresponding 95% confidence intervals were estimated using unconditional multiple logistic regression models including terms for age, center, education, body mass index, physical activity, and family history of prostate cancer. Alcohol consumption showed no consistent association with prostate cancer risk, but a statistically significant inverse trend in risk for BPH. Compared with abstainers, the odds ratio was 0.88 for fewer than three drinks, 0.71 for three to four drinks, 0.79 for five to six drinks, and 0.65 for seven or more drinks per day. The patterns of risk were similar with reference to different alcoholic beverages. The inverse relation between elevated alcohol consumption and BPH was apparently stronger in subjects with a lower body mass index. Alcohol drinking is unrelated to prostate cancer risk. The inverse relationship with BPH may be related to the hormonal correlates (ie, lower androgen levels) of heavy alcohol drinkers.


The role of sulfoglucuronosyl glycosphingolipids in the pathogenesis of monoclonal IgM paraproteinemia and peripheral neuropathy.
In IgM paraproteinemia and peripheral neuropathy, IgM M-protein secretion by B cells leads to a T helper cell response, suggesting that it is antibody-mediated autoimmune disease involving carbohydrate epitopes in myelin sheaths. An immune response against sulfoglucuronosyl glycosphingolipids (SGGLs) is presumed to participate in demyelination or axonal degeneration in the peripheral nervous system (PNS). SGGLs contain a 3-sulfoglucuronic acid residue that interacts with anti-myelin-associated glycoprotein (MAG) and the monoclonal antibody anti-HNK-1. Immunization of animals with sulfoglucuronosyl paragloboside (SGPG) induced anti-SGPG antibodies and sensory neuropathy, which closely resembles the human disease. These animal models might help to understand the disease mechanism and lead to more specific therapeutic strategies. In an in vitro study, destruction or malfunction of the blood-nerve barrier (BNB) was found, resulting in the leakage of circulating antibodies into the PNS parenchyma, which may be considered as the initial key step for development of disease.


Oxidation of microcystin-LR by ferrate(VI): kinetics, degradation pathways, and toxicity assessments.
The presence of the potent cyanotoxin, microcystin-LR (MC-LR), in drinking water sources poses a serious risk to public health. The kinetics of the reactivity of ferrate(VI) (Fe(VI)O4(2-), Fe(VI)) with MC-LR and model compounds (sorbic acid, sorbic alcohol, and glycine anhydride) are reported over a range of solution pH. The degradation of MC-LR followed second-order kinetics with the bimolecular rate constant (kMCLR+Fe(VI)) decreasing from 1.3 ± 0.1 × 10(2) M(-1) s(-1) at pH 7.5 to 8.1 ± 0.08 M(-1) s(-1) at pH 10.0. The specific rate constants for the individual ferrate species were determined and compared with a number of common chemical oxidants employed for water treatment. Detailed product studies using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) indicated the oxidized products (OPs) were primarily the result of hydroxylation of the aromatic ring, double bond of the methyldehydroalanine (Mdha) amino acid residue, and diene functionality. Products studies also indicate fragmentation of the cyclic MC-LR structure occurs under the reaction conditions. The analysis of protein phosphatase (PP1) activity suggested that the degradation byproducts of MC-LR did not possess significant biological toxicity. Fe(VI) was effective for the degradation MC-LR in water containing carbonate ions and fulvic acid (FA) and in lake water samples, but higher Fe(VI) dosages would be needed to completely remove MC-LR in lake water compared to deionized water.


Identification and characterization of genetic cluster groups of Actinobacillus actinomycetemcomitans isolated from the human oral cavity.
Actinobacillus actinomycetemcomitans is recognized as a primary pathogen in localized juvenile periodontitis (LJP). Restriction fragment length polymorphisms (RFLP) within a collection of subgingival plaque isolates of this bacterium were identified and characterized as the first step in understanding the pathogenesis of LJP. Over 800 isolates, from members of 18 families (LJP families) with at least one member with active LJP or a documented history of the disease and one or more siblings, less than 13 years of age, having no clinical evidence of LJP and 32 healthy control subjects, were assigned to one of 13 distinct RFLP groups (II to XIV) by using a previously characterized 4.7-kb DNA probe cloned from the reference strain FDC Y4. Isolates belonging to RFLP groups II, IV, V, and XIII predominated subgingival sites in the subjects. Members of RFLP groups II, IV, VII, VIII, X, and XI were recovered only from LJP family subjects, while group XIII and XIV variants were found exclusively in healthy controls. A synthetic oligonucleotide, homologous to the 5' end of the leukotoxin gene (lktA), and the A. actinomycetemcomitans plasmid, pVT745, were tested for their abilities to subdivide the 13 RFLP groups. The leukotoxin probe specifically identified all RFLP group II variants because of the absence of a HindIII site in the upstream noncoding region of the lkt gene complex. The plasmid probe was not as selective but may be useful for identifying clinical isolates belonging to RFLP group I. The use of these probes for the identification of genetic variants of A. actinomycetemcomitans that may be preferentially colonize diseased and healthy subjects will facilitate the study of the role of this important pathogen in periodontal diseases.


Pretreatment factors predicting the development of postchemotherapy nausea and vomiting in Chinese breast cancer patients.
A prospective longitudinal study was designed to assess the role of pretreatment proneness to nausea and vomiting (NV) in the development of postchemotherapy NV in a group of Chinese breast cancer patients receiving moderately highly emetogenic chemotherapy. Seventy-one chemotherapy-naive subjects participated in the study. Patients were assessed the day before chemotherapy with measurements of their anxiety level, depression, fatigue and proneness to NV, motion sickness, NV experienced in past pregnancies, history of labyrinthitis, expectation of developing NV and expectation of developing pain. Patients also completed daily assessments of frequency, duration and intensity of NV for the 7 days after chemotherapy. Regression analyses revealed that nonpharmacological factors explained part of the variance of NV, the most common predictors being a history of labyrinthitis, expectation of developing NV after chemotherapy, younger age, stage of disease, and state anxiety. The explanatory power of the models ranged from 6% to 23% of the variance of the independent variable. There were different explanatory models for acute and delayed NV. Results indicate that consideration of the role of nonpharmacological factors in the development of NV could lead to more effective management of NV induced by chemotherapy.


Thermoluminescence behaviour of KCL(1-x)Br(x):Pb2+ exposed to gamma radiation.
The thermoluminescence (TL) behaviour of solid solutions of lead doped KCl(1-x)Br(x) (X = 0.02, 0.35, 0.50, 0.65, 0.85, 1) mixed crystals exposed to gamma radiation at different doses from 60Co is reported. The TL glow curves of KCl(1-x)Br(x):Pb2+ crystal exposed in the range of 0-140 Gy is strongly dependent on composition X. The maximum temperature of the main TL glow peak was found to shift towards lower temperatures as composition X increased and a significant enhancement of the TL efficiency in KCl(1-x)Br(x):Pb2+ was found for X = 0.50 which is attributed to an increase in the vacancy concentration of the mixed halides at middle composition. The participation of the F-centre in the TL phenomenon particularly related to the main TL glow peak observed in mixed samples was also confirmed.


Endoscopic transesophageal retrograde drainage tandem with endoscopic closure for management of esophageal leak after peroral endoscopic myotomy for Zenker diverticulum.
Video 1Endoscopic transesophageal retrograde drainage tandem with endoscopic closure for management of esophageal leak after peroral endoscopic myotomy for Zenker diverticulum.


Development of a laser capture microscope-based single-cell-type proteomics tool for studying proteomes of individual cell layers of plant roots.
Single-cell-type proteomics provides the capability to revealing the genomic and proteomics information at cell-level resolution. However, the methodology for this type of research has not been well-developed. This paper reports developing a workflow of laser capture microdissection (LCM) followed by gel-liquid chromatography-tandem mass spectrometry (GeLC-MS/MS)-based proteomics analysis for the identification of proteomes contained in individual cell layers of tomato roots. Thin-sections (~10-μm thick, 10 sections per root tip) were prepared for root tips of tomato germinating seedlings. Epidermal and cortical cells (5000-7000 cells per tissue type) were isolated under a LCM microscope. Proteins were isolated and then separated by SDS-polyacrylamide gel electrophoresis followed by in-gel-tryptic digestion. The MS and MS/MS spectra generated using nanoLC-MS/MS analysis of the tryptic peptides were searched against ITAG2.4 tomato protein database to identify proteins contained in each single-cell-type sample. Based on the biological functions, proteins with proven functions in root hair development were identified in epidermal cells but not in the cortical cells. Several of these proteins were found in Al-treated roots only. The results demonstrated that the cell-type-specific proteome is relevant for tissue-specific functions in tomato roots. Increasing the coverage of proteomes and reducing the inevitable cross-contamination from adjacent cell layers, in both vertical and cross directions when cells are isolated from slides prepared using intact root tips, are the major challenges using the technology in proteomics analysis of plant roots.


Flavobacteria blooms in four eutrophic lakes: linking population dynamics of freshwater bacterioplankton to resource availability.
Heterotrophic bacteria are major contributors to biogeochemical cycles and influence water quality. Still, the lack of representative isolates and the few quantitative surveys leave the ecological role and significance of single bacterial populations to be revealed. Here we analyzed the diversity and dynamics of freshwater Flavobacteria populations in four eutrophic temperate lakes. From each lake, clone libraries were constructed using primers specific for either the class Flavobacteria or Bacteria. Sequencing of 194 Flavobacteria clones from 8 libraries revealed a diverse freshwater Flavobacteria community and distinct differences among lakes. Abundance and seasonal dynamics of Flavobacteria were assessed by quantitative PCR with class-specific primers. In parallel, the dynamics of individual populations within the Flavobacteria community were assessed with terminal restriction fragment length polymorphism analysis using identical primers. The contribution of Flavobacteria to the total bacterioplankton community ranged from 0.4 to almost 100% (average, 24%). Blooms where Flavobacteria represented more than 30% of the bacterioplankton were observed at different times in the four lakes. In general, high proportions of Flavobacteria appeared during episodes of high bacterial production. Phylogenetic analyses combined with Flavobacteria community fingerprints suggested dominance of two Flavobacteria lineages. Both drastic alterations in total Flavobacteria and in community composition of this class significantly correlated with bacterial production, emphasizing that resource availability is an important driver of heterotrophic bacterial succession in eutrophic lakes.


Laparoscopic hepatectomy is safe and effective for the management of patients with colorectal cancer liver metastases in a population-based analysis in Ontario, Canada. A retrospective cohort study.
Laparoscopic hepatectomy (LH) has been deemed safe, and, in the case of minor hepatectomy, the standard of care. Short-, long-term outcomes and costs of LH compared with open hepatectomy (OH) in patients with colorectal cancer liver metastases have not been well described at the population level. Patients diagnosed with colorectal cancer undergoing hepatectomy were included in this population-based retrospective cohort study from 2006- to 2014. Postoperative complications (per Clavien-Dindo) and survival were analyzed using a linear mixed model and Cox-Proportional hazards model respectively. Costs of surgery and the 90-day postoperative period were considered in 2018 Canadian dollars and compared from the perspective of a third-party payer. Over a median follow-up of 56 months, 95% confidence interval (CI): 51 to 68), there were 2991 hepatectomies (OH: 2551 (85%) and LH: 440 (15%)). LH compared to OH was more common for patients >70 years-old (30% vs. 22%, p = 0.004) and for minor hepatectomy (52% vs. 32%, p < 0.001) respectively. By multivariable analyses, OH was associated with similar 90-day mortality (Odds Ratio (OR) 1.05, 95% CI: 0.56-1.97), and overall survival (Hazard Ratio (HR) 1.08, 95% CI: 0.90-1.29), but higher rates of major postoperative complications (OR 1.34, 95% CI: 1.03-1.76), higher cost (median difference $6,163, 95% CI: $3229 to $9096), and longer length of hospital stay (LOS) (mean difference 3.04 days, 95% CI: 2.7 to 3.91). LH was associated with lower postoperative complications, shorter LOS, which translated into lower costs to the healthcare system, without differences in postoperative mortality and survival.


Effect of cognitive fluctuation on neuropsychological performance in aging and dementia.
Cognitive fluctuations are spontaneous alterations in cognition, attention, and arousal. Fluctuations are a core feature of dementia with Lewy bodies, but the impact of fluctuations in healthy brain aging and Alzheimer disease (AD) are unknown. Research participants (n = 511, age 78.1 +/- 8 years, education 14.9 +/- 3 years) enrolled in a longitudinal study of memory and aging at the Washington University Alzheimer Disease Research Center were assessed for the presence and severity of dementia with the Clinical Dementia Rating (CDR) and a neuropsychological test battery. Informant assessments of fluctuations with the Mayo Fluctuations Questionnaire and daytime level of alertness with the Mayo Sleep Questionnaire were completed. After controlling for age and alertness level, participants with cognitive fluctuations (3 or 4 individual symptoms) were 4.6 times more likely to have dementia (95% confidence interval: 2.05, 10.40). Participants who presented with disorganized, illogical thinking were 7.8 times more likely to be rated CDR >0. The risk of being rated CDR 0.5 among those with fluctuations was 13.4 times higher than among those without fluctuations. The risk of being rated CDR 1 increased 34-fold among participants with fluctuations. Compared with participants without fluctuations, the presence of cognitive fluctuations corresponds to a decrease in performance across individual neuropsychological tests as well as composite scores. Cognitive fluctuations occur in Alzheimer disease and, when present, significantly affect both clinical rating of dementia severity and neuropsychological performance. Assessment of fluctuations should be considered in the evaluation of patients for cognitive disorders.


Occult axillary lymph node metastases in "node-negative" breast carcinoma.
The presence of occult axillary nodal metastases was evaluated in 159 patients with "node-negative" invasive breast carcinoma. Multiple additional levels of the lymph nodes were examined with hematoxylin-eosin staining and keratin immunostaining. Occult nodal metastases were detected in 50 (31%) patients; of these, 28 (17%) were detectable by hematoxylin-eosin stain alone, while the other 22 (14%) consisted of mostly single cells or very small clusters and required immunostaining for detection. The size of the metastatic deposit was < or = 0.2 mn in 31 (19%) patients and greater than 0.2 mm in 19 (12%) patients. Occult nodal metastasis correlated with the presence of peritumoral lymphatic invasion (P = .02) and was seen more frequently with larger tumor size, increased microvasculature, and aneuploidy. As a group occult metastases had no significant prognostic impact. However, patients with metastases measuring greater than 0.2 mm had significantly worse recurrence (P = .02), disease-free survival (P = .04), and overall survival (P = .07) rates; those with metastases detectable by hematoxylin-eosin stain alone also had a less favorable, although not significant, outcome. In contrast, patients with occult metastases that were < or = 0.2 mm or that were detected only by immunostaining had a survival rate comparable to and in fact slightly higher than that of the group without occult metastasis; 23 of these patients were without recurrence after a median follow-up of 11 years. Extension into perinodal soft tissue was an unfavorable feature. In a multivariate analysis peritumoral lymphovascular invasion and increased microvasculature were the most important prognostic parameters, and the presence of occult metastases greater than 0.2 mm was no longer significant. Our data suggest that occult metastases < or = 0.2 mm, especially those consisting of single cells, do not add useful prognostic information, and immunohistochemical studies to detect them are probably unnecessary. Larger metastases and extranodal involvement may have important prognostic value, but in this study they accounted for only 20% of patients who had recurrences or 6% of the total population. This underscores the importance of using more than one prognostic parameter in evaluating breast carcinoma.


Intrapulmonary recombinant factor VIIa for diffuse alveolar hemorrhage in children.
Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or autoimmune disorders, and it has a high mortality rate. The current treatment options of corticosteroids, transfusions, and immunosuppressants have been limited and largely unsuccessful, and they can be accompanied by multiple complications. Intrapulmonary administration of recombinant activated factor VII (rFVIIa) has been reported in adults, but there are scarce data on its use in children. The present article reviews our institutional experience with intrapulmonary rFVIIa for the treatment of DAH in children. The study included 6 pediatric patients with acute, bronchoscopically confirmed DAH treated between 2011 and 2013. The median age was 11 years, and patient diagnoses were as follows: acute myeloid leukemia (2 patients), myelodysplastic syndrome (1 patient), hemophagocytic lymphohistiocytosis (1 patient), T-cell lymphoblastic lymphoma (1 patient), and idiopathic pulmonary hemosiderosis (1 patient). These patients were treated with intrapulmonary rFVIIa concurrent with methylprednisolone, fresh-frozen plasma, and maintenance of the platelet count >50 000/mm(3). Complete and sustained hemostasis after rFVIIa treatment and an absence of adverse events were observed in all patients. The PaO2/fraction of inspired oxygen ratio increased significantly, and rapid clinical improvements were observed. Two patients who received hematopoietic stem cell transplantation died of subsequent respiratory syncytial virus and Acinetobacter baumannii infections, but the other 4 patients exhibited rapid improvement, were successfully weaned from ventilators, and experienced long-term survival. Our findings indicate that intrapulmonary administration of rFVIIa is an effective and safe treatment option for children with DAH; however, further clinical studies are needed.


Therapeutic Potential of "Smart" Exosomes in Peripheral Nerve Regeneration.
Peripheral nerve injury results in severe loss of motor and sensory function in the affected limb. The gold standard for peripheral nerve repair is autologous nerve grafts, but their inherent drawbacks limit their use. Satisfactory clinical data are yet to be obtained using tissue engineered nerve grafts with neurotrophic factors introduced in these grafts for nerve repair. Therefore, peripheral nerve regeneration still remains a challenge for clinicians. Exosomes are secreted nanovesicles from the extracellular membrane. They are critical for communication within the cell and play a crucial role in the pathologic process of the peripheral nervous system. Recent research supports the role of exosomes in exhibiting neurotherapeutic effects through axonal growth, Schwann cell activation, and regulating inflammation. Indeed, the use of "smart" exosomes by reprogramming or manipulating the secretome contents and functions are rising as a therapeutic option for treating peripheral nerve defects. This review provides an overview on the promising role of exosomes in the process of peripheral nerve regeneration.


Building-in-Briefcase: A Rapidly-Deployable Environmental Sensor Suite for the Smart Building.
A building's environment has profound influence on occupant comfort and health. Continuous monitoring of building occupancy and environment is essential to fault detection, intelligent control, and building commissioning. Though many solutions for environmental measuring based on wireless sensor networks exist, they are not easily accessible to households and building owners who may lack time or technical expertise needed to set up a system and get quick and detailed overview of environmental conditions. Building-in-Briefcase (BiB) is a portable sensor network platform that is trivially easy to deploy in any building environment. Once the sensors are distributed, the environmental data is collected and communicated to the BiB router via the Transmission Control Protocol/Internet Protocol (TCP/IP) and WiFi technology, which then forwards the data to the central database securely over the internet through a 3G radio. The user, with minimal effort, can access the aggregated data and visualize the trends in real time on the BiB web portal. Paramount to the adoption and continued operation of an indoor sensing platform is battery lifetime. This design has achieved a multi-year lifespan by careful selection of components, an efficient binary communications protocol and data compression. Our BiB sensor is capable of collecting a rich set of environmental parameters, and is expandable to measure others, such as CO 2 . This paper describes the power characteristics of BiB sensors and their occupancy estimation and activity recognition functionality. We have demonstrated large-scale deployment of BiB throughout Singapore. Our vision is that, by monitoring thousands of buildings through BiB, it would provide ample research opportunities and opportunities to identify ways to improve the building environment and energy efficiency.


Characterizing Charge Structure in Central Argentina Thunderstorms During RELAMPAGO Utilizing a New Charge Layer Polarity Identification Method.
A new automated method to retrieve charge layer polarity from flashes, named Chargepol, is presented in this paper. Using data from the NASA Lightning Mapping Array (LMA) deployed during the Remote sensing of Electrification, Lightning, And Mesoscale/microscale Processes with Adaptive Ground Observations (RELAMPAGO) field campaign in Cordoba, Argentina, from November 2018 to April 2019, this method estimates the polarity of vertical charge distributions and their altitudes and thicknesses (or vertical depth) using the very-high frequency (VHF) source emissions detected by LMAs. When this method is applied to LMA data for extended periods of time, it is capable of inferring a storm's bulk electrical charge structure throughout its life cycle. This method reliably predicted the polarity of charge within which lightning flashes propagated and was validated in comparison to methods that require manual assignment of polarities via visual inspection of VHF lightning sources. Examples of normal and anomalous charge structures retrieved using Chargepol for storms in Central Argentina during RELAMPAGO are presented for the first time. Application of Chargepol to five months of LMA data in Central Argentina and several locations in the United States allowed for the characterization of the charge structure in these regions and for a reliable comparison using the same methodology. About 13.3% of Cordoba thunderstorms were defined by an anomalous charge structure, slightly higher than in Oklahoma (12.5%) and West Texas (11.1%), higher than Alabama (7.3%), and considerably lower than in Colorado (82.6%). Some of the Cordoba anomalous thunderstorms presented enhanced low-level positive charge, a feature rarely if ever observed in Colorado thunderstorms.


[E-learning with journal articles].
E-learning is a popular method of continuous medical education (CME) which is becoming increasingly available to doctors. A specific form of E-learning is an online knowledge test accompanying a journal article. CME accreditation points can be obtained by reading an article and then answering test questions on it. This is a user-friendly form of CME which an increasing number of journals are offering as a service to their readers. The Dutch Journal of Medicine (NTvG) has been offering accredited tests to its readers since 2011. On comparison with international journals, a high standard has been set by the development of a test concept in which interpretation and reflection play integral roles. In the Dutch setting, the concept of the test was developed by professional bodies working closely together and it is a concept that is used as an example to other journals.


Risk of retinal diseases in patients with psoriasis: A population-based cohort study in Taiwan.
Psoriasis has been associated with the risk of several ocular complications; however, its relationship with retinal diseases remains unknown. This study aimed to investigate the risk of developing retinal diseases in patients with psoriasis. Study participants were recruited from the National Health Insurance Research Database in Taiwan. A total of 11 729 psoriasis patients and 117 290 matched controls were included, showing an incidence rate of 121.15 and 28.34 cases of retinal diseases per 100 000 person-years, respectively. Compared with controls, patients with psoriasis had an adjusted hazard ratio (aHR) of 3.40 (95% confidence interval [CI], 2.63-4.39) for retinal diseases after adjustment for potential confounders. Regarding the individual retinal disease, psoriasis patients had a significantly higher risk of developing retinal detachment (aHR, 5.07; 95% CI, 2.92-8.79), retinal vascular occlusion (aHR, 3.75; 95% CI 2.42-5.82), and retinopathy (aHR, 2.84; 95% CI, 1.99-4.05) than controls. In conclusion, patients with psoriasis had a significantly higher risk of retinal diseases than controls. Further studies are necessary to investigate the pathophysiology underlying the relationship between psoriasis and retinal diseases.


Ecological change points: The strength of density dependence and the loss of history.
Change points in the dynamics of animal abundances have extensively been recorded in historical time series records. Little attention has been paid to the theoretical dynamic consequences of such change-points. Here we propose a change-point model of stochastic population dynamics. This investigation embodies a shift of attention from the problem of detecting when a change will occur, to another non-trivial puzzle: using ecological theory to understand and predict the post-breakpoint behavior of the population dynamics. The proposed model and the explicit expressions derived here predict and quantify how density dependence modulates the influence of the pre-breakpoint parameters into the post-breakpoint dynamics. Time series transitioning from one stationary distribution to another contain information about where the process was before the change-point, where is it heading and how long it will take to transition, and here this information is explicitly stated. Importantly, our results provide a direct connection of the strength of density dependence with theoretical properties of dynamic systems, such as the concept of resilience. Finally, we illustrate how to harness such information through maximum likelihood estimation for state-space models, and test the model robustness to widely different forms of compensatory dynamics. The model can be used to estimate important quantities in the theory and practice of population recovery.


[Platelet hyperreactivity and antiaggregatory properties of nootropic drugs under conditions of alloxan-induced diabetes in rats].
The effects of nootropic drugs (noopept, pentoxifylline, piracetam, pramiracetam, Ginkgo biloba extract, entrop, cerebrocurin and citicoline) on platelet aggregation in rats with experimental diabetes have been studied. It is established that all these drugs exhibit an inhibitory action of various degrees against platelet hyperreactivity under conditions of chronic hyperglycemia. The maximum universality of the antiaggregatory action is characteristic of pramiracetam, entrop and Ginkgo biloba extract.


A novel fungal gene regulation system based on inducible VPR-dCas9 and nucleosome map-guided sgRNA positioning.
Programmable transcriptional regulation is a powerful tool to study gene functions. Current methods to selectively regulate target genes are mainly based on promoter exchange or on overexpressing transcriptional activators. To expand the discovery toolbox, we designed a dCas9-based RNA-guided synthetic transcription activation system for Aspergillus nidulans that uses enzymatically disabled "dead" Cas9 fused to three consecutive activation domains (VPR-dCas9). The dCas9-encoding gene is under the control of an estrogen-responsive promoter to allow induction timing and to avoid possible negative effects by strong constitutive expression of the highly active VPR domains. Especially in silent genomic regions, facultative heterochromatin and strictly positioned nucleosomes can constitute a relevant obstacle to the transcriptional machinery. To avoid this negative impact and to facilitate optimal positioning of RNA-guided VPR-dCas9 to targeted promoters, we have created a genome-wide nucleosome map from actively growing cells and stationary cultures to identify the cognate nucleosome-free regions (NFRs). Based on these maps, different single-guide RNAs (sgRNAs) were designed and tested for their targeting and activation potential. Our results demonstrate that the system can be used to regulate several genes in parallel and, depending on the VPR-dCas9 positioning, expression can be pushed to very high levels. We have used the system to turn on individual genes within two different biosynthetic gene clusters (BGCs) which are silent under normal growth conditions. This method also opens opportunities to stepwise activate individual genes in a cluster to decipher the correlated biosynthetic pathway. Graphical abstract KEYPOINTS: • An inducible RNA-guided transcriptional regulator based on VPR-dCas9 was established in Aspergillus nidulans. • Genome-wide nucleosome positioning maps were created that facilitate sgRNA positioning. • The system was successfully applied to activate genes within two silent biosynthetic gene clusters.


Secular trend of menarcheal age in southern Chinese girls.
Southern Chinese girls aged 11 years and 9 months to 12 years and 3 months in Hong Kong have a mean menarcheal age of 11.50 years (standard deviation of 0.47) using the recollection method. Highly significant differences are found when compared to the 12-year-old girls in Hong Kong studied in the past decades. Therefore, a secular trend of earlier menarcheal age is demonstrated.


Ex vivo measurement of the cytotoxic capacity of human primary antigen-specific CD8 T cells.
The major function of CD8 T cells is to kill specifically target cells. Moreover in certain incurable diseases, antigen-specific human CD8 T cells are impaired, and assessment of their cytolytic activity could bring insights into their physiopathological role and ways to restore immune dysfunctions for immunotherapeutic purposes. Despite this, T cell cytolytic function has been seldom analyzed thoroughly in humans, due to the lack of approaches well suited for ex vivo assessment of T cell cytotoxicity. Current techniques require prior in vitro expansion of antigen-specific CD8 T cell populations and the use of immortalized cells as targets to measure the cell-mediated killing. Furthermore, bulk cytotoxic activity is frequently measured using percentage of specific lysis calculations that do not quantify actual target cell death and effector numbers at the single cell level. Here we established a new flow cytometry-based assay that allows accurate single-cell analysis of cytotoxic capacity of primary antigen-specific CD8 T cells generated in vivo in humans after antigenic exposure without in vitro amplification that can be used for specificities restricted by different HLAs as target cells are autologous cells. We show that this assay is robust, highly sensitive irrespective of the frequency of antigen-specific CD8 T cells, and allows accurate calculation of the index of cytotoxic capacity in lytic units. This new assay provides a sensitive method to measure the intrinsic cytotoxic activity of antigen-specific CD8 T cells directly ex vivo on human primary cells.


Bioelectric properties of fetal alveolar epithelial monolayers.
To investigate the bioelectric properties on one of the cell types that line the distal lung unit, we isolated type II alveolar epithelium from 18- to 20-day gestation fetal rats (term = 22 days) and grew them on collagen-coated nitrocellulose filters. Amiloride impaired ion transport in a dose-dependent fashion (10(-4) to 10(-6) M) with 10(-4) M decreasing potential difference (PD) (mean +/- SE, 2.0 +/- 0.49 to 0.9 +/- 0.26 mV, P less than 0.01, lumen negative) and short-circuit current (Isc) (7.0 +/- 1.0 to 2.4 +/- 0.64 uA/cm2, P less than 0.01) without affecting resistance (R) (241 +/- 33 to 216 +/- 41 omega. cm2). Benzamil (10(-5) M) but not dimethylamiloride (10(-5) M) decreased Isc. Terbutaline (10(-3) M) increased PD from 1.2 +/- 0.13 to 3.3 +/- 0.40 mV (P less than 0.01), and application of amiloride (10(-4) M) after terbutaline reduced PD and Isc to less than initial base-line values. The Na(+)-K(+)-2Cl- cotransport inhibitors bumetanide (10(-4) M) and furosemide (10(-3) M) had no effect on PD and Isc either before or after terbutaline. Neither the Cl- channel blocker diphenylamine-2-carboxylate (10(-3) M) nor the Na(+)-glucose cotransport inhibitor phloridzin (10(-3) M) affected the bioelectric properties. Fetal type II alveolar epithelium in primary culture actively transport ions and, on the basis of inhibitor-agonist experiments, probably do not secrete Cl- but absorb Na+ through Na+ channels.


A computational theory of visual receptive fields.
A receptive field constitutes a region in the visual field where a visual cell or a visual operator responds to visual stimuli. This paper presents a theory for what types of receptive field profiles can be regarded as natural for an idealized vision system, given a set of structural requirements on the first stages of visual processing that reflect symmetry properties of the surrounding world. These symmetry properties include (i) covariance properties under scale changes, affine image deformations, and Galilean transformations of space-time as occur for real-world image data as well as specific requirements of (ii) temporal causality implying that the future cannot be accessed and (iii) a time-recursive updating mechanism of a limited temporal buffer of the past as is necessary for a genuine real-time system. Fundamental structural requirements are also imposed to ensure (iv) mutual consistency and a proper handling of internal representations at different spatial and temporal scales. It is shown how a set of families of idealized receptive field profiles can be derived by necessity regarding spatial, spatio-chromatic, and spatio-temporal receptive fields in terms of Gaussian kernels, Gaussian derivatives, or closely related operators. Such image filters have been successfully used as a basis for expressing a large number of visual operations in computer vision, regarding feature detection, feature classification, motion estimation, object recognition, spatio-temporal recognition, and shape estimation. Hence, the associated so-called scale-space theory constitutes a both theoretically well-founded and general framework for expressing visual operations. There are very close similarities between receptive field profiles predicted from this scale-space theory and receptive field profiles found by cell recordings in biological vision. Among the family of receptive field profiles derived by necessity from the assumptions, idealized models with very good qualitative agreement are obtained for (i) spatial on-center/off-surround and off-center/on-surround receptive fields in the fovea and the LGN, (ii) simple cells with spatial directional preference in V1, (iii) spatio-chromatic double-opponent neurons in V1, (iv) space-time separable spatio-temporal receptive fields in the LGN and V1, and (v) non-separable space-time tilted receptive fields in V1, all within the same unified theory. In addition, the paper presents a more general framework for relating and interpreting these receptive fields conceptually and possibly predicting new receptive field profiles as well as for pre-wiring covariance under scaling, affine, and Galilean transformations into the representations of visual stimuli. This paper describes the basic structure of the necessity results concerning receptive field profiles regarding the mathematical foundation of the theory and outlines how the proposed theory could be used in further studies and modelling of biological vision. It is also shown how receptive field responses can be interpreted physically, as the superposition of relative variations of surface structure and illumination variations, given a logarithmic brightness scale, and how receptive field measurements will be invariant under multiplicative illumination variations and exposure control mechanisms.


Pleuromutilin Inhibits Proliferation and Migration of A2780 and Caov-3 Ovarian Carcinoma Cells and Growth of Mouse A2780 Tumor Xenografts by Down-Regulation of pFAK2.
BACKGROUND Pleuromutilin is a natural tricyclic, derived from the fungus, Pleurotus mutilus. This study aimed to investigate the effects of pleuromutilin on migration and proliferation of A2780 and Caov-3 human ovarian carcinoma cells and the growth of A2780 tumor xenografts in mice and the molecular mechanisms involved. MATERIAL AND METHODS A2780 and Caov-3 human ovarian carcinoma cells were cultured with and without 40, 160, and 200 μM of pleuromutilin. The Edu fluorescence assay, the wound-healing assay, and Matrigel were used to measure A2780 and Caov-3 cell proliferation, migration, invasion, and adhesion in vitro, respectively. Western blot measured protein levels of FAK, p-FAK, MMP-2, and MMP-9. A2780 cells were injected subcutaneously into mice to determine the effects of pleuromutilin on the growth of tumor xenografts. RESULTS Pleuromutilin significantly reduced A2780 and Caov-3 cell proliferation at 48 h in a dose-dependent manner (P<0.05), and at 200 μM, pleuromutilin reduced cell proliferation by 21.43% and 23.65%, respectively. Treatment of A2780 cells with pleuromutilin significantly reduced cell migration, invasion, and adhesion and the expression of p-FAK, MMP-2, and MMP-9 compared with untreated controls. In the mouse tumor xenograft model, treatment with pleuromutilin significantly reduced tumor size compared with the untreated group and inhibited tumor metastasis to the intestine, spleen, and peritoneal cavity. CONCLUSIONS In A2780 and Caov-3 human ovarian carcinoma cells, pleuromutilin inhibited cell proliferation, migration, invasion, and adhesion in a dose-dependent manner, and reduced tumor growth and metastases in a mouse A2780 cell tumor xenograft model.


Regional lung microvascular permeability using dual isotope scintigraphy.
We have extended the dual isotope probe technique of Basran et al. for the measurement of pulmonary microvascular permeability (PMVP) to include gamma camera data acquisition and functional imaging of the plasma protein accumulation index (PPA) throughout the lung fields. The study group consisted of 11 patients with possible increased PMVP following the drainage of a pleural effusion or the evacuation of air from a pneumothorax, and 11 control patients. The PPA was calculated (1) for probe data, (2) on a pixel by pixel basis for the camera data, the results being stored in a functional image and (3) for four pixel x four pixel regions of interest positioned over the lung fields using the functional image and raw data as a guide. Functional images of the control group showed uniformly low PPAs throughout the lung fields. Nine of the eleven patients in the effusion/pneumothorax group showed discrete areas of increased PPA on the functional images. In the effusion/pneumothorax group, the re-expanded lung four pixel x four pixel ROI PPA values were significantly higher than the nonexpanded lung ROI values (p less than 0.001). The re-expanded lung ROI values were also significantly higher than the mean of the left and right lung ROIs in the control group (p less than 0.01). Five of the eleven patients in the effusion/pneumothorax group had probe PPAs that differed significantly from zero. We believe that probe positioning problems in the absence of sufficient clinical guidelines were largely responsible for there being no overall significant difference in the probe PPAs between the two study groups.


Johnny's story: transfusing a Jehovah's Witness.
Jehovah's Witnesses refuse blood transfusions for themselves and for their children. This action can be difficult for health professionals to understand and can lead to tensions between the staff and family. For one family, their refusal of blood for their child lead to a greater understanding of their religion and its beliefs for those who cared for them. Interspersed with their story are the medical reasons their son required blood, the reasons Jehovah's Witnesses refuse blood transfusions, and what the acceptable alternatives are to Jehovah's Witnesses. This article will share the thoughts and feelings of the family and the nursing staff who cared for the family during this crisis.


Smallholders' uneven capacities to adapt to climate change amid Africa's 'green revolution': Case study of Rwanda's crop intensification program.
Development programs and policies can influence smallholder producers' abilities to adapt to climate change. However, gaps remain in understanding how households' adaptive capacities can become uneven. This paper investigates how development transitions-such as the recent adoption of 'green revolution' agricultural policies throughout sub-Saharan Africa-intersect with cross-scale social-environmental processes to unevenly shape smallholders' adaptive capacities and adaptation pathways. Drawing on quantitative and qualitative material from a multi-season study in Rwanda, we investigate smallholder adaptation processes amid a suite of rural development interventions. Our study finds that adaptive capacities arise differentially across livelihood groups in the context of evolving environmental, social, and political economic processes. We show how social institutions play key roles in shaping differential adaptation pathways by enabling and/or constraining opportunities for smallholders to adapt livelihood and land use strategies. Specifically, Rwanda's Crop Intensification Program enables some wealthier households to adapt livelihoods by generating income through commercial agriculture. At the same time, deactivation of local risk management institutions has diminished climate risk management options for most households. To build and employ alternate livelihood practices such as commercial agriculture and planting woodlots for charcoal production, smallholders must negotiate new institutions, a prerequisite for which is access to capitals (land, labor, and nonfarm income). Those without entitlements to these are pulled deeper into poverty with each successive climatic shock. This illustrates that adaptive capacity is not a static, quantifiable entity that exists in households. We argue that reconceptualizing adaptive capacity as a dynamic, social-environmental process that emerges in places can help clarify complex linkages among development policies, livelihoods, and adaptation pathways. To ensure more equitable and climate-resilient agricultural development, we stress the need to reformulate policies with careful attention to how power structures and entrenched social inequalities can lead to smallholders' uneven capacities to adapt to climate change.


Alcohol consumption and survival of colorectal cancer patients: a population-based study from Germany.
Studies on the association between alcohol consumption and colorectal cancer (CRC) prognosis have yielded inconsistent results. The associations of lifetime and 1-y prediagnostic alcohol consumption with relevant prognostic outcomes were evaluated in a large population-based cohort of CRC patients. In 2003-2010, 3121 patients diagnosed with CRC were interviewed on sociodemographic and lifestyle factors, medication, and comorbidities. Cancer recurrence, vital status, and cause of death were documented for a median follow-up time of 4.8 y. With the use of Cox proportional hazard regression, associations between lifetime and recent alcohol consumption and overall, CRC-specific, recurrence-free, and disease-free survival were analyzed. In this patient cohort with a median age of 69 y at diagnosis, lifetime abstainers showed poorer overall [adjusted HR (aHR): 1.25; 95% CI: 1.03, 1.52] and CRC-specific (aHR: 1.37; 95% CI: 1.10, 1.70) survival than lifetime light drinkers (women: >0-12 g/d; men: >0-24 g/d). Lifetime heavy drinkers showed poorer overall (aHR: 1.37; 95% CI: 1.06, 1.78) and disease-free (aHR: 1.38; 95% CI: 1.09, 1.74) survival. Alcohol abstaining in the year before diagnosis was associated with poorer overall (aHR: 1.42; 95% CI: 1.20, 1.68), CRC-specific (aHR: 1.38; 95% CI: 1.13, 1.68), and disease-free (aHR: 1.23; 95% CI: 1.05, 1.44) survival. Lifetime abstainers with nonmetastatic disease showed poorer CRC-specific (aHR: 1.48; 95% CI: 1.10, 2.00) and recurrence-free (aHR: 1.32; 95% CI: 1.02, 1.70) survival. Wine abstaining but not beer or liquor abstaining was associated with poorer survival. Associations between alcohol consumption and prognosis varied according to presence of diabetes and age. Prediagnostic alcohol abstaining and heavy drinking were associated with poorer survival after a CRC diagnosis than light drinking. The protective effects of light consumption might be restricted to wine, and associations might differ according to age and presence of diabetes mellitus.


Lidocaine as an anti-arrhythmic drug: Are there any indications left?
Lidocaine is classified as a class Ib anti-arrhythmic that blocks voltage- and pH-dependent sodium channels. It exhibits well investigated anti-arrhythmic effects and has been the anti-arrhythmic of choice for the treatment of ventricular arrhythmias for several decades. Lidocaine binds primarily to inactivated sodium channels, decreases the action potential duration, and increases the refractory period. It increases the ventricular fibrillatory threshold and can interrupt life-threatening tachycardias caused by re-entrant mechanisms, especially in ischemic tissue. Its use was pushed into the background in the era of amiodarone and modern electric device therapy. Recently, lidocaine has come back into focus for the treatment of acute sustained ventricular tachyarrhythmias. In this brief overview, we review the clinical pharmacology including possible side effects, the historical course, possible indications, and current Guideline recommendations for the use of lidocaine.


Antibody engineering.
The antibody molecule is a therapeutic agent, designed by nature to bind to a wide range of antigen molecules and to trigger effector functions, such as complement lysis and cell-mediated killing. The genes encoding antibodies can be manipulated in vitro, allowing the binding sites for antigen and effector molecules to be dissected, and new properties to be engineered. The future for the application of engineered antibodies in medicine is reviewed in the context of the past century.


Sulcal Depth-based Cortical Shape Analysis in Normal Healthy Control and Schizophrenia Groups.
Sulcal depth is an important marker of brain anatomy in neuroscience/neurological function. Previously, sulcal depth has been explored at the region-of-interest (ROI) level to increase statistical sensitivity to group differences. In this paper, we present a fully automated method that enables inferences of ROI properties from a sulcal region-focused perspective consisting of two main components: 1) sulcal depth computation and 2) sulcal curve-based refined ROIs. In conventional statistical analysis, the average sulcal depth measurements are employed in several ROIs of the cortical surface. However, taking the average sulcal depth over the full ROI blurs overall sulcal depth measurements which may result in reduced sensitivity to detect sulcal depth changes in neurological and psychiatric disorders. To overcome such a blurring effect, we focus on sulcal fundic regions in each ROI by filtering out other gyral regions. Consequently, the proposed method results in more sensitive to group differences than a traditional ROI approach. In the experiment, we focused on a cortical morphological analysis to sulcal depth reduction in schizophrenia with a comparison to the normal healthy control group. We show that the proposed method is more sensitivity to abnormalities of sulcal depth in schizophrenia; sulcal depth is significantly smaller in most cortical lobes in schizophrenia compared to healthy controls (p < 0.05).


Inhalational anesthesia and histamine release during bronchospasm.
The influence of inhalational anesthetics on histamine released during bronchospasm induced by Ascaris antigen aerosol was studied in Basenji-Greyhound (BG) dogs. Five BG dogs were anesthetized with thiopental and halothane on separate occasions and challenged with Ascaris antigen aerosol for five minutes. Pulmonary resistance (RL), dynamic compliance (Cdyn), and arterial plasma histamine levels were measured over 30 min following antigen exposure. Prior to antigen challenge, RL, Cdyn, and histamine levels were similar in thiopental- and halothane-anesthetized dogs. The peak change in RL and Cdyn occurred 10 min after the start of antigen challenge. RL increased 3.0 +/- 0.4-fold (mean +/- SEM) in thiopental-anesthetized dogs as compared with 1.6 +/- 0.2-fold in halothane-anesthetized dogs (P less than 0.05). Cdyn decreased to a similar extent in both groups, with maximal decreases of 0.53 +/- 0.08 and 0.53 +/- 0.09 times the prechallenge value for thiopental- and halothane-anesthetized dogs, respectively. Plasma histamine levels peaked at 5 min. Plasma histamine increased to 8.0 +/- 5.0 ng/ml in thiopental-anesthetized dogs compared with 10.7 +/- 4.7 ng/ml in halothane-anesthetized dogs. Histamine levels were not significantly different during or after antigen challenge between thiopental- and halothane-anesthetized dogs. Halothane, but not thiopental, significantly attenuated the increase in RL provoked by antigen challenge. However, arterial plasma histamine levels were similar during both anesthetics. Therefore, the authors conclude that the protective effect of halothane on airways was not due to an inhibition of release of histamine from mast cells.


Multiscale Investigation of the Structural, Electrical and Photoluminescence Properties of MoS2 Obtained by MoO3 Sulfurization.
In this paper, we report a multiscale investigation of the compositional, morphological, structural, electrical, and optical emission properties of 2H-MoS2 obtained by sulfurization at 800 °C of very thin MoO3 films (with thickness ranging from ~2.8 nm to ~4.2 nm) on a SiO2/Si substrate. XPS analyses confirmed that the sulfurization was very effective in the reduction of the oxide to MoS2, with only a small percentage of residual MoO3 present in the final film. High-resolution TEM/STEM analyses revealed the formation of few (i.e., 2-3 layers) of MoS2 nearly aligned with the SiO2 surface in the case of the thinnest (~2.8 nm) MoO3 film, whereas multilayers of MoS2 partially standing up with respect to the substrate were observed for the ~4.2 nm one. Such different configurations indicate the prevalence of different mechanisms (i.e., vapour-solid surface reaction or S diffusion within the film) as a function of the thickness. The uniform thickness distribution of the few-layer and multilayer MoS2 was confirmed by Raman mapping. Furthermore, the correlative plot of the characteristic A1g-E2g Raman modes revealed a compressive strain (ε ≈ -0.78 ± 0.18%) and the coexistence of n- and p-type doped areas in the few-layer MoS2 on SiO2, where the p-type doping is probably due to the presence of residual MoO3. Nanoscale resolution current mapping by C-AFM showed local inhomogeneities in the conductivity of the few-layer MoS2, which are well correlated to the lateral changes in the strain detected by Raman. Finally, characteristic spectroscopic signatures of the defects/disorder in MoS2 films produced by sulfurization were identified by a comparative analysis of Raman and photoluminescence (PL) spectra with CVD grown MoS2 flakes.


Acceptability of a Mobile Phone-Based Augmented Reality Game for Rehabilitation of Patients With Upper Limb Deficits from Stroke: Case Study.
Upper limb functional deficits are common after stroke and result from motor weakness, ataxia, spasticity, spatial neglect, and poor stamina. Past studies employing a range of commercial gaming systems to deliver rehabilitation to stroke patients provided short-term efficacy but have not yet demonstrated whether or not those games are acceptable, that is, motivational, comfortable, and engaging, which are all necessary for potential adoption and use by patients. The goal of the study was to assess the acceptability of a smartphone-based augmented reality game as a means of delivering stroke rehabilitation for patients with upper limb motor function loss. Patients aged 50 to 70 years, all of whom experienced motor deficits after acute ischemic stroke, participated in 3 optional therapy sessions using augmented reality therapeutic gaming over the course of 1 week, targeting deficits in upper extremity strength and range of motion. After completion of the game, we administered a 16-item questionnaire to the patients to assess the game's acceptability; 8 questions were answered by rating on a scale from 1 (very negative experience) to 5 (very positive experience); 8 questions were qualitative. Patients (n=5) completed a total of 23 out of 45 scheduled augmented reality game sessions, with patient fatigue as the primary factor for uncompleted sessions. Each patient consented to 9 potential game sessions and completed a mean of 4.6 (SE 1.3) games. Of the 5 patients, 4 (80%) completed the questionnaire at the end of their final gaming session. Of note, patients were motivated to continue to the end of a given gaming session (mean 4.25, 95% CI 3.31-5.19), to try other game-based therapies (mean 3.75, 95% CI 2.81-4.69), to do another session (mean 3.50, 95% CI 2.93-4.07), and to perform other daily rehabilitation exercises (mean 3.25, 95% CI 2.76-3.74). In addition, participants gave mean scores of 4.00 (95% CI 2.87-5.13) for overall experience; 4.25 (95% CI 3.31-5.19) for comfort; 3.25 (95% CI 2.31-4.19) for finding the study fun, enjoyable, and engaging; and 3.50 (95% CI 2.52-4.48) for believing the technology could help them reach their rehabilitation goals. For each of the 4 patients, their reported scores were statistically significantly higher than those generated by a random sampling of values (patient 1: P=.04; patient 2: P=.04; patient 4: P=.004; patient 5: P=.04). Based on the questionnaire scores, the patients with upper limb motor deficits following stroke who participated in our case study found our augmented reality game motivating, comfortable, engaging, and tolerable. Improvements in augmented reality technology motivated by this case study may one day allow patients to work with improved versions of this therapy independently in their own home. We therefore anticipate that smartphone-based augmented reality gaming systems may eventually provide useful postdischarge self-treatment as a supplement to professional therapy for patients with upper limb deficiencies from stroke.


Osteopathic manipulative medicine for carpal tunnel syndrome.
Carpal tunnel syndrome (CTS) is 1 of the most common peripheral nerve entrapment disorders. Osteopathic manipulative medicine can be invaluable in diagnosing and managing CTS. Combined with a patient's history and a standard physical examination, an osteopathic structural examination can facilitate localizing the nerve entrapment, diagnosing CTS, and monitoring the disease process. Osteopathic manipulative treatment is noninvasive and can be used to supplement traditional CTS treatment methods. The authors also review the relevant anatomy involving CTS and the clinical efficacy of osteopathic manipulative medicine in the management of this disorder.


Effects of repeated injections of naltrexone on antagonism of rate decreases by morphine in the pigeon.
Responding of three pigeons was maintained under a multiple schedule of food presentation in which key-pecks produced access to grain under a fixed-interval schedule in the presence of one stimulus and a fixed-ratio schedule in the presence of another stimulus. Repeated daily injections of 1 mg/kg naltrexone had no systematic effect on overall response rate during either schedule component, and the naltrexone continued to antagonize rate decreases of periodic single injections of 10 mg/kg morphine for seven weeks. Tolerance did not occur to the antagonistic effects of naltrexone on rate decreases generally produced by morphine.


A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer.
An E1B 55 kDa gene-deleted adenovirus, Onyx-015, which reportedly selectively replicates in and lyses p53-deficient cells, was administered by a single intratumoral injection to a total of 22 patients with recurrent head and neck cancer. The objectives of this Phase I study were to determine the safety, feasibility, and efficacy of this therapy and determine any correlation to p53 status. Six cohorts were investigated with a dose escalation from 10(7)-10(11) plaque-forming units. Toxicity was assessed using NCIC criteria. Tumor response was assessed by clinical and radiological measurement. Blood samples were taken to detect adenovirus DNA and neutralizing antibody to adenovirus. Tumor biopsies were taken to detect adenovirus by in situ hybridization. Treatment was well tolerated, with the main toxicity being grade 1/2 flu-like symptoms. Dose-limiting toxicity was not reached at the highest dose of 10(11) plaque-forming units. Twenty-one of the 22 patients treated showed an increase in neutralizing antibody to adenovirus. In situ hybridization showed viral replication in 4 of 22 patients treated, all of whom had mutant p53 tumors. Using conventional response criteria, no objective responses were observed. However, magnetic resonance imaging scans were suggestive of tumor necrosis at the site of viral injection in five patients, three of whom were classified using nonconventional criteria as partial responders, and two of whom were classified using nonconventional criteria as minor responders. Of these five cases, four had mutant p53 tumors. The response duration for the three partial responders was 4, 8, and 12 weeks. An additional eight patients had stable disease in the injected tumors lasting from 4-8 weeks. These preliminary results show that intratumoral administration of Onyx-015 is feasible, well tolerated, and associated with biological activity. Further investigation of Onyx-015, particularly with a more frequent injection protocol and in combination with systemic chemotherapy, is warranted.


[Horn fly (Muscidae) fauna and ecology in the area of the Baikal-Amur mainline].
4 species of horn flies were recorded from the territory of the Baikal-Amur railway: Stomoxys calcitrans, Haematobia stimulans, Lyperosia irritans and Lyperosia titillans. The autumn horn fly was found to be most widespread and dangerous. It was especially abundant in Priamurje, in the zone of the monsoon climate, where it behaves as a typical pasture species. The behaviour, daily and seasonal dynamics and flight duration (90 to 150 days) of horn flies changes noticeably depending on natural conditions; they all have a broken distribution area here. The cultivation of the Baikal-Amur railway territory by man favours the spread of horn flies over this territory. Most dangerous they are for man and domestic animals in the western and eastern parts of the Baikal-Amur railway.


[Endometriosis and obstetrical complications].
Approximately 5-10% of the women in the reproductive age are afflicted with endometriosis and many become pregnant after fertility treatment. Women with endometriosis seem to have an increased risk of placental complications, bleeding in pregnancy and during labour as well as possible increased risk of pre-eclampsia, preterm birth and low birthweight. Large epidemiological studies are needed to clarify the magnitude of these risks in order to define the appropriate level of proactive management of pregnant women with endometriosis.


[Study on the effect of some group-specific agents on clostridiopeptidase].
The interaction of clostridiopeptidase of Clostridium histolyticum with EDC, TNM and MA, the specific reagents for COOH-groups, tyrosine and lysine residues was studied. It was shown that at pH 6.0 EDC inactivates the enzyme. The inactivation process follows the pseudo-first order kinetics and is described by a second order rate constant equal to 1 M-1 min-1. The synthetic substrate does not prevent, in practical terms, the enzyme inactivation by EDC. At pH 8.0 TNM modifies about 19 tyrosine residues in the clostridiopeptidase molecule which is accompanied by marked inhibition of the enzyme activity (down to 70-90%). In this case, the inactivation process is not described by simple pseudo-first order kinetics but is characterized by two steps (fast and slow) with second order rate constants of approximately 14 and 3.5 M-1 min-1, respectively. The synthetic substrate partly prevents the inactivation of the enzyme by TNM and protects 11 tyrosine residues. The MA-induced incorporation of 13 +/- 3 maleyl groups into the clostridiopeptidase molecule in partially prevented by the synthetic substrate with protects the enzyme against inactivation. The data obtained suggest that lysine residues are seemingly included into the active center of clostridiopeptidase, whereas tyrosine residues provide for the maintenance of active conformation of the enzyme.


Novel Fecal Biomarkers That Precede Clinical Diagnosis of Ulcerative Colitis.
Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown. We applied 16S ribosomal RNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays, and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at risk for inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs). Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 22,000 gene families that were significantly different between HC, pre-UC, and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. The bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC, or post-UC microbiota. Mice colonized with or born from pre-UC-colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC-colonized mice. We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.


Recurrent Retrobulbar Hemorrhage Associated With CPAP Use After Orbital Fracture Repair.
We present a patient who underwent orbital fracture repair complicated by retrobulbar hemorrhages twice within the first postoperative week. The suspected cause is continuous positive airway pressure (CPAP) use with inappropriate patient-modified settings. The most likely mechanism of action was venous congestion from the extrinsic positive pressure, similar to Valsalva maneuvers increasing orbital vasculature pressure. In our patient, because his orbital blood vessels had recently been cauterized, they were too fragile to handle the engorgement and bled, leading to a retrobulbar hemorrhage. It is possible that at a lower CPAP setting, the vascular congestion would not have been as severe and caused bleeding. We recommend routinely asking patients about CPAP use before orbital surgeries and instructing patients to stop CPAP usage for 1 week after any orbital surgeries if medically cleared.


[Outcomes of circular tunnel keratoplasty].
A new refraction operation for the correction of medium and high myopia, circulatory tunnel keratoplasty, has been theoretically validated, developed, experimentally tested, and tried in clinic. Experiments included 8 tested, in isolated cadaveric eyes and 72 surgeries on 39 rabbits. Experiments helped develop surgical equipment and technique. A relationship between the refraction effect and the diameter of the circulatory tunnel and implant thickness has been revealed. Time course of the refraction effect has been followed up for up to 2 years. The refraction diminished from 4.0 to 11.0 diopters. Thirty eyes of 21 patients with stable myopia of 6.0 to 22.0 diopters were operated on with the resultant refraction of 6.0 to 14.0 diopters. The results have confirmed the relationship between the refraction effect of surgery and the implant thickness. The authors claim that circulatory tunnel keratoplasty is an effective method for the correction of medium and high myopia and recommend it for clinical application.


Factors that protect against poor sleep quality in an adult lifespan sample of non-Hispanic Black and non-Hispanic White adults during COVID-19: A cross-sectional study.
Stress in relation to the Coronavirus disease 19 pandemic (i.e., COVID-19, COVID stress) may be linked with poor sleep quality. The association between stress that is specific to the COVID-19 pandemic and sleep quality has been understudied, particularly in racially diverse people across the adult lifespan. Here, we investigated self-reported sleep quality in relation to COVID stress and factors that may protect against experiencing poor sleep quality from high COVID stress, including social support and religiosity. We recruited non-Hispanic Black (n = 73) and non-Hispanic White (n = 178) participants across the adult lifespan (18-76 years) using an online, cross-sectional design during the COVID-19 pandemic (March 2021-June 2021). We asked participants to report information regarding demographics (age, race/ethnicity, years of education), sleep (sleep quality, sleep habits), and positive (social support, religious activities) and negative (events of discrimination, depression, general stress, COVID stress) psychosocial factors. Across age and racial groups, better sleep habits were associated with better sleep quality, and higher COVID stress was linked to poorer sleep quality. Black participants reported higher quality sleep than White participants (p = 0.006). They also endorsed greater private and internal religiosity (p's < 0.001). Across racial groups, moderation analyses revealed a protective effect of religiosity against poor sleep (p's < 0.006). Specifically, individuals with high religious activity and high COVID stress did not experience poor sleep quality, but individuals with low religious activity and high COVID stress demonstrated poor sleep quality. These results remained significant when controlling for general stress. Protective factors, such as religiosity, may mitigate the negative associations between high COVID stress and poor sleep quality.


To 'gram or not'? Indications for intraoperative cholangiogram.
The purpose of this study was to evaluate the current practice patterns and results for use of intraoperative cholangiogram (IOC) during laparoscopic cholecystectomy (LC). We performed a retrospective review of all patients who underwent LC between January 1, 2005 and December 31, 2009. Data variables included: preoperative laboratory and radiographic studies, indication for and findings of IOC, and perioperative management of choledocholithiasis and retained common bile duct (CBD) stones. There were 1,308 patients who underwent LC by 23 surgeons, of whom 266 also had an IOC (20%) performed. The majority had ultrasonography performed, 242 had an abdominal compute tomography (CT) scan, and 129 patients had a hepatobiliary iminodiacetic acid (HIDA) scan. Indications for an IOC included: diagnosis of choledocholithiasis or gallstone pancreatitis (n = 116), abnormal liver function tests (n = 187), and a dilated CBD ≥ 10 mm (n = 182). Of the 266 IOCs, 36 patients (13.5%) had a CBD stone with the majority (n = 26; 72%) having normal preoperative imaging studies. Only 6 patients (17%) with a CBD calculi on IOC underwent successful clearance of the calculi at the time of LC. Twenty-nine of the remaining 30 patients with a retained calculus on IOC underwent postoperative endoscopic retrograde cholangiopancreatography (ERCP) with extraction of the calculi. Of the 1,042 LCs performed without an IOC, 31 patients (3%) were diagnosed with a retained stone managed successfully by ERCP. Our data reveals that the selective use of IOC is helpful in diagnosing and clearing CBD calculi, that the use of preoperative CBD size aids in selecting patients for IOC, and that choledocholithiasis identified with IOC or after discharge can be managed successfully with ERCP.


Comparative Efficacy of Exercise Training and Conventional Psychotherapies for Adult Depression: A Network Meta-Analysis.
An estimated 3.8% of the global population experiences depression, according to the [2019] WHO report. Evidence supports the efficacy of exercise training (EX) for depression; however, its comparative efficacy to conventional, evidence-supported psychotherapies remains understudied. Therefore, we conducted a network meta-analysis to compare the efficacy of exercise training (EX), behavioral activation therapy (BA), cognitive-behavioral therapy (CBT), and non-directive supportive therapy (NDST). Our search was performed in seven relevant databases (inception to March 10, 2020) and targeted randomized trials comparing psychological interventions head-to-head and/or to a treatment as usual (TAU) or waitlist (WL) control for the treatment of adults (18 years or older) with depression. Included trials assessed depression using a validated psychometric tool. From 28,716 studies, 133 trials with 14,493 patients (mean age of 45.8 years; 71.9% female) were included. All treatment arms significantly outperformed TAU (standard mean difference [SMD] range, -0.49 to -0.95) and WL (SMD range, -0.80 to -1.26) controls. According to surface under the cumulative ranking (SUCRA) probabilities, BA was mostly likely to have the highest efficacy (1.6), followed by CBT (1.9), EX (2.8), and NDST (3.8). Effect size estimates between BA and CBT (SMD = -0.09, 95% CI [-0.50 to 0.31]), BA and EX (-0.22, [-0.68 to 0.24]), and CBT and EX (-0.12, [-0.42 to 0.17]) were very small, suggesting comparable treatment effects of BA, CBT, and EX. With individual comparisons of EX, BA, and CBT to NDST, we found small to moderate effect sizes (0.09 to 0.46), suggesting EX, BA, and CBT may equally outperform NDST. Findings provide preliminary yet cautionary support for the clinical use of exercise training for adult depression. High study heterogeneity and lack of sound investigations of exercise must be considered. Continued research is needed to position exercise training as an evidence-based therapy.


Green synthesis of nanoscale cobalt(ii)-based MOFs: highly efficient photo-induced green catalysts for the degradation of industrially used dyes.
Two new metal-organic frameworks (MOFs) based on cobalt metal, namely, [{Co0.5(5N3-IPA)0.5(1,2-bpe)1.25}]∞ (1) and [{Co(5NH2-IPA)(1,2-bpe)}]∞ (2) (5N3-IPA = 5-azidoisophthalic acid, 5NH2-IPA = 5-aminoisophthalic acid, 1,2-bpe = 1,2-bis(4-pyridyl)ethylene) were synthesized under a solvothermal condition and characterized. MOF 1 has a rare three-dimensional structure with 3-fold interpenetration, while MOF 2 has a 2D "pillar-layered" structure. The particle size of the as-synthesized MOFs was reduced to produce nanoscale MOFs (NMOFs) by a hand grinding technique while retaining the composition and structural regularity of the as-synthesized MOFs. SEM studies revealed that NMOFs 1 and 2 were hexagonal and square shaped, respectively. Since the band gap energy for MOFs 1 and 2 (2.81 eV and 2.65 eV, respectively) falls in the visible region, heterogeneous catalytic activities of NMOFs 1 and 2 in aqueous medium towards Reactive Yellow HE4R (RY84), Reactive Black HFGR (RBH), Rhodamine B (RhB) and methylene blue (MEB) were investigated under visible light irradiation. The introduction of hydrogen peroxide was observed to significantly increase the photocatalytic efficiency via dye degradation. Hydroxyl radical (OH˙) is supposed to act as the main active species during oxidation, which was further verified by performing the degradation experiment in the presence of tert-butyl alcohol, which can act as a radical trapper for hydroxide radicals in the reaction.


Sister Mary Joseph Nodule in a Patient With Advanced Prostate Cancer.
Prostate cancer is the second most common cause of cancer death among US men. Metastasis typically occurs in the bone, lymph nodes, liver, and thorax. This case highlights a patient who was suspected of having prostate cancer several years before presenting to the emergency department with back pain and an umbilical hernia of increasing size. Gross examination revealed fixed masses on the abdominal wall that appeared malignant on computed tomographic imaging. The umbilical mass was a Sister Mary Joseph nodule (SMJN), which is sometimes found in patients with advanced, metastatic abdominal cancer. An SMJN is most commonly suggestive of gastrointestinal or gynecologic cancer, but it is a rarely reported finding in the context of prostate cancer. SMJN is a frequently missed finding that may delay further investigation for malignant neoplasms. This case reinforces the importance of this physical examination finding and provides evidence for adding prostate cancer to the list of possible diagnoses for patients who have an SMJN.


[Therapeutic effects of intrarectal administration of oxybutynin].
Oxybutynin is a drug of choice in the treatment of the detrusor instability. However the therapeutic doses given orally produce very often side effects due to oxybutynin anticholinergic properties (atropine-like action). The responsible compound is mainly the active oxybutynin metabolite-N-desethyl-oxybutynin, which is the result of the oxybutynin metabolism in liver (so-called first pass metabolism). Therefore it seems, that an attempt of the drug administration via the intrarectal route is an interesting alternative, which maintains the high oxybutynin concentration with the simultaneous reduction of the N-desethyl-oxybutynin. We qualified 20 patients for our study (12 men and 8 women, mean age 45.6) with the urodynamically proven detrusor instability. Patients with a neurogenic origin of detrusor instability were excluded from the study. Patients treated with oral oxybutynin in a dose of 5 mg b.i.d. and with strongly pronounced atropine-like side effects, making impossible the continuation of the therapy were offered an intrarectal form of oxybutynin in a dose of 5 mg b.i.d. Treatment efficiency was evaluated on the base of the patients symptoms (side effects, urgency, incontinence, frequency). 15 patients (75%) had pronounced side effects, leading to the oral treatment discontinuation. The average time of the oral oxybutynin treatment was 1.5 weeks (3 days to 4 weeks). During the oral therapy these patients complained of the side effects of different magnitude: dry mouth (15 patients--100%), gastro-intestinal disorders (3 patients--20%), drowsiness (1 patient--6.7%). These side effects forced them to stop the oxybutynin oral therapy. After the change of the drug form from oral to the intrarectal one, none of the patients resigned from the treatment. 13.3% of the patients complained of the mild intensity dry mouth. After the one-month therapy period a complete disappearing of the unstable detrusor symptoms was reported by 5 patients (25%), while all others reported their significant reduction. The intrarectal oxybutynin administration shows the therapeutic efficacy comparable with the intravesical administration with reference to unstable detrusor symptoms reduction. Intrarectal administration reduces the oxybutynin side effects in comparison with the oral one.


Relapsing cerebral amyloid angiopathy-related inflammation: the wax and the wane.
Cerebral amyloid angiopathy-related inflammation (CAA-I) is a rare variant of cerebral amyloid angiopathy (CAA). Its precise pathophysiology remains uncertain and we currently have limited evidence on which immunosuppressive agents are the most effective in its treatment. The disease course of CAA-I disorders can vary from an isolated clinical event to recurrent episodes. We present a case of biopsy-confirmed CAA-I that gives insight into its potential relapsing nature and the challenges of its long-term management.


First genome-wide association study on anxiety-related behaviours in childhood.
Twin studies have shown that anxiety in a general population sample of children involves both domain-general and trait-specific genetic effects. For this reason, in an attempt to identify genes responsible for these effects, we investigated domain-general and trait-specific genetic associations in the first genome-wide association (GWA) study on anxiety-related behaviours (ARBs) in childhood. The sample included 2810 7-year-olds drawn from the Twins Early Development Study (TEDS) with data available for parent-rated anxiety and genome-wide DNA markers. The measure was the Anxiety-Related Behaviours Questionnaire (ARBQ), which assesses four anxiety traits and also yields a general anxiety composite. Affymetrix GeneChip 6.0 DNA arrays were used to genotype nearly 700,000 single-nucleotide polymorphisms (SNPs), and IMPUTE v2 was used to impute more than 1 million SNPs. Several GWA associations from this discovery sample were followed up in another TEDS sample of 4804 children. In addition, Genome-wide Complex Trait Analysis (GCTA) was used on the discovery sample, to estimate the total amount of variance in ARBs that can be accounted for by SNPs on the array. No SNP associations met the demanding criterion of genome-wide significance that corrects for multiple testing across the genome (p<5×10(-8)). Attempts to replicate the top associations did not yield significant results. In contrast to the substantial twin study estimates of heritability which ranged from 0.50 (0.03) to 0.61 (0.01), the GCTA estimates of phenotypic variance accounted for by the SNPs were much lower 0.01 (0.11) to 0.19 (0.12). Taken together, these GWAS and GCTA results suggest that anxiety--similar to height, weight and intelligence--is affected by many genetic variants of small effect, but unlike these other prototypical polygenic traits, genetic influence on anxiety is not well tagged by common SNPs.


Role of protein tyrosine phosphorylation in erythrocyte lysate-induced intracellular free calcium concentration elevation in cerebral smooth-muscle cells.
Tyrosine kinases play an important role in the regulation of systemic vascular smooth-muscle tone. The authors studied the involvement of protein tyrosine kinase activity in erythrocyte lysate-mediated signal transduction in cerebral smooth-muscle cells. Tyrosine kinase phosphorylation and intracellular free Ca++ ([Ca++]i) were measured in rat aortic and basilar artery smooth-muscle cells by using Western blot and fura 2-acetoxymethyl ester microfluorimetry. Erythrocyte lysate enhanced tyrosine phosphorylation in cultured rat aortic and basilar smooth-muscle cells and induced a rapid transient and a prolonged plateau phase of [Ca++]i response in rat basilar smooth-muscle cells. The tyrosine kinase inhibitors genistein and tyrphostin A51 (administered at concentrations of 30 or 100 microM) attenuated both phases of erythrocyte lysate-induced [Ca++]i elevation. Erythrocyte lysate was separated into low- (<10 kD, which contains adenine nucleotides) and high- (>10 kD, which contains hemoglobin) molecular-weight fractions; these fractions were tested separately in these cells. The low-molecular-weight fraction produced a similar [Ca++]i response to that of erythrocyte lysate and the high-molecular-weight fraction produced a small response. The [Ca++]i responses from both fractions were inhibited by tyrosine kinase inhibitors. To the authors' knowledge, this is the first report to show that tyrosine phosphorylation may be involved in erythrocyte lysate-induced signal transduction and [Ca++]i responses in cerebral smooth-muscle cells.