Assessment of Adverse Events in Protocols, Clinical Study Reports, and Published Papers of Trials of Orlistat: A Document Analysis.
Little is known about how adverse events are summarised and reported in trials, as detailed information is usually considered confidential. We have acquired clinical study reports (CSRs) from the European Medicines Agency through the Freedom of Information Act. The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat. The purpose of this study was to study how adverse events were summarised and reported in study protocols, CSRs, and published papers of orlistat trials. We received the CSRs from seven randomised placebo controlled orlistat trials (4,225 participants) submitted by Roche. The CSRs consisted of 8,716 pages and included protocols. Two researchers independently extracted data on adverse events from protocols and CSRs. Corresponding published papers were identified on PubMed and adverse event data were extracted from this source as well. All three sources were compared. Individual adverse events from one trial were summed and compared to the totals in the summary report. None of the protocols or CSRs contained instructions for investigators on how to question participants about adverse events. In CSRs, gastrointestinal adverse events were only coded if the participant reported that they were "bothersome," a condition that was not specified in the protocol for two of the trials. Serious adverse events were assessed for relationship to the drug by the sponsor, and all adverse events were coded by the sponsor using a glossary that could be updated by the sponsor. The criteria for withdrawal due to adverse events were in one case related to efficacy (high fasting glucose led to withdrawal), which meant that one trial had more withdrawals due to adverse events in the placebo group. Finally, only between 3% and 33% of the total number of investigator-reported adverse events from the trials were reported in the publications because of post hoc filters, though six of seven papers stated that "all adverse events were recorded." For one trial, we identified an additional 1,318 adverse events that were not listed or mentioned in the CSR itself but could be identified through manually counting individual adverse events reported in an appendix. We discovered that the majority of patients had multiple episodes of the same adverse event that were only counted once, though this was not described in the CSRs. We also discovered that participants treated with orlistat experienced twice as many days with adverse events as participants treated with placebo (22.7 d versus 14.9 d, p-value < 0.0001, Student's t test). Furthermore, compared with the placebo group, adverse events in the orlistat group were more severe. None of this was stated in the CSR or in the published paper. Our analysis was restricted to one drug tested in the mid-1990s; our results might therefore not be applicable for newer drugs. In the orlistat trials, we identified important disparities in the reporting of adverse events between protocols, clinical study reports, and published papers. Reports of these trials seemed to have systematically understated adverse events. Based on these findings, systematic reviews of drugs might be improved by including protocols and CSRs in addition to published articles.


Instantaneous monitoring of sleep fragmentation by point process heart rate variability and respiratory dynamics.
We present a novel, automatic point-process approach that is able to provide continuous, instantaneous estimates of heart rate variability (HRV) and respiratory sinus arrhythmia (RSA) in long duration data recordings such as those during an entire night of sleep. We analyze subjects with and without sleep apnea who underwent diagnostic polysomnography. The proposed algorithm is able to quantify multi-scale high time resolution autonomic signatures of sleep fragmentation, such as arousals and stage transitions, throughout an entire night. Results demonstrate the ability of our methods to track fast dynamic transitions from sleep to wake and between REM sleep and other sleep stages, providing resolution details not available in sleep scoring summaries. An automatic threshold-based procedure is further able to detect brief arousals, with the instantaneous indices characterizing specific arousal dynamic signatures.


Oral health-related quality of life and unmet dental needs among women living with HIV.
Oral health-related quality of life (OHRQoL) is a multidimensional, perception-based measure of how oral health affects social and physical functioning and self-image. OHRQoL is important for assessing women living with HIV (WLWH) who may have unmet dental needs and experience disparities that impact dental care accessibility. In 2016, the authors conducted an assessment of OHRQoL among a national sample of 1,526 WLWH in the Women's Interagency HIV Study using the Oral Health Impact Profile instrument, which assesses the frequency of 14 oral health impact items. OHRQoL was measured using multivariable linear regression with a negative binomial distribution to assess the association between report of a recent unmet dental need and OHRQoL. "Fair or poor" oral health condition was reported by 37.8% (n = 576) of WLWH. Multivariable linear regression showed that unmet dental needs had the strongest positive association with poor OHRQoL (difference in Oral Health Impact Profile mean, 2.675; P < .001) compared with not having unmet needs. The frequency of dental care utilization was not associated with higher OHRQoL. Older age, fair or poor dental condition, smoking, symptoms of anxiety and loneliness, and poor OHRQoL were also associated with worse OHRQoL. Self-perceived impact of oral health on social and physical function and self-image, as measured by OHRQoL, may be an easily assessable but underrecognized aspect of OHRQoL, particularly among women aging with HIV. Dentists should implement OHRQoL assessments in their management of the care of patients with HIV to identify those who do have significant oral health impacts.


Ruinous resident: the hydroid Ectopleura crocea negatively affects suspended culture of the mussel Mytilus galloprovincialis.
Hydroids are major biofouling organisms in global aquaculture. Colonies of the hydroid Ectopleura crocea have recently established in Australian commercial mussel leases culturing Mytilus galloprovincialis. This study examined the impacts of E. crocea on mussel culture at two stages of the production cycle: spatfall and grow-out. Hydroids most commonly fouled the body, edge and dorsal regions of the mussel shell and cause a reduction in the length (4%) and weight (23%) of juvenile mussels. They also consumed mussel larvae in the field and in the laboratory. Prey numbers of many taxa, including mussel larvae, were consistent in natural hydroid diets regardless of the temporal variation in prey availability, implying some selectivity in hydroid feeding. In the laboratory, E. crocea consumed settling plantigrade mussel larvae more readily than trochophore or veliger larvae. Fouling by E. crocea is detrimental to mussel condition, and may affect the availability of wild mussel larvae in the commercial culture of M. galloprovincialis.


Bright metal coatings from sustainable electrolytes: the effect of molecular additives on electrodeposition of nickel from a deep eutectic solvent.
Organic and inorganic additives are often added to nickel electroplating solutions to improve surface finish, reduce roughness and promote uniform surface morphology of the coatings. Such additives are usually small molecules and often referred to as brighteners or levellers. However, there have been limited investigations into the effect of such additives on electrodeposition from ionic liquids (ILs) and deep eutectic solvents (DESs). Here we study the effect of four additives on electrolytic nickel plating from an ethyleneglycol based DES; these are nicotinic acid (NA), methylnicotinate (MN), 5,5-dimethylhydantoin (DMH) and boric acid (BA). The additives show limited influence on the bulk Ni(ii) speciation but have significant influence on the electrochemical behaviour of Ni deposition. Small concentrations (ca. 15 mM) of NA and MN show inhibition of Ni(ii) reduction whereas high concentrations of DMH and BA are required for a modest difference in behaviour from the additive free system. NA and MN also show that they significantly alter the nucleation and growth mechanism when compared to the additive free system and those with DMH and BA. Each of the additive systems had the effect of producing brighter and flatter bulk electrodeposits with increased coating hardness but XRD shows that NA and MN direct crystal growth to the [111] orientation whereas DMH and BA direct crystal growth to the [220] orientation.


Prognostic value of tumor growth factor levels during chemotherapy in patients with metastatic colorectal cancer.
Tumor growth and angiogenic factors are usually overexpressed in colorectal carcinomas. We aimed to assess the prognostic role of VEGF, bFGF, PDGF-AA, EGF, HGF, and E-selectin in patients with metastatic colorectal cancer treated with capecitabine and oxaliplatin (XELOX) chemotherapy protocol. Thirty-eight colorectal cancer patients who had evidence of distant metastasis were enrolled in the study. Angiogenic factors were measured before and after third cycle of chemotherapy. Patients were randomized into three groups, partial response (PR), stable disease (SD), and progressive disease (PD) groups, according to their clinical and radiologic evaluation after three cycles of XELOX chemotherapy. Eighteen patients (47.3 %) achieved partial response, 10 (26.3 %) stable disease, and 10 (26.3 %) progressive disease. VEGF (63.20 Pg/ml vs. 19,79 Pg/ml; p < 0.001), EGF (7.29 ± 3.08 Pg/ml vs. 4.79 ± 2.05 Pg/ml; p < 0.011), HGF (618.16 ± 340.39 Pg/ml vs. 452.02 ± 217.18 Pg/ml; p < 0.049), and PDGF-AA (691.68 ± 187.10 Pg/ml vs. 404.89 ± 168.47 Pg/ml; p < 0.001) were significantly decreased in PR group. PDGF-AA levels were also decreased in SD group (706.66 ± 206.66 Pg/ml vs. 389.79 ± 143.16 Pg/ml; p < 0,001). HGF levels were significantly increased in PD disease group (449.99 Pg/ml vs. 682.22 Pg/ml; p < 0.046). The baseline E-selectin levels were inversely proportional with overall survival that could be an important prognostic factor at the time of diagnosis. This study demonstrated that tumor growth factors can be helpful to determine colorectal cancer prognosis and overall survival in patients with metastatic disease. VEGF, HGF, EGF, and PDGF-AA levels were decreased in PR group. However, meaningful increment was seen HGF levels in PD group. Angiogenic factors and E-selectin provided unique prognostic information in advanced colorectal carcinoma patients.


ARE WARNING COLORS HANDICAPS?
The handicap theory, in which the cost of waste guarantees honest advertising, is being used increasingly in solutions to the problems of biological signal evolution. However, it is usually applied to systems which are insufficiently understood to allow testing against alternative theories. In particular, the ability of the handicap theory to explain the design of signals has never been properly tested. We test its ability to explain signal design features in an unusually well studied area of biological signalling: warning coloration and mimicry. Since a full handicap model proves immediately unrealistic, we modify the model to incorporate realistic assumptions about predator learning. Using this model we explicitly compare the handicap theory with a purely "conventional" signalling model and with a null model. Predictions relating to three key design features (conspicuousness, pattern similarity, and Batesian mimicry) are compared, and tested against available data. Although many predictions remain to be tested adequately, we conclude that: (i) conspicuousness is most plausibly explained by the conventional signalling theory that ascribes the function of conspicuous coloration to signal efficacy rather than waste; (ii) pattern similarity, within and between species, is unlikely to be the result of the need to produce similar degrees of conspicuousness, as predicted by the handicap theory, but is plausibly explained as the result of pattern generalization amongst discriminating predators, as predicted by the conventional signalling theory; and (iii) Batesian mimicry is predicted by the conventional signalling theory, but not the handicap theory. Therefore the handicap theory fails to provide an adequate explanation of the main design features of at least one major signalling system.


Phenotypic variation in the familial atypical multiple mole-melanoma syndrome (FAMMM).
The familial atypical multiple mole-melanoma syndrome (FAMMM) is characterised by an autosomal dominantly inherited susceptibility to multiple atypical moles which show variable colouration ranging from black to brown, tan, red, or pink, with occasional variegation. These compound naevi may be macular or papular, with regular or irregular borders, and measure 1 cm or more in size. They may be few in number or absent or may exceed 100 in a given patient. They are located predominantly on areas not exposed to the sun. Dysplastic changes in melanocytes, fibroplasia, focal chronic inflammatory cell infiltrate, and new blood vessel formation of the papillary dermis characterise their histopathology. These findings are not uniformly present. Because of these distinctive features, coupled with their propensity for transformation to cutaneous malignant melanoma, little attention has been given to the possibility of either minimal or absent cutaneous expression of the phenotype or more diverse neoplastic involvement in this disease. These latter phenomena, which we ascribe to the pleiotropic effects of the cancer-prone FAMMM genotype, were observed in a single FAMMM kindred, the subject of this report.


Are gender, marital status or parenthood risk factors for outcome of treatment for chronic disabling spinal disorders?
Recent clinical research has suggested that single working mothers may differ in their response to health treatment and outcomes, relative to their married female or male counterparts. The present study explored, on an a priori basis, the existence and extent of differences in chronic pain rehabilitation outcomes of pain report, return-to-work and future health utilization for single working mothers, relative to other patients. A cohort of 1,679 consecutive chronically disabled work related spinal disorder (CDWRSD) patients were placed into one of eight groups as a function of gender, marital status (single/married), and parenthood (with/without children). All patients completed an assessment battery measuring psychosocial variables at pre- and post-treatment, and a structured clinical interview evaluating socioeconomic outcomes at 1 year following completion of a 5-7 week functional restoration program. Results revealed that single females with children differed from all other groups in racial representation, with 57.1% of these individuals being African American, widely disparate from the prevailing local ethnicity. Single females and males with children were represented by a higher incidence of cervical injuries (25.0% and 26.7%, respectively) than all other groups (5.4-16.6%, p < .001). Contrary to expectation, the 8 groups did not differ significantly in program completion rate, work return, work retention, health utilization, recurrent injury or case settlement rates at one-year follow-up. The single females with children group did display greater levels of depression pre-treatment compared to the other groups. However, at post-treatment, these differences no longer existed. This investigation is one of the first to examine if the combination of gender and parenthood distinguishes significantly among CDWRSD patients. Overall, contrary to expectation, the single mothers did not show any significant differences in CDWRSD outcome at one-year post-rehab follow-up, and the single mothers and fathers showed no differences in depression or pain severity post-treatment. Thus, in spite of the societal belief to the contrary, it seems that single parent patients can show similar chronic pain rehabilitation outcomes, relative to other CDWRSD patients, after a prescribed course of tertiary functional restoration rehabilitation.


Mycophenolate mofetil reduces the risk of acute rejection less in African-American than in Caucasian kidney recipients.
Multicenter clinical trials have shown that mycophenolate mofetil (MMF) reduces the risk of acute rejection, but it is unknown whether African-Americans constitute a subgroup of recipients less likely to benefit from MMF. This study compared the acute rejection rates within 6 months of kidney transplantation in MMF-treated transplant patients with those on azathioprine (AZA) at a single center. The study population consisted of 353 consecutive recipients of cadaver or living donor kidney transplants. African-Americans constituted 43% of the patients on AZA and 49% of the patients on MMF. Variables used in a Cox regression analysis included MMF immunosuppression, recipient race, type of transplant, delayed graft function, postoperative immune induction, average cyclosporine trough level, and HLA mismatch. Significantly fewer patients on MMF experienced a biopsy-proven rejection episode than those treated with AZA (24% vs. 42%, respectively; relative risk [RR]=0.57, P=0.001). This decrease in risk was greater in Caucasian transplant recipients (MMF vs. AZA: 16% vs. 46%, RR=0.35, P < 0.001) than in African-American patients (32% vs. 36%, RR=0.88, P=0.6). Within each race stratum, the mean cyclosporine trough levels averaged over 2-week intervals were nearly identical for AZA- compared with MMF-treated patients. In the regression model, the effect of MMF on the incidence of rejection was again less in African-American than in Caucasian patients. Kidney recipients treated with MMF have a significantly lower risk of acute rejection within 6 months of transplantation than those given AZA. This reduction in risk is significantly less in African-American recipients than Caucasians.


Extensor Mechanism Reconstruction for Chronic Patellar Fracture.
Patients with displaced patellar fractures typically present with disruption to the extensor mechanism requiring acute surgical intervention. Chronic patellar fractures with disruption of the extensor mechanism are uncommon, and few surgical options are available. The authors present a patient who sustained a fracture to the inferior pole of the patella in Africa 5 years prior that was managed conservatively with bands and a brace. He decided to pursue surgical intervention because of difficulties with leg extension, weakness, and ambulation. The patient underwent a novel reconstruction of his chronic extensor mechanism loss with a combination of inferior pole patellar fracture excision, z-plasty and lengthening of the quadriceps tendon, and Achilles tendon reconstruction of the patellar tendon with both hamstring autograft and acellular human dermal matrix allograft augmentation of the entire reconstruction construct. At the final 2-year follow-up, the patient had restored active extension with no extensor lag and had returned to his preinjury activities, including running and playing soccer. [Orthopedics. 2018; 41(1):e145-e150.].


Interventions to improve team effectiveness within health care: a systematic review of the past decade.
A high variety of team interventions aims to improve team performance outcomes. In 2008, we conducted a systematic review to provide an overview of the scientific studies focused on these interventions. However, over the past decade, the literature on team interventions has rapidly evolved. An updated overview is therefore required, and it will focus on all possible team interventions without restrictions to a type of intervention, setting, or research design. To review the literature from the past decade on interventions with the goal of improving team effectiveness within healthcare organizations and identify the "evidence base" levels of the research. Seven major databases were systematically searched for relevant articles published between 2008 and July 2018. Of the original search yield of 6025 studies, 297 studies met the inclusion criteria according to three independent authors and were subsequently included for analysis. The Grading of Recommendations, Assessment, Development, and Evaluation Scale was used to assess the level of empirical evidence. Three types of interventions were distinguished: (1) Training, which is sub-divided into training that is based on predefined principles (i.e. CRM: crew resource management and TeamSTEPPS: Team Strategies and Tools to Enhance Performance and Patient Safety), on a specific method (i.e. simulation), or on general team training. (2) Tools covers tools that structure (i.e. SBAR: Situation, Background, Assessment, and Recommendation, (de)briefing checklists, and rounds), facilitate (through communication technology), or trigger (through monitoring and feedback) teamwork. (3) Organizational (re)design is about (re)designing structures to stimulate team processes and team functioning. (4) A programme is a combination of the previous types. The majority of studies evaluated a training focused on the (acute) hospital care setting. Most of the evaluated interventions focused on improving non-technical skills and provided evidence of improvements. Over the last decade, the number of studies on team interventions has increased exponentially. At the same time, research tends to focus on certain interventions, settings, and/or outcomes. Principle-based training (i.e. CRM and TeamSTEPPS) and simulation-based training seem to provide the greatest opportunities for reaching the improvement goals in team functioning.


Differential regulation of steroidogenesis by bone morphogenetic proteins in granulosa cells: involvement of extracellularly regulated kinase signaling and oocyte actions in follicle-stimulating hormone-induced estrogen production.
In the present study, we investigated the cellular mechanism by which oocytes and bone morphogenetic proteins (BMPs) govern FSH-induced steroidogenesis using rat primary granulosa cells. BMP-6 and BMP-7 both inhibited FSH- and forskolin (FSK)-induced progesterone synthesis and reduced cAMP synthesis independent of the presence or absence of oocytes. BMP-7 also increased FSH-induced estradiol production, and the response was further augmented in the presence of oocytes. In contrast, BMP-6 had no impact on estradiol synthesis regardless of the presence of oocytes. Because BMP-7 changed neither FSK- nor cAMP-induced estradiol production, the BMP-7 action was mediated through a FSH receptor signaling mechanism that was independent of cAMP-protein kinase A pathway. Treatment with FSH but not cAMP activated ERK1/2 phosphorylation in granulosa cells, which was further accelerated by oocytes. A specific ERK inhibitor, U0126, increased estradiol production and decreased FSH- and FSK-induced progesterone production and cAMP synthesis. This suggests that ERK activation is directly linked to inhibition of estradiol synthesis and amplification of cAMP. Moreover, FSH-induced ERK1/2 phosphorylation was inhibited by BMP-7 but not influenced by BMP-6. In contrast, BMP signaling including Smad1/5/8 phosphorylation and Id-1 transcription was up-regulated by FSH and oocytes in granulosa cells through inhibition of Smad6/7 expression. Collectively, oocytes enhance FSH-induced MAPK activation and BMP signaling in granulosa cells, which leads to differential regulation of steroidogenesis elicited by BMPs in the presence of FSH in developing follicles.


Efficacy and safety of N-acetylcysteine therapy for idiopathic pulmonary fibrosis: An updated systematic review and meta-analysis.
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal lung disease with poor prognosis and limited treatment options. N-acetylcysteine (NAC), an anti-oxidant drug, has promising potential in the treatment of IPF. In the present systematic review and meta-analysis, the efficacy and safety of NAC for IPF were investigated. The following databases were comprehensively searched for relevant studies published until August 2018: Pubmed, Embase, Cochrane library, Chinese National Knowledge Infrastructure, Wangfang Database, VIP and the Chinese Biology Medical Database. A total of 21 controlled trials assessing the efficacy and safety of NAC therapy for IPF were identified and primary outcomes [forced vital capacity (FVC), adverse side effects] and secondary outcomes [diffusing capacity for carbon monoxide (DLCO) and its percentage predicted value (DLCO%), vital capacity (VC), partial arterial oxygen pressure (PaO2), 6-min walking distance test and mortality] were extracted for the meta-analysis. The risk ratio and mean difference or standardized mean difference with 95% confidence interval were calculated using RevMan 5.3 software. Analysis of the pooled data revealed that, compared with control treatments (routine treatment or drugs other than anti-oxidants), NAC therapy reduced the decline in lung function, as indicated by the FVC and DLCO, and slowed the progression of the disease, as indicated by the PaO2, while complications and mortality were similar. These results suggest good efficacy, tolerability and safety of the treatment. Furthermore, subgroup analysis revealed that combined therapy including NAC for IPF might be more effective than NAC monotherapy, while oral administration of NAC was safer than inhalation. In conclusion, the results of the present review and meta-analysis provide important information that may serve as a guide regarding NAC therapy for IPF in clinical practice.


Childhood cancer incidence by ethnic group in England, 2001-2007: a descriptive epidemiological study.
After the first year of life, cancers are the commonest cause of death in children. Incidence rates vary between ethnic groups, and recent advances in data linkage allow for a more accurate estimation of these variations. Identifying such differences may help identify potential risk or protective factors for certain childhood cancers. This study thus aims to ascertain whether such differences do indeed exist using nationwide data across seven years, as have previously been described in adult cancers. We obtained data for all cancer registrations for children (aged 0-14) in England from January 2001 to December 2007. Ethnicity (self-assigned) was established through record linkage to the Hospital Episodes Statistics database or cancer registry data. Cancers were classified morphologically according to the International Classification of Childhood Cancer into four groups - leukaemias; lymphomas; central nervous system; and other solid tumours. Age standardised incidence rates were estimated for each ethnic group, as well as incidence rate ratios comparing each individual ethnic group (Indian, Pakistani, Bangladeshi, Black African, Black Carribean, Chinese) to Whites, adjusting for sex, age and deprivation. The majority of children in the study are UK born. Black children (RR = 1.18, 99% CI: 1.01-1.39), and amongst South Asians, Pakistani children (RR = 1.19, 99% CI: 1.02-1.39) appear to have an increased risk of all cancers. There is an increased risk of leukaemia in South Asians (RR = 1.31, 99% CI: 1.08-1.58), and of lymphoma in Black (RR = 1.72, 99% CI: 1.13-2.63) and South Asian children (RR = 1.51, 99% CI: 1.10-2.06). South Asians appear to have a decreased risk of CNS cancers (RR = 0.71, 99% CI: 0.54-0.95). In the tradition of past migrant studies, such descriptive studies within ethnic minority groups permit a better understanding of disease incidence within the population, but also allow for the generation of hypotheses to begin to understand why such differences might exist. Though a major cause of mortality in this age group, childhood cancer remains a relatively rare disease; however, the methods used here have permitted the first nationwide estimation of childhood cancer by individual ethnic group.


Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation.
Clonal haematopoiesis of indeterminate potential (CHIP), defined as the presence of an expanded somatic blood cell clone without other haematological abnormalities, was recently shown to increase with age and is associated with coronary artery disease and calcification. The most commonly mutated CHIP genes, DNMT3A and TET2, were shown to regulate inflammatory potential of circulating leucocytes. The incidence of degenerative calcified aortic valve (AV) stenosis increases with age and correlates with chronic inflammation. We assessed the incidence of CHIP and its association with inflammatory blood cell phenotypes in patients with AV stenosis undergoing transfemoral aortic valve implantation (TAVI). Targeted amplicon sequencing for DNMT3A and TET2 was performed in 279 patients with severe AV stenosis undergoing TAVI. Somatic DNMT3A- or TET2-CHIP-driver mutations with a VAF ≥ 2% were detected in 93 out of 279 patients (33.3%), with an age-dependent increase in the incidence from 25% (55-69 years) to 52.9% (90-100 years). Patients with DNMT3A- or TET2-CHIP-driver mutations did not differ from patients without such mutations in clinical parameters, concomitant atherosclerotic disease, blood cell counts, inflammatory markers, or procedural characteristics. However, patients with DNMT3A- or TET2-CHIP-driver mutations had a profoundly increased medium-term all-cause mortality following successful TAVI. Differential myeloid and T-cell distributions revealed pro-inflammatory T-cell polarization in DNMT3A-mutation carriers and increased pro-inflammatory non-classical monocytes in TET2-mutation carriers. This is the first study to show that acquired somatic mutations in the most commonly mutated CHIP-driver genes occur frequently in patients with severe degenerative AV stenosis, are associated with increased pro-inflammatory leucocyte subsets, and confer a profound increase in mortality following successful TAVI.


Electron microscopy techniques employed to explore mitochondrial defects in the developing rat brain following ketamine treatment.
Ketamine, an FDA-approved N-methyl-D-aspartate (NMDA) receptor antagonist, is commonly used for general pediatric anesthesia. Accumulating evidence has indicated that prolonged exposure to ketamine induces widespread apoptotic cell death in the developing brains of experimental animals. Although mitochondria are known to play a pivotal role in cell death, little is known about the alterations in mitochondrial ultrastructure that occur during ketamine-induced neurotoxicity. The objective of this pilot study was to utilize classic and contemporary methods in electron microscopy to study the impact of ketamine on the structure of mitochondria in the developing rat brain. While transmission electron microscopy (TEM) was employed to comprehensively study mitochondrial inner membrane topology, serial block-face scanning electron microscopy (SBF-SEM) was used as a complementary technique to compare the overall mitochondrial morphology from a representative treated and untreated neuron. In this study, postnatal day 7 (PND-7) Sprague-Dawley rats were treated with ketamine or saline (6 subcutaneous injections × 20 mg/kg or 10 ml/kg, respectively, at 2-h intervals with a 6-h withdrawal period after the last injection, n=6 each group). Samples from the frontal cortex were harvested and analyzed using TEM or SBF-SEM. While classic TEM revealed that repeated ketamine exposure induces significant mitochondrial swelling in neurons, the newer technique of SBF-SEM confirmed the mitochondrial swelling in three dimensions (3D) and showed that ketamine exposure may also induce mitochondrial fission, which was not observable in the two dimensions (2D) of TEM. Furthermore, 3D statistical analysis of these reconstructed mitochondria appeared to show that ketamine-treated mitochondria had significantly larger volumes per unit surface area than mitochondria from the untreated neuron. The ultrastructural mitochondrial alterations demonstrated here by TEM and SBF-SEM support ketamine's proposed mechanism of neurotoxicity in the developing rat brain.


The Ankyrin Repeat Domain Controls Presynaptic Localization of Drosophila Ankyrin2 and Is Essential for Synaptic Stability.
The structural integrity of synaptic connections critically depends on the interaction between synaptic cell adhesion molecules (CAMs) and the underlying actin and microtubule cytoskeleton. This interaction is mediated by giant Ankyrins, that act as specialized adaptors to establish and maintain axonal and synaptic compartments. In Drosophila, two giant isoforms of Ankyrin2 (Ank2) control synapse stability and organization at the larval neuromuscular junction (NMJ). Both Ank2-L and Ank2-XL are highly abundant in motoneuron axons and within the presynaptic terminal, where they control synaptic CAMs distribution and organization of microtubules. Here, we address the role of the conserved N-terminal ankyrin repeat domain (ARD) for subcellular localization and function of these giant Ankyrins in vivo. We used a P[acman] based rescue approach to generate deletions of ARD subdomains, that contain putative binding sites of interacting transmembrane proteins. We show that specific subdomains control synaptic but not axonal localization of Ank2-L. These domains contain binding sites to L1-family member CAMs, and we demonstrate that these regions are necessary for the organization of synaptic CAMs and for the control of synaptic stability. In contrast, presynaptic Ank2-XL localization only partially depends on the ARD but strictly requires the presynaptic presence of Ank2-L demonstrating a critical co-dependence of the two isoforms at the NMJ. Ank2-XL dependent control of microtubule organization correlates with presynaptic abundance of the protein and is thus only partially affected by ARD deletions. Together, our data provides novel insights into the synaptic targeting of giant Ankyrins with relevance for the control of synaptic plasticity and maintenance.


Radical cystectomy in patients with preexisting three-piece inflatable penile prosthesis.
Radical cystectomy with urinary diversion is the treatment of choice for muscle-invasive, and certain populations with non-invasive, urothelial carcinoma of the bladder. There have not been any reports to date on patients undergoing this surgery who have had previous placement of an inflatable penile prosthesis. To present the outcomes of four patients with pre-existing inflatable penile prostheses (IPP) with reservoirs within the space of Retzius who were subsequently treated with radical cystectomy for bladder cancer management. After obtaining institutional review board approval, the demographic, clinical, and pathologic data were reviewed in the Johns Hopkins Cystectomy Database for patients who underwent radical cystectomy for bladder cancer from 1994 to 2012. A case series of four patients is presented who had a preexisting IPP and their post-operative course and long-term outcomes are reviewed. All four patients had radical cystectomy and ileal conduit urinary diversion with no intra-operative or post-operative complications. One patient was not sexually active and therefore had the reservoir explanted and not replaced. The other three patients had the reservoir removed prior to bladder extirpation and the tubing capped, with reservoir replacement in the pseudocapsule at the termination of the procedure. In one patient an omental flap was used to ensure separation between the reservoir and ileal conduit. The devices were all functional intra-operatively and on follow-up. As erectile dysfunction is more commonly being diagnosed and treated with IPP insertion at younger ages, surgeons will increasingly encounter pre-placed abdominal reservoirs when performing pelvic surgery. This case series of four patients undergoing radical cystectomy with prior-placed IPPs reveals that the functionality of the IPP can be preserved while still performing oncologically sound extirpative procedures.


Determinants of sensitivity of human T-cell leukemia CCRF-CEM cells to immucillin-H.
Immucillin-H (BCX-1777, forodesine) is a transition state analogue and potent inhibitor of PNP that shows promise as a specific agent against activated human T-cells and T-cell leukemias. The immunosuppressive or antileukemic effects of Immucillin-H (ImmH) in cultured cells require co-administration with deoxyguanosine (dGuo) to attain therapeutic levels of intracellular dGTP. In this study we investigated the requirements for sensitivity and resistance to ImmH and dGuo. (3)H-ImmH transport assays demonstrated that the equilibrative nucleoside transporters (ENT1 and ENT2) facilitated the uptake of ImmH in human leukemia CCRF-CEM cells whereas (3)H-dGuo uptake was primarily dependent upon concentrative nucleoside transporters (CNTs). Analysis of lysates from ImmH-resistant CCRF-CEM-AraC-8D cells demonstrated undetectable deoxycytidine kinase (dCK) activity, suggesting that dCK and not deoxyguanosine kinase (dGK) was the rate-limiting enzyme for phosphorylation of dGuo in these cells. Examination of ImmH cytotoxicity in a hypoxanthine-guanine phosphoribosyltransferase (HGPRT)-deficient cell line CCRF-CEM-AraC-8C, demonstrated enhanced sensitivity to low concentrations of ImmH and dGuo. RT-PCR and sequencing of HGPRT from the HGPRT-deficient CCRF-CEM-AraC-8C cells identified an Exon 8 deletion mutation in this enzyme. Thus these studies show that specific nucleoside transporters are required for ImmH cytotoxicity and predict that ImmH may be more cytotoxic to 6-thioguanine (6-TG) or 6-thiopurine-resistant leukemia cells caused by HGPRT deficiency.


Oil Exposure Impairs In Situ Cardiac Function in Response to β-Adrenergic Stimulation in Cobia (Rachycentron canadum).
Aqueous crude oil spills expose fish to varying concentrations of dissolved polycyclic aromatic hydrocarbons (PAHs), which can have lethal and sublethal effects. The heart is particularly vulnerable in early life stages, as PAH toxicity causes developmental cardiac abnormalities and impaired cardiovascular function. However, cardiac responses of juvenile and adult fish to acute oil exposure remain poorly understood. We sought to assess cardiac function in a pelagic fish species, the cobia (Rachycentron canadum), following acute (24 h) exposure to two ecologically relevant levels of dissolved PAHs. Cardiac power output (CPO) was used to quantify cardiovascular performance using an in situ heart preparation. Cardiovascular performance was varied using multiple concentrations of the β-adrenoceptor agonist isoproterenol (ISO) and by varying afterload pressures. Oil exposure adversely affected CPO with control fish achieving maximum CPO's (4 mW g-1 Mv) greater than that of oil-exposed fish (1 mW g-1 Mv) at ISO concentrations of 1 × 10-6 M. However, the highest concentration of ISO (1 × 10-5 M) rescued cardiac function. This indicates an interactive effect between oil-exposure and β-adrenergic stimulation and suggests if animals achieve very large increases in β-adrenergic stimulation it could play a compensatory role that may mitigate some adverse effects of oil-exposure in vivo.


Numerical grading of astrocytomas.
Ninety-three astrocytomas from biopsy material including glioblastomas ('astrocytomas grade 4') were graded according to Kernohan (1949) by light microscopy. Feulgen sections were subjected to an automated microscopic analysis to obtain morphometric-densitometric data of the tumour cell nuclei. These quantitative and reproducible data showed a significant correlation with malignancy expressed in terms of Kernohan and prove automated image analysis to be a valuable tool in the grading of gliomas. This is in particular true if the nuclear parameters determined by image analysis are completed by histologic features which were recorded semiquantitatively by subjective light microscopic evaluation as is usual in clinic pathologic diagnosis of brain tumours. A quadratic discriminant analysis of morphometric-densitometric data of tumour cell nuclei and semiquantitative microscopic data gave a 94% agreement with subjective grading.


Improved production of a heterologous amylase in Saccharomyces cerevisiae by inverse metabolic engineering.
The increasing demand for industrial enzymes and biopharmaceutical proteins relies on robust production hosts with high protein yield and productivity. Being one of the best-studied model organisms and capable of performing posttranslational modifications, the yeast Saccharomyces cerevisiae is widely used as a cell factory for recombinant protein production. However, many recombinant proteins are produced at only 1% (or less) of the theoretical capacity due to the complexity of the secretory pathway, which has not been fully exploited. In this study, we applied the concept of inverse metabolic engineering to identify novel targets for improving protein secretion. Screening that combined UV-random mutagenesis and selection for growth on starch was performed to find mutant strains producing heterologous amylase 5-fold above the level produced by the reference strain. Genomic mutations that could be associated with higher amylase secretion were identified through whole-genome sequencing. Several single-point mutations, including an S196I point mutation in the VTA1 gene coding for a protein involved in vacuolar sorting, were evaluated by introducing these to the starting strain. By applying this modification alone, the amylase secretion could be improved by 35%. As a complement to the identification of genomic variants, transcriptome analysis was also performed in order to understand on a global level the transcriptional changes associated with the improved amylase production caused by UV mutagenesis.


Role of sulfhydryls in mucosal injury caused by ethanol: relation to microvascular permeability, gastric motility and cytoprotection.
The relationship between gastric mucosal glutathione (GSH) levels, vascular permeability, gastric motility and mucosal injury caused by ethanol was investigated in rats. Oral administration of 50% ethanol (1 ml) produced elongated reddish bands of lesions in the mucosa with a significant reduction of GSH levels and increase of microvascular permeability. These lesions were significantly inhibited by pretreatment with s.c. administered diethylmaleate (DEM: 1 ml/kg), cysteamine (100 mg/kg) and 16, 16-dimethyl prostaglandin E2 (dmPGE2, 10 micrograms/kg) but worsened markedly by N-ethylmaleimide (NEM: 10 mg/kg). Irrespective of whether the animals were treated with 50% ethanol or not, the mucosal GSH levels were significantly decreased or increased, respectively, by DEM or cysteamine, and were not affected by both NEM and dmPGE2. NEM significantly enhanced the vascular permeability in the absence or presence of ethanol (greater than 10%), whereas other agents significantly inhibited only the increased vascular permeability caused by ethanol. On the other hand, gastric motility was potently and persistently inhibited by either DEM, cysteamine or dmPGE2 at the doses which prevented ethanol-induced mucosal injury, whereas NEM had no effect on the motility. These results suggest that 1) the mucosal GSH levels do not relate directly to either development or prevention of ethanol-induced gastric injury, 2) potentiation by NEM of the mucosal injury may be accounted for by its enhancement of the vascular permeability and 3) inhibition of gastric motility may be associated with prevention of mucosal lesions.


Optical coupling to nanoscale optomechanical cavities for near quantum-limited motion transduction.
A significant challenge in the development of chip-scale cavity-optomechanical devices as testbeds for quantum experiments and classical metrology lies in the coupling of light from nanoscale optical mode volumes to conventional optical components such as lenses and fibers. In this work we demonstrate a high-efficiency, single-sided fiber-optic coupling platform for optomechanical cavities. By utilizing an adiabatic waveguide taper to transform a single optical mode between a photonic crystal zipper cavity and a permanently mounted fiber, we achieve a collection efficiency for intracavity photons of 52% at the cavity resonance wavelength of λ ≈ 1538 nm. An optical balanced homodyne measurement of the displacement fluctuations of the fundamental in-plane mechanical resonance at 3.3 MHz reveals that the imprecision noise floor lies a factor of 2.8 above the standard quantum limit (SQL) for continuous position measurement, with a predicted total added noise of 1.4 phonons at the optimal probe power. The combination of extremely low measurement noise and robust fiber alignment presents significant progress towards single-phonon sensitivity for these sorts of integrated micro-optomechanical cavities.


Good fences: the importance of setting boundaries for peaceful coexistence.
We consider the conditions of peace and violence among ethnic groups, testing a theory designed to predict the locations of violence and interventions that can promote peace. Characterizing the model's success in predicting peace requires examples where peace prevails despite diversity. Switzerland is recognized as a country of peace, stability and prosperity. This is surprising because of its linguistic and religious diversity that in other parts of the world lead to conflict and violence. Here we analyze how peaceful stability is maintained. Our analysis shows that peace does not depend on integrated coexistence, but rather on well defined topographical and political boundaries separating groups, allowing for partial autonomy within a single country. In Switzerland, mountains and lakes are an important part of the boundaries between sharply defined linguistic areas. Political canton and circle (sub-canton) boundaries often separate religious groups. Where such boundaries do not appear to be sufficient, we find that specific aspects of the population distribution guarantee either sufficient separation or sufficient mixing to inhibit intergroup violence according to the quantitative theory of conflict. In exactly one region, a porous mountain range does not adequately separate linguistic groups and that region has experienced significant violent conflict, leading to the recent creation of the canton of Jura. Our analysis supports the hypothesis that violence between groups can be inhibited by physical and political boundaries. A similar analysis of the area of the former Yugoslavia shows that during widespread ethnic violence existing political boundaries did not coincide with the boundaries of distinct groups, but peace prevailed in specific areas where they did coincide. The success of peace in Switzerland may serve as a model to resolve conflict in other ethnically diverse countries and regions of the world.


16S rRNA gene-targeted TTGE in determining diversity of gut microbiota during acute diarrhoea and convalescence.
The human gut microbiota play a vital role in health and nutrition but are greatly modified during severe diarrhoea due to purging and pathogenic colonization. To understand the extent of loss during and after diarrhoea, faecal samples collected from children (n=21) suffering from acute diarrhoea and from their healthy siblings (n=9) were analyzed by 16S rRNA gene-targeted universal primer polymerase chain reaction (PCR), followed by temporal temperature gradient gel electrophoresis (TTGE). The gut microbiota decreased significantly as indicated by the number of TTGE bands at day 0 of acute diarrhoea [patients vs healthy siblings: 11±0.9 vs 21.8±1.1 (mean ± standard error), p<0.01]. The number of bands showed a steady increase from day 1 to day 7; however, it remained significantly less than that in healthy siblings (15±0.9, p<0.01). These results suggest that appropriate therapeutic and post-diarrhoeal nutritional intervention might be beneficial for the early microbial restoration and recovery.


Scent Chemicals of the Tail Gland of the Red Fox, Vulpes vulpes.
Like all animals, the red fox uses chemical signals for social communication. The supracaudal or tail gland smells of violets, attributed to the presence of carotenoid degradation products, or apocarotenoids, which commonly occur as aromatics in flowers. We have more fully characterized the scent chemistry of the fox tail gland. Volatile chemicals were analyzed by gas chromatography-mass spectrometry (GC-MS) and identified from their electron ionization mass spectra and Kovats retention indices. The 3 previously reported apocarotenoids were confirmed, and many additional compounds found. These include the apocarotenoids β-cyclocitral, β-homocitral, β-ionone, cyclic β-ionone, β-ionone-5,6-epoxide, α-ionene, α-ionone, 2,6,6-trimethylcyclohexanone (IUPAC 2,2,6-), 2,6,6-trimethyl-2-cyclohexen-1-one, 6-methyl-5-hepten-2-one (sulcatone), and geranyl acetone. Notably, sulcatone is a semiochemical in several species. 3,3-Dimethyl-2,7-octanedione was identified as a probable apocarotenoid which is likely to be a significant fox scent chemical. The γ-lactone of 4-hydroxyhexadecanoic acid (hexadecan-4-olide) was also found, one of a group of known mammalian signaling compounds. This rich mixture of volatile apocarotenoids implies an adequate consumption of plant carotenoids, which are known to be necessary for optimal health. Dietary carotenoids color the skin and feathers of some birds, used as a visual signal to conspecifics, and the floral aroma of the fox tail gland may provide an olfactory signal to other foxes.


Assessing the specific psychopathology of binge eating disorder patients: interview or self-report?
Research addressing the assessment of binge eating and associated eating disorder psychopathology has steadily increased in recent years. Few studies have examined the relationship between the various assessment methods. This study compared an investigator-based interview, the Eating Disorder Examination (EDE), with a self-report version of that interview, the EDE-Q. Fifty-two individuals (six men and 46 women) with binge eating disorder (BED) completed both instruments. Modest-to-good agreement and significant correlations (P < 0.0001) were found between the two methods on all four subscales assessing specific eating disorder psychopathology (i.e., Restraint, Eating Concern, Weight Concern, and Shape Concern subscales). However, higher levels of disturbance were consistently reported on the EDE-Q than the EDE interview. The two methods were not significantly or reliably related to one another when assessing binge eating. This may be due in part to the difficulty inherent in identifying binges in subjects with BED. Examination of individual item scores suggest that it might be possible to improve the performance of the EDE-Q by clarifying the definitions of certain complex features, although this should not be at the expense of compromising the practical utility of its self-report format.


[Surgical treatment of renal tumours with venous extension].
Renal carcinoma accounts for 3% of malignant urological tumors. The existence of tumor thrombus in the venous system is more infrequent, and, despite it was believed until recently its presence worsened the diagnosis of the disease, currently it is accepted that in the absence of metastatic or lymph node disease, surgery is the treatment of choice and potentially curative for these tumors. Between June 2003 and November 2007 eight patients with renal disease and venous thrombus underwent surgery; two of them wereT3c and six T3b; in five of them surgery was carried out in association with the heart surgery team in our centre. Three of them underwent surgery with extracorporeal circulation. Mean patient age was 56 years. Tumor thrombus was grade I in one patient, grade II in 4 patients, grade III in one patient, and grade IV in two patients. In all patients with tumor grade > or = III, as well as two with grade II, surgery was performed in conjunction with the department of heart surgery. The operation with extracorporeal circulation, deep hypothermia, cardioplegia, and antegrade and retrograde brain perfusion was performed in grades III and IV. Midline incision was performed, with or without sternotomy, depending on the level of the thrombus. Hemorrhage was the most frequent perioperative complication. It is essential to know the exact level of the cephalic extreme of the tumor thrombus to design the proper surgical strategy; for that, we can use MRI, CT scan or ultrasound. Therefore, surgical approach, multidisciplinary cooperation and use of extracorporeal circulation will depend on such extension of the thrombus and concurrent factors of the patient. A good surgical strategy, as well as early surgery may avoid the use of venous filters preoperatively. Venous wall invasion seems to be related with a greater incidence of lymph node disease, but these patients are candidates to intention-to-cure radical surgery. Thrombus level is not a prognostic factor per se, but it should be taken into consideration for surgical planning. After radical surgery survival rates achieved are similar to those of tumors without venous thrombus.


A pilot study of the feasibility of a vaginal washing cessation intervention among Kenyan female sex workers.
Intravaginal practices including vaginal washing have been associated with HIV-1 acquisition. This association may be mediated by mucosal disruption, changes in vaginal flora or genital tract inflammatory responses. Reducing vaginal washing could lower women's risk of HIV-1 acquisition. 23 HIV-1 seronegative women who reported current vaginal washing were recruited from a prospective cohort study of high-risk women in Mombasa, Kenya. A theoretical framework including information-motivation-behavioural skills and harm reduction was implemented to encourage participants to reduce or eliminate vaginal washing. At baseline and after 1 month, we evaluated vaginal epithelial lesions by colposcopy, vaginal microbiota by Nugent's criteria and vaginal cytokine milieu using ELISA on cervicovaginal lavage specimens. The most commonly reported vaginal washing substance was soap with water (N=14, 60.9%). The median frequency of vaginal washing was 7 (IQR 7-14) times per week. After 1 month, all participants reported cessation of vaginal washing (p=0.01). The probability of detecting cervicovaginal epithelial lesions was lower (OR 0.48; 95% CI 0.20 to 1.16; p=0.10) and the likelihood of detecting Lactobacillus by culture was higher (OR 3.71, 95% CI 0.73 to 18.76, p=0.11) compared with baseline, although these results were not statistically significant. There was no change in the prevalence of bacterial vaginosis. Most cytokine levels were reduced, but these changes were not statistically significant. A theory-based intervention appeared to have a positive effect in reducing vaginal washing over 1 month. Larger studies with longer follow-up are important to further characterise the effects of vaginal washing cessation on biological markers.


Mitochondrial biogenesis and energy production in differentiating murine stem cells: a functional metabolic study.
The significance of metabolic networks in guiding the fate of the stem cell differentiation is only beginning to emerge. Oxidative metabolism has been suggested to play a major role during this process. Therefore, it is critical to understand the underlying mechanisms of metabolic alterations occurring in stem cells to manipulate the ultimate outcome of these pluripotent cells. Here, using P19 murine embryonal carcinoma cells as a model system, the role of mitochondrial biogenesis and the modulation of metabolic networks during dimethyl sulfoxide (DMSO)-induced differentiation are revealed. Blue native polyacrylamide gel electrophoresis (BN-PAGE) technology aided in profiling key enzymes, such as hexokinase (HK) [EC 126.96.36.199], glucose-6-phosphate isomerase (GPI) [EC 220.127.116.11], pyruvate kinase (PK) [EC 22.214.171.124], Complex I [EC 22.214.171.124], and Complex IV [EC 22.214.171.124], that are involved in the energy budget of the differentiated cells. Mitochondrial adenosine triphosphate (ATP) production was shown to be increased in DMSO-treated cells upon exposure to the tricarboxylic acid (TCA) cycle substrates, such as succinate and malate. The increased mitochondrial activity and biogenesis were further confirmed by immunofluorescence microscopy. Collectively, the results indicate that oxidative energy metabolism and mitochondrial biogenesis were sharply upregulated in DMSO-differentiated P19 cells. This functional metabolic and proteomic study provides further evidence that modulation of mitochondrial energy metabolism is a pivotal component of the cellular differentiation process and may dictate the final destiny of stem cells.


Two Cases of Chronic Intestinal Pseudo-obstruction: A Comparison of Staining Characteristics of Enteric Visceral Myopathy With Hirschsprung Disease.
Chronic intestinal pseudo-obstruction (CIPO), a rare, debilitating disorder of bowel motility dysfunction, is largely a clinical diagnosis, without any universally accepted diagnostic criteria. Three subgroups are generally acknowledged based on the cell-type affected: enteric visceral myopathy (the most common subgroup), neuropathy, and mesenchymopathy. A fourth subgroup includes abnormalities of neurohormonal peptides. Although immunohistochemical staining is reportedly useful for identifying the mesenchymopathic type, its role in diagnosing enteric visceral myopathy and neuropathy has been fraught with difficulties. We present two cases of chronic intestinal pseudo-obstruction that are clinically and histopathologically suggestive of type III visceral enteric myopathy, aiming to expound upon the diagnostic and pathogenic features. We found that the outer-longitudinal layer of the muscularis propria was more severely affected as compared with the inner circular layer. To investigate the value of this finding, we performed immunostains in the one case in which a paraffin block was available. We found increased peripherin and calretinin immunopositive nerve fibers in the outer layer as compared with inner, but without any significant increase in S-100 positivity or alteration in neuronal morphology of myenteric plexus, a novel finding. This differential staining pattern was completely different from Hirschsprung disease, in which we found rare to absent peripherin and calretinin staining. It is unclear if this increase in the outer layer in visceral myopathy reflects a reactive change or dysfunctional axons. In addition, the history of volvulus in one patient and transmural inflammatory changes in the second raise concerns about the higher propensity of clinical complications secondary to the attenuated outer muscular layer. This study suggests that enteric visceral myopathy has histologic and staining characteristics different from Hirschsprung disease, a finding of diagnostic significance in the differential diagnosis of bowel obstruction. Moreover, these features may have pathogenic value and need further confirmation.


Vitamin D and the prevention of hypertension and cardiovascular diseases: a review of the current evidence.
Vitamin D plays an essential role in bone mineralization and calcium homeostasis. More recently, there has been growing evidence for a role of vitamin D in extraskeletal health, including beneficial effects in the cardiovascular system. Daylight exposure and vitamin D intake in many western populations are insufficient for maintaining an adequate vitamin D status. It is at present unclear whether vitamin D supplementation could improve cardiovascular health. This paper summarizes the evidence from observational studies and randomized-controlled trials on the relation of vitamin D with blood pressure (BP) and risk of cardiovascular diseases (CVDs). Epidemiological data suggest that optimal vitamin D status is important for CVD prevention, but results from different studies are conflicting and confounding cannot be ruled out. Randomized-controlled trials of vitamin D supplementation and BP have yielded inconsistent results, and trials that addressed the effect of vitamin D on CVDs are lacking. It is therefore premature to recommend supplemental vitamin D intake specifically for the prevention of hypertension or CVDs. Data from large, well-controlled clinical trials in this field with vitamin D supplements of sufficiently high doses are awaited to settle this issue.


[Transverse submammary skin incision for congenital cardiac surgery].
Submammary skin incision has been accepted as cosmetic approach for open heart surgery. During November 1990 to February 1995, 39 ASD patients under 15 years old were operated with either median or submammary skin incision in Okayama University Medical School. For these patients, retrospective study was carried out to determine whether submammary skin incision made surgical procedure complex and whether patients were satisfied with the scar by submammary skin incision. There were 14 submammary skin incision (Group S) and 25 median skin incision (Group M). There was no significant difference in patients profile between the two groups except for sex. Operative time, cardiopulmonary bypass time and aortic cross clamp time had no significant difference between the two groups. Postoperative ICU stay and hospital stay also did not differed between the two groups. Questionnaires for evaluation of the subjective operation scar was sent with 32 answers (82%). There was no significant difference on questionnaire findings. However for the patients without hypertrophic scar, more patients in Group S were significantly satisfied with their scars. Submammary skin incision was safe and easy. It could be alternative of median skin incision. If hypertrophic scar formation could be prevented, more patients would be satisfied with submammary skin incision than median skin incision.


Neuroimaging markers of human immunodeficiency virus infection in South Africa.
Previous studies have reported cognitive deficits among HIV-positive individuals infected with clade C virus. However, no study has examined whether individuals predominately infected with clade C virus exhibit brain atrophy relative to healthy controls. This study examined volumetric differences between 28 HIV+ individuals and 23 HIV- controls from South Africa. Volumetric measures were obtained from six regions of interest -- caudate, thalamus, corpus callosum, total cortex, total gray matter, and total white matter. HIV+ participants had significantly lower volumes in the total white matter (p<0.01), thalamus (p<0.01) and total gray matter (inclusive of cortical and subcortical regions, p<0.01). This study is the first to provide evidence of brain atrophy among HIV+ individuals in South Africa, where HIV clade C predominates. Additional research that integrates neuroimaging, comprehensive neuropsychological testing, genetic variance in clade-specific proteins, and the impact of treatment with Antiretrovirals (ARV) are necessary to understand the development of HIV-related neurocognitive disorders in South Africa.


Opioid growth factor (OGF) for hepatoblastoma: a novel non-toxic treatment.
Hepatoblastoma is the most common liver malignancy in children, typically diagnosed before age 2. The survival rate for hepatoblastoma has increased dramatically in the last 30 years, but the typical chemotherapeutic agents used for treatment are associated with significant toxicity. In this report, the authors present two cases of hepatoblastoma treated with surgical resection and a novel biotherapeutic regimen that included opioid growth factor (OGF). Case #1 is an infant diagnosed with a large mass on prenatal ultrasound. After subsequent diagnosis of hepatoblastoma, she was treated with one course of neoadjuvant chemotherapy at approximately 1 week of age. Following significant complications from the chemotherapy (neutropenic fever, pneumonia and sepsis), the patient's parents declined further chemotherapy, and the infant was treated with surgical resection and opioid growth factor (OGF)/low dose naltrexone (LDN). She is currently at close to 10 years disease-free survival. Case #2 is a child diagnosed with a liver mass on ultrasound at 20 months of age, later biopsy-proven to represent hepatoblastoma. Due to existing co-morbidities including autosomal recessive polycystic kidney disease and hypertension, and indications from the biopsy that the tumor might be insensitive to chemotherapy, the parents elected not to proceed with neoadjuvant chemotherapy. The patient was treated with surgical resection and OGF/LDN, and is currently at more than 5 years disease-free survival. This case series highlights the need for less toxic treatment options than conventional chemotherapy. Modulation of the OGF-OGF receptor axis represents a promising safe and therapeutic avenue for effective treatment of hepatoblastoma.


Factors predicting skeletal-related events in patients with bone metastatic castration-resistant prostate cancer.
Skeletal-related events (SREs) are common complications of bone metastatic castration-resistant prostate cancer (mCRPC). To the authors' knowledge, there are limited data regarding which factors predict SREs. The authors identified risk factors for SREs in men with bone mCRPC using characteristics commonly available in the medical record. Data from 454 patients with nonmetastatic CRPC were identified from 2 Veteran Affairs Medical Centers from 2000 through 2013. Among these men, 233 (51%) developed bone metastases during follow-up and represented the study cohort. First occurrence of an SRE was abstracted from the medical records. A stepwise multivariable Cox model was used to select the strongest predictors of time to SRE. The median age of the patients at the time of diagnosis of bone mCRPC was 75 years (interquartile range, 68-81 years), and there were 153 nonblack patients (66%). During follow-up (median, 7.8 months [interquartile range, 2.9-18.3 months]), 88 patients (38%) had an SRE. On univariable analysis, more recent year of metastasis (hazard ratio [HR], 0.91), prostate-specific antigen doubling time of ≥9 months versus <9 months (HR, 0.50), and bone pain (HR, 3.34) were all found to be associated with SRE risk. On multivariable analysis, year of metastasis (HR, 0.93), biopsy Gleason score of 7 versus ≤6 (HR, 1.74), radiotherapy as the primary localized treatment versus none (HR, 2.33), and bone pain (HR, 3.64) were associated with SRE risk. The area under the curve for a multivariable model based upon these risk factors was 0.744. The authors identified several significant predictors of SREs among men with mCRPC. In particular, men with bone pain are at high risk of an SRE. If confirmed, future trials should focus on prolonging life and reducing SRE risk in patients with mCRPC with bone pain. Cancer 2017;123:1528-1535. © 2017 American Cancer Society.


Vibration arthrometry. A preview.
Throughout the ages, physicians have listened to sounds and felt vibrations from human joints in their attempts to diagnose pathology. They have used a wide vocabulary to describe these phenomena, but technology has been slow to provide recording and analytic equipment. Lately, accelerometers have been used with considerable success in a new noninvasive method now known as vibration arthrometry (formerly "arthrography"). The technique has been used in early detection of congenital dislocation of the hip and also in diagnosis of meniscal pathology. More recently, patellar vibration has been used to assess the mechanical properties of articular cartilage. Vibration arthrometry has also yielded new information on a possible damage mechanism associated with shock vibration that arises during cavitation of synovial fluid. Joint vibrations are therefore useful aids to diagnosis and may even be etiologic in orthopedic disease.


Von Willebrand Factor Multimers during Transcatheter Aortic-Valve Replacement.
Postprocedural aortic regurgitation occurs in 10 to 20% of patients undergoing transcatheter aortic-valve replacement (TAVR) for aortic stenosis. We hypothesized that assessment of defects in high-molecular-weight (HMW) multimers of von Willebrand factor or point-of-care assessment of hemostasis could be used to monitor aortic regurgitation during TAVR. We enrolled 183 patients undergoing TAVR. Patients with aortic regurgitation after the initial implantation, as identified by means of transesophageal echocardiography, underwent additional balloon dilation to correct aortic regurgitation. HMW multimers and the closure time with adenosine diphosphate (CT-ADP), a point-of-care measure of hemostasis, were assessed at baseline and 5 minutes after each step of the procedure. Mortality was evaluated at 1 year. A second cohort (201 patients) was studied to validate the use of CT-ADP in order to identify patients with aortic regurgitation. After the initial implantation, HMW multimers normalized in patients without aortic regurgitation (137 patients). Among the 46 patients with aortic regurgitation, normalization occurred in 20 patients in whom additional balloon dilation was successful but did not occur in the 26 patients with persistent aortic regurgitation. A similar sequence of changes was observed with CT-ADP. A CT-ADP value of more than 180 seconds had sensitivity, specificity, and negative predictive value of 92.3%, 92.4%, and 98.6%, respectively, for aortic regurgitation, with similar results in the validation cohort. Multivariable analyses showed that the values for HMW multimers and CT-ADP at the end of TAVR were each associated with mortality at 1 year. The presence of HMW-multimer defects and a high value for a point-of-care hemostatic test, the CT-ADP, were each predictive of the presence of aortic regurgitation after TAVR and were associated with higher mortality 1 year after the procedure. (Funded by Lille 2 University and others; ClinicalTrials.gov number, NCT02628509.).


Apn1 AP-endonuclease is essential for the repair of oxidatively damaged DNA bases in yeast frataxin-deficient cells.
Frataxin deficiency results in mitochondrial dysfunction and oxidative stress and it is the cause of the hereditary neurodegenerative disease Friedreich ataxia (FA). Here, we present evidence that one of the pleiotropic effects of oxidative stress in frataxin-deficient yeast cells (Δyfh1 mutant) is damage to nuclear DNA and that repair requires the Apn1 AP-endonuclease of the base excision repair pathway. Major phenotypes of Δyfh1 cells are respiratory deficit, disturbed iron homeostasis and sensitivity to oxidants. These phenotypes are weak or absent under anaerobiosis. We show here that exposure of anaerobically grown Δyfh1 cells to oxygen leads to down-regulation of antioxidant defenses, increase in reactive oxygen species, delay in G1- and S-phases of the cell cycle and damage to mitochondrial and nuclear DNA. Nuclear DNA lesions in Δyfh1 cells are primarily caused by oxidized bases and single-strand breaks that can be detected 15-30 min after oxygen exposition. The Apn1 enzyme is essential for the repair of the DNA lesions in Δyfh1 cells. Compared with Δyfh1, the double Δyfh1Δapn1 mutant shows growth impairment, increased mutagenesis and extreme sensitivity to H(2)O(2). On the contrary, overexpression of the APN1 gene in Δyfh1 cells decreases spontaneous and induced mutagenesis. Our results show that frataxin deficiency in yeast cells leads to increased DNA base oxidation and requirement of Apn1 for repair, suggesting that DNA damage and repair could be important features in FA disease progression.


Safety and effectiveness of new embolization microspheres SCBRM for intermediate-stage hepatocellular carcinoma: A feasibility study.
Transarterial chemoembolization (TACE) is, currently, the recommended treatment for hepatocellular carcinoma (HCC). However, long-term chemoembolization triggers the inflammatory response and may lead to postembolization syndrome (PES). Although several types of degradable microspheres have been developed to reduce drug toxicity and PES incidence, the clinical outcomes remain unsatisfactory. Previously, we have developed a new type of spherical, calibrated, biodegradable, radiopaque microspheres (SCBRM) and demonstrated their safety and efficacy in a pig model. Thus, the goal of this feasibility study was to determine the clinical safety and efficacy of the new SCBRM in intermediate-stage HCC patients. In this study, 12 intermediate-stage HCC patients underwent TACE using SCBRM with a calibrated size of 100-250 μm. The disease control rates at 1 month and 3 months after TACE-SCBRM treatment were 100% and 75.0%, respectively. The objective response rates at 1 month and 3 months after treatment were 66.7% and 58.3%, respectively. Very few adverse events were observed with one patient developing nausea. One day after the treatment, alanine aminotransferase, alanine aminotransferase, and total bilirubin levels were slightly elevated in the patients, but all returned to baseline on day 7. The median and mean overall survival times were 33 months (interquartile range, 12.8-42.0) and 29.2 ± 14.3 months, respectively. The 1-year and 2-year survival rates were 91.7% and 58.3%, respectively. In conclusion, TACE with the new SCBRM microspheres is clinically safe and effective, and it represents a promising approach in the management of intermediate-stage HCC.


Voltage-polarity dependent multi-mode resistive switching on sputtered MgO nanostructures.
Resistive switching in metal-insulator-metal nanosctructures is being intensively studied for nonvolatile memory applications. Here, we report unipolar resistive switching in Pt/MgO/Ta/Ru structures, with a 30 nm oxide barrier. A forming process was needed to initiate the resistive switching, which was then observed for all Set and Reset voltage polarity combinations. We studied the influence of the voltage polarity on the variability of the Set/Reset voltages and ON/OFF resistances and revealed the importance of a thin TaOx layer working as an oxygen revervoir for resistive switching. The mechanism behind this phenomenon can be understood in terms of conductive filaments formation/rupture with a contribution from Joule heating. Resistance change is thus caused by a voltage-driven oxygen vacancy motion in the MgO layer and a filament model was proposed for each polarity mode. A OFF/ON resistance ratio of at least 2 orders of magnitude was obtained with resistive states stable up to 104 s. Our results open the prospect to improve switching performance in other resistive switching systems, by proving a better understanding of the differences between operation modes.


Increase of bone marrow-derived secretory lineage epithelial cells during regeneration in the human intestine.
We have previously reported that bone marrow (BM)-derived cells contribute to the regeneration of the human intestinal epithelium. To analyze further how these cells arise, proliferate, and differentiate as epithelial cells, histologic analysis was conducted using endoscopic specimens. Thirty biopsy specimens from 14 female, sex-mismatched BM-transplantation recipients were examined. BM-derived cells were identified by fluorescent in situ hybridization (FISH) for the Y chromosome and immunohistochemistry. Multicolor FISH was used to exclude cell fusion. These cells were further analyzed for various differentiation or proliferation markers. No evidence of cell fusion was detected. BM-derived cells did not distribute within the crypt as stem cells and rarely expressed Musashi-1. However, BM-derived epithelial cells frequently expressed Ki-67, and some of these cells appeared as pairs of adjacent cells. These cells also expressed markers of all 4 lineages of terminally differentiated cells. During regeneration following graft-vs-host disease, the number of BM-derived cells was substantially increased within Ki-67-positive cells. Interestingly, the number of cells expressing markers for secretory lineage cells was significantly increased within BM-derived cells. This change was unique for BM-derived cells, resulting in a significantly increased proportion of BM-derived cells among secretory lineage cells. BM-derived epithelial cells arise via a mechanism other than cell fusion and rarely give rise to stem cells. However, a small proportion of these cells express proliferation markers, and a majority reside as terminally differentiated cells. During regeneration BM-derived cells increase as secretory lineage cells, thereby contributing to restore epithelial functions.


Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG.
In spite of intensive efforts, understanding of the genetic aspects of familial prostate cancer (PC) remains largely incomplete. In a previous microsatellite-based linkage scan of 1,233 PC families, we identified suggestive evidence for linkage (i.e., LOD ≥ 1.86) at 5q12, 15q11, 17q21, 22q12, and two loci on 8p, with additional regions implicated in subsets of families defined by age at diagnosis, disease aggressiveness, or number of affected members. In an attempt to replicate these findings and increase linkage resolution, we used the Illumina 6000 SNP linkage panel to perform a genome-wide linkage scan of an independent set of 762 multiplex PC families, collected by 11 International Consortium for Prostate Cancer Genetics (ICPCG) groups. Of the regions identified previously, modest evidence of replication was observed only on the short arm of chromosome 8, where HLOD scores of 1.63 and 3.60 were observed in the complete set of families and families with young average age at diagnosis, respectively. The most significant linkage signals found in the complete set of families were observed across a broad, 37 cM interval on 4q13-25, with LOD scores ranging from 2.02 to 2.62, increasing to 4.50 in families with older average age at diagnosis. In families with multiple cases presenting with more aggressive disease, LOD scores over 3.0 were observed at 8q24 in the vicinity of previously identified common PC risk variants, as well as MYC, an important gene in PC biology. These results will be useful in prioritizing future susceptibility gene discovery efforts in this common cancer.


Effect of Soil Texture on the Distribution and Infectivity of Neoaplectana carpocapsae (Nematoda: Steinernematidae).
The vertical migration of N. carpocapsae infective juveniles applied to the soil surface or introduced 14 cm below the soil surface was studied in four different soil types (pure silica sand, coarse sandy loam, silty clay loam, and clay). The percentage of juveniles able to migrate and infect wax moth pupae placed in the soil decreased as the percentage of clay and silt increased. Most nematodes placed on the soil surface remained within 2 cm of the surface, but some penetrated to a depth of 10 cm in pure silica sand and coarse sandy loam to infect pupae. Some pupae at the same depth were also infected with nematodes in silty clay loam soil. In pure silica sand and coarse sandy loam, nematodes introduced 14 cm below the soil surface were able to infect wax moth pupae located between 4 and 24 cm. Movement was least in clay soil and limited in silty clay loam. Nematodes showed a tendency to disperse upwards from the point of application. In all cases the number of migrating nematodes was greatest when wax moth pupae were present.


[Prevention of virus hepatitis A to E].
Infection with hepatitis viruses can lead to acute hepatitis with the risk of developing liver failure. Chronic viral hepatitis may evolve into liver cirrhosis and hepatocellular carcinoma. Thus, prevention of viral hepatitis and its sequels is essential. Vaccination against hepatitis A is successful in almost all individuals. Protective antibodies maintain for at least 20 years. Booster vaccinations are not necessary. Since the introduction of hepatitis A vaccines, the incidence of new HAV-infections has declined significantly. Hepatitis B vaccines are safe and highly effective. Special populations such as dialysis patients or immunocompromised patients require special vaccine schedules. New vaccines with improved adjuvants are currently being tested in clinical trials. So far there is no hepatitis C vaccine on the horizon. Prophylaxis of HCV-infections relies primarily on hygiene measures. Early therapy of acute hepatitis C can prevent chronic hepatitis C. HDV-infection can only be established if HBsAg is present. Thus, prevention of hepatitis B or elimination of HBsAg means prevention of hepatitis delta. Hepatitis E vaccines have been evaluated in phase III studies. The development of HEV vaccines becomes more relevant since chronic HEV infections have been reported in immunosuppressed individuals.


Desorption kinetics of Cd, Zn, and Ni measured in soils by DGT.
DGT (diffusive gradients in thin films) was used to measure the distribution and rates of exchange of Zn, Cd, and Ni between solid phase and solution in five different soils. Soil texture ranged from sandy loam to clay, pH ranged from 4.9 to 7.1, and organic carbon content ranged from 0.8% to 5.8%. DGT devices continuously remove metal to a Chelex gel layer after passage through a well-defined diffusion layer. The magnitude of the induced remobilization flux from the solid phase is related to the pool size of labile metal and the exchange kinetics between dissolved and sorbed metal. DGT devices were deployed over a series of times (4 h to 3 weeks), and the DIFS model (DGT induced fluxes in soils) was used to derive distribution coefficients for labile metal (Kdl) and the rate at which the soil system can supply metal from solid phase to solution, expressed as a response time. Response times for Zn and Cd were short generally (<8 min). They were so short in some soils (<1 min) that no distinction could be made between supply of metal being controlled by diffusion or the rate of release. Generally longer response times for Ni (5-20 min) were consistent with its slow desorption. The major factor influencing Kdl for Zn and Cd was pH, but association with humic substances in the solid phase also appeared to be important. The systematic decline, with increasing pH, in both the pool size of Ni available to the DGT device and the rate constant for its release is consistent with a part of the soil Ni pool being unavailable within a time scale of 1-20 min. This kinetic limitation is likely to limit the availability of Ni to plants.


IBM Watson: How Cognitive Computing Can Be Applied to Big Data Challenges in Life Sciences Research.
Life sciences researchers are under pressure to innovate faster than ever. Big data offer the promise of unlocking novel insights and accelerating breakthroughs. Ironically, although more data are available than ever, only a fraction is being integrated, understood, and analyzed. The challenge lies in harnessing volumes of data, integrating the data from hundreds of sources, and understanding their various formats. New technologies such as cognitive computing offer promise for addressing this challenge because cognitive solutions are specifically designed to integrate and analyze big datasets. Cognitive solutions can understand different types of data such as lab values in a structured database or the text of a scientific publication. Cognitive solutions are trained to understand technical, industry-specific content and use advanced reasoning, predictive modeling, and machine learning techniques to advance research faster. Watson, a cognitive computing technology, has been configured to support life sciences research. This version of Watson includes medical literature, patents, genomics, and chemical and pharmacological data that researchers would typically use in their work. Watson has also been developed with specific comprehension of scientific terminology so it can make novel connections in millions of pages of text. Watson has been applied to a few pilot studies in the areas of drug target identification and drug repurposing. The pilot results suggest that Watson can accelerate identification of novel drug candidates and novel drug targets by harnessing the potential of big data.


Emergency endovascular repair for ruptured abdominal aneurysms--a feasibility study and report of 10 cases.
Endovascular aneurysm repair (EVAR) has been proved to be effective and safe in the elective management of abdominal aortic aneurysms (AAAs). Initial reports concerning endovascular management of ruptured aneurysms have been promising. To determine the outcome of endovascular repair of ruptured aneurysms in the local setting. Materials and methods. Patients who presented with ruptured AAAs were considered for endovascular repair if they were haemodynamically stable and had suitable aneurysm morphology for EVAR. Ten patients (9 males, 1 female) with a mean age of 74.9 years were treated. All aneurysms were successfully excluded using aorta uni-iliac stent grafts in 7 patients and bifurcated stent grafts in 2 patients. In 1 patient who had had a previous EVAR, a proximal extension device was used. Two patients died in the peri-operative period (30-day mortality of 20%) and 1 patient died after 2 months. Seven patients are still alive. No endo-leaks occurred in any of the survivors. Endovascular repair of ruptured AAAs is feasible with acceptable peri-operative mortality and short- to medium-term results.


Growth improvements in children above 3 years of age: the Cali Study.
The Cali Study involved the random assignment of 301 malnourished children to be exposed to one (CT1, n = 113), two (CT2, n = 64), three (CT3, n = 62) or four (CT4, n = 62) 9-mo periods of a multifocal day care-based intervention (i.e., education, health and nutrition). The ages at which the intervention was initiated for Groups CT4, CT3, CT2 and CT1 were 3.5, 4.2, 5.2 and 6.1 y, respectively. After the experimental phase, children were followed up in elementary school until they were 10.4 y old. Our secondary data analyses show that children who were exposed at an earlier age and for a longer period of time showed the highest degree (P < or = 0.05) of improvement in weight and linear growth during the pre-school period. These improvements in physical growth could no longer be detected 3 y after the termination of the intervention.


Healthy Plant Foods Intake Could Protect Against Prostate Cancer Risk: A Case-Control Study
Background: Several studies have investigated the association between healthy plant foods intake and prostate cancer risk with inconsistent results. So this study was conducted to examine the existence of any possible association between healthy plant foods and prostate cancer risk. Materials and Methods: Sixty newly diagnosed prostate cancer cases and 60 controls engaged in a hospital-based case-control study. A validated 16o-items semi-quantitative FFQ was used to assess usual dietary intakes. Energy-adjusted amounts of healthy plant foods intake were calculated using the residual method. Logistic regression model was also used to derive beta estimates and odds ratios. Results: Cases were older and more likely to be inactive. In crude model, individuals in the highest tertile vs lowest tertile of total healthy plant foods (OR= 0.12; 95 % CI 0.04, 0.34), total fruits (OR= 0.11; 95 % CI 0.04, 0.30), total vegetables (OR= 0.08; 95 % CI 0.03, 0.24), fresh fruits (OR= 0.11; 95 % CI 0.04, 0.30), and raw vegetables (OR= 0.06; 95 % CI 0.02, 0.18) had significantly lower risk of prostate cancer. After controlling for potential confounders (age, BMI, total energy intake, job, education, smoking, physical activity, some drug usage, and also dietary intakes), just total healthy plant foods (OR= 0.12; 95 % CI 0.02, 0.55), total vegetables (OR=0.03; 95 % CI 0.00, 0.25), and raw vegetables (OR= 0.01; 95 % CI 0.00, 0.12) were associated with lower prostate cancer risk. Conclusions: The results of this study suggest that a diet rich in healthy plant foods and especially total or raw vegetable may protect against prostate cancer.


Total Correlation Spectroscopy across All NMR-Active Nuclei by Mixing at Zero Field.
Multidimensional nuclear magnetic resonance (NMR) is based on a combination of well-established building blocks for polarization transfer. These blocks are used to design correlation experiments through one or a few chemical bonds or through space. Here, we introduce a building block that enables polarization transfer across all NMR-active nuclei in a coupled network of spins: isotropic mixing at zero and ultralow field (ZULF). Exploiting mixing under ZULF-NMR conditions, heteronuclear TOtal Correlation SpectroscopY (TOCSY) experiments were developed to highlight coupled spin networks. We demonstrate 1H-13C and 1H-15N correlations in ZULF-TOCSY spectra of labeled amino acids, which allow one to obtain cross-peaks among all heteronuclei belonging to the same coupled network, even when the direct interaction between them is negligible. We also demonstrate the potential of ZULF-TOCSY to analyze complex mixtures on a growth medium of isotope-labeled biomolecules. ZULF-TOCSY enables the quick identification of individual compounds in the mixture by their coupled spin networks. The ZULF-TOCSY method will lead to the development of a new toolbox of experiments to analyze complex mixtures by NMR.


The structural and functional brain networks that support human social networks.
Social skills rely on a specific set of cognitive processes, raising the possibility that individual differences in social networks are related to differences in specific brain structural and functional networks. Here, we tested this hypothesis with multimodality neuroimaging. With diffusion MRI (DMRI), we showed that differences in structural integrity of particular white matter (WM) tracts, including cingulum bundle, extreme capsule and arcuate fasciculus were associated with an individual's social network size (SNS). A voxel-based morphology analysis demonstrated correlations between gray matter (GM) volume and SNS in limbic and temporal lobe regions. These structural changes co-occured with functional network differences. As a function of SNS, dorsomedial and dorsolateral prefrontal cortex showed altered resting-state functional connectivity with the default mode network (DMN). Finally, we integrated these three complementary methods, interrogating the relationship between social GM clusters and specific WM and resting-state networks (RSNs). Probabilistic tractography seeded in these GM nodes utilized the SNS-related WM pathways. Further, the spatial and functional overlap between the social GM clusters and the DMN was significantly closer than other control RSNs. These integrative analyses provide convergent evidence of the role of specific circuits in SNS, likely supporting the adaptive behavior necessary for success in extensive social environments.


Mild cutaneous reactions to drugs.
Adverse reactions to drugs are not frequent in childhood. Cutaneous reactions are the most frequent in this age group. Mild cutaneous reactions are immediate or delayed adverse reactions that do not seriously compromise the clinical condition of children. The patients usually early improve and recover the state of health. Although it is difficult to define the prevalence accurately, we could affirm that the rate adverse reaction to drugs are often over estimated by both the families and the physicians. Therefore, children may be prone to loss of school days and inappropriate or sub-optimal treatments. However, the identification of a true adverse reaction to drugs allows adequate treatment and alert to further exposure to harmful drugs.


Substantia nigra hyperechogenicity correlates with clinical status and number of Parkin mutated alleles.
To further evaluate (1) transcranial sonography (TCS) for (pre)clinical diagnosis of Parkinson's disease (PD) and (2) to examine asymptomatic carriers of Parkin mutations we investigated substantia nigra (SN) hyperechogenicity in PD patients and unaffected subjects with and without Parkin mutations. The area (aSN) of the hyperechogenic SN were calculated bilaterally and study subjects were assigned to high versus low value groups. Eleven of the (affected and unaffected) mutation carriers had previously undergone 18-fluoro-dopa-(FDOPA)-PET scans. Fifty-eight individuals were investigated, including 24 with clinically definite and 34 without symptoms or signs of PD. Of the patients, three had one mutated and six had two mutated Parkin alleles. Of the unaffected subjects, 13 carried a single Parkin mutated allele. After dichotomization, 21 subjects had high and 37 subjects low values of mean aSN. Regarding the clinical status, 13 (62%) of the individuals with a high mean aSN had PD,while 26 (70%) of the study subjects with low values did not show signs of PD (p = 0.0393). Similarly, probands with high mean aSN values more frequently carried Parkin mutations (58%) than probands with low values (27%, p = 0.0234). A negative correlation between FDOPA uptake in the posterior putamen and maximum aSN was found in the group of mutation carriers (r = -0.809, p = 0.0234). In conclusion, hyperechogenicity of the SN is found in both idiopathic and Parkin-associated PD. Further strengthening the notion of a potential relationship between SN hyperechogenicity and Parkin mutational status, a larger aSN was associated with an increasing number of mutated alleles in our study.


Microglial voltage-gated proton channel Hv1 in spinal cord injury.
After spinal cord injury, microglia as the first responders to the lesion display both beneficial and detrimental characteristics. Activated microglia phagocyte and eliminate cell debris, release cytokines to recruit peripheral immune cells to the injury site. Excessively activated microglia can aggravate the secondary damage by producing extravagant reactive oxygen species and pro-inflammatory cytokines. Recent studies demonstrated that the voltage-gated proton channel Hv1 is selectively expressed in microglia and regulates microglial activation upon injury. In mouse models of spinal cord injury, Hv1 deficiency ameliorates microglia activation, resulting in alleviated production of reactive oxygen species and pro-inflammatory cytokines. The reduced secondary damage subsequently decreases neuronal loss and correlates with improved locomotor recovery. This review provides a brief historical perspective of advances in investigating voltage-gated proton channel Hv1 and home in on microglial Hv1. We discuss recent studies on the roles of Hv1 activation in pathophysiological activities of microglia, such as production of NOX-dependent reactive oxygen species, microglia polarization, and tissue acidosis, particularly in the context of spinal cord injury. Further, we highlight the rationale for targeting Hv1 for the treatment of spinal cord injury and related disorders.


Sertraline: a review of its use in the management of major depressive disorder in elderly patients.
Sertraline is a selective serotonin reuptake inhibitor (SSRI) with well established antidepressant and anxiolytic activity. Results from several well designed trials show that sertraline (50 to 200 mg/day) is effective in the treatment of major depressive disorder in elderly patients (> or =60 years of age). Primary endpoints in most studies included the Hamilton Depression Rating Scale (HDRS), Clinical Global Impression (CGI) score and the Montgomery-Asberg Depression Rating Scale (MADRS). Sertraline was significantly more effective than placebo, and was as effective as fluoxetine, nortriptyline and imipramine in elderly patients. During one trial, amitriptyline was significantly more effective than sertraline [mean reduction from baseline on one of six primary outcomes (HDRS)], although no quantitative data were provided. Subgroup analysis of data from a randomised, double-blind trial in elderly patients with major depressive disorder suggests that vascular morbidity, diabetes mellitus or arthritis does not affect the antidepressant effect of sertraline. Secondary endpoints from these clinical trials suggest that sertraline has significant benefits over nortriptyline in terms of quality of life. In addition, significant differences favouring sertraline in comparison with nortriptyline and fluoxetine have been recorded for a number of cognitive functioning parameters. Sertraline is generally well tolerated in elderly patients with major depressive disorder, and lacks the marked anticholinergic effects that characterise the adverse event profiles of tricyclic antidepressants (TCAs). The most frequently reported adverse events in patients aged > or =60 years with major depressive disorder receiving sertraline 50 to 150 mg/day were dry mouth, headache, diarrhoea, nausea, insomnia, somnolence, constipation, dizziness, sweating and taste abnormalities. The tolerability profile of sertraline is generally similar in younger and elderly patients. Sertraline has a low potential for drug interactions at the level of the cytochrome P450 enzyme system. In addition, no dosage adjustments are warranted for elderly patients solely based on age. Sertraline is an effective and well tolerated antidepressant for the treatment of major depressive disorder in patients aged > or =60 years. Since elderly patients are particularly prone to the anticholinergic effects of TCAs as a class, SSRIs such as sertraline are likely to be a better choice for the treatment of major depressive disorder in this age group. In addition, sertraline may have advantages over the SSRIs paroxetine, fluoxetine and fluvoxamine in elderly patients because of the drug's comparatively low potential for drug interactions, which is of importance in patient groups such as the elderly who are likely to receive more than one drug regimen.