Estimating the effect of cardiovascular risk factors on all-cause mortality and incidence of coronary heart disease using G-estimation: the atherosclerosis risk in communities study.
Standard methods for analysis of cohort studies may give biased estimates of exposure effects in the presence of time-varying confounding. Such effects may instead be estimated by using G-estimation. This study aimed to examine the relations between important cardiovascular risk factors and all-cause mortality and risk of coronary heart disease (CHD), accounting for confounding between exposures over time using G-estimation. Results were compared with those from standard survival analyses (e.g., Weibull regression) with time-updated covariates. The dataset consisted of all participants in the Atherosclerosis Risk in Communities cohort study who had complete data on the first two of four visits, giving a sample of 13,898 people at baseline. Death and occurrence of CHD or stroke were recorded. G-estimated associations between several risk factors and mortality/CHD incidence differed from those estimated using standard survival analysis. The associations between mortality/CHD incidence and smoking, presence of diabetes, and use of antihypertensives were stronger than the standard survival estimates, while the G-estimated effect of low density lipoprotein and high density lipoprotein cholesterol on CHD incidence were more linear than the standard estimate. Complex relations between exposures over time may lead to biased exposure effect estimates in standard survival analyses. G-Estimation can be used to overcome such biases, and thus may have important implications for the analysis of observational studies.


Diagnosis of Leptospirosis: Comparison between Microscopic Agglutination Test, IgM-ELISA and IgM Rapid Immunochromatography Test.
Leptospirosis is diagnosed on clinical grounds, and confirmed by microscopic agglutination test (MAT). IgM-ELISA (Serion-Virion) and immunochromatography test (Leptocheck-WB) are two immunodiagnostic assays for leptospirosis. Their sensitivity, specificity and applicability in Sri Lanka have not been systematically evaluated. Clinically diagnosed leptospirosis patients (n = 919) were recruited from three hospitals in the Western Province of Sri Lanka, during June 2012 to December 2013. MAT, IgM-ELISA and Leptocheck-WB were performed on all patient sera. MAT titer of ≥ 400 in single sample, four-fold rise or seroconversion ≥ 100 in paired samples were considered as positive for MAT. For diagnostic confirmation, MAT was performed during both acute and convalescent phases. Anti-leptospiral IgM ≥ 20 IU/ml and appearance of a band in the test window were considered as positive for IgM-ELISA and Leptocheck-WB test respectively. Patients with an alternative diagnosis (n = 31) were excluded. Data analysis was performed using two methods, i) considering MAT as reference standard and ii) using Bayesian latent class model analysis (BLCM) which considers each test as imperfect. MAT, IgM-ELISA and Leptocheck-WB positivity were 39.8%, 45.8% and 38.7% respectively during the acute phase. Acute-phase MAT had specificity and sensitivity of 95.7% and 55.3% respectively, when compared to overall MAT positivity. IgM-ELISA and Leptocheck-WB had similar diagnostic sensitivity when compared with acute-phase MAT as the gold standard, although IgM-ELISA showed higher specificity (84.5%) than Leptocheck-WB (73.3%). BLCM analysis showed that IgM-ELISA and Leptocheck-WB had similar sensitivities (86.0% and 87.4%), while acute-phase MAT had the lowest sensitivity (77.4%). However, acute-phase MAT had high specificity (97.6%), while IgM-ELISA and Leptocheck-WB showed similar but lower specificity (84.5% and 82.9%). Both IgM-ELISA and Leptocheck-WB shows similar sensitivities and specificities. IgM-ELISA may be superior to MAT during the acute phase and suitable for early diagnosis of leptospirosis. Leptocheck-WB is suitable as a rapid immunodiagnostic screening test for resource limited settings.


Mastalgia: evaluation and management.
Mastalgia, defined as breast pain, is a common, often distressing complaint among women. It is the most common breast-related complaint in primary care clinics, with a prevalence in working women of approximately 66%. An underlying fear of breast cancer is what prompts these patients to seek health care. A comprehensive history and thorough clinical breast exam is essential to evaluation. Once significant breast disease is ruled out, the majority of these patients respond to simple reassurance.


Assessment of Severity of Long QT Syndrome Phenotype and Risk of Fetal Death.
It has been postulated that long QT syndrome (LQTS) can cause fetal loss through putative adverse effects of the channelopathy on placenta and myometrial function. The authors aimed to describe the fetal death rate in a population of pregnant women with long QT syndrome and investigate whether women with more severe phenotype had worse fetal outcomes. The authors retrospectively evaluated fetal outcomes of 64 pregnancies from 23 women with long QT syndrome followed during pregnancy in a tertiary pregnancy and heart disease program. Thirteen of 64 pregnancies (20%) resulted in a fetal loss, 12 miscarriages (19%), and 1 stillbirth (1.6%). Baseline maternal characteristics, including age and use of β-blockers, did not differ between women who experienced a fetal death or not. Maternal corrected QT interval (QTc) was significantly longer in pregnancies that resulted in fetal death compared with live births (median, 518 ms [interquartile range (IQR), 482-519 ms] versus 479 ms [IQR, 454-496 ms], P<0.001). Mothers treated with β-blockers had babies born at term with lower birth weight compared with untreated women (2973±298 g versus 3470±338 g, P=0.002). In addition, the birth weight of babies born at term to treated women with QTc >500 ms was significantly lower compared with women with QTc <500 ms (2783±283 g versus 3084±256 g, P=0.029). Women with long QT syndrome with more severe phenotypes have a higher incidence of fetal death. Maternal QTc is longer in pregnancies that result in fetal loss, and the birth weight of babies born to patients taking β-blockers with a QTc >500 ms is lower, suggesting that patients with more marked phenotype may experience worse fetal outcomes.


Proteomic analysis of apoplastic fluid of Coffea arabica leaves highlights novel biomarkers for resistance against Hemileia vastatrix.
A proteomic analysis of the apoplastic fluid (APF) of coffee leaves was conducted to investigate the cellular processes associated with incompatible (resistant) and compatible (susceptible) Coffea arabica-Hemileia vastatrix interactions, during the 24-96 hai period. The APF proteins were extracted by leaf vacuum infiltration and protein profiles were obtained by 2-DE. The comparative analysis of the gels revealed 210 polypeptide spots whose volume changed in abundance between samples (control, resistant and susceptible) during the 24-96 hai period. The proteins identified were involved mainly in protein degradation, cell wall metabolism and stress/defense responses, most of them being hydrolases (around 70%), particularly sugar hydrolases and peptidases/proteases. The changes in the APF proteome along the infection process revealed two distinct phases of defense responses, an initial/basal one (24-48 hai) and a late/specific one (72-96 hai). Compared to susceptibility, resistance was associated with a higher number of proteins, which was more evident in the late/specific phase. Proteins involved in the resistance response were mainly, glycohydrolases of the cell wall, serine proteases and pathogen related-like proteins (PR-proteins), suggesting that some of these proteins could be putative candidates for resistant markers of coffee to H. vastatrix. Antibodies were produced against chitinase, pectin methylesterase, serine carboxypeptidase, reticuline oxidase and subtilase and by an immunodetection assay it was observed an increase of these proteins in the resistant sample. With this methodology we have identified proteins that are candidate markers of resistance and that will be useful in coffee breeding programs to assist in the selection of cultivars with resistance to H. vastatrix.


How to utilise your time effectively during the Covid-19 pandemic.
This article was migrated. The article was marked as recommended. United Kingdom (UK) medical schools have decided to temporarily discontinue face-to-face teaching and clinical placements, due to the Covid-19 pandemic. This has meant that medical students across the country are to study remotely and having no exams for a long period of time can seem strange to a group of people who are continuously assessed. As a current fourth-year medical student at the University of Exeter and a future medical practitioner, it is nevertheless important to appreciate that doctors have a duty of keeping their knowledge and skills up to date (GMC, 2019). This article will highlight the key ways medical students can spend their time productively during lockdown.


The physiology and pathogenicity of Mycobacterium tuberculosis grown under controlled conditions in a defined medium.
A chemically-defined culture medium was developed which supported batch growth of Mycobacterium tuberculosis, strain H37Rv, at a minimum doubling time of 14.7 h. This medium also facilitated chemostat culture of M. tuberculosis at a constant doubling time of 24 h. Chemostat growth was optimized at a dissolved oxygen tension of 20% (v/v) and 0.2% (v/v) Tween-80. Chemostat cultures were dispersed suspensions of single bacilli (1.5-3 microm long), or small aggregates, at a mean density of log10 8.3 cfu ml-1. A limited number of amino acids was utilized (alanine, asparagine, aspartate and serine were depleted by >50%; glycine, arginine, isoleucine, leucine and phenylalanine, by approximately 40%). Chemostat-grown cells were pathogenic in aerosol-infected guinea pigs, producing disseminated infection similar to that caused by plate-grown cells. Cells from chemostat culture were significantly more invasive for J774A.1 mouse macrophages than agar- or batch-grown cells. This study demonstrates the suitability of chemostat culture for the growth of pathogenic mycobacteria in a defined physiological state with potential applications for the controlled production of mycobacterial components for therapeutic and vaccine applications.


"A Labour of Love": Active Lifestyle Entrepreneurship (Occupational Devotion) During a Time of COVID-19.
The Novel Coronavirus (COVID-19) crisis management strategies adopted by world leaders across the globe in 2020 impacted the work-life balance of billions of people. Entire populations were forced to stay at home and maintain a safe distance from family members, friends, colleagues, and customers. Occupational devotion is defined as a feeling of strong, positive attachment to a form of self-enhancing employment, where achievement and fulfillment are high, and the core activity has such intense appeal that the line between this work and leisure is virtually erased. Although it is not a new concept, this area of the serious leisure perspective has been largely overlooked by scholars observing the world of sport events and entrepreneurship. Using Creative Analytical Practice (CAP), a post-qualitative methodology, we present the personal narrative of a New Zealand-based active lifestyle entrepreneur who, as a result of a nationwide COVID19 lockdown, was forced to re-assess his long-established occupational devotion. Our co-constructed story offers an emotive insight into the personal cost and consequences of finding yourself living in a lockdown.


Opioid-related bowel dysfunction: prevalence and identification of predictive factors in a large sample of Italian patients on chronic treatment.
Opioid-bowel dysfunction (OBD) is a broad range of symptoms potentially associated with opioid therapy. This prospective, multicentric study assesses the prevalence of OBD in patients on analgesic therapy for the treatment of pain from any cause and identifies the factors associated with the onset of this side effect. Consecutive patients aged > 18 years, on analgesic treatment with opioids, non-steroidal anti-inflammatory drugs (NSAIDs) or other therapies for chronic pain of any aetiology were included in the study. The association of OBD with gender, age, pain aetiology and analgesic treatment was analyzed by multivariate analysis and logistic analysis. In total, 2324 patients were included in the study. The prevalence of OBD symptoms was 63.5%, despite that the wide majority of patients (89.5%) were receiving laxatives. OBD symptoms were judged as directly correlated with analgesic therapy in 85.1% of cases. The highest prevalence of constipation was reported with morphine, whereas the lowest was observed in patients on oxycodone CR and buprenorphine TTS. Statistical analysis showed that patients on opioids have a higher likelihood of experiencing OBD symptoms than those on NSAIDs or other treatments (66.2% vs 37.0%), and this probability is even higher in those with cancer-related pain (69.3%). Female gender and age > 70 years also appeared as risk factors. The logistic analysis indicated that cancer-related pain, increased age and the use of fentanyl are positive predictors of the presence of OBD, whereas the administration of oxycodone CR was associated with a decreased incidence of these symptoms. Even with the limitation of any observational experience, this study suggests, for the first time, the existence of some factors predictive of the onset of OBD symptoms in patients on analgesic treatment. Moreover, different opioids seem to be associated with a different risk of experiencing these symptoms.


A comparison of more and less aggressive bone debridement protocols for the treatment of open supracondylar femur fractures.
This study compared results of aggressive and nonaggressive debridement protocols for the treatment of high-energy, open supracondylar femur fractures after the primary procedure, with respect to the requirement for secondary bone grafting procedures, and deep infection. Retrospective review. Level I and level II trauma centers. Twenty-nine consecutive patients with high-grade, open (Gustilo types II and III) supracondylar femur fractures (OTA/AO 33A and C) treated with debridement and locked plating. Surgeons at 2 different level I trauma centers had different debridement protocols for open supracondylar femur fractures. One center used a more aggressive (MA) protocol in their patients (n = 17) that included removal of all devitalized bone and placement of antibiotic cement spacers to fill large segmental defects. The other center used a less aggressive (LA) protocol in their patients (n = 12) that included debridement of grossly contaminated bone with retention of other bone fragments and no use of antibiotic cement spacers. All other aspects of the treatment protocol at the 2 centers were similar: definitive fixation with locked plates in all cases, IV antibiotics were used until definitive wound closure, and weight bearing was advanced upon clinical and radiographic evidence of fracture healing. Healing after the primary procedure, requirement for secondary bone grafting procedures, and the presence of deep infection. Demographics were similar between included patients at each center with regard to age, gender, rate of open fractures, open fracture classification, mechanism, and smoking (P > 0.05). Patients at the MA center were more often diabetic (P < 0.05). Cement spacers to fill segmental defects were used more often after MA debridement (35% vs. 0%, P < 0.006), and more patients had a plan for staged bone grafting after MA debridement (71% vs. 8%, P < 0.006). Healing after the index fixation procedure occurred more often after LA debridement (92% vs. 35%, P < 0.003). There was no difference in infection rate between the 2 protocols: 25% with the LA protocol and 18% with the MA protocol (P = 0.63). All patients in both groups eventually healed and were without evidence of infection at an average of 1.8 years of follow-up. The degree to which bone should be debrided after a high-energy, high-grade, open supracondylar femur fracture is a matter of surgeon judgment and falls along a continuous spectrum. Based on the results of the current study, the theoretic trade-off between infection risk and osseous healing potential seems to favor an LA approach toward bone debridement in the initial treatment. Therapeutic level III.


The Katayama syndrome in Saudis.
Five Saudi boys visited an endemic area of schistosomiasis and developed 'swimmers itch' after swimming for the first time in infected ponds. After 4-6 weeks, they were admitted to hospital with fever and other symptoms. They were diagnosed as exhibiting Katayama syndrome because of marked eosinophilia and because the faeces showed Schistosoma mansoni eggs. On admission, schistosomal serological tests showed evidence of exposure in three patients. Four patients were treated with praziquantel, and the fifth was given oxamniquine. Following 3-6 days (mean 4.8 days) of treatment, they became asymptomatic. The eosinophilia decreased, liver functions improved and were normal 3 months later. Evidence is presented that early treatment of Katayama syndrome with anti-schistosomal drugs will alter the course of the acute illness and will halt the progress of the disease.


Feasibility study of automated framework for estimating lung tumor locations for target-based patient positioning in stereotactic body radiotherapy.
To investigate the feasibility of an automated framework for estimating the lung tumor locations for tumor-based patient positioning with megavolt-cone-beam computed tomography (MV-CBCT) during stereotactic body radiotherapy (SBRT). A lung screening phantom and ten lung cancer cases with solid lung tumors, who were treated with SBRT, were employed to this study. The locations of tumors in MV-CBCT images were estimated using a tumor-template matching technique between a tumor template and the MV-CBCT. Tumor templates were produced by cropping the gross tumor volume (GTV) regions, which were enhanced by a Sobel filter or a blob structure enhancement (BSE) filter. Reference tumor locations (grand truth) were determined based on a consensus between a radiation oncologist and a medical physicist. According to the results of the phantom study, the average Euclidean distances of the location errors in the original, Sobel-filtered, and BSE-filtered images were 2.0 ± 4.1 mm, 12.8 ± 9.4 mm, and 0.4 ± 0.5 mm, respectively. For clinical cases, these were 3.4 ± 7.1 mm, 7.2 ± 11.6 mm, and 1.6 ± 1.2 mm, respectively. The feasibility study suggests that our proposed framework based on the BSE filter may be a useful tool for tumor-based patient positioning in SBRT.


Glucose tolerance and insulin action in healthy centenarians.
Advancing age has been found to be associated with a decline in insulin action. Nevertheless, no study has been conducted in healthy centenarians. Our study investigates glucose tolerance and insulin action in centenarians. Fifty-two subjects were enrolled. The subjects were divided in three groups as follows: 1) adults (< 50 yr; n = 20);2) aged subjects (> 75 yr; n = 22); and 3) centenarians (> 100 yr; n = 14). Body composition was studied by bioimpedance analysis. In all subjects, an oral glucose tolerance test and euglycemic glucose clamp were performed. Centenarians have a lower fat-free mass (FFM) than aged subjects and adults, whereas fasting plasma glucose, triglycerides, free fatty acids, urea, and creatinine were not different in the groups studies. Centenarians had a 2-h plasma glucose concentration (6.0 +/- 0.2 mmol/l) that was lower than that in aged subjects (6.6 +/- 0.5 mmol/l, P < 0.05) but not different from adults [6.4 +/- 0.4 mmol/l, P = not significant (NS)]. During the clamp, plasma glucose and insulin concentrations were similar in the three groups. In these conditions, centenarians had a whole body glucose disposal (34.1 +/- 0.6 mumol.kg FFM-1.min 1) that was greater than that in aged subjects (23.3 +/- 0.5 mumol.kg FFM-1.min-1 P < 0.01) but not different from adults (34.6 +/- 0.5 mumol/kg x min, P = NS). In conclusion, our study demonstrates that centenarians compared with aged subjects had a preserved glucose tolerance and insulin action.


Discovery and characterization of inhibitors of human palmitoyl acyltransferases.
The covalent attachment of palmitate to specific proteins by the action of palmitoyl acyltransferases (PAT) plays critical roles in the biological activities of several oncoproteins. Two PAT activities are expressed by human cells: type 1 PATs that modify the farnesyl-dependent palmitoylation motif found in H- and N-Ras, and type 2 PATs that modify the myristoyl-dependent palmitoylation motif found in the Src family of tyrosine kinases. We have previously shown that the type 1 PAT HIP14 causes cellular transformation. In the current study, we show that mRNA encoding HIP14 is up-regulated in a number of types of human tumors. To assess the potential of HIP14 and other PATs as targets for new anticancer drugs, we developed three cell-based assays suitable for high-throughput screening to identify inhibitors of these enzymes. Using these screens, five chemotypes, with activity toward either type 1 or type 2 PAT activity, were identified. The activity of the hits were confirmed using assays that quantify the in vitro inhibition of PAT activity, as well as a cell-based assay that determines the abilities of the compounds to prevent the localization of palmitoylated green fluorescent proteins to the plasma membrane. Representative compounds from each chemotype showed broad antiproliferative activity toward a panel of human tumor cell lines and inhibited the growth of tumors in vivo. Together, these data show that PATs, and HIP14 in particular, are interesting new targets for anticancer compounds, and that small molecules with such activity can be identified by high-throughput screening.


Room temperature strong coupling in a semiconductor microcavity with embedded AlGaAs quantum wells designed for polariton lasing.
We report a systematic study of the temperature and excitation density behavior of an AlAs/AlGaAs, vertically emitting microcavity with embedded ternary Al0.20Ga0.80As/AlAs quantum wells in the strong coupling regime. Temperature-dependent photoluminescence measurements of the bare quantum wells indicate a crossover from the type-II indirect to the type-I direct transition. The resulting mixing of quantum well and barrier ground states in the conduction band leads to an estimated exciton binding energy systematically exceeding 25 meV. The formation of exciton-polaritons is evidenced in our quantum well microcavity via reflection measurements with Rabi splittings ranging from (13.93 ± 0.15) meV at low temperature (30 K) to (8.58 ± 0.40) meV at room temperature (300 K). Furthermore, the feasibility of polariton laser operation is demonstrated under non-resonant optical excitation conditions at 20 K and emission around 1.835 eV.


Audit to optimize antibiotics use in neonatal septicemia.
To assess appropriate antibiotics use in neonatal sepsis and to highlight the need for developing an Antibiotic stewardship program at local levels. A clinical audit was conducted in the neonatal ward of the tertiary care hospital of Lahore for one year from May 2019 to May 2020. Reports of blood culture and drugs susceptibility were gathered from the microbiology department, and clinical records were evaluated about the choice of the antimicrobials, dosage, frequency, and clinical prognosis. The statistics were applied using SPSS software. Eighty five neonates with the mean age of five days were treated in tertiary care hospital for septicemia. Every patient received more than one antibiotic empirically. The most prescribed drug combination (90.6%) was Cefotaxime and Amikacin. Optimum antibiotics dose was prescribed in only 70.2% of cases. Blood isolates showed gram-negative bacilli in 69 (81.2%) cases, gram positive cocci in 14 (16.5%) cases, two (2.3%) culture susceptibility reports showed growth of candida. Gram negative organisms were most susceptible to Imipenem (54%), Piperacillin-Tazobactam (48%) and Gentamicin (48%). Gram-positive organisms showed the most susceptibility to Vancomycin (100%), Amikacin (92%), and Co-amoxiclav (85%). Meropenem (39%), Linezolid (28%), and Vancomycin (27%) were the most commonly given alternate antibiotics. All the patients (n=10, 11.8%) whose culture sensitivity reporting showed susceptibility to empirical therapy survived. Due to poor availability of latest data about local antibacterial resistance pattern and lack of knowledge among pediatricians about latest antibiotic prescribing protocols, many inconsistencies were noted in the use of antibiotics in neonatal sepsis which resulted in a poor outcome hence, reflecting in international key health indicators (neonatal mortality rate) of country. Concerning the change in the resistance pattern of microorganisms to antimicrobials, it is high time to collect local data about antibacterial susceptibility and develop an antibiotic stewardship program to stop inappropriate use of antibiotics.


High-Intensity Care in the End-of-Life Phase of Castration-Resistant Prostate Cancer Patients: Results from the Dutch CAPRI-Registry.
Background: Intensive end-of-life care (i.e., the overuse of treatments and hospital resources in the last months of life), is undesirable since it has a minimal clinical benefit with a substantial financial burden. The aim was to investigate the care in the last three months of life (end-of-life [EOL]) in castration-resistant prostate cancer (CRPC). Methods: Castration-resistant prostate cancer registry (CAPRI) is an investigator-initiated, observational multicenter cohort study in 20 hospitals retrospectively including patients diagnosed with CRPC between 2010 and 2016. High-intensity care was defined as the initiation of life-prolonging drugs (LPDs) in the last month, continuation of LPD in last 14 days, >1 admission, admission duration ≥14 days, and/or intensive care admission in last three months of life. Descriptive and binary logistic regression analyses were performed. Results: High-intensity care was experienced by 41% of 2429 patients in the EOL period. Multivariable analysis showed that age (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.97-0.99), performance status (OR 0.57, 95% CI 0.33-0.97), time from CRPC to EOL (OR 0.98, 95% CI 0.97-0.98), referral to a medical oncologist (OR 1.99, 95% CI 1.55-2.55), prior LPD treatment (>1 line OR 1.72, 95% CI 1.31-2.28), and opioid use (OR 1.45, 95% CI 1.08-1.95) were significantly associated with high-intensity care. Conclusions: High-intensity care in EOL is not easily justifiable due to high economic cost and little effect on life span, but further research is awaited to give insight in the effect on patients' and their caregivers' quality of life.


Decreased plasma membrane expression of striatal dopamine transporter in aging.
Aging in rodents, monkeys, and man is correlated with a reduction in dopamine transporter (DAT) ligand binding and DAT function. Using Western blot techniques, we investigated whether the source of these age-related changes in DAT was correlated with decreases in DAT protein levels in the striatum, substantia nigra (SN), nucleus accumbens (NAc), and ventral tegmental area (VTA) of 6, 18, and 24-month-old male Fischer 344 rats. The relative levels of tyrosine hydroxylase (TH) were also determined in each region. In the striatum, we also assessed [3H]-DA uptake and DAT plasma membrane expression using a membrane-impermeant biotin analog in crude synaptosomes prepared from these age groups. There was no significant age-related difference in DAT immunoreactivity per total protein or per total TH in striatum, NAc, SN, or VTA. Significant age-related changes in TH were only seen in the VTA of the 24-month-old rats (approximately 60% decrease). However, [3H]-DA uptake and DAT protein recovered in the biotinylated fraction in 24-month-old rats were significantly decreased (approximately 30%) compared to 6-month-old animals in the striatal synaptosomes. These data suggest that age-related decreases in striatal DAT function and ligand binding are related to a decrease in plasma membrane expression of DAT and not a decrease in the steady-state levels of DAT protein or loss of dopaminergic neuropil.


A microtiter peg lid with ziggurat geometry for medium-throughput antibiotic testing and in situ imaging of biofilms.
Bacteria biofilm responses to disinfectants and antibiotics are quantified and observed using multiple methods, though microscopy, particularly confocal laser scanning microscopy (CLSM) is preferred due to speed, a reduction in user error, and in situ analysis. CLSM can resolve biological and spatial heterogeneity of biofilms in 3D with limited throughput. The microplate peg-lid-based assay, described in ASTM E2799-22, is a medium-throughput method for testing biofilms but does not permit in situ imaging. Breaking off the peg, as recommended by the manufacturer, risks sample damage, and is limited to easily accessible pegs. Here we report modifications to the peg optimized for in situ visualization and visualization of all pegs. We report similar antibiotic challenge recovery via colony formation following the ASTM E2799-22 protocol and in situ imaging. We report novel quantifiable effects of antibiotics on biofilm morphologies, specifically biofilm streamers. The new design bridges the MBEC® assays design that selects for biofilm phenotypes with in situ imaging needs.


Roles of lysophosphatidic acid (LPA) receptor-2 (LPA2) in the regulation of cellular responses induced by X-ray irradiation and hydrogen peroxide in pancreatic cancer cells.
Lysophosphatidic acid (LPA) receptor-mediated signaling regulates various biological functions in cancer cells. This study aimed to evaluate the roles of LPA receptor-2 (LPA2) in cellular responses induced by X-ray irradiation in pancreatic cancer PANC-1 cells. Since X-ray irradiation generates reactive oxygen species (ROS), PANC-1 cells were treated with hydrogen peroxide (H2O2). H2O2 is a key member of ROS. To investigate the cell survival rate to X-ray irradiation, PANC-1 cells were irradiated with X-rays (2.5-15 Gy). LPAR2 expression levels were measured by quantitative real-time RT-PCR analysis. The effects of LPA2 on the cell survival and motility were evaluated using LPA2 knockdown cells. To establish H2O2 treated cells, PANC-1 cells were cultured in 10% FBS-DMEM with H2O2 (30 µM) for 2 weeks. The cell motility and survival rate to cisplatin (CDDP) of H2O2 treated cells were examined. LPAR2 expression was significantly increased in PANC-1 cells irradiated with X-rays. PANC-1 cell motility was markedly decreased by X-ray irradiation. The reduced cell motility activity by X-ray irradiation was enhanced by LPA2 knockdown. The cell survival to X-ray irradiation was elevated in PANC-1 cells treated with GRI-977143 (LPA2 agonist) and suppressed by LPA2 knockdown. On the other hand, LPAR2 expression was markedly higher in H2O2 treated cells than in H2O2 untreated cells. H2O2 treated cells showed the high cell survival to CDDP in comparison with H2O2 untreated cells. GRI-977143 increased the cell survival to CDDP of H2O2 treated cells, while LPA2 knockdown suppressed. The present results suggest that the activation of LPA2-mediated signaling plays an important role in the modulation of cellular functions induced by X-ray irradiation and H2O2 in PANC-1 cells.


Apolipoprotein B gene polymorphisms in Taiwanese ischemic stroke patients.
We analyzed the AluI restriction fragment length polymorphism (RFLP) of the apolipoprotein B (apoB) gene to determine the association between AluI allelic distribution and the occurrence of ischemic stroke in Taiwan. A total of 44 healthy volunteers and 159 ischemic stroke patients were included in the study. The allele frequency of AluI was very similar in the two groups, 0.87 in the patient group and 0.89 in the control group, for the major allele A-. The distribution of A-/A-, A-/A+, and A+/A+ genotypes of the patients was not significantly different from that of the controls. Among ischemic stroke patients, the A+ allele of the AluI restriction site was significantly associated with elevated apoB levels. The results of this study suggest that the presence of the rare AluI RFLP may contribute to an elevated plasma apoB level, which is a known risk factor for ischemic stroke.


The aspect ratio effect on the cytotoxicity of inert nano-particles flips depending on particle thickness, and is one of the reasons for the literature inconsistency.
The interaction of inert nano-particles with cells has significant effect on the potential cytotoxicity of the particles. The role of particle aspect ratio in the interaction with cells was largely studied in the literature; however non consistent conclusions were obtained. In the present study a detailed physical model is presented as well as a set of experimental work and a scan of literature data. The aim was to investigate the role of particle size and aspect ratio in cell uptake, and to examine possible sources of the literature inconsistency. Cells which provide the first line of contact with particles in the human body were incubated with seven types of particles. These included spherical and rod gold nanoparticles, as well as larger spherical polystyrene particles in various sizes. We stress that in order to achieve comparative insight careful attention needs to be given to the experimental conditions and to the data analysis. Furthermore, our physical model shows that conclusions regarding the role of aspect ratio in NP uptake largely depend on the radius of the particles. The aspect ratio cannot be regarded as a sole geometrical parameter which determines the interaction of inert nano-particles with cells. When discussing particles larger than 10 nm (for which passive diffusion is irrelevant), the effect of the aspect ratio flips depending on the particle thickness. For particles thicker than ∼35 nm, the longer they are the more toxic they would be, however this trend opposes for thinner NPs, where larger aspect ratio results in reduced uptake and toxicity. Therefore, rod non-functionalized particles whose thickness is between 15 and 30 nm, and are relatively long, are expected to be the safest, with minimal cytotoxicity.


Progressive supranuclear palsy. Report of 14 cases with special reference to unusual features.
The clinical features and course of 14 patients with progressive supranuclear palsy (PSP) were analysed. PSP formed 2.3 percent of the parkinsonian population. Blepharospasm, hypersomnia, athetosis, action dystonia, action myoclonus and family history of dementia were the unusual features. Half of the patients had dementia at presentation. Drug therapy was uniformly disappointing. The mean duration from onset to death in 4 patients who died was 4.5 years. The histopathological features in a patient with the disease for one year and who died of acute myocardial infarction showed moderately severe changes characteristic of the disease.


An enhanced automatic algorithm for estimation of respiratory variations in arterial pulse pressure during regions of abrupt hemodynamic changes.
We describe an improved automatic algorithm to estimate the pulse-pressure-variation (PPV) index from arterial blood pressure (ABP) signals. This enhanced algorithm enables for PPV estimation during periods of abrupt hemodynamic changes. Numerous studies have shown PPV to be one of most specific and sensitive predictors of fluid responsiveness in mechanically ventilated patients. The algorithm uses a beat detection algorithm to perform beat segmentation, kernel smoothers for envelope detection, and a suboptimal Kalman filter for PPV estimation and artifact removal. In this paper, we provide a detailed description of the algorithm and assess its performance on over 40 h of ABP signals obtained from 18 mechanically ventilated crossbred Yorkshire swine. The subjects underwent grade V liver injury after splenectomy, while receiving mechanical ventilation, and general anesthesia with isoflurane. All subjects in the database underwent a period of abrupt hemodynamic change after an induced grade V liver injury involving severe blood loss resulting in hemorrhagic shock, followed by fluid resuscitation with either 0.9% normal saline or lactated ringers solutions. Trained experts manually calculated PPV at five time instances during the period of abrupt hemodynamic changes. We report validation results comparing the proposed algorithm against a commercial system (pulse contour cardiac output, PICCO) with continuous PPV monitoring capabilities. Both systems were assessed during periods of abrupt hemodynamic changes against the "gold-standard" PPV, calculated and manually annotated by experts. Our results indicate that the proposed algorithm performs considerably better than the PICCO system during regions of abrupt hemodynamic changes.


PI3K pathway activation provides a novel therapeutic target for pediatric ependymoma and is an independent marker of progression-free survival.
Currently, there are few effective adjuvant therapies for pediatric ependymoma outside confocal radiation, and prognosis remains poor. The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly activated pathways in cancer. PI3Ks transduce signals from growth factors and cytokines, resulting in the phosphorylation and activation of AKT, which in turn induces changes in cell growth, proliferation, and apoptosis. PI3K pathway status was analyzed in ependymoma using gene expression data and immunohistochemical analysis of phosphorylated AKT (P-AKT). The effect of the PI3K pathway on cell proliferation was investigated by immunohistochemical analysis of cyclin D1 and Ki67, plus in vitro functional analysis. To identify a potential mechanism of PI3K pathway activation, PTEN protein expression and the mutation status of PI3K catalytic subunit α-isoform gene (PIK3CA) was investigated. Genes in the pathway displayed significantly higher expression in supratentorial than in posterior fossa and spinal ependymomas. P-AKT protein expression, indicating pathway activation, was seen in 72% of tumors (n = 169) and P-AKT expression was found to be an independent marker of a poorer progression-free survival. A significant association between PI3K pathway activation and cell proliferation was identified, suggesting that pathway activation was influencing this process. PTEN protein loss was not associated with P-AKT staining and no mutations were identified in PIK3CA. Our results suggest that the PI3K pathway could act as a biomarker, not only identifying patients with a worse prognosis but also those that could be treated with therapies targeted against the pathway, a strategy potentially effective in a high percentage of ependymoma patients.


Intracranial EEG in predicting surgical outcome in frontal lobe epilepsy.
Surgery in frontal lobe epilepsy (FLE) has a worse prognosis regarding seizure freedom than anterior lobectomy in temporal lobe epilepsy. The current study aimed to assess whether intracranial interictal and ictal EEG findings in addition to clinical and scalp EEG data help to predict outcome in a series of patients who needed invasive recording for FLE surgery. Patients with FLE who had resective surgery after chronic intracranial EEG recording were included. Outcome predictors were compared in patients with seizure freedom (group 1) and those with recurrent seizures (group 2) at 19-24 months after surgery. Twenty-five patients (16 female) were included in this study. Mean age of patients at epilepsy surgery was 32.3 ± 15.6 years (range 12-70); mean duration of epilepsy was 16.9 ± 13.4 years (range 1-48). In each outcome group, magnetic resonance imaging revealed frontal lobe lesions in three patients. Fifteen patients (60%) were seizure-free (Engel class 1), 10 patients (40%) continued to have seizures (two were class II, three were class III, and five were class IV). Lack of seizure freedom was seen more often in patients with epilepsy surgery on the left frontal lobe (group 1, 13%; group 2, 70%; p = 0.009) and on the dominant (27%; 70%; p = 0.049) hemisphere as well as in patients without aura (29%; 80%; p = 0.036), whereas sex, age at surgery, duration of epilepsy, and presence of an MRI lesion in the frontal lobe or extrafrontal structures were not different between groups. Electroencephalographic characteristics associated with lack of seizure freedom included presence of interictal epileptiform discharges in scalp recordings (31%; 90%; p = 0.01). Detailed analysis of intracranial EEG revealed widespread (>2 cm) (13%; 70%; p = 0.01) in contrast to focal seizure onset as well as shorter latency to onset of seizure spread (5.8 ± 6.1 s; 1.5 ± 2.3 s; p = 0.016) and to ictal involvement of brain structures beyond the frontal lobe (23.5 ± 22.4 s; 5.8 ± 5.4 s; p = 0.025) in patients without seizure freedom. The distribution of ictal onset patterns was similar in both groups, and fast rhythmic activity in the beta to gamma range was found in 57% of seizure-free patients compared to 70% of patients with recurrent seizures. Analysis of the temporal relation between first clinical alterations and EEG seizure onset did not reveal significant differences between both groups of patients. In multivariate analysis, resection in the left hemisphere (odds ratio [OR] 12.197 95% confidence interval [95% CI] 1.33-111.832; p = 0.027) and onset of seizure spread (odds ratio [OR] 0.733, 95% CI 0.549-0.978, p = 0.035) were independent predictors of ongoing seizures. Widespread epileptogenicity as indicated by rapid onset of spread of ictal activity likely explains lack of seizure freedom following frontal resective surgery. The negative prognostic effect of surgery on the left hemisphere is less clear. Future study is needed to determine if neuronal network properties in this hemisphere point to intrinsic interhemispheric differences or if neurosurgeons are restrained by proximity to eloquent cortex.


Plasticity in the Brainstem: Prenatal and Postnatal Experience Can Alter Laterodorsal Tegmental (LDT) Structure and Function.
The brainstem has traditionally been considered an area of the brain with autonomous control of mostly homeostatic functions such as heart rate, respiration, and the sleep and wakefulness state, which would preclude the necessity to exhibit the high degree of synaptic or cellular mechanisms of plasticity typical of regions of the brain responsible for flexible, executive control, such as the medial prefrontal cortex or the hippocampus. The perception that the brainstem does not share the same degree of flexibility to alter synaptic strength and/or wiring within local circuits makes intuitive sense, as it is not easy to understand how "soft wiring" would be an advantage when considering the importance of faithful and consistent performance of the homeostatic, autonomic functions that are controlled by the brainstem. However, many of the molecular and cellular requirements which underlie strengthening of synapses seen in brain regions involved in higher-level processing are present in brainstem nuclei, and recent research suggest that the view of the brainstem as "hard wired," with rigid and static connectivity and with unchanging synaptic strength, is outdated. In fact, information from studies within the last decades, including work conducted in our group, leads us to propose that the brainstem can dynamically alter synaptic proteins, and change synaptic connections in response to prenatal or postnatal stimuli, and this would likely alter functionality and output. This article reviews recent research that has provided information resulting in our revision of the view of the brainstem as static and non-changing by using as example recent information gleaned from a brainstem pontine nucleus, the laterodorsal tegmentum (LDT). The LDT has demonstrated mechanisms underlying synaptic plasticity, and plasticity has been exhibited in the postnatal LDT following exposure to drugs of abuse. Further, exposure of the brain during gestation to drugs of abuse results in alterations in development of signaling pathways in the LDT. As the LDT provides a high degree of innervation of mesoaccumbal and mesocortical circuits involved in salience, as well as thalamocortical circuits involved in control of arousal and orientation, changes in synaptic strength would be expected to alter output, which would significantly impact behavioral state, motivated behavior and directed attention. Further, alterations in developmental trajectory within the LDT following prenatal exposure to drugs of abuse would be expected to impact on later life expression of motivation and arousal.


Discovery of 8-Trifluoromethyl-3-cyclopropylmethyl-7-[(4-(2,4-difluorophenyl)-1-piperazinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine (JNJ-46356479), a Selective and Orally Bioavailable mGlu2 Receptor Positive Allosteric Modulator (PAM).
Positive allosteric modulators of the metabotropic glutamate 2 receptor have generated great interest in the past decade. There is mounting evidence of their potential as therapeutic agents in the treatment of multiple central nervous system disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs. However, finding compounds with the optimal combination of in vitro potency and good druglike properties has remained elusive, in part because of the hydrophobic nature of the allosteric binding site. Herein, we report on the lead optimization process to overcome the poor solubility inherent to the advanced lead 6. Initial prototypes already showed significant improvements in solubility while retaining good functional activity but displayed new liabilities associated with metabolism and hERG inhibition. Subsequent subtle modifications efficiently addressed those issues leading to the identification of compound 27 (JNJ-46356479). This new lead represents a more balanced profile that offers a significant improvement on the druglike attributes compared to previously reported leads.


The body of knowledge: On the role of the living body in grounding embodied cognition.
Embodied cognition is a hot topic in both cognitive science and AI, despite the fact that there still is relatively little consensus regarding what exactly constitutes 'embodiment'. While most embodied AI and cognitive robotics research views the body as the physical/sensorimotor interface that allows to ground computational cognitive processes in sensorimotor interactions with the environment, more biologically-based notions of embodied cognition emphasize the fundamental role that the living body - and more specifically its homeostatic/allostatic self-regulation - plays in grounding both sensorimotor interactions and embodied cognitive processes. Adopting the latter position - a multi-tiered affectively embodied view of cognition in living systems - it is further argued that modeling organisms as layered networks of bodily self-regulation mechanisms can make significant contributions to our scientific understanding of embodied cognition.


[A case of ophthalmic artery obstruction following autologous fat injection in the glabellar area].
We report a case of blindness due to occlusion of the ophthalmic artery following injection of autologous fat into the glabellar region for cosmetic surgery. A 30-year-old woman underwent aspiration of autologous fat from her gluteal region and injection of it into her breasts, nose, and glabellar area. At the time of injection into the glabellar area, she suffered nausea, pain, and visual loss in her right eye. She consulted an ophthalmologist. The first examination revealed that her right eye had loss of light perception, widespread retinal whitening, and obstruction of the retinal vessels of the fundus. It was suspected that she had occlusion of the central retinal artery, and drip infusion of urokinase and hyperbaric oxygen therapy were implemented. Since no improvement was seen, she was referred to Shinshu University hospital. Fundoscopy showed remarkable edema of the entire right retina and whitened retinal vessels. Fluorescein angiography showed no filling of the right retinal arterioles. Cerebral angiography showed complete obstruction of the right ophthalmic artery at its bifurcation. Subsequent administration of urokinase and corticosteroid had no effect. We considered that occlusion of the ophthalmic artery happened when autologous fat was injected into the glabellar area.


Trajectories of Multidimensional Caregiver Burden in Chinese Informal Caregivers for Dementia: Evidence from Exploratory and Confirmatory Factor Analysis of the Zarit Burden Interview.
Despite its popularity, the latent structure of 22-item Zarit Burden Interview (ZBI) remains unclear. There has been no study exploring how caregiver multidimensional burden changed. The aim of the work was to validate the latent structure of ZBI and to investigate how multidimensional burden evolves with increasing global burden. We studied 1,132 dyads of dementia patients and their informal caregivers. The caregivers completed the ZBI and a questionnaire regarding caregiving. The total sample was randomly split into two equal subsamples. Exploratory factor analysis (EFA) was performed in the first subsample. In the second subsample, confirmatory factor analysis (CFA) was conducted to validate models generated from EFA. The mean of weighted factor score was calculated to assess the change of dimension burden against the increasing ZBI total score. The result of EFA and CFA supported that a five-factor structure, including role strain, personal strain, incompetency, dependency, and guilt, had the best goodness-of-fit. The trajectories of multidimensional burden suggested that three different dimensions (guilt, role strain and personal strain) became the main subtype of burden in sequence as the ZBI total score increased from mild to moderate. Factor dependency contributed prominently to the total burden in severe stage. The five-factor ZBI is a psychometrically robust measure for assessing multidimensional burden in Chinese caregivers. The changes of multidimensional burden have deepened our understanding of the psychological characteristics of caregiving beyond a single total score and may be useful for developing interventions to reduce caregiver burden.


Biodiesel production using microbial lipids derived from food waste discarded by catering services.
Biodiesel production using microbial oil derived from food waste discarded by the hospilatity sector could provide a sustainable replacement for diesel fuel. Discarded potato peels were used in solid-state fermentations of Aspergillus awamori for the production of glucoamylase (30 U/g) and protease (50 U/g). Hospitality food waste hydrolysis led to 98% (w/w) starch to glucose conversion yields. Crude hydrolyzates were used in shake flask fermentations with the oleaginous yeast Rhodosporidium toruloides Y-27012 leading to 32.9 g/L total dry weight (TDW) with 36.4% (w/w) intracellular lipid content. Fed-bath bioreactor cultures resulted in TDW of 53.9 g/L and lipid concentration of 26.7 g/L. Principal component analysis showed a fatty acid profile similar to soybean oil and solid food waste oil. Microbial oil was transesterified into biodiesel with satisfactory performance considering the European standard EN 14214. This work demonstrated that valorization of food waste for biodiesel production is feasible.


Transvaginal ultrasonography combined with color velocity imaging and pulsed Doppler to detect residual trophoblastic tissue.
The value of transvaginal B-mode ultrasonography combined with color velocity imaging and pulsed Doppler to detect retained trophoblastic tissue was evaluated prospectively in a series of 40 patients with postpartum (n = 15) or postabortion (n = 25) bleeding. Color velocity imaging was used to identify color-coded blood flow signals within myometrium and/or endometrium. Flow was subjectively quantified as absent, scanty or abundant. Pulsed Doppler was used to assess blood flow impedance by calculating the resistance index. The presence of abundant flow with a lowest resistance index of less than 0.45 was considered as suspicious of residual trophoblastic tissue. Twenty-two (55%) out of the 40 patients underwent dilatation and curettage and chorionic villi were demonstrated in 15 of these. Eighteen (45%) patients were managed conservatively. None of these patients suffered complications or needed readmission for curettage, and all of them were considered as not having retained tissue. On color pulsed Doppler ultrasound examination, 15 patients had suspected retained tissue; all of these underwent curettage and residual trophoblast was found in 14 (93.3%). Out of 25 patients considered as having no residual tissue on color pulsed Doppler ultrasound examination, seven underwent curettage and chorionic villi were found in one patient (false-negative rate 6.7%) All patients managed conservatively had an unsuspicious scan. We concluded that transvaginal ultrasonography combined with color velocity imaging and pulsed Doppler could be useful to detect retained trophoblastic tissue and to select patients suitable for conservative management.


Do emotion regulation difficulties in depression extend to social context? Everyday interpersonal emotion regulation in current and remitted major depressive disorder.
Individuals with major depressive disorder (MDD) have difficulties regulating emotion on their own. As people also use social resources to regulate emotion (i.e., interpersonal emotion regulation [IER]), we examined whether these difficulties extend to IER in current and remitted MDD compared to those with no psychiatric disorders (i.e., controls). Adults with current MDD (n = 48), remitted MDD (n = 80), and controls (n = 87) assessed via diagnostic interviewing completed 2-week experience sampling, reporting on how frequently (IER frequency), from whom (sharing partners), and why (IER goals) they sought IER; how the sharing partners responded (sharing partner's extrinsic IER strategies and warmth); and how their feelings about the problem and the sharing partner changed following IER (IER outcomes). Using multilevel modeling, the current-MDD group did not differ from controls in IER frequency and sharing partners, but the current-MDD group demonstrated a more mixed (albeit generally adaptive) profile of received IER strategies and benefited similarly or more from certain IER strategies than the other two groups, suggesting that IER may be a promising avenue for effective emotion regulation in current MDD. The remitted-MDD group sought IER most frequently and demonstrated the most adaptive profile of received IER strategies, and they and the current-MDD group reported seeking more types of IER goals than controls. People with remitted MDD seem highly motivated to pursue IER support and their pursuit takes place in particularly supportive social contexts. Research is needed to examine mechanisms driving these group differences and how IER predicts the course of MDD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Characterization of beef transcripts correlated with tenderness and moisture.
To identify transcriptional markers for beef traits related to meat tenderness and moisture, we measured the transcriptome of the Longissimus dorsi skeletal muscle in 10 Korean native cattle (KNC). We analyzed the correlation between the beef transcriptome and measurements of four different beef traits, shear force (SF), water holding capacity (WHC), cooking loss (CL), and loin eye area (LEA). We obtained non-overlapping and unique panels of genes showing strong correlations (|r|>0.8) with SF, WHC, CL, and LEA, respectively. Functional studies of these genes indicated that SF was mainly related to energy metabolism, and LEA to rRNA processing. Interestingly, our data suggested that WHC is influenced by protein metabolism. Overall, the skeletal muscle transcriptome pointed to the importance of energy and protein metabolism in determining meat quality after the aging process. The panels of transcripts for beef traits may be useful for predicting meat tenderness and moisture.


Does obesity modify the effect of blood pressure on the risk of cardiovascular disease? A population-based cohort study of more than one million Swedish men.
Some studies have suggested that increased blood pressure has a stronger effect on the risk of cardiovascular disease (CVD) in lean persons than in obese persons, although this is not a universal finding. Given the inconsistency of this result, we tested it using a large population-based cohort data set. Systolic and diastolic blood pressures (BPs) and body mass index were measured in 1 145 758 Swedish men born between 1951 and 1976 who were in young adulthood (median age 18.2 years). During the register-based follow-up, which lasted until the end of 2006, 65 611 new CVD events took place, including 6799 myocardial infarctions and 8827 strokes. Hazard ratios (HRs) per 1-SD increase in systolic and diastolic BP were computed within established body mass index categories (underweight, normal, overweight, or obese) with Cox proportional hazards models. The strongest associations of diastolic BP with CVD (HR 1.18), myocardial infarction (HR 1.22), and stroke (HR 1.13) were observed in the obese category. For systolic BP, the strongest associations were observed in the obese category with CVD (HR 1.16) and stroke (HR 1.29) but in the overweight category with myocardial infarction (HR 1.19). We observed statistically significant interactions (P<0.0001) with body mass index for diastolic BP in relation to CVD and for systolic BP in relation to CVD and stroke. In contrast to the findings of previous studies, we observed a general increase in the magnitude of the association between blood pressure and subsequent CVD with increasing body mass index. Hypertension should not be regarded as a less serious risk factor in obese than in lean or normal-weight persons.


Network-based decoupling of local gyrification in obsessive-compulsive disorder.
Gyrification is associated with cortical maturation and closely linked to neurodevelopmental processes. Obsessive-compulsive disorder has previously been associated with neurodevelopmental risk factors. Using graph theoretical modeling we examined structural covariance patterns to assess potential disruptions in processes associated with neurodevelopment in OCD. In total 97 patients and 92 healthy controls underwent magnetic resonance imaging. Structural covariance networks based on local gyrification indices were constructed using an atlas-based parcellation scheme. Network properties were assessed using the network-based statistic as well as global and local graph theoretical measures. Correlations between gyrification and symptom severity as well as age of disease onset were examined. Network-based statistic analysis revealed one cluster with significantly decreased structural covariance in patients comprising mainly ventral brain regions (p = .041). Normalized characteristic path length was found to be impaired in patients (p = .051). On a nodal level, left middle frontal sulcus displayed a significantly decreased local clustering coefficient (p < .001). Finally, gyrification in several inferior frontal nodes significantly correlated with age of onset but not symptom severity. The decrease in a gyrification-based covariance network in OCD appears to be mostly confined to ventral areas in which gyrification starts the latest during development. This pattern may indicate that alterations taking place during development are potentially time locked to specific periods. Correlations between gyrification in inferio-frontal nodes and age of onset potentially indicate a structural trait rather than state marker for OCD. Finally, a trend in impaired global integration capabilities may point towards potentially widespread global alterations during neurodevelopment in patients.


Diagnosis and treatment of bipolar disorder in children and adolescents.
Bipolar disorder is a serious illness in children that adversely affects social, academic, emotional, and family functioning. Its prevalence in adolescents is estimated to be as high as 1%. The diagnosis of bipolar disorder in young children is often a challenge, largely because the symptoms may differ from those exhibited in late adolescence and adulthood. The occurrence of comorbid disorders such as attention-deficit/hyperactivity disorder also may complicate the diagnosis. Despite the significant severity and chronicity of this disorder in youths, very few controlled data are available to guide treatment decisions in children and adolescents. The treatment literature consists largely of open studies, case series, and case reports. Therefore, a pressing need exists for controlled trials to determine whether medications commonly used to treat the disorder in children are significantly superior to placebo, as well as to determine whether initial monotherapy or combination treatment is warranted. This article will review the epidemiology, diagnosis, course of illness, and treatment of bipolar disorder in children and adolescents.


Observations of health-care professionals sharing and contributing responsibility in paediatric caring situations.
This study aimed to identify, describe and generate concepts regarding health care professionals' information exchanges with minors and/or their parents/guardians in paediatric caring situations. The study took place at three paediatric outpatient units at a university hospital and there were 15 health care professionals involved. Using the grounded theory and the constant comparative analysis methods, the data collection and analysis was undertaken simultaneously, using participant observation, review of medical records and follow-up interviews. The main concern of the health care professionals that emerged as the core category was: sharing and contributing responsibility, interrelated with the six categories; interchanging of knowledge, relationship-creating chat, calculated confirming, encouraging, dichotomous talking and of situation related effects. This research has explored the elements of information exchange in caring situations and highlighted the interaction between the involved persons. These findings could be valuable to health care professionals in order to develop and improve their caring skills.


SelenzymeRF: updated enzyme suggestion software for unbalanced biochemical reactions.
Selenzyme is a retrobiosynthesis tool that suggests candidate enzymes for user query reactions. Enzyme suggestions are based on identical reactions, as well as similar reactions, since enzymes are often capable of promiscuous substrate binding. Selenzyme is a user-friendly, widely used web-tool for ranking enzymes based on reaction similarity and additional features, including the phylogenetic distance between the source species of the enzyme and the intended host. While Selenzyme has proved invaluable in assisting with enzyme selection for known reactions, as well as many novel or orphan reactions, weaknesses have been exposed in its ability to rank functionally related enzymes. Within this update, we introduce a new reaction similarity scoring algorithm, which is used in conjunction with the previous similarity calculation, to improve the accuracy of enzyme suggestions based on non-identical similar reactions, across a range of EC reaction classes. This allows enzymes to be suggested for reactions not found within the database, even if the reaction is unbalanced. A database update was also carried out, to ensure that reaction and enzyme knowledge remains current. This update can be accessed at http://selenzymeRF.synbiochem.co.uk/.


Fresnel light drag in a coherently driven moving medium.
We theoretically study how the phase of a light plane wave propagating in a resonant medium under electromagnetically induced transparency (EIT) is affected by the uniform motion of the medium. For cuprous oxide (Cu2O), where EIT can be implemented through a typical pump-probe configuration, the resonant probe beam experiences a phase shift (Fresnel-Fizeau effect) that may vary over a wide range of values, positive or negative, and even vanishing, due to the combined effects of the strong frequency dispersion and anisotropy both induced by the pump. The use of such a coherently driven dragging medium may improve by at least 1 order of magnitude the sensitivity at low velocity in optical drag experiments.


Hospital Readmission Penalties: Coming Soon to a Nursing Home Near You!
The Protecting Access to Medicare Act of 2014 includes provisions for hospital readmission penalties for skilled nursing facilities (SNFs) starting in 2018. This presents an opportunity for care improvement but also raises several concerns regarding quality of care. The readmission measure for SNFs is similar to the current readmission measure for hospitals mandated under the Affordable Care Act, with the exception of adjustments made for sex. Because these measures for hospitals are similar, lessons can be learned from implementation of the existing hospital readmission penalties. In addition, there are three specific concerns that the authors relate to implementing the proposed measure in SNFs. There is poor communication and care coordination between care settings, including posthospitalization and post-SNF care in the current healthcare system. Adding readmission penalties to SNF regulations may create perverse incentives for prolonged SNF stays. The evidence base for the best means of caring for individuals after a brief stay in a SNF needs enrichment. These challenges need to be addressed as part of implementation of these new hospital readmission penalties for SNFs to improve care and prevent new unintended consequences.


NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma.
Medulloblastoma (MB) is the most common malignant solid paediatric brain tumour. The standard treatment for MB is surgical resection of the tumour, radiation and chemotherapy. This therapy is associated with high morbidity and adverse side effects. Hence, more targeted and less toxic therapies are vitally needed to improve the quality of life of survivors. NPI-0052 is a novel proteasome inhibitor that irreversibly binds the 20S proteasome subunit. This compound has anti-tumour activity in metastatic solid tumours, glioblastoma and multiple myeloma with a good safety profile. Importantly, NPI-0052 has a lipophilic structure and can penetrate the blood-brain barrier, making it a suitable treatment for brain tumours. In the present study, we performed an in silico gene expression analysis to evaluate the proteasome subunit expression in MB. To evaluate the anticancer activity of NPI-0052, we used a range of MB patient-derived MB cells and cell lines. The synergistic cell death of NPI-0052 with γ-radiation was evaluated in tumour organoids derived from patient-derived MB cells. We show that high expression of proteasome subunits is a poor prognostic factor for MB patients. Also, our preclinical work demonstrated that NPI-0052 can inhibit proteasome activity and activate apoptosis in MB cells. Moreover, we observe that NPI-0052 has a synergistic apoptotic effect with γ-radiation, a component of the current MB therapy. Here, we present compelling preclinical evidence that NPI-0052 can be used as an adjuvant treatment for p53-family-expressing MB tumours.


Disrupted state transition learning as a computational marker of compulsivity.
Disorders involving compulsivity, fear, and anxiety are linked to beliefs that the world is less predictable. We lack a mechanistic explanation for how such beliefs arise. Here, we test a hypothesis that in people with compulsivity, fear, and anxiety, learning a probabilistic mapping between actions and environmental states is compromised. In Study 1 (n = 174), we designed a novel online task that isolated state transition learning from other facets of learning and planning. To determine whether this impairment is due to learning that is too fast or too slow, we estimated state transition learning rates by fitting computational models to two independent datasets, which tested learning in environments in which state transitions were either stable (Study 2: n = 1413) or changing (Study 3: n = 192). Study 1 established that individuals with higher levels of compulsivity are more likely to demonstrate an impairment in state transition learning. Preliminary evidence here linked this impairment to a common factor comprising compulsivity and fear. Studies 2 and 3 showed that compulsivity is associated with learning that is too fast when it should be slow (i.e. when state transition are stable) and too slow when it should be fast (i.e. when state transitions change). Together, these findings indicate that compulsivity is associated with a dysregulation of state transition learning, wherein the rate of learning is not well adapted to the task environment. Thus, dysregulated state transition learning might provide a key target for therapeutic intervention in compulsivity.


Odor-evoked category reactivation in human ventromedial prefrontal cortex during sleep promotes memory consolidation.
Slow-wave sleep is an optimal opportunity for memory consolidation: when encoding occurs in the presence of a sensory cue, delivery of that cue during sleep enhances retrieval of associated memories. Recent studies suggest that cues might promote consolidation by inducing neural reinstatement of cue-associated content during sleep, but direct evidence for such mechanisms is scant, and the relevant brain areas supporting these processes are poorly understood. Here, we address these gaps by combining a novel olfactory cueing paradigm with an object-location memory task and simultaneous EEG-fMRI recording in human subjects. Using pattern analysis of fMRI ensemble activity, we find that presentation of odor cues during sleep promotes reactivation of category-level information in ventromedial prefrontal cortex that significantly correlates with post-sleep memory performance. In identifying the potential mechanisms by which odor cues selectively modulate memory in the sleeping brain, these findings bring unique insights into elucidating how and what we remember.


Does psychological distress influence reporting of demands and control at work?
To investigate whether self reporting of psychological demands and control at work is as valid for psychologically distressed subjects as for subjects with psychological wellbeing. Self reported demands and control (according to the model of Karasek) were compared to expert assessments through direct observations of each subject's work conditions concerning time pressure, hindrances, qualification for work tasks, and possibility of having influence. The comparison was made between respondents reporting and not reporting psychological distress as measured by the general health questionnaire with 12 questions (GHQ-12). The sample consisted of 203 men and women in 85 occupations. No systematic differences between self reported and externally assessed working conditions for respondents reporting different levels of psychological distress were found. Over-reporting of work demands or under-reporting of work control is unlikely at the levels of psychological distress studied.


Near-infrared light triggered and separable microneedles for transdermal delivery of metformin in diabetic rats.
Near-infrared light triggered and separable microneedles (MNs) were fabricated by a unique molding method. The photothermal conversion agent (Prussian blue nanoparticles, PB NPs) and hypoglycemic drug (metformin) were embedded into the separable polycaprolactone (PCL) MNs arrowheads. These MNs arrowheads were capped on dissolving polyvinyl alcohol/polyvinyl pyrrolidone (PVA/PVP) solid supporting substrate. The as-fabricated MNs exhibited excellent photothermal conversion properties under near-infrared light (NIR) irradiation, causing the MNs arrowheads to melt due to the photothermal conversion of PB NPs. After applying on skin, the separable MNs arrowheads could be embedded in the skin due to the dissolution of supporting substrates after absorbing the interstitial fluid. When the embedded MNs arrowheads were exposed to NIR irradiation, the MNs arrowheads underwent a rapid thermal ablation from a solid to a liquid state, thus enabling the release of encapsulated metformin to be NIR modulated. They allowed on-demand control of timing and dose of the drug released. This suggests that the developed NIR-triggered and separable MNs are a promising transdermal drug delivery system that enables the patient or physician to adjust therapy precisely in an active manner, thus improving treatment efficiency and reducing side-effects.


[Correlations of lipoprotein metabolism indicators in persons with low and high cholesterol ester transport activity].
For clarifying the role of plasma cholesterol ester transfer activity (CETA) in forming hyperlipoproteinemia (HLP) and determination of high density lipoproteins cholesterol (Ch HDL) level, lipoprotein metabolism indicators were compared for individuals with high and low CETA. 257 subjects were investigated: 195 patients with different forms of hereditary HLP and individuals without HLP: 34 healthy and 28 with coronary heart disease (CHD). Lipids were determined enzymatically, apoproteins content by immunoturbodimetric and immunodiffusion methods. CETA and cholesterol esterification rate (CER) were measured through autological methods. Selected groups of patients with high and low CETA were significantly distinguished only by plasma Ch level (average Ch > 6.2 mmol/l in both groups), free Ch HDL and CER. The groups were not significantly different by men-women ratio (chi 2 = 0.016, p = 0.9) and CHD patients share (chi 2 = 0.126, p = 0.723). The correlation between CETA and Ch levels was significant for healthy individuals only. The data does not correspond to assumption of exclusively atherogenic influence of high CETA: 1) no correlation between CETA and atherogenic parameters of LP metabolism among different HLP forms was found; 2) Ch HDL levels were not distinguished at high and low CETA; 3) no domination of CHD patients among the subjects with high CETA was found.


Linked functional network abnormalities during intrinsic and extrinsic activity in schizophrenia as revealed by a data-fusion approach.
Abnormalities in functional brain networks in schizophrenia have been studied by examining intrinsic and extrinsic brain activity under various experimental paradigms. However, the identified patterns of abnormal functional connectivity (FC) vary depending on the adopted paradigms. Thus, it is unclear whether and how these patterns are inter-related. In order to assess relationships between abnormal patterns of FC during intrinsic activity and those during extrinsic activity, we adopted a data-fusion approach and applied partial least square (PLS) analyses to FC datasets from 25 patients with chronic schizophrenia and 25 age- and sex-matched normal controls. For the input to the PLS analyses, we generated a pair of FC maps during the resting state (REST) and the auditory deviance response (ADR) from each participant using the common seed region in the left middle temporal gyrus, which is a focus of activity associated with auditory verbal hallucinations (AVHs). PLS correlation (PLS-C) analysis revealed that patients with schizophrenia have significantly lower loadings of a component containing positive FCs in default-mode network regions during REST and a component containing positive FCs in the auditory and attention-related networks during ADR. Specifically, loadings of the REST component were significantly correlated with the severities of positive symptoms and AVH in patients with schizophrenia. The co-occurrence of such altered FC patterns during REST and ADR was replicated using PLS regression, wherein FC patterns during REST are modeled to predict patterns during ADR. These findings provide an integrative understanding of altered FCs during intrinsic and extrinsic activity underlying core schizophrenia symptoms.


Optical coherence tomography findings in ocular argyrosis.
A 68-year-old Caucasian man with a remote history of daily colloidal silver ingestion presented for ophthalmic examination in which he was noted to have a distinct slate gray skin discoloration. Funduscopy revealed confluent perimacular drusenoid deposits bilaterally, most of which localized at the level of or anterior to the inner segment ellipsoid band by optical coherence tomography (OCT) imaging. Enhanced depth imaging OCT demonstrated marked choroidal thinning. Fluorescein angiogram displayed a dark or silent choroid. Confirmatory serum silver levels were found to be markedly elevated. This report describes a unique geographic maculopathy with large drusenoid deposits anterior to the ellipsoid layer and severe choroidal thinning in association with ocular argyrosis.


Efficacy of sinecatechins 10% as proactive sequential therapy of external genital warts after laser CO2 ablative therapy: The PACT study (post-ablation immunomodulator treatment of condylomata with sinecatechins): a randomized, masked outcome assessment, multicenter trial.
External genital warts (EGW) are the most common viral sexually transmitted infection. Ablative treatments like cryotherapy, curettage, and CO2 laser therapies offer rapid onset of effect, fast clearance, and reduction of virus load. However, these procedures are associated with high recurrence rates (RRs) ranging from 20% to 77% in the short and medium terms and do not provide sustained clearance. After laser therapy removal of EGW, an RR up to 77% has been reported. Topical sinecatechins (TS) 10% is a patient-applied regimen for the treatment of EGW with a low RR (<6.5%) at three months after completion of the therapy in the pivotal trials conducted so far. Sinecatechins can be considered a suitable proactive sequential therapy (PST) after ablative strategies to obtain a low RR. So far, no prospective data are available regarding the efficacy of sinecatechins 10% as PST. We evaluated the efficacy and tolerability of TS 10% ointment applied twice daily in subjects with "difficult to treat" EGW after CO2 laser ablative treatment in a prospective controlled trial. A total of 87 subjects (76 men and 11 women; mean age 42 years) were enrolled in this three-month masked outcome assessment parallel group trial with imbalanced randomization allocation (2:1). One week after a successful CO2 laser treatment, 60 subjects were randomized to TS 10% treatment and 27 subjects to no treatment (control group: ConTRol (CTR); no sequential therapy). All patients had a history of an average of 4.5 previous ablative treatments in the last 12 months due to recurrent EGW. Mean (standard deviation) baseline number of treated lesions was 6.5 (2.7). One subject in the TS arm dropped out due to burning sensation after the application of the product. Therefore, 86 subjects completed the study. After three months, in the TS group, three subjects presented new EGW lesions (RR: 5%) on treated sites. In the CTR group, eight subjects presented new EGW lesions (RR: 29%) on treated sites (p = 0.0024; odds ratio: 0.16; 95% confidence interval: 0.04-0.68). In the TS group, 34 subjects (56%) reported mild to moderate erythema or burning sensation at the application site. In this prospective multicenter trial, the use of TS 10% as PST after ablative treatment with CO2 laser was associated with a lower recurrence rate of new EGW lesions in the short term in comparison with the control group. Comparative larger trials are warranted to evaluate the role of this approach as PST (Trial Registration Number: ISRCTN44037479).


Hoe 694, a new Na+/H+ exchange inhibitor and its effects in cardiac ischaemia.
1. The benzoylguanidine derivative Hoe 694 ((3-methylsulphonyl-4- piperidino-benzoyl) guanidine methanesulphonate) was characterized as an inhibitor of Na+/H+ exchange in rabbit erythrocytes, rat platelets and bovine endothelial cells. The potency of the compound was slightly lower or comparable to ethylisopropyl amiloride (EIPA). 2. To investigate a possible cardioprotective role of the Na+/H+ exchange inhibitor Hoe 694, rat isolated working hearts were subjected to ischaemia and reperfusion. In these experiments all untreated hearts suffered ventricular fibrillation on reperfusion. Addition of 10(-7) M Hoe 694 to the perfusate almost abolished reperfusion arrhythmias in the rat isolated working hearts. 3. Hoe 694 reduced the release of lactate dehydrogenase (LDH) and creatine kinase (CK), which are indicators of cellular damage during ischaemia, into the venous effluent of the hearts by 60% and 54%, respectively. 4. The tissue content of glycogen at the end of the experiments was increased by 60% and the high energy phosphates ATP and creatine phosphate were increased by 240% and 270% respectively in the treated hearts as compared to control hearts. 5. Antiischaemic effects of the Na+/H+ exchange inhibitor, Hoe 694, were investigated in a second experiment in anaesthetized rats undergoing coronary artery ligation. In these animals, pretreatment with Hoe 694 caused a dose-dependent reduction of ventricular premature beats and ventricular tachycardia as well as a complete suppression of ventricular fibrillation down to doses of 0.1 mg kg-1, i.v. Blood pressure and heart rate remained unchanged. 6. We conclude that the new Na+/H+ exchange inhibitor, Hoe 694, shows cardioprotective and antiarrhythmic effects in ischaemia and reperfusion in rat isolated hearts and in anaesthetized rats. In view of the role which Na+/H+ exchange seems to play in the pathophysiology of cardiac ischaemia these effects could probably be attributed to Na+/H+ exchange inhibition.


[Gravidaprotective action of phenibut in experimental pre-eclampsia].
It was established that the replacement of drinking water by 1.8% NaCl solution in female rats during pregnancy causes experimental pre-eclampsia (EP), as evidenced by an increase in the blood pressure, proteinuria, and edema in the control group as compared to pregnant female rats with normal drinking regime. Animals with EP exhibited disturbance of vasodilating endothelial function, microcirculation disorder, and increased coagulation and thrombogenic potential of blood. In addition, the group with EP showed evidence of the activation of lipid peroxidation (LPO) due to lower activity of antioxidant enzymes. Daily oral administration ofphenibut (25 mg/kg) in female rats with EP during pregnancy prevents the increase in blood pressure and the severity of proteinuria and edemation. Phenibut improves the vasodilator and antithrombotic endothelial functions, increases uterine blood flow, improves microcirculation, limits LPO, and increases the activity of antioxidant enzymes.


The Antiepileptic Ketogenic Diet Alters Hippocampal Transporter Levels and Reduces Adiposity in Aged Rats.
Nutritional ketosis is induced by high fat/low carbohydrate dietary regimens, which produce high levels of circulating ketone bodies, shifting metabolism away from glucose utilization. While ketogenic diets (KD) were initially introduced to suppress seizures, they are garnering attention for their potential to treat a myriad of neurodegenerative and metabolic disorders that are associated with advanced age. The feasibility and physiological impact of implementing a long-term KD in old animals, however, has not been systematically examined. In this study, young and aged rats consumed a calorically- and nutritionally-matched KD or control diet for 12 weeks. All KD-fed rats maintained higher levels of BHB and lower levels of glucose relative to controls. However, it took the aged rats longer to reach asymptotic levels of BHB compared to young animals. Moreover, KD-fed rats had significantly less visceral white and brown adipose tissue than controls without a loss of lean mass. Interestingly, the KD led to significant alterations in protein levels of hippocampal transporters for monocarboxylates, glucose, and vesicular glutamate and gamma-aminobutyric acid. Most notably, the age-related decline in vesicular glutamate transporter expression was reversed by the KD. These data demonstrate the feasibility and potential benefits of KDs for treating age-associated neural dysfunction.


Getting CLOSLER ("Closer to Osler"): Developing an Online Community Focused on Clinical Excellence.
This article was migrated. The article was marked as recommended. Clinical excellence is the goal in healthcare delivery, at both the provider and system level. At Johns Hopkins University School of Medicine, The Miller Coulson Academy of Clinical Excellence (MCACE) was established to celebrate and promote clinical excellence in hopes of optimizing the care experienced by patients. The MCACE describes clinical excellence as achieving a level of mastery in several areas including, but not limited to, communication and interpersonal skills, professionalism and humanism, diagnostic acumen, and negotiation of the healthcare system. The Academy's definition also puts an emphasis on teaching others to serve our patients and being a role model for clinical excellence. To have a positive influence on those beyond their immediate reach at Hopkins, the MCACE team launched CLOSLER, a free and open access medical education website ( closler.org). With the goal of sharing thoughtful clinical stories and perspectives to stimulate reflection about providing exceptional care to every patient, CLOSLER takes its name from William Osler, the founder of academic medicine in the United States and an early champion of patient-centered care worldwide. CLOSLER offers articles written by healthcare professionals relaying pearls and lessons from practice for all, organized into four sections: Connecting with Patients, Clinical Reasoning, Passion in the Medical Profession, and Lifelong Learning in Clinical Excellence. CLOSLER has ushered in a new era of education that can help to move us closer to Osler and clinical excellence; it pushes the perspectives of outstanding role models to all who are interested in developing in this realm.


A survey of the FAERS database concerning the adverse event profiles of α1-adrenoreceptor blockers for lower urinary tract symptoms.
Current guidelines recommend α1-adrenoreceptor blockers (A1Bs) for treating lower urinary tract symptoms suggestive of benign prostatic hyperplasia, but their adverse effects can be problematic. In this study, reports submitted to the US Food and Drug Administration Adverse Event Reporting System (FAERS) between 1997 and 2011 were reviewed to assess the safety profiles of A1Bs. After deleting duplicated submissions and revising arbitrary drug names, reports involving A1Bs for male patients were analyzed. Data mining algorisms were used for the quantitative detection of signals, where a signal represents an association between a drug and an adverse event or a drug-associated adverse event, including the proportional reporting ratio, reporting odds ratio, information component given by a Bayesian confidence propagation neural network, and empirical Bayes geometric mean. The total number of reports used was 1,260,182. Signal scores suggested the associations of alfuzosin, doxazosin, tamsulosin, and terazosin with dizziness/vertigo, orthostatic hypotension, erectile dysfunction, ejaculation dysfunction (EjD), thirst/dry mouth, and constipation; however, reports on naftopidil, silodosin, and urapidil were not enough to compare with the other 4 A1Bs. Signal scores for EjD were higher for tamsulosin, and those for dizziness/vertigo were lower for doxazosin than for the other 3 drugs. Tamsulosin-associated EjD, which was found in clinical studies, was reproduced in this analysis with markedly higher signal scores, and these results strongly suggest the necessity of well-organized clinical studies on A1B-associated adverse events.


Commitment to sporulation in Bacillus megaterium and uptake of specific compounds.
Commitment of Bacillus megaterium cells to continue the sporulation process was tested at different times during the developmental period with respect to either addition of different carbon sources (sugars or amino acids) or dilution into media containing these. Organisms grown in minimal medium containing sucrose as sole carbon source were committed earliest with respect to aspartic or glutamic acid as sole carbon source, later with respect to fructose, glucose, glycerol or sucrose, and latest with respect to nutrient medium supplemented with casein hydrolysate. Addition of both aspartate and a carbohydrate resulted in later commitment than addition of either compound alone. The initial uptake rates of aspartate, glutamate, glucose and sucrose increased toward the end of growth in complex medium (but not in minimal medium for glucose and sucrose) and then decreased during the developmental period.


[Generation of isolated words in normal subjects].
This study aims at analyzing the performance according to age, sex, and educational level in 112 French normal subjects on word generation tests, i.e., time-limited production of a noun or a verb semantically linked to a target "noun" or "verb". The nature of hits (exclusively production of nouns) has moreover been analyzed according to different features of the targets: noun vs verb, names of natural objects vs handmade objects, transitive vs intransitive verbs. Results show 1) a significant effect of age and educational level on performance, 2) a degree of difficulty, the verb/verb production test being significantly more difficult than the three other tests, 3) a convergency effect according to the natural vs handmade dichotomy, as subjects tend to produce, without specific instruction, an item belonging to the same category as that of the stimulus, and 4) object nouns tend to be produced in response to transitive verbs whereas subject nouns are not predominantly produced in response to intransitive verbs.


Association of childhood leukemia with residential exposure to petrochemical air pollution in taiwan.
To investigate the relationship between petrochemical air pollution and childhood leukemia (19 yr of age or younger), the authors conducted a matched case-control study using childhood deaths that occurred in Taiwan from 1995 through 2005. Data on all eligible childhood leukemia deaths were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. The control group consisted of children who died from causes other than neoplasms or diseases that were not associated with respiratory problems. The controls were pair matched to the cases by sex, year of birth, and year of death. Each matched control was selected randomly from the set of possible controls for each case. The proportion of a municipality's total population employed in the petrochemical industry in a municipality was used as an indicator of a resident's exposure to air emissions from the petrochemical industry. The subjects were divided into three levels (< or =25th percentile; 25th-75th percentile; > 75th percentile) according to the levels of the index just described. After controlling for possible confounders, results showed that children who lived in the group of municipalities characterized by the highest levels of petrochemical air pollution had a statistically significant higher risk of developing leukemia than the group that lived in municipalities with the lowest petrochemical air pollution levels. The results of this study shed important light on the relationship between the Taiwan petrochemical industry and human health risks.


Electrochemical investigation of the role of MnO2 nanorod catalysts in water containing and anhydrous electrolytes for Li-O2 battery applications.
The electrochemical behaviour of MnO2 nanorod and Super P carbon based Li-O2 battery cathodes in water-containing sulfolane and anhydrous DMSO electrolytes are shown to be linked to specific discharge product formation. During discharge, large layered spherical agglomerates of LiOH were characteristically formed on the MnO2 cathodes while smaller, toroidal, spherical Li2O2 particles and films were formed on the Super P cathodes. In an anhydrous DMSO based electrolyte the LiOH structures were also found on cathodes discharged in the anhydrous electrolyte, suggesting that MnO2 initiates electrochemical decomposition of the DMSO electrolyte to form LiOH via H2O reactions with Li2O2. The LiOH crystals are uniquely formed on MnO2, and segregated to this phase even in mixed oxide-carbon cathodes. In contrast, no Li2O2 toroids were noted on Super P cathodes discharged in the DMSO based electrolytes. Instead, the morphology varied from smaller sheets (at high discharge current) to much larger agglomerates (at low discharge currents). In mixed carbon-MnO2 nanorod cathodes, the use of PVDF initiates H2O formation that affects discharge products and an overall mechanism governing phase formation at MnO2 in sulfolane and anhydrous DMSO with and without PVDF binder is presented. This work highlights the importance of careful consideration of electrolyte-cathode material-discharge product interactions in the search for more stable Li-O2 systems.


[The effects of the infection caused by Toxoplasma gondii on the cat duodenal wall].
This paper analyzes the effects of the infection caused by Toxoplasma gondii on the cat duodenal wall. Six cats (Felis catus) with 3-month-old were randomly divided into Control Group (G1; n = 3) and Infected Group (G2; n = 3). The animals from G2 received orarilly 200 T. gondii tissye cysts of ME49-strain (type II). After 40 days, the animals were submitted to euthanasia, laparotomy and had their duodenum removed, fixed in Bouin solution and submitted to histological routine obtaining 3 μm transverse cuts. The cuts were stained with Hematoxylin-Eosin (HE), Azan, Periodic acid-Schiff (PAS), Alcian-Blue, and Mallory trichrome. Qualitative assessment of the intestine wall as well as comparative measurements with respect to the thickness of mucosa, muscle tunic, total wall, the height of the villous, the depth of the crypts, and the height of the enterocytes and their nuclei were carried out. Calciform cells, the intraepithelial lymphocytes, and the Paneth cells were quantified. The results showed that the infection led to the atrophy of the mucosa, muscle tunic, and the intestinal wall of the duodenum of G2 cats (p < 0.05). The enterocytes height presented significant (p < 0.05) increase for G2 animals. According to the qualitative analysis, the collagen fibers were visibly taken a broader area on the intestinal wall layers, what suggests they have increased in size. Decrease in the sulphomucins secretion and the increase of Paneth cells were observed for these animals (p < 0.05).


Peroxisome degradation in Saccharomyces cerevisiae is dependent on machinery of macroautophagy and the Cvt pathway.
Organelle biogenesis and turnover are necessary to maintain biochemical processes that are appropriate to the needs of the eukaryotic cell. Specific degradation of organelles in response to changing environmental cues is one aspect of achieving proper metabolic function. For example, the yeast Saccharomyces cerevisiae adjusts the level of peroxisomes in response to differing nutritional sources. When cells are grown on oleic acid as the sole carbon source, peroxisome biogenesis is induced. Conversely, a subsequent shift to glucose-rich or nitrogen-limiting conditions results in peroxisome degradation. The degradation process, pexophagy, requires the activity of vacuolar hydrolases. In addition, peroxisome degradation is specific. Analyses of cellular marker proteins indicate that peroxisome degradation under these conditions occurs more rapidly and to a greater extent than mitochondrial, Golgi, or cytosolic protein delivery to the vacuole by the non-selective autophagy pathway. To elucidate the molecular mechanism of selective peroxisome degradation, we examined pexophagy in mutants that are defective in autophagy (apg) and the selective targeting of aminopeptidase I to the vacuole by the cytoplasm to vacuole targeting (Cvt) pathway. Inhibition of peroxisome degradation in cvt and apg mutants indicates that these pathways overlap and that peroxisomes are delivered to the vacuole by a mechanism that utilizes protein components of the Cvt/autophagy pathways.


Evolution of Reproduction Periods in Seasonal Environments.
AbstractMany species are subject to seasonal cycles in resource availability, affecting the timing of their reproduction. Using a stage-structured consumer-resource model in which juvenile development and maturation are resource dependent, we study how a species' reproductive schedule evolves, dependent on the seasonality of its resource. We find three qualitatively different reproduction modes. First, continuous income breeding (with adults reproducing throughout the year) evolves in the absence of significant seasonality. Second, seasonal income breeding (with adults reproducing unless they are starving) evolves when resource availability is sufficiently seasonal and juveniles are more efficient resource foragers. Third, seasonal capital breeding (with adults reproducing partly through the use of energy reserves) evolves when resource availability is sufficiently seasonal and adults are more efficient resource foragers. Such capital breeders start reproduction already while their offspring are still experiencing starvation. Changes in seasonality lead to continuous transitions between continuous and seasonal income breeding, but the change between income and capital breeding involves a hysteresis pattern, such that a population's evolutionarily stable reproduction pattern depends on its initial one. Taken together, our findings show how adaptation to seasonal environments can result in a rich array of outcomes, exhibiting seasonal or continuous reproduction with or without energy reserves.