Estrogen-mediated regulation of steroid metabolism in rat glial cells; effects on neurosteroid levels via regulation of CYP7B1-mediated catalysis.
Many neuroactive steroids, including dehydroepiandrosterone (DHEA), pregnenolone, 27-hydroxycholesterol and 17β-estradiol, are known to affect development and function of the brain and nervous system. These and other steroids can undergo tissue and/or cell-specific enzymatic conversions into steroid metabolites. Carefully regulated production of steroids with various physiological effects is important for cells of the nervous system. Astrocytes express many steroidogenic enzymes and are considered important producers of brain steroids. The quantitative roles of different pathways for steroid metabolism in rat astrocytes are not clear. In the current study we examined effects of estrogens on steroid metabolism catalyzed by CYP7B1 and other enzymes in primary cultures of rat astrocytes. The CYP7B1 enzyme, which has been linked to neurodegenerative disease, is involved in the metabolism of several important neurosteroids. In the present study, we found that 7α-hydroxylation, performed by CYP7B1, is the quantitatively most important pathway for DHEA metabolism in rat astrocytes. In addition, our present experiments on catalytic steroid conversions revealed that estrogens significantly suppress the CYP7B1-catalyzed metabolism of not only DHEA but also of pregnenolone and 27-hydroxycholesterol in rat astrocytes. These novel findings point to a regulatory mechanism for control of the cellular levels of these neurosteroids via CYP7B1. Our hypothesis that estrogens can regulate neurosteroid levels via this enzymatic reaction was supported by experiments using ELISA to assay levels of DHEA and pregnenolone in the presence or absence of estrogen. Furthermore, the present results show that estrogen suppresses CYP7B1-catalyzed 7α-hydroxylation also in primary cultures of rat Schwann cells, indicating that regulation by estrogen via this enzyme may be of relevance in both the CNS and the PNS.


Effect of Ocrelizumab in Blood Leukocytes of Patients With Primary Progressive MS.
To analyze the changes induced by ocrelizumab in blood immune cells of patients with primary progressive MS (PPMS). In this multicenter prospective study including 53 patients with PPMS who initiated ocrelizumab treatment, we determined effector, memory, and regulatory cells by flow cytometry at baseline and after 6 months of therapy. Wilcoxon matched paired tests were used to assess differences between baseline and 6 months' results. p Values were corrected using the Bonferroni test. Ocrelizumab reduced the numbers of naive and memory B cells (p < 0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNFα) (p < 0.0001 in all cases). By contrast, the proportions of plasmablasts and B cells producing GM-CSF and TNFα increased significantly, suggesting the need for treatment continuation. We also observed a decrease in CD20+ T-cell numbers (p < 0.0001) and percentages (p < 0.0001), and a clear remodeling of the T-cell compartment characterized by relative increases of the naive/effector ratios in CD4+ (p = 0.002) and CD8+ (p = 0.002) T cells and relative decreases of CD4+ (p = 0.03) and CD8+ (p = 0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p = 0.002), but no changes were observed in those producing inflammatory cytokines. The immunologic variations were associated with a reduction of serum neurofilament light chain (sNfL) levels (p = 0.008). The reduction was observed in patients with Gd-enhanced lesions at baseline and in Gd- patients with baseline sNfL >10 pg/mL. In PPMS, effector B-cell depletion changed T-cell response toward a low inflammatory profile, resulting in decreased sNfL levels.


A two-level hybrid evolutionary algorithm for modeling one-dimensional dynamic systems by higher-order ODE models.
This paper presents a new algorithm for modeling one-dimensional (1-D) dynamic systems by higher-order ordinary differential equation (HODE) models instead of the ARMA models as used in traditional time series analysis. A two-level hybrid evolutionary modeling algorithm (THEMA) is used to approach the modeling problem of HODE's for dynamic systems. The main idea of this modeling algorithm is to embed a genetic algorithm (GA) into genetic programming (GP), where GP is employed to optimize the structure of a model (the upper level), while a GA is employed to optimize the parameters of the model (the lower level). In the GA, we use a novel crossover operator based on a nonconvex linear combination of multiple parents which works efficiently and quickly in parameter optimization tasks. Two practical examples of time series are used to demonstrate the THEMA's effectiveness and advantages.


XtalFluor-E® mediated proto-functionalization of N-vinyl amides: access to N-acetyl N,O-acetals.
XtalFluor-E® has been extensively used in a broad range of reactions in the past few years. Here we report its use with protic nucleophiles in a catalytic manner for the in situ generation of protons that lead to the proto-functionalization of activated olefins. Utilizing the latter protocol, proto etherification of enamides gives rise to N,O-acetals in nearly quantitative yields.


Assessing efficacy of N-Acetyl-l-Cysteine-Sodium Hydroxide on bacterial viability and enhanced recovery of Mycobacterium avium subsp. paratuberculosis from bovine colostrum.
The standard procedure for the improved cultural recovery of viable Mycobacterium spp. from diverse samples mainly depends on reducing the viability of background microbiota using different chemical compounds. This study was designed to i) evaluate the efficacy and comparison between N-Acetyl-l-Cysteine-Sodium hydroxide (NALC-2% NaOH) and hexadecylpyridinium chloride (0.75% HPC) treatment and exposure time on reducing the viability of undesirable microorganisms with minimal impact on colostrum consistency; and ii) assess the impact of NALC-2% NaOH on improved and enhanced recovery of Mycobacterium avium subsp. paratuberculosis (MAP) in spiked postpartum colostrum samples and consistency of colostrum. A total of 40 samples, each treated with NALC-2% NaOH for 15 min or 0.75% HPC for 5 h, were investigated for total mesophilic aerobic bacteria (MAB) and enterobacteria (EB) (CFU mL-1). The results showed that treatment of colostrum samples with NALC-2% NaOH completely eliminated EB and significantly reduced MAB (3.6 log10 CFU mL-1). Conversely, samples treated with 0.75% HPC produced a complex mixture following interaction with the colostrum protein and showed non-significant and variable results. In addition, the spiked colostrum treated with NALC-2% NaOH for 15 min revealed recovery of viable MAP cells with a minimum limit of detection of 1.36 log10 CFU 10 mL-1 where no change in the consistency of colostrum was observed. In conclusion, 15-min NALC-2% NaOH treatment of colostrum may significantly reduce the viability of undesirable microorganisms and help to enhance the efficient recovery of MAP without impacting the consistency of high quality postpartum colostrum. This rapid procedure is suitable for efficient recovery and early detection of MAP as well as preventing its transmission to neonates and young calves in MAP infected herds.


Megalencephaly syndromes associated with mutations of core components of the PI3K-AKT-MTOR pathway: PIK3CA, PIK3R2, AKT3, and MTOR.
Megalencephaly (MEG) is a developmental abnormality of brain growth characterized by early onset, often progressive, brain overgrowth. Focal forms of megalencephaly associated with cortical dysplasia, such as hemimegalencephaly and focal cortical dysplasia, are common causes of focal intractable epilepsy in children. The increasing use of high throughput sequencing methods, including high depth sequencing to more accurately detect and quantify mosaic mutations, has allowed us to identify the molecular etiologies of many MEG syndromes, including most notably the PI3K-AKT-MTOR related MEG disorders. Thorough molecular and clinical characterization of affected individuals further allow us to derive preliminary genotype-phenotype correlations depending on the gene, mutation, level of mosaicism, and tissue distribution. Our review of published data on these disorders so far shows that mildly activating variants (that are typically constitutional or germline) are associated with diffuse megalencephaly with intellectual disability and/or autism spectrum disorder; moderately activating variants (that are typically high-level mosaic) are associated with megalencephaly with pigmentary abnormalities of the skin; and strongly activating variants (that are usually very low-level mosaic) are associated with focal brain malformations including hemimegalencephaly and focal cortical dysplasia. Accurate molecular diagnosis of these disorders is undoubtedly crucial to more optimally treat children with these disorders using PI3K-AKT-MTOR pathway inhibitors.


Antibiotic prophylaxis in cardiac surgery: systematic review and meta-analysis.
Antibiotic prophylaxis is recommended in cardiac surgery. Current debate concerns the type of antibiotic(s), dosing and the duration of prophylaxis. Systematic review of randomized controlled trials comparing one antibiotic regimen versus another in cardiac surgery. We searched The Cochrane Library, PubMed, LILACS, conference proceedings and bibliographies. Two reviewers independently extracted the data. The primary outcome was deep sternal wound infections (DSWIs). Meta-analysis was performed using the Mantel-Haenszel fixed-effect method. Risk ratios (RRs) with 95% confidence intervals (95% CIs) are reported. Fifty-nine trials were included. There were no significant differences in DSWI or all other categories of surgical site infections (SSIs) for antibiotic prophylaxis with β-lactams comprising a Gram-negative spectrum of coverage versus prophylaxis targeting Gram-positive bacteria, but the former led to a significantly lower rate of post-operative pneumonia (RR 0.68, 95% CI 0.51-0.90) and all-cause mortality (RR 0.66, 95% CI 0.47-0.92). In trials comparing different antibiotic regimens for different durations, prophylaxis duration of ≤24 h post-operation led to higher rates of DSWI (RR 1.83, 95% CI 1.25-2.66), any sternal SSI, surgical interventions for SSI and endocarditis compared with longer duration prophylaxis. There was no advantage of regimens lasting >48 h post-operation. In the comparison of glycopeptides versus β-lactams, an advantage of glycopeptides was observed when comparators were given for similar duration and for β-lactams when given for a longer duration than the glycopeptides. There was no significant advantage of high antibiotic dosing. Evidence supports second- or third-generation cephalosporins for cardiac surgery prophylaxis and points at a possible advantage of prophylaxis prolongation up to 48 h post-operatively.


Astrocyte-derived tissue Transglutaminase affects fibronectin deposition, but not aggregation, during cuprizone-induced demyelination.
Astrogliosis as seen in Multiple Sclerosis (MS) develops into astroglial scarring, which is beneficial because it seals off the site of central nervous system (CNS) damage. However, astroglial scarring also forms an obstacle that inhibits axon outgrowth and (re)myelination in brain lesions. This is possibly an important cause for incomplete remyelination in the CNS of early stage MS patients and for failure in remyelination when the disease progresses. In this study we address whether under demyelinating conditions in vivo, tissue Transglutaminase (TG2), a Ca2+ -dependent enzyme that catalyses posttranslational modification of proteins, contributes to extracellular matrix (ECM) deposition and/or aggregation. We used the cuprizone model for de- and remyelination. TG2 immunoreactivity and enzymatic activity time-dependently appeared in astrocytes and ECM, respectively, in the corpus callosum of cuprizone-treated mice. Enhanced presence of soluble monomeric and multimeric fibronectin was detected during demyelination, and fibronectin immunoreactivity was slightly decreased in cuprizone-treated TG2-/- mice. In vitro TG2 overexpression in astrocytes coincided with more, while knock-down of TG2 with less fibronectin production. TG2 contributes, at least partly, to fibronectin production, and may play a role in fibronectin deposition during cuprizone-induced demyelination. Our observations are of interest in understanding the functional implications of TG2 during astrogliosis.


Isolation, expansion and neural differentiation of stem cells from human plucked hair: a further step towards autologous nerve recovery.
Stem cells from the adult hair follicle bulge can differentiate into neurons and glia, which is advantageous for the development of an autologous cell-based therapy for neurological diseases. Consequently, bulge stem cells from plucked hair may increase opportunities for personalized neuroregenerative therapy. Hairs were plucked from the scalps of healthy donors, and the bulges were cultured without prior tissue treatment. Shortly after outgrowth from the bulge, cellular protein expression was established immunohistochemically. The doubling time was calculated upon expansion, and the viability of expanded, cryopreserved cells was assessed after shear stress. The neuroglial differentiation potential was assessed from cryopreserved cells. Shortly after outgrowth, the cells were immunopositive for nestin, SLUG, AP-2α and SOX9, and negative for SOX10. Each bulge yielded approximately 1 × 10(4) cells after three passages. Doubling time was 3.3 (±1.5) days. Cellular viability did not differ significantly from control cells after shear stress. The cells expressed class III β-tubulin (TUBB3) and synapsin-1 after 3 weeks of neuronal differentiation. Glial differentiation yielded KROX20- and MPZ-immunopositive cells after 2 weeks. We demonstrated that human hair follicle bulge-derived stem cells can be cultivated easily, expanded efficiently and kept frozen until needed. After cryopreservation, the cells were viable and displayed both neuronal and glial differentiation potential.


Fistula recurrence, pregnancy, and childbirth following successful closure of female genital fistula in Guinea: a longitudinal study.
Female genital fistula is a devastating maternal complication of delivery in developing countries. We sought to analyse the incidence and proportion of fistula recurrence, residual urinary incontinence, and pregnancy after successful fistula closure in Guinea, and describe the delivery-associated maternal and child health outcomes. We did a longitudinal study in women discharged with a closed fistula from three repair hospitals supported by EngenderHealth in Guinea. We recruited women retrospectively (via medical record review) and prospectively at hospital discharge. We used Kaplan-Meier methods to analyse the cumulative incidence, incidence proportion, and incidence ratio of fistula recurrence, associated outcomes, and pregnancy after successful fistula closure. The primary outcome was recurrence of fistula following discharge from repair hospital in all eligible women who consented to inclusion and could provide follow-up data. 481 women eligible for analysis were identified retrospectively (from Jan 1, 2012, to Dec 31, 2014; 348 women) or prospectively (Jan 1 to June 20, 2015; 133 women), and followed up until June 30, 2016. Median follow-up was 28·0 months (IQR 14·6-36·6). 73 recurrent fistulas occurred, corresponding to a cumulative incidence of 71 per 1000 person-years (95% CI 56·5-89·3) and an incidence proportion of 18·4% (14·8-22·8). In 447 women who were continent at hospital discharge, we recorded 24 cases of post-repair residual urinary incontinence, equivalent to a cumulative incidence of 23·1 per 1000 person-years (14·0-36·2), and corresponding to 10·3% (5·2-19·6). In 305 women at risk of pregnancy, the cumulative incidence of pregnancy was 106·0 per 1000 person-years, corresponding to 28·4% (22·8-35·0) of these women. Of 50 women who had delivered by the time of follow-up, only nine delivered by elective caesarean section. There were 12 stillbirths, seven delivery-related fistula recurrences, and one maternal death. Recurrence of female genital fistula and adverse pregnancy-related maternal and child health outcomes were frequent in women after fistula repair in Guinea. Interventions are needed to safeguard the health of women after fistula repair. Belgian Development Cooperation (DGD), Institute of Tropical Medicine of Antwerp (ITM), and Maferinyah Training and Research Center in Rural Health (Guinea).


The assessment of acute kidney injury in critically ill patients.
Acute kidney injury (AKI) is common in critically ill patients and is associated with high morbidity and mortality. The availability of several biomarkers of kidney injury offers new tools for its early recognition and management. The early identification of high-risk patients provides an opportunity to develop strategies for the prevention, early diagnosis and treatment of AKI. Despite progress in critical care medicine over the past decade, the treatment strategies for AKI in critically ill patients, such as when to start renal replacement therapy, remain controversial. A recently proposed risk prediction score for AKI, based on routinely available clinical variables, presents a new means of identifying patients at high risk of AKI.


Severity of the metabolic syndrome as a predictor of prediabetes and type 2 diabetes in first degree relatives of type 2 diabetic patients: A 15-year prospective cohort study.
Type 2 diabetes mellitus (T2DM) has high morbidity and mortality worldwide, therefore there is of paramount importance to identify the risk factors in the populations at risk early in the course of illness. A strong correlation between severity of metabolic syndrome (MetS) and HbA1c, fasting insulin and insulin resistance has been reported. Accordingly, the MetS severity score (or MestS Z-score) can potentially be used to predict the risk of T2DM progression over time. To evaluate the association the of MestS Z-score in first degree relatives (FDRs) of T2DM with the risk of prediabetes and type 2 diabetes in future. A prospective open cohort study was conducted between 2003-2018. At baseline, the sample comprised of 1766 FDRs of patients with T2DM who had a normal glucose tolerance test. Relative risk (RR) and 95% confidence interval were calculated based on logistic regression. The receiver-operator characteristic analysis and area under the curve based on MetS Z-score were used to evaluate the risk of prediabetes and diabetes among the FDR population. Baseline MetS Z-scores were associated with the its latest values (P < 0.0001). Compared with individuals who were T2DM free at the end of follow up, those who developed T2DM had higher MetS Z-score at baseline (P < 0.001). In multivariable logistic regression analyses for every unit elevation in MetS Z-score at the baseline, the RR for developing future T2DM and prediabetes was (RR = 1.94, RR = 3.84), (RR = 1.5, RR = 2.17) in total population and female group, respectively (P < 0.05). The associations remained significant after adjusting the potential confounding variables. A cut off value of 0.97 and 0.94 was defined in the receiver-operator characteristic curve based on the MetS Z-score for differentiating female patients with diabetes and prediabetes from the normal population, respectively. The MetS Z-score was associated with an increased risk of future T2DM. Appropriate interventions at earlier stages for preventing and attenuating MetS effects may be considered as an effective strategy for FDR as at-risk population.


E series prostaglandins alter the proliferative, apoptotic and migratory properties of T98G human glioma cells in vitro.
In many types of cancer, prostaglandin E2 (PGE2) is associated with tumour related processes including proliferation, migration, angiogenesis and apoptosis. However in gliomas the role of this prostanoid is poorly understood. Here, we report on the proliferative, migratory, and apoptotic effects of PGE(1), PGE(2) and Ibuprofen (IBP) observed in the T98G human glioma cell line in vitro. T98G human glioma cells were treated with IBP, PGE(1) or PGE(2) at varying concentrations for 24-72 hours. Cell proliferation, mitotic index and apoptotic index were determined for each treatment. Caspase-9 and caspase-3 activity was measured using fluorescent probes in live cells (FITC-LEHD-FMK and FITC-DEVD-FMK respectively). The migratory capacity of the cells was quantified using a scratch migration assay and a transwell migration assay. A significant decrease was seen in cell number (54%) in the presence of 50 μM IBP. Mitotic index and bromodeoxyuridine (BrdU) incorporation were also decreased 57% and 65%, respectively, by IBP. The apoptotic index was increased (167%) and the in situ activity of caspase-9 and caspase-3 was evident in IBP treated cells. The inhibition of COX activity by IBP also caused a significant inhibition of cell migration in the monolayer scratch assay (74%) and the transwell migration assay (36%). In contrast, the presence of exogenous PGE(1) or PGE(2) caused significant increases in cell number (37% PGE(1) and 45% PGE(2)). When mitotic index was measured no change was found for either PG treatment. However, the BrdU incorporation rate was significantly increased by PGE(1) (62%) and to a greater extent by PGE(2) (100%). The apoptotic index was unchanged by exogenous PGs. The addition of exogenous PGs caused an increase in cell migration in the monolayer scratch assay (43% PGE(1) and 44% PGE(2)) and the transwell migration assay (28% PGE(1) and 68% PGE(2)). The present study demonstrated that treatments which alter PGE(1) and PGE(2) metabolism influence the proliferative and apoptotic indices of T98G glioma cells. The migratory capacity of the cells was also significantly affected by the change in prostaglandin metabolism. Modifying PG metabolism remains an interesting target for future studies in gliomas.


Angiostrongylus cantonensis: proof of direct transmission with its epidemiological implications.
Infective larvae of the rat lungworm Angiostrongylus cantonensis, presumed cause of human eosinophilic meningoencephalitis, are shed in mucus exuded by naturally infected Malayan slugs (Microparmarion malayanus). Larvae passed by slug hosts were recovered from lettuce and produced normal infection in white rats. Lettuce sold in the local public market also yielded small numbers of infective larvae. Experimental evidence from rats suggests that the local human population, exposed to repeated low-level infections, may become immunized against the rare massive exposure and against clinical disease that might otherwise result after ingestion of heavily infected raw mollusks.


Cross-subject EMG hand gesture recognition based on dynamic domain generalization.
Electromyography (EMG) signal based cross-subject gesture recognition methods reduce the influence of individual differences using transfer learning technology. These methods generally require calibration data collected from new subjects to adapt the pre-trained model to existing subjects. However, collecting calibration data is usually trivial and inconvenient for new subjects. This is currently a major obstacle to the daily use of hand gesture recognition based on EMG signals. To tackle the problem, we propose a novel dynamic domain generalization (DDG) method which is able to achieve accurate recognition on the hand gesture of new subjects without any calibration data. In order to extract more robust and adaptable features, a meta-adjuster is leveraged to generate a series of template coefficients to dynamically adjust dynamic network parameters. Specifically, two different kinds of templates are designed, in which the first one is different kinds of features, such as temporal features, spatial features, and spatial-temporal features, and the second one is different normalization layers. Meanwhile, a mix-style data augmentation method is introduced to make the meta-adjuster's training data more diversified. Experimental results on a public dataset verify that the proposed DDG outperforms the counterpart methods.


Versatile membrane deformation potential of activated pacsin.
Endocytosis is a fundamental process in signaling and membrane trafficking. The formation of vesicles at the plasma membrane is mediated by the G protein dynamin that catalyzes the final fission step, the actin cytoskeleton, and proteins that sense or induce membrane curvature. One such protein, the F-BAR domain-containing protein pacsin, contributes to this process and has been shown to induce a spectrum of membrane morphologies, including tubules and tube constrictions in vitro. Full-length pacsin isoform 1 (pacsin-1) has reduced activity compared to its isolated F-BAR domain, implicating an inhibitory role for its C-terminal Src homology 3 (SH3) domain. Here we show that the autoinhibitory, intramolecular interactions in pacsin-1 can be released upon binding to the entire proline-rich domain (PRD) of dynamin-1, resulting in potent membrane deformation activity that is distinct from the isolated F-BAR domain. Most strikingly, we observe the generation of small, homogenous vesicles with the activated protein complex under certain experimental conditions. In addition, liposomes prepared with different methods yield distinct membrane deformation morphologies of BAR domain proteins and apparent activation barriers to pacsin-1's activity. Theoretical free energy calculations suggest bimodality of the protein-membrane system as a possible source for the different outcomes, which could account for the coexistence of energetically equivalent membrane structures induced by BAR domain-containing proteins in vitro. Taken together, our results suggest a versatile role for pacsin-1 in sculpting cellular membranes that is likely dependent both on protein structure and membrane properties.


Dietary raw peas (Pisum sativum L.) reduce plasma total and LDL cholesterol and hepatic esterified cholesterol in intact and ileorectal anastomosed pigs fed cholesterol-rich diets.
Previous studies demonstrated the cholesterol-lowering effect of dietary legumes (mainly soybeans) in animals and humans, but the mechanisms by which they exert this effect are not completely understood. The contribution of the hindgut to this hypocholesterolemic effect is also not well documented. The present work was undertaken to investigate the effect of cholesterol-enriched (2.8 g/kg) casein (C) and raw pea seed (RP) diets on the cholesterol metabolism of intact (I) and ileorectal anastomosed (IRA) growing pigs. Four groups of 6 pigs were allocated to the treatments (C-I, C-IRA, RP-I, and RP-IRA pigs) for 3 wk. Plasma total cholesterol was lowered by the RP diet through a significant decrease in LDL cholesterol. The RP diet also decreased the hepatic concentration of esterified cholesterol and increased 3-hydroxy-3-methylglutaryl CoA reductase activity and LDL receptor synthesis. The biliary total cholesterol and bile acid concentrations were greater in RP- than in C-fed pigs. In addition, fecal bile acid output was higher in RP-fed pigs. The cecum-colon by-pass inhibited cholesterol and beta-sitosterol microbial transformation, lowered the bile acid output, and increased the primary to secondary bile acid output ratio, but its influence on cholesterolemia was negligible. These results suggest a hypocholesterolemic effect of the raw pea diet probably due to increased fecal bile acid output and an increased biliary bile acid concentration.


Pharmacological and Nonpharmacological Interventions to Arrest Neuroprogression in Psychiatric Disorders.
The concept of neuroprogression describes the progressive course of the disorder and stresses the progressive, recurrent, and chronic course of the disease entity under consideration. It subsumes clinical manifestations of the disease process and may also entail morphological, biochemical, neurochemical, immunological, physiological, and genetic aspects that contribute to the progressive course of the disease in question. In an attempt to identify the appropriate agent or method that could arrest neuroprogression in psychiatric patients, we conducted an evaluation of the use of anti-inflammatory drugs under the perspective of current pharmacological and neurophysiological data. This evaluation included the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as adjunctive treatment to conventional pharmacotherapy as well as the use of natural products exerting anti-inflammatory properties (i.e., ω-3 fatty acids) given as adjunctive or monotherapeutic treatments in less severe cases. The therapeutic significance of nonpharmacological methods, such as psychotherapy, physical exercise, and body-mind therapies, was also considered and will be discussed in this chapter. In conclusion, the role of psychotropic and select anti-inflammatory drugs in arresting neuroprogression is a very promising new frontier in psychiatric research and clinical practice. Modulators of a specific prostanoid synthase or receptor across the cyclooxygenase (COX)-2 downstream pathway along with new multitarget NSAIDs are expected to be tested by the pharmaceutical industry as potential agents to antagonize neuroprogression. Meanwhile, salicylates and selective COX-2 inhibitors could still be used in carefully selected subgroups of patients. Psychotherapy and nonpharmacological, stress-relieving methods should be considered as adjunctive tools to aid in arresting neuroprogression.


Structure alignment of membrane proteins: Accuracy of available tools and a consensus strategy.
Protein structure alignment methods are used for the detection of evolutionary and functionally related positions in proteins. A wide array of different methods are available, but the choice of the best method is often not apparent to the user. Several studies have assessed the alignment accuracy and consistency of structure alignment methods, but none of these explicitly considered membrane proteins, which are important targets for drug development and have distinct structural features. Here, we compared 13 widely used pairwise structural alignment methods on a test set of homologous membrane protein structures (called HOMEP3). Each pair of structures was aligned and the corresponding sequence alignment was used to construct homology models. The model accuracy compared to the known structures was assessed using scoring functions not incorporated in the tested structural alignment methods. The analysis shows that fragment-based approaches such as FR-TM-align are the most useful for aligning structures of membrane proteins. Moreover, fragment-based approaches are more suitable for comparison of protein structures that have undergone large conformational changes. Nevertheless, no method was clearly superior to all other methods. Additionally, all methods lack a measure to rate the reliability of a position within a structure alignment. To solve both of these problems, we propose a consensus-type approach, combining alignments from four different methods, namely FR-TM-align, DaliLite, MATT, and FATCAT. Agreement between the methods is used to assign confidence values to each position of the alignment. Overall, we conclude that there remains scope for the improvement of structural alignment methods for membrane proteins.


Self-reported health and comfort in 'modern' office buildings: first results from the European OFFICAIR study.
In the European research project OFFICAIR, a procedure was developed to determine associations between characteristics of European offices and health and comfort of office workers, through a checklist and a self-administered questionnaire including environmental, physiological, psychological, and social aspects. This procedure was applied in 167 office buildings in eight European countries (Portugal, Spain, Italy, Greece, France, Hungary, the Netherlands, and Finland) during the winter of 2011-2012. About 26 735 survey invitation e-mails were sent, and 7441 office workers were included in the survey. Among respondents who rated an overall comfort less than 4 (23%), 'noise (other than from building systems)', air 'too dry', and temperature 'too variable' were the main complaints selected. An increase of perceived control over indoor climate was positively associated with the perceived indoor environment quality. Almost one-third of office workers suffered from dry eyes and headache in the last 4 weeks. Physical building characteristics were associated with occupants' overall satisfaction (acoustical solutions, mold growth, complaints procedure, cleaning activities) and health (number of occupants, lack of operable windows, presence of carpet and cleaning activities). OFFICAIR project provides a useful database to identify stressors related to indoor environmental quality and office worker's health.


Impact of intermittent hypoxia and exercise on blood pressure and metabolic features from obese subjects suffering sleep apnea-hypopnea syndrome.
Strategies designed to reduce adiposity and cardiovascular-accompanying manifestations have been based on nutritional interventions conjointly with physical activity programs. The aim of this 13-week study was to investigate the putative benefits associated to hypoxia plus exercise on weight loss and relevant metabolic and cardiorespiratory variables, when prescribed to obese subjects with sleep apnea syndrome following dietary advice. The participants were randomly distributed in the following three groups: control, normoxia, and hypoxia. All the subjects received dietary advice while, additionally, normoxia group was trained under normal oxygen concentration and Hypoxia group under hypoxic conditions. There was a statistically significant decrease in fat-free mass (Kg) and water (%) on the control compared to normoxia group (p < 0.05 and p < 0.01, respectively). Body weight, body mass index, and waist circumference decreased in all the groups after the study. Moreover, leukocyte count was increased after the intervention in hypoxia compared to control group (p < 0.05). There were no statistically significant variations within groups in other variables, although changes in appetite were found after the 13-week period. In addition, associations between the variations in the leukocyte count and fat mass have been found. The hypoxia group showed some specific benefits concerning appetite and cardiometabolic-related measurements as exertion time and diastolic blood pressure, with a therapeutical potential.


Immune-stimulating effects of lactic acid bacteria in vivo and in vitro.
The health-promoting effects of lactic acid bacteria (LAB) are well recognised, making them a popular functional food ingredient. Commercially available probiotic products are often promoted as capable of improving immune defences also in healthy subjects. However, while strain-specific differences exist in the effects of LAB, conventional yoghurt bacteria have proved beneficial as well. For comparing the immunological effects of conventional and probiotic LAB, young healthy women received either a commercially available probiotic fermented milk product or a conventional yoghurt for four weeks. Both treatments showed comparable effects resulting in a stronger immunological reaction to stimuli (natural cytotoxicity against cancer cells, mitogen-induced T-lymphocyte activation and stimulated cytokine production). To study the mechanisms behind these effects, conventional (Lactobacillus delbrueckii) and probiotic (Lactobacillus rhamnosus GG), LAB were compared in vitro at the cellular level. Interestingly, L. rhamnosus GG was more potent in inducing maturation of dendritic cells (DC) that play a substantial role in directing the immune response to stimuli. In turn, L. delbrueckii provoked a higher secretion of proinflammatory cytokines as well as IL-10. These effects were, however, observed only after direct incubation of DC and LAB, not when both were separated by a layer of enterocyte-like Caco-2 cells. LAB also induced cytokine secretion in peripheral blood mononuclear cells in a similar manner and this effect was reduced in a Caco-2 cell model, suggesting a modulating influence of gut epithelial cells. While both conventional and probiotic strains modulate the immune response, specific properties may offer therapeutic options in the treatment of certain diseases.


Luminescent and Hydrophobic Wood Films as Optical Lighting Materials.
Most materials used for optical lighting applications need to produce a uniform illumination and require high mechanical and hydrophobic properties. However, they are rarely eco-friendly. Herein, a bio-based, polymer matrix-free, luminescent, and hydrophobic film with excellent mechanical properties for optical lighting purposes is demonstrated. A template is prepared by turning a wood veneer into porous scaffold from which most of the lignin and half of the hemicelluloses are removed. The infiltration of quantum dots (CdSe/ZnS) into the porous template prior to densification resulted in almost uniform luminescence (isotropic light scattering) and could be extended to various quantum dot particles, generating different light colors. In a subsequent step, the luminescent wood film is coated with hexadecyltrimethoxysilane (HDTMS) via chemical vapor deposition. The presence of the quantum dots coupled with the HDTMS coating renders the film hydrophobic (water contact angle ≈ 140°). This top-down process strongly eliminates lumen cavities and preserves the orientation of the original cellulose fibrils to create luminescent and polymer matrix-free films with high modulus and strength in the direction of fibers. The proposed optical lighting material could be attractive for interior designs (e.g., lamps and laminated cover panels), photonics, and laser devices.


Dialysis fluid endotoxin level and mortality in maintenance hemodialysis: a nationwide cohort study.
The quality of dialysis fluid water might play an important role in hemodialysis patient outcomes. Although targeted endotoxin levels of dialysis fluid vary among countries, evidence of the contribution of these levels to mortality in hemodialysis patients is lacking. Retrospective cohort study using data from the Japan Renal Data Registry, a nationwide annual survey. 130,781 patients receiving thrice-weekly in-center hemodialysis for more than 6 months were enrolled at 2,746 facilities in Japan at the end of 2006. None of the patients changed facility or treatment modality during 2007. Highest endotoxin level in dialysis fluid reported by each facility during 2006. Patients were categorized by facility endotoxin level into the following groups: <0.001, 0.001 to <0.01, 0.01 to <0.05, 0.05 to <0.1, and ≥0.1EU/mL. Age, sex, dialysis vintage, diabetes mellitus as a primary cause of end-stage renal disease, Kt/V, normalized protein catabolic rate, dialysis session duration, serum albumin, and hemoglobin were measured as potential confounders. All-cause mortality, censored by transplantation; withdrawal from dialysis treatment; or end of follow-up. Of 130,781 hemodialysis patients, 91.2% had facility endotoxin levels below the limit set for dialysis fluid in Japan (<0.05EU/mL). During a 1-year follow-up, 8,978 (6.9%) patients died of all causes. The rate of all-cause mortality at 1 year was highest in the ≥0.1-EU/mL category (88.0 deaths/1,000 person-years). Patients in the ≥0.1-EU/mL group exhibited an increased risk of all-cause mortality of 28% (95% CI, 10%-48%) compared to the <0.001-EU/mL group. Endotoxin level in dialysis fluid is reported as categorical data. No information about variation in endotoxin levels in dialysis fluid over time. Higher facility endotoxin levels in dialysis fluid may be related to increased risk for all-cause mortality among hemodialysis patients. Correcting this modifiable facility water management practice might improve the outcome of hemodialysis patients.


[The Raffia-swamps as sources or sinks of avifauna: a first approach to the problem].
In the Tortuguero region, northeastern Costa Rica, tropical forests are home to over 300 species of birds. Within this ecosystem, wetlands dominated by the raffia palm Raphia taedigera and the royal palm Manicaria saccifera extend in large monospecific swamps locally known as yolillales. These wetlands are characterized by low plant diversity, simple structure, waterlogged soils, and extended hydroperiod. There is hardly any information on the bird communities that inhabit or uses yolillales. We describe this omitofauna, comparing the species that inhabit the palm-swams and in the adjacent forest in terms of species richness and diversity. During October-November 2008, we used transects and hearing stations in both habitats in four locations in the region. We located a total of 11 bird species in the palm-swamps and 31 in the adjacent forests. Our observations suggest that palm-swamps have lower species richness than adjacent forests and that these environments also differ in species composition. Despite their low diversity, yolillales are employed by species with different degrees of vulnerability, so that they may be important for bird conservation in the region. Sampling in yolillales is very hard, so our data should be considered preliminary. Further efforts in these environments are needed to improve our knowledge on the bird community that uses them.


Effectiveness of routine psychotherapy: Method matters.
Though many studies have shown that psychotherapy can be effective, psychotherapy available in routine practice may not be adequate. Several methods have been proposed to evaluate routine psychological treatments. The aim of this paper is to demonstrate the combined utility of complementary methods, change-based benchmarking, and end-state normative comparisons, across a range of self-reported psychological symptoms. Benchmarks derived from randomized controlled trials (RCTs) and normative comparisons were used to evaluate the effectiveness of psychotherapy in a large (N = 9895) sample of clients in university counseling centers (UCCs). Overall, routine psychotherapy was associated with significant improvement across all symptoms examined. For clients whose initial severity was similar to RCT participants, the observed pre-post effect sizes were equivalent to those in RCTs. However, treatment tended to lead to normative end-state functioning only for those clients who were moderately, but not severely, distressed at the start of psychotherapy. This suggests that although psychotherapy is associated with an effective magnitude of symptom improvement in routine practice, additional services for highly distressed individuals may be necessary. The methods described here comprise a comprehensive analysis of the quality of routine care, and we recommend using both methods in concert. Clinical or methodological significance of this article: This study examines the effectiveness of routine psychotherapy provided in a large network of counseling centers. By comparing multiple established methods to define outcomes in this sample we provide a detailed understanding of typical outcomes. The findings show that, across several different problem areas, routine psychotherapy provided substantial benefit, particularly to clients in the most distress. However, there is room to improve, especially by increasing the number of clients who return to normal functioning by the end of treatment. Using distinct methods provides complementary answers to the question: How effective is routine psychotherapy?


The Costs of Customer Service Citizenship Behaviors: A Qualitative Study.
Organizational citizenship behaviors (OCBs) - behaviors not formally required or rewarded by the organization, but which promote its effectiveness - can be directed at coworkers, the organization itself or other stakeholders. OCBs directed at customers (customer-oriented citizenship behavior or OCBC) have received surprisingly little attention. Preliminary studies examined the unique contribution that OCBCs make in terms of perceived service quality and customer loyalty. In the current study, OCBCs were conceptualized in terms of supplying informal resources, which are- resources provided outside the worker's formal role or the organization's formal goals, or formal resources offered in informal ways (after hours, off duty). Applying a qualitative design, we uncovered types of informal resources and their associated costs. We also examined differences in informal resource provision and costs between occupational groups. Participants were 214 Israeli professionals who offer customer service in the education, health and welfare domains. All participants reported investing informal resources in their customers. Data demonstrated a remarkable range of types of informal resources, including emotional, instrumental and material resources. The most prevalent associated costs were interference with workers' family life, followed by such personal costs as loss of free time, physical and emotional exhaustion, and material expenditures. Professional costs, which were rarely reported, included time taken from other customers and reduced in-role performance. No differences were detected in the pattern of informal resources between occupational groups: all employees reported high informal investment aimed at increasing customers' well-being. Some of the implications discussed include the potential organizational costs associated with OCBCs. While such behaviors can improve service quality ratings, they can also lead to depleted employee resources and higher strain, negatively impacting productivity in the long term.


Clinical anticachexia treatments.
Cachexia involves progressive loss of adipose tissue and skeletal muscle mass and is common in a number of end-stage diseases. Cachexia causes weakness and immobility, reduces the quality of life of the patient, and eventually results in death. We reviewed the medical literature concentrating upon agents that have undergone clinical evaluation for the treatment of patients with cachexia. These agents are discussed, together with their mechanisms of action. Megestrol acetate, corticosteroids, eicosapentaenoic acid, and thalidomide have shown some success in the treatment of cachexia. beta-hydroxy-beta-methylbutyrate, cyclooxygenase inhibitors, adenosine 5'-triphosphate, and growth hormone are undergoing clinical evaluation. Appetite stimulants such as cannabinoids and antiserotonic agents have been shown to be ineffective in preventing progressive weight loss in cachexia. Much of the success in the treatment of cachexia has come from agents capable of blocking protein degradation through the ubiquitin-proteasome proteolytic pathway. Muscle mass can be increased when such agents are combined with agents that stimulate protein synthesis. In order to develop new agents, more fundamental research is required on the cellular mechanisms governing protein synthesis and degradation in skeletal muscle in cachexia.


Vanadate stimulates oxygen consumption and tyrosine phosphorylation in electropermeabilized human neutrophils.
To determine the role of protein phosphorylation in neutrophil activation, electropermeabilized cells were treated with vanadate, a phosphatase inhibitor. Micromolar concentrations of vanadate elicited a NADPH-dependent burst of oxygen utilization in permeabilized, but not in intact cells, indicating an intracellular site of action. Stimulation of oxygen consumption by vanadate was reversible, concentration dependent and required the presence of ATP and Mg2+. Generation of a respiratory burst by vanadate was associated with accumulation of phosphorylated proteins. Such accumulation was due, at least in part, to inhibition of phosphoprotein phosphatase activity, as indicated by pulse-chase experiments. No evidence for stimulation of protein kinases by vanadate was found. Phosphoamino acid analysis revealed that a large fraction of the vanadate-induced phosphorylation occurred on tyrosine residues. The pronounced accumulation of tyrosine-phosphorylated proteins was confirmed by immunoblotting with anti-phosphotyrosine antibodies. The data suggest that neutrophils possess one or more constitutively active tyrosine kinases and that phosphoprotein accumulation is normally prevented by vigorous concomitant phosphatase activity. Inhibition of the latter by vanadate leads to phosphoprotein accumulation and is accompanied by stimulation of oxygen consumption.


Meta-analysis of survival in African American and white American patients with breast cancer: ethnicity compared with socioeconomic status.
The extent to which socioeconomic disadvantages and inadequate health care access account for the disproportionately elevated mortality hazard observed in African American compared with white American patients with breast cancer is poorly defined. We identified 20 studies reported between January 1980 and June 2005 that provided survival analyses in patients with breast cancer after adjusting for ethnicity and some measurement of socioeconomic status. These studies also adjusted for age and stage of disease at time of diagnosis. The pooled outcome data yielded estimates for the mortality hazard in 14,013 African American and 76,111 white American patients with breast cancer. Studies varied in their methods for assigning socioeconomic status, with most relying on area-wide measures such as census tract and census block data. The combined analysis (adjusted for age, stage, and socioeconomic status) revealed that African American ethnicity was associated with a statistically significant excess mortality risk in overall survival (mortality hazard, 1.27; 95% CI, 1.18 to 1.38) and in breast cancer-specific survival (mortality hazard, 1.19; 95% CI, 1.10 to 1.29). Our pooled analysis demonstrated that African American ethnicity is a significant and independent predictor of poor outcome from breast cancer, even after accounting for socioeconomic status by conventional measures. These findings support the need for further investigation of the biologic, genetic, and sociocultural factors that may influence survival in African American patients with breast cancer.


Total Scalp Replantation: Surgical Tricks and Pitfalls.
Two patients were successfully operated on for total scalp avulsions. Ages were between 11 and 35 years, and both patients were female. Bilateral temporal artery and veins were used as the recipient pedicles. Interpositional vein graft harvested from the left forearm was used in 1 patient. No nerve repair was performed. The scalp was successfully replanted in both cases. Venous congestion and arterial insufficiency were observed in 1 patient. Successful revision of the vascular anastomosis was performed. Total necrosis of the upper helical rim was observed in 1 patient. A mean size of 3 × 3 cm of tissue necrosis was observed in the occipital region of all patients. One patient was treated with split-thickness skin grafting, whereas the other one was left for secondary healing. The "replace like tissue with like tissue" represents the philosophy in replantation surgery. Although reconstructive surgeries imply advanced surgical methods, scalp replantation remains the only ideal surgical modality to create an embellishing natural-looking hair-bearing scalp. In this article, we present some tricks and pitfalls of total avulsed scalp replantation as well as our skills and literature review.


Inhibition of an early stage of rhinovirus replication by dichloroflavan (BW683C).
The mechanism of action of a new anti-rhinovirus compound, dichloroflavan, was examined using a variety of techniques. Dichloroflavan was shown to bind to the highly sensitive rhinovirus type 1B (50% inhibitory concentration 0.007 microM) and at a much lower level to the insensitive rhinovirus type 4 (50% inhibitory concentration greater than 25 microM). Binding of the compound to rhinovirus 1B was accompanied by a reduction (about 0.5 log10 units) in virus infectivity which could be restored by treatment with chloroform. Maximum inhibition of virus yield (about 2 log10 units) occurred only when compound and virus were added together, but some inhibition (about 0.7 log10 units) occurred even when the compound was added near the end of a single cycle of replication. This late reduction in infectivity could be abolished by treating with chloroform, and was therefore caused by the compound binding to progeny virus. The compound did not interfere with adsorption of virus to cells, nor with uncoating of the viral RNA. However, little or no viral RNA and protein synthesis occurred in the presence of dichloroflavan provided that the compound was added with the virus. Addition of the compound after virus adsorption had no effect on either viral RNA or protein synthesis. These results indicate that dichloroflavan binds directly to rhinovirus 1B and appears to prevent virus replication at a point immediately after uncoating of the viral RNA.


The Electrical and Optical Properties of Organometal Halide Perovskites Relevant to Optoelectronic Performance.
Organometal halide perovskites are under intense study for use in optoelectronics. Methylammonium and formamidinium lead iodide show impressive performance as photovoltaic materials; a premise that has spurred investigations into light-emitting devices and photodetectors. Herein, the optical and electrical material properties of organometal halide perovskites are reviewed. An overview is given on how the material composition and morphology are tied to these properties, and how these properties ultimately affect device performance. Material attributes and techniques used to estimate them are analyzed for different perovskite materials, with a particular focus on the bandgap, mobility, diffusion length, carrier lifetime, and trap-state density.


Fine Tuning the Performance of Multiorbital Radical Conductors by Substituent Effects.
A critical feature of the electronic structure of oxobenzene-bridged bisdithiazolyl radicals 2 is the presence of a low-lying LUMO which, in the solid state, improves charge transport by providing additional degrees of freedom for electron transfer. The magnitude of this multiorbital effect can be fine-tuned by variations in the π-electron releasing/accepting nature of the basal ligand. Here we demonstrate that incorporation of a nitro group significantly stabilizes the LUMO, and hence lowers Ueff, the effective Coulombic barrier to charge transfer. The effect is echoed, at the molecular level, in the observed trend in Ecell, the electrochemical cell potential for 2 with R = F, H and NO2. The crystal structures of the MeCN and EtCN solvates of 2 with R = NO2 have been determined. In the EtCN solvate the radicals are dimerized, but in the MeCN solvate the radicals form superimposed and evenly spaced π-stacked arrays. This highly 1D material displays Pauli-like temperature independent paramagnetic behavior, with χTIP = 6 × 10-4 emu mol-1, but its charge transport behavior, with σRT near 0.04 S cm-1 and Eact = 0.05 eV, is more consistent with a Mott insulating ground state. High pressure crystallographic measurements confirm uniform compression of the π-stacked architecture with no phase change apparent up to 8 GPa. High pressure conductivity measurements indicate that the charge gap between the Mott insulator and metallic states can be closed near 6 GPa. These results are discussed in the light of DFT band structure calculations.


Screening for syphilis among men who have sex with men in various clinical settings.
To assess the prevalence of syphilis infections among men who have sex with men (MSM) accessing the Brisbane Sexual Health Clinic during the period 1997 up to May 2003, data were collated through three clinical programmes conducted by the service-a large inner city mainstream sexual health clinic and two small outreach sessional clinics conducted on the site of male sex on premises venues (SOPV). Data analysis also provided the opportunity to evaluate the effectiveness of the smaller outreach clinics to access populations of MSM less likely to attend or identify at the larger mainstream clinic, and therefore enhance the detection of previously undiagnosed sexually transmissible infections. Computerised records from 1997-2003 were collated for a statistical analysis of syphilis and other STI pathology results for all MSM accessing the mainstream clinic, and two outreach clinics. A review of client charts showed that 16 new syphilis diagnoses were made over the previous 5 years, but only two of these infections (both through the mainstream clinic) were early syphilis and therefore transmissible. All other cases were latent infections. A higher proportion of bisexual men was identified with positive syphilis serology but this was just below significance (p=0.06). Significantly, almost a third of syphilis diagnoses (all latent) were made at SOPV outreach clinics, despite the much lower proportion of clients seen overall through the SOPV clinics. For other sexually transmissible infections, the mainstream clinic demonstrated greater efficiency at case detection. Outreach clinics located in male saunas may serve an effective function in syphilis screening by facilitating access for a particular subpopulation of MSM (bisexual, married men). These outreach clinics may provide important outlets for education and opportunistic screening of asymptomatic MSM and foster a greater willingness for men to honestly self identify. However, larger, mainstream clinics serve a more anonymous venue for the testing of symptomatic men.


Acute pancreatitis and Cushing's disease.
A 64-year-old woman with Cushing's disease died of acute necrotizing pancreatitis. This is the second case of this rare condition, in which acute necrotizing pancreatitis followed an ACTH-dependent hypercortisolism. The possibility that the tricyclic antidepressant drug, amitriptyline hydrochloride, induced the acute pancreatitis could not be ruled out; nevertheless, the present case may serve to add ACTH-dependent hypercortisolism to the possible causes of acute necrotizing pancreatitis.


Improving Surgical Informed Consent: Unanswered Questions.
This study reviews randomized clinical trials that have attempted to improve the process of informed consent. Consent should be guided by the ethical imperatives of autonomy, beneficence, and social justice. Informed consent is constantly evolving. Yet our review of the randomized trials done to improve the surgical informed consent process raises a number of questions: How does one define surgical informed consent? What interventions have been tried to measure and improve informed consent? Have the interventions in informed consent actually led to improvements? What efforts have been made to improve informed consent? And what steps can be taken to improve the process further? A literature search for randomized controlled trials (RCTs)on informed consent identified 70 trials. Demographics, interventions, assessments, and a semi-quantitative summary of the findings were tabulated. The assessments done in the RCTs, show the surrogate for patient autonomy was comprehension; for beneficence, satisfaction and mental state (anxiety or depression); and, for social justice, language, literacy, learning needs, and cost. There were 4 basic categories of interventions: printed matter; non-interactive audiovisual tools; interactive multimedia; and a smaller group defying easy description. Improvement was documented in 46 of the 65 trials that studied comprehension. Thirteen of 33 trials showed improved satisfaction. Three of 30 studies showed an increase in anxiety. Few studies tried to assess primary language or literacy, and none looked at learning needs or cost. No single study improved all 3 principles of informed consent. Validated interventions and assessments were associated with greater impact on outcomes. All 3 ethical principles should be assessed; autonomy (as comprehension), beneficence (as satisfaction, anxiety), and social justice. Not enough consideration has been given to social justice; appropriate language translation, standardized reading levels, assessment of learning needs, and cost to the individual are all important elements worthy of future study.


Pain in pediatric oncology: do the experiences of children and parents differ from those of nurses and physicians?
Diagnosis and treatment of pain are central components in the care of children with cancer. The aim of the present study was to compare the viewpoints of children and parents with those of professionals, on different aspects of pain in children with cancer. Information was collected through questionnaires and interviews. In particular, we focused on the extent and causes of pain, strategies to reduce procedural pain, pain evaluation, and attitudes to pain treatment. We found that both families and professionals shared the opinion that pain was a common symptom during different phases of cancer treatment but, surprisingly, professionals regarded it as more frequent than families. The groups agreed that treatment related pain is the most critical problem, followed by procedure and cancer related pain. Concerning strategies to decrease procedural pain, there was a high concordance in views between groups. Nurses and physicians more often claimed that failing pain treatment was associated with psychological factors such as high levels of anxiety in parents and children, loneliness, and lack of preparation. The self-report, according to both parents and professionals, is a feasible procedure even in young children from 4 years of age. Both groups asserted that parents were better in ascertaining the extent of their child's pain. In conclusion, although the families and professionals in this study have many comparable views concerning pain in children with cancer, divergences also exist. To acquire a more accurate picture of the situation we must focus on the views of the children first, and then those of parents and professionals. A tendency to overestimate the problems was observed in professionals. Hopefully this reflects a keen awareness of the current situation.


Strain typing of German transmissible spongiform encephalopathies field cases in small ruminants by biochemical methods.
Following the implementation of a large scale transmissible spongiform encephalopathies (TSE) surveillance programme of small ruminants, evidence for a natural transmission of bovine spongiform encephalopathy (BSE) to a French goat has been found. During the years 2002-2004, a massive TSE rapid testing programme on >250,000 small ruminants was carried out in Germany. In this national survey, 186 scrapie-affected sheep were found which originated from 78 flocks. The majority of these cases were of the classical TSE type (115 sheep belonging to 14 outbreaks). However, 71 cases coming from 64 flocks were of the novel atypical scrapie type. According to the regulation EU 999/2001, all TSE cases in small ruminants have to be examined by strain typing methods to explore any possibility of the existence of BSE cases in the field sheep population. Here we report on a biochemical typing strategy (termed FLI-test), which includes the determination of molecular masses, antibody binding affinities and glycosylation pattern of the TSE induced abnormal prion protein. Based on this typing approach none of the analysed German classical TSE outbreaks (total number of analysed sheep: 36) displayed biochemical features indicative for a BSE infection. However, in two cases distinct but BSE-unrelated PrP(Sc) types were found, which alludes to the existence of different scrapie strains in the German sheep population.


Oral health-related knowledge, attitudes and self-efficacy of Australian rural older adults.
A cross-sectional study was conducted involving older adults from social clubs within a regional local government area in the state of Victoria, Australia, to identify factors associated with knowledge, and attitudes about oral health, as well as perceived self-efficacy. Participants underwent an oral health interview, followed by a comprehensive oral clinical examination. A total of 225 older adults participated in this study. The mean age was 70.7 (range: 55-96) years. The majority was females (62.0%) and had incomplete secondary education or less (56.1%); 34.2% were fully edentulous. The mean oral health knowledge score was 24.7 (SD 3.8). None of the socio-demographic and oral health variables yielded a significant effect on the knowledge score. The attitude score had a mean of 5.0 (SD 1.6). Four variables remained significant in the multivariate analysis [p < 0.0001]. A dentate female, with tertiary education, had better oral health attitudes. Higher oral health knowledge scores were associated with a better attitude. The overall self-efficacy mean value was 83.1% (SD 10.6). Dental visits and oral health knowledge remained significant in the attitudes multivariate analysis [p < 0.01]. Findings indicate that there were some misconceptions in oral health among this group of older adults. These are important influences on the success/failure of an oral health programme. Oral health education is needed to increase older adults' oral health knowledge, in particular of oral cancer, and to some extent periodontal disease, and improves attitudes and oral health self-efficacy. Oral health knowledge, attitudes and self-efficacy were minimally explained by socio-demographic and clinical variables.


[Comparative study on clinical effect of postoperative arterial infusion chemotherapy and systemic chemotherapy in gastric cancer].
To compare the clinical effect of postoperative arterial infusion chemotherapy and systemic chemotherapy in gastric cancer. From July 1997 to July 2002, the patients undergoing radical gastric resection were randomly divided into two groups, and received systemic or arterial infusion chemotherapy three weeks after radical resection. Systemic chemotherapy was carried out for two courses with 5-fluorouracil (5-FU), pirarubicin (THP), and mitomycin (MMC) administered according to FAM program, while arterial infusion chemotherapy for four courses with the same anticancer drugs infused via the celiac artery. The outcomes were compared. Systemic chemotherapy was carried out in 188 cases, and arterial infusion chemotherapy in 180 cases. There were no significant differences in sex, age, tumor location, histological type, TNM stage and surgical procedure between the two groups (P > 0.05). The 1, 3, 5 year survival rates were 87.2%, 53.7% and 43.1% in systemic chemotherapy, and 93.3%, 72.2% and 53.6% in arterial infusion chemotherapy respectively (P< 0.01). The survival rate of the patients with arterial infusion chemotherapy is higher than that with systemic chemotherapy, which indicates that arterial infusion chemotherapy can remarkably improve the prognosis of the patients with gastric cancer.


Considerations for use of acupuncture as supplemental therapy for patients with allergic asthma.
This study examines the clinical and immunomodulatory effects of acupuncture in the treatment of patients with allergic asthma. The acupuncture points GV14, BL12, and BL13 were selected based on the theory of traditional Chinese medicine in treating asthma. Manual acupuncture was performed once every other day (three times per week) for 5 weeks. The needles were twisted approximately 360° evenly at the rate of 60 times/min for 20 s, manipulated every 10 min and withdrawn after 30 min. Concentrations of sIgA and total IgA in secretions were determined by the combination of sucrose density gradient ultracentrifugation and RIA. Levels of cortisol in the plasma were measured by RIA. Total IgE in the sera was examined by ELISA. Flow cytometry was used to detect the numbers of CD3+, CD4+, CD8+, and IL-2R + T lymphocytes in the peripheral blood. The absolute and differential numbers of eosinophils in peripheral blood were counted with eosin staining. The total efficacy of the acupuncture treatment in patients with allergic asthma at the end of one course of treatment was 85 %. After treatment, the concentrations of sIgA and total IgA in the saliva (P<0.01, P<0.02) and nasal secretions (P<0.02, P<0.02) were significantly decreased in patients with allergic asthma. The levels of total IgE in sera (P<0.001), the counts of IL-2R + T lymphocytes (P<0.001), and the absolute and differential numbers of eosinophils (P<0.01, P<0.01) in the peripheral blood were also significantly decreased. The numbers of CD3+, CD4+, and CD8+ T lymphocytes in the peripheral blood were significantly increased in the allergic asthmatics treated by acupuncture (P<0.001, P<0.01, and P<0.001, respectively). The concentration of cortisol in the plasma of asthmatic patients did not change significantly after the acupuncture treatment (P>0.05). Acupuncture has regulatory effects on mucosal and cellular immunity in patients with allergic asthma and may be an adjunctive therapy for allergic asthma.


Strengthening our child abuse response system.
Medical professionals are often the people who see children first, whether in the safety of a private office, clinic or an emergency room. Your ability to recognize and understand the symptoms of child abuse and neglect, your readiness to report findings to the report line and your availability to provide expert witness testimony are critical to the effectiveness of the child abuse response system in Delaware.


Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study.
Multiple studies have examined the risk of prenatal antidepressant exposure and risk for autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD), with inconsistent results. Precisely estimating such risk, if any, is of great importance in light of the need to balance such risk with the benefit of depression and anxiety treatment. We developed a method to integrate data from multiple New England health systems, matching offspring and maternal health data in electronic health records to characterize diagnoses and medication exposure. Children with ASD or ADHD were matched 1:3 with children without neurodevelopmental disorders. Association between maternal antidepressant exposure and ASD or ADHD liability was examined using logistic regression, adjusting for potential sociodemographic and psychiatric confounding variables. In new cohorts of 1245 ASD cases and 1701 ADHD cases, along with age-, sex- and socioeconomic status matched controls, neither disorder was significantly associated with prenatal antidepressant exposure in crude or adjusted models (adjusted odds ratio 0.90, 95% confidence interval 0.50-1.54 for ASD; 0.97, 95% confidence interval 0.53-1.69 for ADHD). Pre-pregnancy antidepressant exposure significantly increased risk for both disorders. These results suggest that prior reports of association between prenatal antidepressant exposure and neurodevelopmental disease are likely to represent a false-positive finding, which may arise in part through confounding by indication. They further demonstrate the potential to integrate data across electronic health records studies spanning multiple health systems to enable efficient pharmacovigilance investigation.


Rehabilitation after acute vestibular disorders.
To assess the efficacy of rehabilitation for dizzy patients after recent acute vestibular disturbance. Forty patients recently hospitalised for an acute episode of rotational vertigo which lasted days were randomly divided into two groups. The first group (20 patients; group R) underwent active rehabilitation, while the second group (20 patients; group C) were told only to 'perform their daily activities'. Group R subjects underwent a total of 10 sessions of rehabilitation, including exercises on a stabilometric platform, point de mire and a series of five exercises repeated five times daily. All patients performed static stabilometry (posturography), undertook the dynamic gait index test, and completed a dizziness handicap questionnaire and a visual analogue scale for anxiety, at baseline and on completion. At 25 days, the rehabilitated patients obtained better results for all recorded outcomes, compared with the control group. The greatest difference in the rehabilitated subjects, compared with the control group, was for the dynamic gait index test; however, this difference was not statistically significant. The visual analogue scale anxiety score was statistically significantly more reduced in rehabilitated patients compared with control patients. Control patients maintained a higher visual dependence for postural control. These results would appear to support the effectiveness of a supervised exercise programme for patients following acute onset of vestibular disturbance. A correlation was found in both groups between dynamic gait index results and anxiety. In our experience, a rehabilitation programme seems to reduce dependence on visual cues for postural control.


Comparison of three methods of targeting the subthalamic nucleus for chronic stimulation in Parkinson's disease.
The success of subthalamic nucleus (STN) surgery for Parkinson's disease depends on accuracy in target determination. The objective of this study was to determine which of the following techniques was most accurate and precise in identifying the location for stimulation in STN deep brain stimulation surgery that is most clinically effective: direct targeting, indirect targeting using the positions of the anterior and posterior commissures, or a technique using the red nucleus (RN) as an internal fiducial marker. We reviewed 14 patients with Parkinson's disease treated with bilateral STN deep brain stimulation (28 STN targets). Electrode implantation was based on direct and indirect targeting using two-dimensional magnetic resonance imaging with refinement using microelectrode recording. Optimal settings, including the contacts used, were determined during the clinical follow-up. The position of the best contact was defined with postoperative magnetic resonance imaging. This location was compared with the modified direct, indirect, and RN-based targets. The mean distances between the targets and the final position of the optimal contact were calculated. The accuracy and variance of each target were analyzed. The mean position of the best contact was x = 12.12 (standard deviation [SD], 1.45 mm), y = -2.41 (SD, 1.63 mm), and z = -2.39 (SD, 1.49 mm) relative to the midcommissural point. The mean distance between the optimal contact position and the planned target was 3.19 mm (SD, 1.19 mm) using the RN-based method, 3.42 mm (SD, 1.34 mm) using indirect targeting, and 4.66 mm (SD, 1.33 mm) using a modified direct target. The mean distance between the optimal contact and the RN-based target was significantly smaller than the mean distance between the optimal contact and the direct target (post hoc with Tamhane's correction, P < 0.001) but not between the optimal contact and the indirect target. The RN-based target had the smallest variance (F test, P < 0.001), indicating greater precision. The use of the RN as an internal fiducial marker for targeting the optimal region of STN stimulation was reliable and closely approximates the position of the electrode contact that provides the optimal clinical results.


The GH/IGF-1 Axis and Heart Failure.
The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis regulates cardiac growth, stimulates myocardial contractility and influences the vascular system. The GH/IGF-1 axis controls intrinsic cardiac contractility by enhancing the intracellular calcium availability and regulating expression of contractile proteins; stimulates cardiac growth, by increasing protein synthesis; modifies systemic vascular resistance, by activating the nitric oxide system and regulating non-endothelial-dependent actions. The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous experimental studies and confirmed by the cardiac derangements secondary to both GH excess and deficiency. Several years ago, a clinical non-blinded study showed, in seven patients with idiopathic dilated cardiomyopathy and chronic heart failure (CHF), a significant improvement in cardiac function and structure after three months of treatment with recombinant GH plus standard therapy for heart failure. More recent studies, including a small double-blind placebo-controlled study on GH effects on exercise tolerance and cardiopulmonary performance, have shown that GH benefits patients with CHF secondary to both ischemic and idiopathic dilated cardiomyopathy. However, conflicting results emerge from other placebo-controlled trials. These discordant findings may be explained by the degree of CHF-associated GH resistance. In conclusion, we believe that more clinical and experimental studies are necessary to exactly understand the mechanisms that determine the variable sensitivity to GH and its positive effects in the failing heart.


Quantitative diffusion tensor tractography of association and projection fibers in normally developing children and adolescents.
Whole-brain diffusion tensor tractography (DTT) at high signal-to-noise ratio and angular and spatial resolutions were utilized to study the effects of age, sex differences, and lateral asymmetries of 6 white matter pathways (arcuate fasciculus [AF], inferior longitudinal fasciculus, inferior fronto-occipital fasciculus [IFOF], uncinate fasciculus [UF], corticospinal tract [CST], and somatosensory pathway [SS]) in 31 right-handed children (6-17 years). Fractional anisotropy (FA), a measure of the orientational variance in water molecular diffusivity, and the magnitude of water diffusivity (parallel, perpendicular, and mean diffusivity) along the pathways were quantified. Three major patterns of maturation were observed: 1) significant increase in FA with age, accompanied by significant decreases in all 3 diffusivities (e.g., left IFOF); 2) significant decreases in all three diffusivities with age without significant changes in FA (e.g., left CST); and 3) no significant age-related changes in FA or diffusivity (e.g., SS). Sex differences were minimal. Many pathways showed lateral asymmetries. In the right hemisphere, the frontotemporal (FT) segment of AF was not visualized in a substantial (29%) number of participants. FA was higher in the left hemisphere in the FT segment of AF, UF, and CST, whereas it was lower in the frontoparietal segment of AF. This study provides normative data essential for the interpretation of pediatric brain DTT measurements in both health and disease.


Studies of qingyangshen (I): Differential expression of hippocampal c-fos proto-oncogene during kainic acid induced acute and chronic seizures.
We previously reported that Qingyangshen (QYS), a traditional Chinese medicine with antiepileptic property, had therapeutic effect on kainic acid (KA) induced experimental seizures (see JTCM 13 (4): 281-286, 1993 for reference). To investigate the mechanisms underlying the anticonvulsant action of QYS, we analyzed the modulatory effect of QYS on rat hippocampal c-fos proto-oncogene expression during KA-induced epileptogenesis in this and the following paper. The expression of hippocampal c-fos gene during KA-induced seizures were examined first. Rats were intraperitoneally injected with kainic acid (KA, 12 mg/kg) and hippocampal c-fos mRNA level was determined by Northern blot analysis during both acute (within one day after KA injection) and chronic (15 days after KA treatment) seizures. A mild increase in hippocampal c-fos mRNA level was observed 30 min after KA injection (being 1.98 +/- 0.70 times of control level), which corresponded temporally to the occurrence of the first limbic seizures. There was an 11.02 +/- 3.33 fold maximal induction of c-fos mRNA at 2 h after KA administration, which remained relatively stable even when behavioral seizures continued to aggravate 4 h after KA treatment. Twelve hours after KA administration, c-fos mRNA in the hippocampus returned to control level when acute seizures began to gradually disappear. In contrast, the induction of hippocampal c-fos mRNA during chronic seizures was inhibited significantly, being reduced by 55.40% compared to control. This suggested that c-fos is in different functional states at acute and chronic stages of epileptogenesis induced by KA.


Full-dimensional theoretical description of vibrationally resolved valence-shell photoionization of H2O.
We have performed a full-dimensional theoretical study of vibrationally resolved photoelectron emission from the valence shell of the water molecule by using an extension of the static-exchange density functional theory that accounts for ionization as well as for vibrational motion in the symmetric stretching, antisymmetric stretching, and bending modes. At variance with previous studies performed in centrosymmetric molecules, where vibrationally resolved spectra are mostly dominated by the symmetric stretching mode, in the present case, all three modes contribute to the calculated spectra, including intermode couplings. We have found that diffraction of the ejected electron by the various atomic centers is barely visible in the ratios between vibrationally resolved photoelectron spectra corresponding to different vibrational states of the remaining H2O+ cation (the so-called v-ratios), in contrast to the prominent oscillations observed in K-shell ionization of centrosymmetric molecules, including those that only contain hydrogen atoms around the central atoms, e.g., CH4. To validate the conclusions of our work, we have carried out synchrotron radiation experiments at the SOLEIL synchrotron and determined photoelectron spectra and v-ratios for H2O in a wide range of photon energies, from threshold up to 150 eV. The agreement with the theoretical predictions is good.


MRI blood-brain barrier permeability measurements to predict hemorrhagic transformation in a rat model of ischemic stroke.
Permeability imaging might add valuable information in the risk assessment of hemorrhagic transformation. This study evaluates the predictive value of blood-brain barrier permeability (BBBP) measurements extracted from dynamic contrast-enhanced MRI for hemorrhagic transformation in ischemic stroke. Spontaneously hypertensive and Wistar rats with 2 h filament occlusion of the right MCA underwent MRI during occlusion, at 4 and 24 h post reperfusion. BBBP was imaged by DCE imaging and quantified by Patlak analysis. Cresyl-violet staining was used to characterize hemorrhage in sacrificed rats at 24 h, immediately following the last imaging study. BBBP changes were evaluated at baseline, 4 and 24 h after reperfusion. Receiver-operating characteristic (ROC) analysis was performed to determine the most accurate BBBP threshold to predict hemorrhagic transformation. In animals showing macroscopic hemorrhage at 24 h, 95th BBBP percentile values ipsilateral were 0.323 [0.260, 0.387], 0.685 [0.385, 0.985], and 0.412 [0.210, 0.613] ml/min·100 g (marginal mean [95%CI]) during occlusion, at 4 and 24 h post reperfusion, respectively. The BBBP values on the infarcted and contralateral side were significantly different at 4 (p = 0.034) and 24 h post reperfusion (p = 0.031). The predictive value of BBBP in terms of macroscopic hemorrhage was highest 4 h after reperfusion (ROC area under the curve = 84 %) with a high negative predictive value (98.3 %) and limited positive predictive value (14.9 %) for a threshold of 0.35 ml/min·100g. Altered BBBP is a necessary but not sufficient condition to cause hemorrhagic transformation in rats with an infarct. Further research is needed to identify those additional risk factors that are required for hemorrhagic transformation to develop in the setting of ischemic stroke.


Early pathogenic care and the development of ADHD-like symptoms.
Early pathogenic care that is characterised by disregard for the child's basic emotional needs can lead to severe global psychosocial and cognitive dysfunction and deviant developmental trajectories of brain maturation. Reactive attachment disorder (RAD) is a developmental disorder associated with early pathogenic care that is characterised by markedly disturbed ways of relating socially in most contexts. In addition to other severe emotional dysfunctions, children suffering from RAD often display a high number of comorbid attention deficit/hyperactivity disorder (ADHD) symptoms such as inattention, impulsivity and hyperactivity. It is not yet clear whether ADHD-like symptoms in children exposed to pathogenic care represent a true comorbidity of ADHD or similarities in behavioural dysfunction with a different neurodevelopmental pathway in terms of a phenocopy. In this review, we summarise the findings on the neurobiological consequences of early pathogenic care. Pathogenic care is considered a form of care by a primary caretaker involving a lack or a loss of expectable care, e.g., by early separation, frequent change in caregivers, institutionalisation or neglect. The reviewed studies suggest that a primary dysfunction of limbic brain circuits after early pathogenic care might lead to an interference by motivational or emotional cues impinging on prefrontal executive functions resulting in behavioural similarities with ADHD. Thus, the complex phenotype observed after early pathogenic care might be best described by a dimensional approach with behavioural and neurobiological similarities to ADHD coinciding to a certain degree as a function of early experience. Based on this evidence, suggestions for the treatment of ADHD-like symptoms in children after adverse early life experiences are provided.


Accuracy of Colposcopically Directed Biopsy: Results from an Online Quality Assurance Programme for Colposcopy in a Population-Based Cervical Screening Setting in Italy.
To report the accuracy of colposcopically directed biopsy in an internet-based colposcopy quality assurance programme in northern Italy. A web application was made accessible on the website of the regional Administration. Fifty-nine colposcopists out of the registered 65 logged in, viewed a posted set of 50 digital colpophotographs, classified them for colposcopic impression and need for biopsy, and indicated the most appropriate site for biopsy with a left-button mouse click on the image. Total biopsy failure rate, comprising both nonbiopsy and incorrect selection of biopsy site, was 0.20 in CIN1, 0.11 in CIN2, 0.09 in CIN3, and 0.02 in carcinoma. Errors in the selection of biopsy site were stable between 0.08 and 0.09 in the three grades of CIN while decreasing to 0.01 in carcinoma. In multivariate analysis, the risk of incorrect selection of biopsy site was 1.97 for CIN2, 2.52 for CIN3, and 0.29 for carcinoma versus CIN1. Although total biopsy failure rate decreased regularly with increasing severity of histological diagnosis, the rate of incorrect selection of biopsy site was stable up to CIN3. In multivariate analysis, CIN2 and CIN3 had an independently increased risk of incorrect selection of biopsy site.


The Muscle Fiber Profiles, Mitochondrial Content, and Enzyme Activities of the Exceptionally Well-Trained Arm and Leg Muscles of Elite Cross-Country Skiers.
As one of the most physically demanding sports in the Olympic Games, cross-country skiing poses considerable challenges with respect to both force generation and endurance during the combined upper- and lower-body effort of varying intensity and duration. The isoforms of myosin in skeletal muscle have long been considered not only to define the contractile properties, but also to determine metabolic capacities. The current investigation was designed to explore the relationship between these isoforms and metabolic profiles in the arms (triceps brachii) and legs (vastus lateralis) as well as the range of training responses in the muscle fibers of elite cross-country skiers with equally and exceptionally well-trained upper and lower bodies. The proportion of myosin heavy chain (MHC)-1 was higher in the leg (58 ± 2% [34-69%]) than arm (40 ± 3% [24-57%]), although the mitochondrial volume percentages [8.6 ± 1.6 (leg) and 9.0 ± 2.0 (arm)], and average number of capillaries per fiber [5.8 ± 0.8 (leg) and 6.3 ± 0.3 (arm)] were the same. In these comparable highly trained leg and arm muscles, the maximal citrate synthase (CS) activity was the same. Still, 3-hydroxy-acyl-CoA-dehydrogenase (HAD) capacity was 52% higher (P < 0.05) in the leg compared to arm muscles, suggesting a relatively higher capacity for lipid oxidation in leg muscle, which cannot be explained by the different fiber type distributions. For both limbs combined, HAD activity was correlated with the content of MHC-1 (r2 = 0.32, P = 0.011), whereas CS activity was not. Thus, in these highly trained cross-country skiers capillarization of and mitochondrial volume in type 2 fiber can be at least as high as in type 1 fibers, indicating a divergence between fiber type pattern and aerobic metabolic capacity. The considerable variability in oxidative metabolism with similar MHC profiles provides a new perspective on exercise training. Furthermore, the clear differences between equally well-trained arm and leg muscles regarding HAD activity cannot be explained by training status or MHC distribution, thereby indicating an intrinsic metabolic difference between the upper and lower body. Moreover, trained type 1 and type 2A muscle fibers exhibited similar aerobic capacity regardless of whether they were located in an arm or leg muscle.


Effects of ursolic and oleanolic on SK‑MEL‑2 melanoma cells: In vitro and in vivo assays.
Among the triterpenoids, oleanolic acid (OA) and its isomer, ursolic acid (UA) are promising therapeutic candidates, with potential benefits in the management of melanoma. In this study, we aimed to examine the in vitro and in vivo anti‑invasive and anti‑metastatic activity of OA and UA to determine their possible usefulness as chemopreventive or chemotherapeutic agents in melanoma. For the in vitro experiments, the anti‑proliferative activity of the triterpenic compounds on SK‑MEL‑2 melanoma cells was examined. The anti‑invasive potential was assessed by testing the effects of the active compound on vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) adhesion to melanoma cells. Normal and tumor angiogenesis were evaluated in vivo by chicken embryo chorioallantoic membrane (CAM) assay. The two test triterpenoid acids, UA and OA, exerted differential effects in vitro and in vivo on the SK‑MEL‑2 melanoma cells. UA exerted a significant and dose‑dependent anti‑proliferative effect in vitro, compared to OA. The cytotoxic effects in vitro on the melanoma cells were determined by the examining alterations in the cell cycle phases induced by UA that lead to cell arrest in the S phase. Moreover, UA was found to affect SK‑MEL‑2 melanoma cell invasiveness by limiting the cell adhesion capacity to ICAM molecules, but not influencing their adhesion to VCAM molecules. On the whole, in this study, by assessing the effects of the two triterpenoids in vivo, our results revealed that OA had a greater potential to impair the invasive capacity and tumor angiogenesis compared with UA.


Nasal carriage of Mycobacterium leprae DNA in healthy individuals in Lega Robi village, Ethiopia.
The number of registered leprosy patients world-wide has decreased dramatically after extensive application of WHO recommended Multiple Drug Therapy (MDT). The annual number of new cases has, however, been almost unchanged in several populations, indicating that the infection is still present at community level. Nasal carriage of Mycobacterium leprae DNA was studied in Lega Robi village in Ethiopia. MDT had been applied for more than ten years, and 718 residents over 5 years old were eligible for the study. During the first survey nasal swab samples were collected from 664 (92.5%) individuals. The results of a Peptide Nucleic Acid-ELISA test for M. leprae DNA interpreted by stringent statistical criteria were available for 589 (88.7%) subjects. Thirty-five (5.9%) individuals without clinical signs of leprosy were positive for M. leprae DNA. Seven PCR positive individuals lived in a household where one or two other members were also positive for M. leprae DNA. During a second survey 8 (46%) of 175 interpretable PNA-ELISA tests were positive. Of 137 individuals tested twice, only two were positive on both occasions whereas 10 were PCR positive only once. The study confirms the widespread distribution of M. leprae DNA in healthy individuals. The feasibility of curbing possible transmission of subclinical infection needs further consideration.


Psychosocial Conditions and Resilience Status of Street Children in Jimma Town.
Traditional research and practices focused on an investigation of risk factors to handle psychosocial problems street children faced while surviving on the street. However, more recently, attention has been given to how knowledge can be developed in the area to devise interventions that reflect the promotion of resilience as a means of achieving positive outcomes for the children. The purpose of this study was to explore the psychosocial conditions and resilience status of street children in Jimma Town. Explanatory sequential research design was employed. Out of 246 teenager street children, 137 were selected using simple random sampling. Questionnaire, interview guide and FGD probes were used in data collection. Mean and standard deviation, multiple regression analysis and Man Whitney U T-test were used to analyze quantitative data; while discourse analysis was used to analyze qualitative data. The result of multiple regression analysis indicated that anxiety significantly predicted resilience status, b=.623, t (109) =8.418, p<.001. Anxiety also explained a significant proportion of the variance in resilience status, R2=.388, F (112) = 70.86, p <.001. Further, the result revealed that street children had slow growing resilience status in which boys were more resilient than girls. Street children in Jimma Town faced various psychosocial challenges and had low resilience status. Thus, Jimma Town Women and Children Affairs Office ought to work to build resilience status of street children, in collaboration with different stakeholders in and around the town.


Interaction of gentamicin, dibekacin, netilmicin and amikacin with various penicillins, cephalosporins, minocycline and new fluoro-quinolones against Enterobacteriaceae and Pseudomonas aeruginosa.
Thirty strains of Enterobacteriaceae and ten strains of Pseudomonas aeruginosa were selected to study the in-vitro activity of various combinations containing aminoglycosides, by the checkerboard method. The following aminoglycosides: gentamicin, dibekacin, netilmicin and amikacin were used in combination with each of the following: ampicillin, ticarcillin, piperacillin, cefazolin, cefuroxime, ceftazidime, norfloxacin, enoxacin and minocycline. Synergy was not a constant feature of beta-lactam+aminoglycoside combinations. Discrepancies occurred with the same strain submitted to combinations containing different aminoglycosides. The combinations containing new quinolones+aminoglycosides were usually additive, although occasionally synergy occurred. The combination minocycline+aminoglycoside was usually additive but partial antagonism (FIC or FBC index: 1 X 5- less than 2) occurred in 10 to 40% of the strains depending on the aminoglycoside. The combinations of beta-lactams with dibekacin or netilmicin most frequently produced partial or full synergy against strains of Ps. aeruginosa susceptible to all four aminoglycosides tested.


Effects of transcranial direct current stimulation for treating depression: A modeling study.
Transcranial direct current stimulation (tDCS) above the left dorsolateral prefrontal cortex (lDLPFC) has been widely used to improve symptoms of major depressive disorder (MDD). However, the effects of different stimulation protocols in the entire frontal lobe have not been investigated in a large sample including patient data. We used 38 head models created from structural magnetic resonance imaging data of 19 healthy adults and 19 MDD patients and applied computational modeling to simulate the spatial distribution of tDCS-induced electric fields (EFs) in 20 frontal regions. We evaluated effects of seven bipolar and two multi-electrode 4 × 1 tDCS protocols. For bipolar montages, EFs were of comparable strength in the lDLPFC and in the medial prefrontal cortex (MPFC). Depending on stimulation parameters, EF cortical maps varied to a considerable degree, but were found to be similar in controls and patients. 4 × 1 montages produced more localized, albeit weaker effects. White matter anisotropy was not modeled. The relationship between EF strength and clinical response to tDCS could not be evaluated. In addition to lDLPFC stimulation, excitability changes in the MPFC should also be considered as a potential mechanism underlying clinical efficacy of bipolar montages. MDD-associated anatomical variations are not likely to substantially influence current flow. Individual modeling of tDCS protocols can substantially improve cortical targeting. We make recommendations for future research to explicitly test the contribution of lDLPFC vs. MPFC stimulation to therapeutic outcomes of tDCS in this disorder.