High Intake of Free Sugars, Fructose, and Sucrose Is Associated with Weight Gain in Japanese Men.
Available evidence for associations between sugar intake and body weight is largely from short-term controlled trials and studies focusing on sugar-sweetened beverages. Studies on long-term weight change related to the intake of types of sugar are thus needed. We examined the associations between weight change and the intake of various types of carbohydrates, including starch, total sugars, and free or naturally occurring sugars and saccharides (i.e., glucose, fructose, sucrose, and lactose), among Japanese men and women. This prospective cohort study included 14,971 residents of Takayama City in Japan who were aged 35-69 y at the first survey in 1992 and responded to a self-administrated questionnaire at the second survey in 2002. We excluded those with cancer, coronary artery disease, stroke, or diabetes on the first survey and those with missing information about body weight on both surveys, leaving 13,229 participants for analysis (5879 men and 7350 women). Mean (95% CI) values of 10-y weight change according to types of carbohydrates were estimated using linear regression models with adjustment for total energy intake and other dietary and lifestyle factors. Dietary intake was assessed at the first survey using a validated FFQ. Among men, free sugar intake was associated with weight gain and the estimated means (95% CIs) of weight change were -0.60 (-0.67, -0.54), -0.31 (-0.38, -0.24), -0.12 (-0.19, -0.05), and 0.20 (0.13, 0.27) kg from the first to fourth quartiles (P-trend = 0.002). Moreover, high intakes of sucrose and fructose were associated with weight gain (P-trend: 0.018 for sucrose and 0.001 for fructose). Among women, the intake of any type of carbohydrate was not significantly associated with weight change. These results suggested that high intakes of free sugars, sucrose, and fructose were associated with long-term weight gain among Japanese men.


Biochemical recurrence after radical prostatectomy: Current status of its use as a treatment endpoint and early management strategies.
Prostate cancer is one of the most common urological malignancies managed by a practicing urologist. Treatment strategies are varied, but radical prostatectomy (RP) remains a viable and commonly used option for many patients. A continuing challenge in the management is how to approach a patient who has biochemical recurrence (BCR) after RP. There are no consensus guidelines on the appropriate strategy, and the current recommendations, although useful, are at times confusing. The natural history of BCR is heterogeneous. Published studies aid in the clinician's ability to predict patients most likely to recur; however, this remains inexact. In addition, recent changes in the recommendations for disease screening, as well as technological advances, have added to the already challenging task of the clinician. The objective of this review is to provide an up-to-date summary of the definitions, diagnosis, and management strategies of BCR after RP. This narrative review was conducted by searching Medline for all relevant articles in English with the key terms of biochemical recurrence, prostate cancer, management, and other relevant terms. Information was compiled and reviewed for relevance to the article. Consideration was given to all articles with sufficient evidence including systematic review, retrospective studies, and clinical trials.


What is the yield of malaria reactive case detection in the Greater Mekong Sub-region? A review of published data and meta-analysis.
Reactive malaria case detection involves the screening of those in contact with index cases and is used in countries in the Greater Mekong Sub-region. The yield of reactive case detection, defined here as the percentage of positive malaria cases among potential contacts who were screened, was assessed. A literature search was conducted on PubMed to identify studies on reactive case detection in the Greater Mekong Sub-region. Eligible published articles were reviewed and pooled estimates from the studies were calculated, by type of malaria test used. Eighty-five publications were retrieved, of which 8 (9.4%) eligible articles were included in the analysis. The yield from reactive case detection ranged from 0.1 to 4.2%, with higher rates from PCR testing compared with microscopy and/or rapid diagnostic test. The overall yield from microscopy and/or rapid diagnostic test was 0.56% (95% CI 0.31-0.88%), while that from PCR was 2.35% (95% CI 1.19-3.87%). The two studies comparing different target groups showed higher yield from co-workers/co-travellers, compared with household contacts. In low malaria transmission settings, the effectiveness of reactive case detection is diminishing. In the Greater Mekong Sub-region, modifying reactive case detection from household contacts to co-workers/co-travellers and from testing to presumptive treatment of targeted contacts, could increase the impact of this approach.


Stimulus specificity of matrix metalloproteinase dependence of human T cell migration through a model basement membrane.
Chemotaxis of human T lymphoblastoma cells of the Tsup-1 line, which migrate similarly to blood T cells, through a layer of basement membrane-like Matrigel on a polycarbonate micropore filter was evoked by vasoactive intestinal peptide (VIP; concentration for a maximal response, 10(-7)M), IL-2 (10(-9)M), and the chemokines RANTES (10(-10)M) and macrophage inflammatory protein-1 alpha (10(-10)M). Chemotactic concentrations of each factor increased Tsup-1 cell secretion of matrix metalloproteinase-9 (MMP-9), with significant responses by 4 h for VIP, IL-2, and IL-4, but only after 24 h for macrophage inflammatory protein-1 alpha and RANTES, as quantified by Western blots and zymography. 3H-Labeled type IV human collagen incorporated in the Matrigel layer was degraded by migrating Tsup-1 cells, as assessed by release of radioactive fragments of the collagen. The in situ degradation of type IV collagen in Matrigel by migrating Tsup-1 cells was enhanced most significantly by VIP, IL-2, and IL-4 after 4 h at concentrations that increased the secretion of MMP-9 optimally, but only after 24 h by macrophage inflammatory protein-1 alpha and RANTES. The specific MMP inhibitor GM6001 suppressed Tsup-1 cell MMP activity evoked by all stimuli, as determined by zymography and in situ degradation of 3H-Labeled type IV human collagen. The chemotactic migration of Tsup-1 cells through Matrigel, but not through a filter alone, in response to optimal concentrations of VIP, IL-2, and IL-4, but not the chemokines, was inhibited by GM6001, with a concentration dependence similar to that for suppression of MMP activity. Thus elicitation of T cell chemotactic migration through a model basement membrane by stimuli that increase MMP activity early in the response depends on degradation of matrix proteins by MMP, whereas stimuli that recruit MMP late may rely on early activation of other proteases.


Use of the Corail stem for revision total hip arthroplasty: evaluation of clinical outcomes and cost
With the growing number of total hip arthroplasty (THA) procedures performed, revision surgery is also proportionately increasing, resulting in greater health care expenditures. The purpose of this study was to assess clinical outcomes and cost when using a collared, fully hydroxyapatite-coated primary femoral stem for revision THA compared to commonly used revision femoral stems. We retrospectively identified patients who underwent revision THA with a primary stem between 2011 and 2016 and matched them on demographic variables and reason for revision to a similar cohort who underwent revision THA. We extracted operative data and information on in-hospital resource use from the patients' charts to calculate average cost per procedure. Patient-reported outcomes were recorded preoperatively and 1 year postoperatively. We included 20 patients in our analysis, of whom 10 received a primary stem and 10, a typical revision stem. There were no significant between-group differences in mean Western Ontario and McMaster Universities Osteoarthritis Index score, Harris Hip Score, 12-Item Short Form Health Survey (SF-12) Mental Composite Scale score or Physical Composite Scale score at 1 year. Operative time was significantly shorter and total cost was significantly lower (mean difference –3707.64, 95% confidence interval –5532.85 to –1882.43) with a primary stem than with other revision femoral stems. We found similar clinical outcomes and significant institutional cost savings with a primary femoral stem in revision THA. This suggests a role for a primary femoral stem such as a collared, fully hydroxyapatite-coated stem for revision THA.


Can mental health treatments help prevent or reduce intimate partner violence in low- and middle-income countries? A systematic review.
Epidemiological research suggests an interrelationship between mental health problems and the (re)occurrence of intimate partner violence (IPV). However, little is known about the impact of mental health treatments on IPV victimization or perpetration, especially in low- and middle-income countries (LMIC). We conducted a systematic review to identify prospective, controlled studies of mental health treatments in LMIC. We defined 'mental health treatment' as an intervention for individuals experiencing mental ill health (including substance misuse) including a substantial psychosocial or pharmacological component. Studies had to measure a mental health and IPV outcome. We searched across multi-disciplinary databases using a structured search strategy. Screening of title/abstracts and full-text eligibility assessments were conducted by two researchers independently, data were extracted using a piloted spreadsheet, and a narrative synthesis was generated. We identified seven studies reported in 11 papers conducted in five middle-income countries. With the exception of blinding, studies overall showed acceptable levels of risk of bias. Four of the seven studies focused on dedicated mental health treatments in various populations, including: common mental disorders in earthquake survivors; depression in primary care; alcohol misuse in men; and alcohol misuse in female adult sex workers. The dedicated mental health treatments targeting depression or alcohol misuse consistently reduced levels of these outcomes. The two studies targeting depression also reduced short-term IPV, but no IPV benefits were identified in the two alcohol-focused studies. The other three studies evaluated integrated interventions, in which a focus on substance misuse was part of efforts to reduce HIV/AIDS and violence against particularly vulnerable women. In contrast to the dedicated mental health interventions, the integrated interventions did not consistently reduce mental ill health or alcohol misuse compared to control conditions. Too few studies have been conducted to judge whether mental health treatments may provide a beneficial strategy to prevent or reduce IPV in LMIC. Key future research questions include: whether promising initial evidence on the effects of depression interventions on reducing IPV hold more broadly, the required intensity of mental health components in integrated interventions, and the identification of mechanisms of IPV that are amenable to mental health intervention.


Quantitative modelling of nutrient-limited growth of bacterial colonies in microfluidic cultivation.
Nutrient gradients and limitations play a pivotal role in the life of all microbes, both in their natural habitat as well as in artificial, microfluidic systems. Spatial concentration gradients of nutrients in densely packed cell configurations may locally affect the bacterial growth leading to heterogeneous micropopulations. A detailed understanding and quantitative modelling of cellular behaviour under nutrient limitations is thus highly desirable. We use microfluidic cultivations to investigate growth and microbial behaviour of the model organism Corynebacterium glutamicum under well-controlled conditions. With a reaction-diffusion-type model, parameters are extracted from steady-state experiments with a one-dimensional nutrient gradient. Subsequently, we employ particle-based simulations with these parameters to predict the dynamical growth of a colony in two dimensions. Comparing the results of those simulations with microfluidic experiments yields excellent agreement. Our modelling approach lays the foundation for a better understanding of dynamic microbial growth processes, both in nature and in applied biotechnology.


A prospective cohort study on antioxidant and folate intake and male lung cancer risk.
Many studies have reported inverse associations between vegetable and fruit consumption and lung cancer risk. The aim of the present study was to elucidate the role of several antioxidants and folate in this relationship. In the Netherlands Cohort Study on Diet and Cancer, 58,279 men of ages 55-69 years at baseline in 1986 returned a questionnaire including a 150-item food frequency questionnaire. After 6.3 years of follow-up, 939 male lung cancer cases were registered. A new Dutch carotenoid database was used to estimate intake of alpha-carotene, beta-carotene, lutein + zeaxanthin, beta-cryptoxanthin, and lycopene, completed with the antioxidant vitamins C and E and folate. Using case-cohort analysis, rate ratios were calculated, adjusted for age, smoking, educational level, and family history of lung cancer. Protective effects on lung cancer incidence were found for lutein + zeaxanthin, beta-cryptoxanthin, folate, and vitamin C. Other carotenoids (alpha-carotene, beta-carotene, and lycopene) and vitamin E did not show significant associations. After adjustment for vitamin C, only folate remained inversely associated, and after adjustment for folate, only beta-cryptoxanthin and vitamin C remained significantly associated. Inverse associations were strongest among current smokers and weaker for former smokers at baseline. Inverse associations with carotenes, lutein + zeaxanthin, and beta-cryptoxanthin seemed to be limited to small cell and squamous cell carcinomas. Only folate and vitamin C intake appeared to be inversely related to small cell and squamous cell carcinomas and adenocarcinomas. Folate, vitamin C, and beta-cryptoxanthin might be better protective agents against lung cancer in smokers than alpha-carotene, beta-carotene, lutein + zeaxanthin, and lycopene.


A randomized controlled trial of vitamin D supplementation on preventing postmenopausal bone loss and modifying bone metabolism using identical twin pairs.
Vitamin D supplementation, when given with calcium, has been shown to increase bone mineral density (BMD) and reduce the incidence of hip fracture in elderly subjects. Despite its widespread use, the benefits of vitamin D supplementation in younger women and as a single agent are less clear. We performed a randomized co-twin, placebo-controlled, double-blind trial over 2 years to measure the effect of vitamin D3 supplementation on bone density and bone metabolism in young postmenopausal women. Seventy-nine monozygotic (MZ) twin pairs (mean age, 58.7 years; range, 47-70 years) were recruited. For each twin pair, one was randomized to 800 IU cholecalciferol/day for 2 years and the other was randomized to placebo. BMD was measured at the spine and hip and heel ultrasound at baseline, 12, 18, and 24 months. Samples were collected at 0, 3, and 6 months to measure serum calcium, 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), osteocalcin, and urinary deoxypyridinoline (DPD). In total, 64 pairs completed the study. No differences in baseline characteristics were seen between the groups. At 6 months, the treatment group had an increase in serum vitamin D [mean +/- SEM intrapair difference, 14.1+/-2.4 microg/liter (p < 0.001)]. There were no significant differences in other serum measurements or bone markers at 3 months or 6 months. At 24 months, no significant treatment effect was seen on BMD or calcaneal ultrasound change within pairs. Subanalysis of treatment response by vitamin D receptor (VDR) genotype revealed no significant difference in effect on BMD variables with treatment. On the basis of these results, vitamin D supplementation, on its own, cannot be recommended routinely as an osteoporosis prevention for healthy postmenopausal women with normal vitamin D levels under the age of 70 years.


Phase I study of 506U78 administered on a consecutive 5-day schedule in children and adults with refractory hematologic malignancies.
A phase I study was conducted to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of a novel purine nucleoside, nelarabine, a soluble prodrug of 9-beta-D-arabinosylguanine (araG; Nelarabine), in pediatric and adult patients with refractory hematologic malignancies. Between April 1994 and April 1997, 93 patients with refractory hematologic malignancies were treated with one to 16 cycles of study drug. Nelarabine was administered daily, as a 1-hour intravenous infusion for 5 consecutive days, every 21 to 28 days. First-cycle pharmacokinetic data, including plasma nelarabine and araG levels, were obtained on all patients treated. Intracellular phosphorylation of araG was studied in samples of leukemic blasts from selected patients. The MTDs were defined at 60 mg/kg/dose and 40 mg/kg/dose daily x 5 days in children and adults, respectively. Dose-limiting toxicity (DLT) was neurologic in both children and adults. Myelosuppression and other significant organ toxicities did not occur. Pharmacokinetic parameters were similar in children and adults. Accumulation of araGTP in leukemic blasts was correlated with cytotoxic activity. The overall response rate was 31%. Major responses were seen in patients with T-cell malignancies, with 54% of patients with T-lineage acute lymphoblastic leukemia achieving a complete or partial response after one to two courses of drug. Nelarabine is a novel nucleoside with significant cytotoxic activity against malignant T cells. DLT is neurologic. Phase II and III trials in patients with T-cell malignancies are encouraged.


Effect of a rosmarinic acid supplemented hemodialysis fluid on inflammation of human vascular endothelial cells.
Chronic systemic inflammation and repetitive damage of vascular endothelia by incompatible dialysis system are probable causes of cardiovascular disease in patients on dialysis. The present study aimed to assess in vitro biocompatibility and anti-inflammatory effect of hemodialysis fluid supplemented with rosmarinic acid (RA) using human umbilical vein endothelial cells (HUVEC). HUVECs (5×106 cells/mL) were pre-exposed to 1 μg/mL of lipopolysaccharides (LPS) and incubated with RA-supplemented hemodialysis fluid (HDF). Cytotoxicity was assessed qualitatively by morphologic assessment and quantitatively by MTT assay. Expressions of proinflammatory mediators were assessed using quantitative real-time PCR and production of NO was quantified. Phosphorylation of AKT and nuclear localization of nuclear factor kappa B (NF-κB) were examined using western blotting. Exposure of HUVECs to RA-supplemented HDF had no influence on morphology and viability. Inhibition of proinflammatory mediator production in HUVECs by RA supplementation to HDF was significant in a dose-dependent manner. Exposure to RA-supplemented HDF resulted in a decrease in nitric oxide synthase expression and reduction of NO production in LPS-stimulated HUVECs. RA supplementation of HDF suppressed Akt activation in LPS-stimulated HUVECs. In addition, the level of cellular IκB was increased in parallel to a reduced nuclear translocation of NF-κB in LPS-induced endothelial cells. Our results suggest that RA-supplemented HDF is biocompatible and significantly suppressed inflammation induced in endothelial cells. In this respect, the use of HDF supplemented with RA could alleviate inflammation and improve long-term treatment of patients with renal failure on dialysis. Further clinical studies are required to confirm the effects.


Cervical auscultation in the diagnosis of oropharyngeal aspiration in children: a study protocol for a randomised controlled trial.
Oropharyngeal aspiration (OPA) can lead to recurrent respiratory illnesses and chronic lung disease in children. Current clinical feeding evaluations performed by speech pathologists have poor reliability in detecting OPA when compared to radiological procedures such as the modified barium swallow (MBS). Improved ability to diagnose OPA accurately via clinical evaluation potentially reduces reliance on expensive, less readily available radiological procedures. Our study investigates the utility of adding cervical auscultation (CA), a technique of listening to swallowing sounds, in improving the diagnostic accuracy of a clinical evaluation for the detection of OPA. We plan an open, unblinded, randomised controlled trial at a paediatric tertiary teaching hospital. Two hundred and sixteen children fulfilling the inclusion criteria will be randomised to one of the two clinical assessment techniques for the clinical detection of OPA: (1) clinical feeding evaluation only (CFE) group or (2) clinical feeding evaluation with cervical auscultation (CFE + CA) group. All children will then undergo an MBS to determine radiologically assessed OPA. The primary outcome is the presence or absence of OPA, as determined on MBS using the Penetration-Aspiration Scale. Our main objective is to determine the sensitivity, specificity, negative and positive predictive values of 'CFE + CA' versus 'CFE' only compared to MBS-identified OPA. Early detection and appropriate management of OPA is important to prevent chronic pulmonary disease and poor growth in children. As the reliability of CFE to detect OPA is low, a technique that can improve the diagnostic accuracy of the CFE will help minimise consequences to the paediatric respiratory system. Cervical auscultation is a technique that has previously been documented as a clinical adjunct to the CFE; however, no published RCTs addressing the reliability of this technique in children exist. Our study will be the first to establish the utility of CA in assessing and diagnosing OPA risk in young children. Australia and New Zealand Clinical Trials Register (ANZCTR) number ACTRN12613000589785.


Evolution of a minimally invasive mitral valve program.
Minimally invasive valve surgery is evolving into a procedure of choice in the treatment of mitral regurgitation (MR). Visualization techniques have improved vastly over the past decades. With the use of 3D technology rib retractors can be avoided, incision size has come down to a minimum without reducing and even improving the surgeons view.


Multiligament Knee Injuries in Older Adolescents: A 2-Year Minimum Follow-up Study.
Multiligament knee injuries cause significant functional impairment. Adults undergoing anatomic reconstruction of multiligament knee injuries have excellent outcomes postoperatively. However, less is known about the outcomes in adolescent patients following multiligament reconstruction. We aimed to assess patient outcomes and failure rates following unstaged multiligament reconstruction in an adolescent population at a minimum 2-year follow-up. We hypothesized that outcomes of multiligament reconstruction in these patients would be comparable to previously reported outcomes in the adult population. Case series; Level of evidence, 4. The study included patients who had undergone multiligament knee reconstruction at 19 years of age or younger and had at least 2 years of follow-up. All procedures were performed by the same surgeon. Exclusion criteria included patient age 14 years or younger at the time of surgery, open physes, prior ipsilateral meniscal or knee ligament surgery, or a tibial plateau fracture at the time of injury. Multiligament reconstruction was defined as a reconstruction of at least 1 cruciate ligament and at least 1 component of the posterolateral corner or the medial knee. Patients were evaluated according to Lysholm score, Tegner score, Short Form-12 physical component summary (SF-12 PCS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and postoperative patient satisfaction. Twenty patients (mean age, 17.7 years; mean follow-up, 37.1 months) were included in this study. No patient required additional ligament surgery after the index surgery because of graft failure. The median preoperative Lysholm score was 49.5 (range, 18-90), and the median postoperative Lysholm score was 86 (range, 44-100) (P < .001). The median preoperative Tegner activity score was 2 (range, 0-9), and the median postoperative Tegner activity score was 6 (range, 2-10) (P = .012). The median SF-12 PCS improved from 40.5 preoperatively to a median of 56.1 postoperatively (P < .001). WOMAC total score improved from a median of 26.5 preoperatively to a median of 2 postoperatively (P < .001). Median postoperative patient satisfaction was 10 (range, 5-10). Single-stage multiligament knee reconstruction is a reliable procedure that improves knee function at 2-year follow-up in adolescent patients. Patient satisfaction was excellent, but longer follow-up in a larger series of patients is required to determine the long-term benefits of multiligament reconstruction in this patient population.


Shape dependent catalytic activity of nanoflowers and nanospheres of Pd4S generated via one pot synthesis and grafted on graphene oxide for Suzuki coupling.
Nanoflowers and nanospheres of Pd4S have been prepared for the first time from a single source precursor complex, [PdCl2(PhS-CH2CH2CH2-NH2)] (), by its one pot thermolysis at 195 °C. In oleylamine, flower shaped nanoparticles of Pd4S were formed but in an oleic acid (OA) and octadecene (ODE) mixture (1 : 1) the product was nanospheres of Pd4S (size in the range ∼23-38 nm and 15-28 nm, respectively). These nanoparticles (NPs) were grafted on graphene oxide (GO) at room temperature to prepare nanocomposites, GO-Pd4S. HRTEM, powder X-ray diffraction (PXRD) and TEM-EDX have been used to authenticate the nanoparticles and their composites. XPS of Pd4S NPs indicates the oxidation states of Pd and S are both zero with a Pd : S ratio ∼4.1 : 0.9. For the catalysis of Suzuki-Miyaura coupling reactions the nanoparticles individually and in the form of composites with GO were explored. The flower shaped NPs are superior than the spherical ones for this catalysis in aqueous ethanol and the catalytic efficiency increases on grafting the nanoflowers/spheres onto GO. The conversion was ∼99% (in 5 h; at 80 °C) for the composite of graphene oxide (GO) with the Pd4S nanoflowers (Pd: 0.2 mol%). The catalytic efficiency follows the order GO-Pd4S-nanoflowers > GO-Pd4S-nanospheres > Pd4S nanoflowers > Pd4S nanospheres. The recyclability of the GO-Pd4S nanoflower catalyst was examined for the coupling reaction and conversion was found to be ∼46% in the fourth run even after increasing the reaction time to 12 h. To understand whether the catalytic process with the GO-Pd4S nanoflowers was homogeneous or heterogeneous mercury poisoning, triphenylphosphine and three phase tests were carried out. They suggest that active Pd leached from GO-Pd4S nanoflowers does the catalysis significantly in a homogeneous fashion. Overall the catalysis appears to be a cocktail of homogeneous and some heterogeneous nature.


Characterization of VHL missense mutations in sporadic clear cell renal cell carcinoma: hotspots, affected binding domains, functional impact on pVHL and therapeutic relevance.
The VHL protein (pVHL) is a multiadaptor protein that interacts with more than 30 different binding partners involved in many oncogenic processes. About 70 % of clear cell renal cell carcinoma (ccRCC) have VHL mutations with varying impact on pVHL function. Loss of pVHL function leads to the accumulation of Hypoxia Inducible Factor (HIF), which is targeted by current targeted treatments. In contrast to nonsense and frameshift mutations that highly likely nullify pVHL multipurpose functions, missense mutations may rather specifically influence the binding capability of pVHL to its partners. The affected pathways may offer predictive clues to therapy and response to treatment. In this study we focused on the VHL missense mutation pattern in ccRCC, and studied their potential effects on pVHL protein stability and binding partners and discussed treatment options. We sequenced VHL in 360 sporadic ccRCC FFPE samples and compared observed and expected frequency of missense mutations in 32 different binding domains. The prediction of the impact of those mutations on protein stability and function was assessed in silico. The response to HIF-related, anti-angiogenic treatment of 30 patients with known VHL mutation status was also investigated. We identified 254 VHL mutations (68.3 % of the cases) including 89 missense mutations (35 %). Codons Ser65, Asn78, Ser80, Trp117 and Leu184 represented hotspots and missense mutations in Trp117 and Leu 184 were predicted to highly destabilize pVHL. About 40 % of VHL missense mutations were predicted to cause severe protein malfunction. The pVHL binding domains for HIF1AN, BCL2L11, HIF1/2α, RPB1, PRKCZ, aPKC-λ/ι, EEF1A1, CCT-ζ-2, and Cullin2 were preferentially affected. These binding partners are mainly acting in transcriptional regulation, apoptosis and ubiquitin ligation. There was no correlation between VHL mutation status and response to treatment. VHL missense mutations may exert mild, moderate or strong impact on pVHL stability. Besides the HIF binding domain, other pVHL binding sites seem to be non-randomly altered by missense mutations. In contrast to LOF mutations that affect all the different pathways normally controlled by pVHL, missense mutations may be rather appropriate for designing tailor-made treatment strategies for ccRCC.


An analysis of surveillance screening for SDHB-related disease in childhood and adolescence.
Objective Phaeochromocytomas (PCC) and paragangliomas (PGL) are rare in children. A large proportion of these are now understood to be due to underlying germline mutations. Here we focus on succinate dehydrogenase subunit B (SDHB) gene mutation carriers as these tumours carry a high risk of malignant transformation. There remains no current consensus with respect to optimal surveillance for asymptomatic carriers and those in whom the presenting tumour has been resected. Method We undertook a retrospective analysis of longitudinal clinical data of all children and adolescents with SDHB mutations followed up in a single UK tertiary referral centre. This included index cases that pre-dated the introduction of surveillance screening and asymptomatic carriers identified through cascade genetic testing. We also conducted a literature review to inform a suggested surveillance protocol for children and adolescents harbouring SDHB mutations. Results Clinical outcomes of a total of 38 children are presented: 8 index cases and 30 mutation-positive asymptomatic carriers with 175 patient years of follow-up data. Three of the eight index cases developed metachronous disease and two developed metastatic disease. Of the 30 asymptomatic carriers, 3 were found to have PGLs on surveillance screening. Conclusions Surveillance screening was well tolerated in our paediatric cohort and asymptomatic paediatric subjects. Screening can identify tumours before they become secretory and/or symptomatic, thereby facilitating surgical resection and reducing the chance of distant spread. We propose a regular screening protocol commencing at age 5 years in this at-risk cohort of patients.


The salmeterol anomaly and the need for a urine threshold.
Salmeterol is a long acting beta2-agonist (LABA) used widely for the treatment of airways disease. There is evidence that beta2-agonists, including salmeterol, have the potential for performance enhancing effects when delivered at supratherapeutic doses. For this reason, all beta2-agonists are currently on the Prohibited List issued by the World Anti-Doping Agency (WADA), regardless of dosing route with some exemptions for inhaled salbutamol, formoterol, and salmeterol when used at therapeutic inhaled doses. For 2020, salmeterol use is permitted up to a therapeutic dosing threshold of 200 μg daily, but unlike salbutamol and formoterol, there is an anomaly; currently there is no urine threshold to control for supratherapeutic dosing beyond this dosing threshold. Salmeterol, however, is reportable as an adverse analytical finding (AAF) at levels above 10 ng/mL. Complicating matters is that following inhalation, salmeterol parent drug is present at relatively low levels compared with other beta2-agonists due to rapid metabolism to the metabolite, alpha-hydroxysalmeterol, which is typically present at higher levels than the parent drug. Moreover, peak parent drug levels following permitted therapeutic dosing are below the minimum required performance level (MRPL) of 10 ng/mL for salmeterol (50% of the MRPL that analytical laboratories are required to meet for non-threshold beta2-agonists), hence the presence of salmeterol may be unreported. For consistency, a urine threshold should be introduced for salmeterol as a matter of priority, to balance the needs of athletes who use salmeterol therapeutically up to the agreed dosing threshold, with the need to control supratherapeutic dosing for doping intentions and athlete harm minimization.


A bi-dimensional genome scan for prolificacy traits in pigs shows the existence of multiple epistatic QTL.
Prolificacy is the most important trait influencing the reproductive efficiency of pig production systems. The low heritability and sex-limited expression of prolificacy have hindered to some extent the improvement of this trait through artificial selection. Moreover, the relative contributions of additive, dominant and epistatic QTL to the genetic variance of pig prolificacy remain to be defined. In this work, we have undertaken this issue by performing one-dimensional and bi-dimensional genome scans for number of piglets born alive (NBA) and total number of piglets born (TNB) in a three generation Iberian by Meishan F(2) intercross. The one-dimensional genome scan for NBA and TNB revealed the existence of two genome-wide highly significant QTL located on SSC13 (P < 0.001) and SSC17 (P < 0.01) with effects on both traits. This relative paucity of significant results contrasted very strongly with the wide array of highly significant epistatic QTL that emerged in the bi-dimensional genome-wide scan analysis. As much as 18 epistatic QTL were found for NBA (four at P < 0.01 and five at P < 0.05) and TNB (three at P < 0.01 and six at P < 0.05), respectively. These epistatic QTL were distributed in multiple genomic regions, which covered 13 of the 18 pig autosomes, and they had small individual effects that ranged between 3 to 4% of the phenotypic variance. Different patterns of interactions (a x a, a x d, d x a and d x d) were found amongst the epistatic QTL pairs identified in the current work. The complex inheritance of prolificacy traits in pigs has been evidenced by identifying multiple additive (SSC13 and SSC17), dominant and epistatic QTL in an Iberian x Meishan F(2) intercross. Our results demonstrate that a significant fraction of the phenotypic variance of swine prolificacy traits can be attributed to first-order gene-by-gene interactions emphasizing that the phenotypic effects of alleles might be strongly modulated by the genetic background where they segregate.


Understanding Motivators and Challenges to Involving Urban Parents as Collaborators in HIV Prevention Research Efforts.
This study was designed to explore the experiences of urban parents in their role as Collaborative Board members as part of the CHAMP (Collaborative HIV prevention and Adolescent Mental health Project) Family Program Study. The CHAMP Collaborative Board is comprised of urban parents, representatives from schools and community-based agencies and university-based researchers and is charged with overseeing the design, delivery and testing of a family-based HIV prevention program for pre and early adolescent youth. The current qualitative study, guided by the Theory of Unified Behavior Change, is meant to elucidate: (1) pathways to involvement by urban parents; (2) benefits and costs of participating in this collaborative HIV prevention research effort; and (3) the role of social relationships in influencing initial and ongoing participation by parent participants. Twenty-nine parent Collaborative Board members were interviewed for this study. In-depth interviews were audio recorded and ranged from 30 to 90 minutes in length. Transcripts were coded and analyzed using NUD*IST, computerized software used for examining narratives. Findings include community parent members identifying social support and learning opportunities as major reasons for involvement with the Collaborative Board. Prior involvement with other community-based projects and knowledge of at least one other person on the Board also influenced members to join the Board and remain involved over time. Further, recommendations for future collaborative partnerships are made. Findings have direct implication for participatory HIV prevention research activities.


Targeting cancer cells by synthetic lethality: autophagy and VHL in cancer therapeutics.
Standard cytotoxic agents for treating cancer were developed based on their effectiveness to kill rapidly dividing cells, not on their ability to selectively kill cancer cells and spare normal tissue. Much of contemporary cancer research is aimed at identifying specific molecular features of cancers to directly target tumor cells with the hope of reducing or eliminating unwanted side effects. Targeted therapy for the treatment of cancer can be divided into two main categories: monoclonal antibodies and small molecules. In this Perspective, we review the approach of synthetic lethality to target cancer, specifically renal cell carcinoma. The concept of synthetic lethality is used to describe a genetic interaction of two non-allelic and non-lethal genes that when mutated simultaneously results in cell death. Recently, we identified a compound, STF-62247, that functions in a synthetic lethal manner to the loss of VHL, a mutation found in the majority of renal cell carcinomas.


Frequency of cryptococcal meningitis in HIV-1 infected patients in north central Nigeria.
Cryptococcal meningitis (CM) is the most common severe life threatening fungal infection in AIDS patients. It is an important cause of morbidity and mortality There is paucity of data on the prevalence of CM in Nigeria. We aimed to determine the frequency of CM, the clinical presentation and immunological profile. A cross sectional study was carried out at the Jos University Teaching Hospital (JUTH). A total of 100 HIV-1 infected patients suspected of having meningitis or meningoencephalitis were subjected to cerebrospinal fluid (CSF) analysis (including Indian ink preparation and fungal culture by conventional methods) and CD4 count was determined using flow cytometry (count bit Y-R 1004 Partec Muster Germany). The freguency of CM was 36% in our cohort. The commonest clinical presentation included headache (100.0%), neck stiffness (77.8%), fever (72.0%), vomiting 55.6%), personality changes (55.6%), photophobia (27.8%) and convulsions (27.8%). The mean duration of symptoms was 24 +/- 22 days with a median of 17 days. The mean CD4 count was 89 +/- 60 cells/mm3 with a median of 82 cells/mm3. The high prevalence of CM and the associated severe immunosuppression underscores the importance of early diagnosis of HIV infection which may reduce the incidence of CM. There is the urgent need for access to Amphotericin B and fluconazole in resource constrained settings in addition to a wide access to HAART.


Technical considerations for the use of CRISPR/Cas9 in hematology research.
The hematopoietic system is responsible for transporting oxygen and nutrients, fighting infections, and repairing tissue damage. Hematopoietic system dysfunction therefore causes a range of serious health consequences. Lifelong hematopoiesis is maintained by repopulating multipotent hematopoietic stem cells (HSCs) that replenish shorter-lived, mature blood cell types. A prokaryotic mechanism of immunity, the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 nuclease system, has been recently "repurposed" to mutate mammalian genomes efficiently and in a sequence-specific manner. The application of this genome-editing technology to hematology has afforded new approaches for functional genomics and even the prospect of "correcting" dysfunctional HSCs in the treatment of serious genetic hematological diseases. In this Perspective, we provide an overview of three recent CRISPR/Cas9 methods in hematology: gene disruption, gene targeting, and saturating mutagenesis. We also summarize the technical considerations and advice provided during the May 2017 International Society of Experimental Hematology New Investigator Committee webinar on the same topic.


Erythropoietin Attenuates the Brain Edema Response after Experimental Traumatic Brain Injury.
Erythropoietin (EPO) has neuroprotective effects in multiple central nervous system (CNS) injury models; however EPO's effects on traumatic brain edema are elusive. To explore EPO as an intervention in traumatic brain edema, male Sprague-Dawley (SD) rats were subjected to blunt, controlled traumatic brain injury (TBI). Animals were randomized to EPO 5000 IU/kg or saline (control group) intraperitoneally within 30 min after trauma and once daily for 4 consecutive days. Brain MRI, immunohistofluorescence, immunohistochemistry, and quantitative protein analysis were performed at days 1 and 4 post- trauma. EPO significantly prevented the loss of the tight junction protein zona occludens 1 (ZO-1) observed in control animals after trauma. The decrease of ZO-1 in the control group was associated with an immunoglobulin (Ig)G increase in the perilesional parenchyma, indicating blood-brain barrier (BBB) dysfunction and increased permeability. EPO treatment attenuated decrease in apparent diffusion coefficient (ADC) after trauma, suggesting a reduction of cytotoxic edema, and reduced the IgG leakage, indicating that EPO contributed to preserve BBB integrity and attenuated vasogenic edema. Animals treated with EPO demonstrated conserved levels of aquaporin 4 (AQP4) protein expression in the perilesional area, whereas control animals showed a reduction of AQP4. We show that post TBI administration of EPO decreases early cytotoxic brain edema and preserves structural and functional properties of the BBB, leading to attenuation of the vasogenic edema response. The data support that the mechanisms involve preservation of the tight junction protein ZO-1 and the water channel AQP4, and indicate that treatment with EPO may have beneficial effects on the brain edema response following TBI.


Membranes for specific adsorption: immobilizing molecularly imprinted polymer microspheres using electrospun nanofibers.
Molecularly imprinted polymer microspheres were immobilized within a polymer nanofiber membrane by electrospinning. Such membranes simplify the handling of functional microspheres and provide specific recognition capabilities for solid-phase extraction and filtration applications. In this study, microspheres were prepared by precipitation polymerization of methacrylic acid and divinylbenzene as a cross-linker with the target molecule (-)-cinchonidine and then, they were electrospun into a non-woven polyacrylonitrile nanofiber membrane. The composite membrane showed specific affinity for (-)-cinchonidine which was attributed to the functional microspheres as confirmed by Raman microscopy. The target molecule capturing capacity of the composite membrane was 5 mg/g or 25 mg/g immobilized functional microsphere. No difference in target affinity was observed between the immobilized microspheres and the free microspheres. These results reveal that electrospun composite membranes are a feasible approach to immobilizing functional microspheres.


Using surface electromyography to assess sex differences in neuromuscular response characteristics.
To provide an overview of the continuum of muscular responses that typically occur with joint perturbation. The applications and limitations of surface electromyography (sEMG) in evaluating these responses are also addressed. Research applications assessing sex differences in these neuromuscular response characteristics are discussed along with suggestions for future research. MEDLINE was searched from 1969 through 1998. Sport DISCUS was searched from 1975 through 1998. Terms searched included "anterior cruciate ligament," "epidemiology," "neuromuscular control," "neuromuscular performance," "electromyography," "latency," "reflex," "electromechanical delay," "dynamic stability," "intrinsic stiffness," "short-range stiffness," "muscle," "mechanoreceptors," and "reaction time." It is widely accepted that efficient neuromuscular control is essential to dynamic joint stability and protection. Many studies have established the significant role of the muscles, and particularly the hamstrings, in providing knee stability. By observing the timing, phasing, and recruitment of reflexive muscular activation after a loading stress to the knee, we can better understand the coordinative mechanisms necessary to protect the joint and prevent ligament injury. A number of research models have employed the use of sEMG to evaluate neuromuscular responses at the knee after joint loading or perturbation. However, very few studies have specifically addressed potential sex differences in these response characteristics. From the limited research available, it appears that a sex difference may exist in some aspects of neuromuscular responses. However, further research is needed to explore these differences at the knee and their potential role as predisposing factors to the higher incidence of anterior cruciate ligament injuries in females. Future studies should examine sex differences in neuromuscular response characteristics at the knee under functional, weight-bearing conditions while controlling for training and other confounding variables. The limitations of sEMG should be considered when interpreting neuromuscular response studies.


Immunochemical characterization of Micrurus nigrocinctus nigrocinctus venom with monoclonal and polyclonal antibodies.
Eleven murine monoclonal antibodies (MAbs) against Micrurus nigrocinctus nigrocinctus venom were produced and partially characterized. When M. n. nigrocinctus venom proteins were separated by SDS-PAGE under non-reducing conditions four sharp and three diffuse bands were observed. The sharp bands had migration rates comparable to reduced standards of 10, 12, 50 and 72 kDa. The diffuse bands migrate in the range of reduced standards from 14.5 to 32 kDa. When venom proteins were separated under reducing conditions the same sharp bands and an additional prominent 14.5 kDa band were observed. Three antibodies (MAbs 4, 21 and 28) recognized the diffuse bands in western blots of non-reducing SDS-PAGE, whereas MAbs 7G, 22 and 26 reacted with only the 72 kDa protein. MAbs 21 and 28 reacted with the 14.5 kDa band whereas MAb 7G recognized the 72 kDa band in blots of reducing SDS-PAGE. Two M. nigrocinctus antivenoms cross-reacted by ELISA against nine neurotoxic snake venoms, as well as with gamma-toxin from Naja nigricollis and notexin. One antibody (MAb 9A) was used to affinity purify a fraction (called nigroxin) from M. n. nigrocinctus venom. Nigroxin showed phospholipase and myotoxic activities and appeared as a single 15 kDa band in SDS-PAGE under reducing conditions. However, three bands with slight differences in charge were resolved by urea-PAGE, representing isoforms named nigroxin a, b, and c. Nigroxin induced a dose-dependent release of peroxidase trapped in negatively charged liposomes. Nigroxin induced myonecrosis and increased the plasma creatine kinase levels in mice, when injected intramuscularly. The plasma membrane of cultured L6 myoblasts was permeabilized by nigroxin, as evidenced by the release of 3H-uridine nucleotides from prelabelled cells. This effect was completely abolished after preincubation with MAb 9A, although this antibody failed to neutralize the enzymatic activity of nigroxin. Nigroxin was also recognized by MAbs 4, 7H, 21, 27 and 28. Additionally, the epitope recognized by MAb 27 is also present in notexin and beta-bungarotoxin.


Who benefits from intervention in, as opposed to screening of, overweight and obese children?
StEP TWO is a school- and family-based intervention consisting of extra lessons, healthy nutrition and physical education for overweight and obese children in primary schools, aimed at reducing body mass index by maintenance or reduction of weight, and improving motor abilities. We analysed differences in changes in anthropometric, cardiovascular and obesity parameters between children who underwent intervention, non-participants in intervention, and controls. Anthropometric data and waist circumference were recorded for 1678 children; body mass index and body mass index-standard deviation score were calculated. Blood pressure was measured after 5 minutes at rest. 121 overweight and obese children enrolled at 3 schools involved in programmes of intervention were invited to take part; 40 of them completed the programme from November 2003 to July 2004. Of these overweight children, 74 were invited, but did not take part. As controls, we enrolled 155 overweight and obese children from 4 other schools. After the programme, the children involved in intervention showed a lower increase in the body mass index (0.3 plus or minus 1.3 versus 0.7 plus or minus 1.2 kilograms per metre squared) and an approximately three times higher diminution of the body mass index-standard deviation score in comparison with their controls (-0.15 plus or minus 0.26 versus 0.05 plus or minus 0.27). Systolic blood pressure was significantly lowered by 9.5 plus or minus 19.6 millimetres of mercury in those involved in intervention, but increased in the control group by 0.5 plus or minus 16.5 millimetres of mercury. Among those invited but not participating, the increase of the body mass index (0.5 plus or minus 1.3 kilograms per metre squared) was less, and the reduction of the body mass index-standard deviation score (-0.09 plus or minus 0.31) and systolic blood pressure (-5.3 plus or minus 15.6 millimetres of mercury) was higher than in the control group. Overweight but not obese children seem to benefit from a screening examination alone. Early preventive measures in schools are necessary and effective for overweight and obese primary school children. The screening itself seems also to have a minor positive effect, especially for overweight children. Sustainability of the observed improvements over a longer period remains to be confirmed.


PCR-mediated recombination in amplification products derived from polyploid cotton.
PCR recombination describes a process of in vitro chimera formation from non-identical templates. The key requirement of this process is the inclusion of two partially homologous templates in one reaction, a condition met when amplifying any locus from polyploid organisms and members of multigene families from diploid organisms. Because polyploids possess two or more divergent genomes ("homoeologues") in a common nucleus, intergenic chimeras can form during the PCR amplification of any gene. Here we report a high frequency of PCR-induced recombination for four low-copy genes from allotetraploid cotton ( Gossypium hirsutum). Amplification products from these genes ( Myb3, Myb5, G1262 and CesA1) range in length from 860 to 4,050 bp. Intergenomic recombinants were formed frequently, accounting for 23 of the 74 (31.1%) amplicons evaluated, with the frequency of recombination in individual reactions ranging from 0% to approximately 89%. Inspection of the putative recombination zones failed to reveal sequence-specific attributes that promote recombination. The high levels of observed in vitro recombination indicate that the tacit assumption of exclusive amplification of target templates may often be violated, particularly from polyploid genomes. This conclusion has profound implications for population and evolutionary genetic studies, where unrecognized artifactually recombinant molecules may bias results or alter interpretations.


Toward accurate molecular identification of species in complex environmental samples: testing the performance of sequence filtering and clustering methods.
Metabarcoding has the potential to become a rapid, sensitive, and effective approach for identifying species in complex environmental samples. Accurate molecular identification of species depends on the ability to generate operational taxonomic units (OTUs) that correspond to biological species. Due to the sometimes enormous estimates of biodiversity using this method, there is a great need to test the efficacy of data analysis methods used to derive OTUs. Here, we evaluate the performance of various methods for clustering length variable 18S amplicons from complex samples into OTUs using a mock community and a natural community of zooplankton species. We compare analytic procedures consisting of a combination of (1) stringent and relaxed data filtering, (2) singleton sequences included and removed, (3) three commonly used clustering algorithms (mothur, UCLUST, and UPARSE), and (4) three methods of treating alignment gaps when calculating sequence divergence. Depending on the combination of methods used, the number of OTUs varied by nearly two orders of magnitude for the mock community (60-5068 OTUs) and three orders of magnitude for the natural community (22-22191 OTUs). The use of relaxed filtering and the inclusion of singletons greatly inflated OTU numbers without increasing the ability to recover species. Our results also suggest that the method used to treat gaps when calculating sequence divergence can have a great impact on the number of OTUs. Our findings are particularly relevant to studies that cover taxonomically diverse species and employ markers such as rRNA genes in which length variation is extensive.


Estrogen receptor-1 (Esr1) and -2 (Esr2) regulate the severity of clinical experimental allergic encephalomyelitis in male mice.
Estrogens and estrogen-receptor signaling function in establishing and regulating the female immune system and it is becoming increasingly evident that they may play a similar role in males. We report that B10.PL/SnJ male mice with a disrupted estrogen receptor-1 (alpha) gene (Esr1(-/-)) develop less severe clinical experimental allergic encephalomyelitis (EAE) compared to either Esr1(+/-) or wild-type (Esr1(+/+)) controls when immunized with myelin basic protein peptide Ac1-11 (MBP(Ac1-11)). In contrast, the disease course in B10.PL/SnJ male mice with a disrupted estrogen receptor-2 (beta) gene (Esr2(-/-)) does not differ from that of wild-type (Esr2(+/+)) mice. However, Esr2(+/-) mice do develop more severe clinical disease with an earlier onset indicating that heterosis at Esr2 plays a significant role in regulating EAE in males. No significant differences in central nervous system histopathology or MBP(Ac1-11)-specific T-cell responses as assessed by proliferation and interleukin-2 production were observed as a function of either Esr1 or Esr2 genotype. An analysis of cytokine/chemokine secretion by MBP(Ac1-11)-specific T cells revealed unique Esr1 and Esr2 genotype-dependent regulation. Interferon-gamma secretion was found to be negatively regulated by Esr1 whereas interleukin-6 and tumor necrosis factor-alpha secretion exhibited classical Esr2 gene dose responses. Interestingly, MCP-1 displayed distinctively unique patterns of genotype-dependent regulation by Esr1 and Esr2. The contribution of the hematopoietic and nonhematopoietic cellular compartments associated with the heterotic effect at Esr2 in regulating the severity of clinical EAE was identified using reciprocal hematopoietic radiation bone marrow chimeras generated between male wild-type and Esr2(+/-) mice. Wild-type --> Esr2(+/-) mice exhibited EAE equivalent in severity to that seen in Esr2(+/-) --> Esr2(+/-) control constructs; both of which were more severe than the clinical signs observed in Esr2(+/-) --> wild-type and wild-type --> wild-type mice. These results indicate that the heterotic effect at Esr2 is a function of the nonhematopoietic compartment.


Are angiotensin-converting enzyme inhibitors the best treatment for hypertension in type 2 diabetes?
The influence of hypertension on the clinical course and complications of type 2 diabetes is well established. With a special focus on angiotensin-converting enzyme inhibitors, this paper will review recently published results of prospective studies addressing two important aspects: the degree of blood pressure control, and the choice of antihypertensive regimen, in the prevention of complications in hypertensive type 2 diabetic patients. None of the recent studies have shown worse outcomes in patients treated with angiotensin-converting enzyme inhibitor-based regimens compared with alternative treatments. Some studies have suggested that angiotensin-converting enzyme inhibitor-based antihypertensive regimens may be superior to alternative treatments in reducing the risk of micro- and macrovascular complications, whereas other studies found similar effects for beta-blockers or calcium antagonists. Several trials showed beneficial effects of angiotensin-converting enzyme inhibitors over calcium antagonists, and have raised concerns about the use of dihydropyridine calcium antagonists in these patients. However, it remains to be determined whether there should be more reserved use of calcium antagonists in such patients, in the light of more major trials showing the safety and efficacy of calcium antagonists in preventing cardiovascular and renal endpoints. The degree of reduction of blood pressure rather than the choice of a particular drug may be the most important factor. Studies focusing on renal endpoints suggest that angiotensin-converting enzyme inhibitors have a better antiproteinuric effect than other agents, but this phenomenon is not always reflected by a more beneficial effect of angiotensin-converting enzyme inhibitors on the decline in glomerular filtration rate. In many ways, the question of whether angiotensin-converting enzyme inhibitors are the best class of agent in these patients is academic. Angiotensin-converting enzyme inhibitors are sufficiently safe, and, according to recent evidence, equally or more effective than other classes of agents. Tight blood pressure control is usually achievable only with a combination of agents. On the basis of available evidence, it appears that angiotensin-converting enzyme inhibitors, together with a low-dose cardioselective beta-blocker and a diuretic, should be used in most hypertensive type 2 diabetes patients, with calcium antagonists serving as reserve drugs in case of insufficient blood pressure control.


Modeling the effects of positive and negative feedback in kidney blood flow control.
Blood flow in the mammalian kidney is tightly autoregulated. One of the important autoregulation mechanisms is the myogenic response, which is activated by perturbations in blood pressure along the afferent arteriole. Another is the tubuloglomerular feedback, which is a negative feedback that responds to variations in tubular fluid [Cl(-)] at the macula densa.(1) When initiated, both the myogenic response and the tubuloglomerular feedback adjust the afferent arteriole muscle tone. A third mechanism is the connecting tubule glomerular feedback, which is a positive feedback mechanism located at the connecting tubule, downstream of the macula densa. The connecting tubule glomerular feedback is much less well studied. The goal of this study is to investigate the interactions among these feedback mechanisms and to better understand the effects of their interactions. To that end, we have developed a mathematical model of solute transport and blood flow control in the rat kidney. The model represents the myogenic response, tubuloglomerular feedback, and connecting tubule glomerular feedback. By conducting a bifurcation analysis, we studied the stability of the system under a range of physiologically-relevant parameters. The bifurcation results were confirmed by means of a comparison with numerical simulations. Additionally, we conducted numerical simulations to test the hypothesis that the interactions between the tubuloglomerular feedback and the connecting tubule glomerular feedback may give rise to a yet-to-be-explained low-frequency oscillation that has been observed in experimental records.


Effect of recombinant human bone morphogenetic protein-2/absorbable collagen sponge (rhBMP-2/ACS) on healing in 3-wall intrabony defects in dogs.
Recombinant human bone morphogenetic protein-2 (rhBMP-2) in an absorbable collagen sponge (ACS) carrier is being evaluated as a candidate therapy for periodontal regeneration. The objective of this study was to evaluate regeneration of alveolar bone and cementum, and associated root resorption and ankylosis following surgical implantation of rhBMP-2/ACS in a canine clinical model. Bilateral 3-wall intrabony periodontal defects were surgically induced in the premolar region in the maxilla and mandible in 8 young adult Korean mongrel dogs. The defects in each animal received rhBMP-2/ACS (rhBMP-2 at 0.2 mg/ml, total implant volume/defect approximately 0.1 ml) or buffer/ACS, or served as sham-operated controls. Surgeries were sequenced for each animal to provide postmortem observations following 8- and 24-week healing intervals. Treatment outcomes were evaluated using clinical, radiographic, and histometric parameters. Surgical implantation of rhBMP-2/ACS resulted in accelerated enhanced bone formation in the 3-wall intrabony periodontal defects but in no apparent enhancement of cementum regeneration. rhBMP-2/ACS did not appear to be associated with aberrant healing events such as root resorption and ankylosis under these simulated clinical conditions. Surgical implantation of rhBMP-2/ACS may be used safely to support regeneration of alveolar bone in intrabony periodontal defects in dogs without aberrant events such as root resorption or ankylosis complicating the regenerative procedure. rhBMP-2/ACS does not appear to have a significant effect on cementum regeneration and formation of a functional periodontal ligament in this model.


Optimizing Cholesterol Treatment in Patients With Muscle Complaints.
Statins are highly effective for preventing cardiovascular events by reducing low-density lipoprotein cholesterol (LDL-C). However, many patients taking statins report muscle-related symptoms that prevent the use of guideline recommended doses. Patients with reported intolerance to statins have a high risk of cardiovascular events. Clinical strategies that optimize cardiovascular risk reduction through LDL-C lowering need to be applied in patients experiencing intolerable side effects that they attribute to statins. In this paper, the authors review definitions of statin intolerance, propose algorithms to better define statin intolerance, and describe approaches to optimize cardiovascular risk reduction among individuals reporting statin-associated muscle symptoms.


New thermoluminescence age estimates for the Nyos maar eruption (Cameroon Volcanic Line).
Nyos maar is located in the Cameroon Volcanic Line and generates a multitude of primary and secondary hazards to the local population. For risk assessment and hazard mitigation, the age of the Nyos maar eruption provides some vital information. Since previous dating efforts using a range of techniques resulted in vastly varying eruption ages, we applied thermoluminescence (TL) methods to obtain independent and direct chronological constraints for the time of maar formation. Target minerals were granitic quartz clasts contained in pyroclastic surge deposits. Thermoluminescence plateau results prove that heat and/or pressure during the phreatomagmatic eruption was sufficient to reset the inherited luminescence signal of granitic bedrock quartz. Parallel application of three TL measurement protocols to one of the two samples gave consistent equivalent doses for the quartz ultra-violet emission. Despite the robustness of our dose estimates, the assessment of the dose rate was accompanied by methodological challenges, such as estimation of the original size distribution of quartz grains in the pyroclastic deposits. Considering results from additional laboratory analyses to constrain these uncertainties, we calculate an average maximum TL age of 12.3 ± 1.5 ka for the Nyos maar eruption. Based on these new data, a more solid risk assessment can be envisaged.


The effectiveness of electroconvulsive therapy: a literature review.
To review the literature on the efficacy of electroconvulsive therapy [ECT], with a particular focus on depression, its primary target group. PsycINFO, Medline, previous reviews and meta-analyses were searched in an attempt to identify all studies comparing ECT with simulated-ECT [SECT]. These placebo controlled studies show minimal support for effectiveness with either depression or 'schizophrenia' during the course of treatment (i.e., only for some patients, on some measures, sometimes perceived only by psychiatrists but not by other raters), and no evidence, for either diagnostic group, of any benefits beyond the treatment period. There are no placebo-controlled studies evaluating the hypothesis that ECT prevents suicide, and no robust evidence from other kinds of studies to support the hypothesis. Given the strong evidence (summarised here) of persistent and, for some, permanent brain dysfunction, primarily evidenced in the form of retrograde and anterograde amnesia, and the evidence of a slight but significant increased risk of death, the cost-benefit analysis for ECT is so poor that its use cannot be scientifically justified.


Trends, demographics and disparities in outpatient antibiotic consumption in New Zealand: a national study.
Knowledge of the patterns of antibiotic consumption within a population provides valuable information on when, where and to whom antibiotics are prescribed. Such knowledge is critical in informing possible public health interventions to reduce inappropriate antibiotic use. The aims of this study were to (i) determine national patterns of antibiotic consumption, including assessment of seasonal variation in prescribing, and (ii) explore potential associations between antibiotic consumption and patient characteristics, such as age, sex and ethnicity. Data on all subsidized antibiotic dispensing in New Zealand between 1 January 2006 and 31 December 2014 were obtained and stratified according to age, sex and ethnicity. Antibiotic dispensing was expressed as the number of DDDs per 1000 population per day (DID). Total antibiotic consumption in New Zealand increased by 49% from 17.3 DID in 2006 to 25.8 DID in 2014. The increase in antibiotic consumption occurred in all ages and amongst all ethnic groups. The use of extended-spectrum penicillins, which almost doubled in the study period, made a major contribution to the overall increase and was highest in young children and in Pacific peoples. Consumption of quinolones increased early in the study period and then declined from 2011 onwards. Future work should focus on identifying the appropriateness of antibiotic prescribing, particularly for penicillin prescribing in Pacific peoples and children, and on both reducing unwarranted antibiotic use and improving antibiotic selection when therapy is indicated.


Long-term nutrient addition increased CH4 emission from a bog through direct and indirect effects.
Peatlands are globally significant sources of atmospheric methane (CH4). While several studies have examined the effects of nutrient addition on CH4 dynamics, there are few long-term peatland fertilization experiments, which are needed to understand the aggregated effects of nutrient deposition on ecosystem functioning. We investigated responses of CH4 flux and production to long-term field treatments with three levels of N (1.6-6.4 g m-2 yr-1 as NH4NO3), potassium and phosphorus (PK, 5.0 g P and 6.3 g K m-2 yr-1 as KH2PO4), and NPK in a temperate bog. Methane fluxes were measured in the field from May to August in 2005 and 2015. In 2015 CH4 flux was higher in the NPK treatment with 16 years of 6.4 g N m-2 yr-1 than in the control (50.5 vs. 8.6 mg CH4 m-2 d-1). The increase in CH4 flux was associated with wetter conditions derived from peat subsidence. Incubation of peat samples, with and without short-term PK amendment, showed that potential CH4 production was enhanced in the PK treatments, both from field application and by amending the incubation. We suggest that changes in this bog ecosystem originate from long-term vegetation change, increased decomposition and direct nutrient effects on microbial dynamics.


Drifting through Basic Subprocesses of Reading: A Hierarchical Diffusion Model Analysis of Age Effects on Visual Word Recognition.
Reading is one of the most popular leisure activities and it is routinely performed by most individuals even in old age. Successful reading enables older people to master and actively participate in everyday life and maintain functional independence. Yet, reading comprises a multitude of subprocesses and it is undoubtedly one of the most complex accomplishments of the human brain. Not surprisingly, findings of age-related effects on word recognition and reading have been partly contradictory and are often confined to only one of four central reading subprocesses, i.e., sublexical, orthographic, phonological and lexico-semantic processing. The aim of the present study was therefore to systematically investigate the impact of age on each of these subprocesses. A total of 1,807 participants (young, N = 384; old, N = 1,423) performed four decision tasks specifically designed to tap one of the subprocesses. To account for the behavioral heterogeneity in older adults, this subsample was split into high and low performing readers. Data were analyzed using a hierarchical diffusion modeling approach, which provides more information than standard response time/accuracy analyses. Taking into account incorrect and correct response times, their distributions and accuracy data, hierarchical diffusion modeling allowed us to differentiate between age-related changes in decision threshold, non-decision time and the speed of information uptake. We observed longer non-decision times for older adults and a more conservative decision threshold. More importantly, high-performing older readers outperformed younger adults at the speed of information uptake in orthographic and lexico-semantic processing, whereas a general age-disadvantage was observed at the sublexical and phonological levels. Low-performing older readers were slowest in information uptake in all four subprocesses. Discussing these results in terms of computational models of word recognition, we propose age-related disadvantages for older readers to be caused by inefficiencies in temporal sampling and activation and/or inhibition processes.


Alternating immunochemotherapy of advanced gastric carcinoma: a randomized comparison of carbazilquinone and PSK to carbazilquinone in patients with curative gastric resection.
A total of 103 patients with advanced gastric carcinoma were randomized after curative surgery to receive an alternate administration of carbazilquinone (CQ) and PSK (Krestin) or carbazilquinone alone. Each course of therapies started 1 week after the surgical operation and therapy schedules consisted of 9 courses. In each course of 6 weeks, CQ (2 mg/m2/week) was administered on day 0, 8, and 15. In combined immunochemotherapy group, PSK was given orally in 3-divided doses of 2 g/m2/day from the day of the third CQ administration for consecutive 4 weeks. Estimated survival rate and cumulative survival curve were compared utilizing the data up to 7 years after the operation. There was no overall significant difference in survival rates between the CQ plus PSK group and the CQ alone group, but a group of patients whose disease was classified as S1 + S2(N1-2) survived significantly longer when treated with the combination of CQ and PSK. Neither in more advanced cases (greater than S3 or greater than N3) nor in cancers of early stages, the addition of PSK provided an additive effect. The favorable result obtained in one subgroup treated with PSK, suggests that the use of this agent in treating gastric cancers should be carefully evaluated in terms of serosal infiltration and nodal metastasis.


Multidirectional cross-species painting illuminates the history of karyotypic evolution in Perissodactyla.
The order Perissodactyla, the group of odd-toed ungulates, includes three extant families: Equidae, Tapiridae, and Rhinocerotidae. The extremely rapid karyotypic diversification in perissodactyls has so far prevented the establishment of genome-wide homology maps between these three families by traditional cytogenetic approaches. Here we report the first genome-wide comparative chromosome maps of African rhinoceroses, four tapir species, four equine species, and humans. These maps were established by multidirectional chromosome painting, with paint probes derived from flow-sorted chromosomes of Equus grevyi, Tapirus indicus, and Ceratotherium simum as well as painting probes from horse and human. The Malayan tapir (Tapirus indicus), Baird's tapir (T. bairdii), mountain tapir (T. pinchaque), lowland tapir (T. terrestris), and onager (E. hemionus onager), were studied by cross-species chromosome painting for the first time. Our results, when integrated with previously published comparative chromosome maps of the other perissodactyl species, have enabled the reconstruction of perissodactyl, ceratomorph, and equid ancestral karyotypes, and the identification of the defining evolutionary chromosomal rearrangements along each lineage. Our results allow a more reliable estimate of the mode and tempo of evolutionary chromosomal rearrangements, revealing a striking switch between the slowly evolving ceratomorphs and extremely rapidly evolving equids.


Overexpression of Spexin 1 in the Dorsal Habenula Reduces Anxiety in Zebrafish.
Spexin (SPX) is an evolutionarily conserved neuropeptide that is expressed in the mammalian brain and peripheral tissue. Two orthologs are present in the teleost, SPX1 and SPX2. SPX1 is involved in reproduction and food intake. Recently, SPX1 neurons have been found to be located in the specific nuclei of dorsal habenula (dHb) and to project into the interpeduncular nucleus (IPN), in which galanin receptor 2a/2b (GALR2a/2b) expression was also observed. This indicates that habenula SPX1 neurons may interact with GALR2a/2b in the IPN; however, the function of SPX1 in the dHb-IPN neuronal circuit remains unknown. To determine the role of SPX1 in the dHb-IPN neural circuit, we generated transgenic zebrafish overexpressing SPX1 specifically in the dHb. We found that transgenic zebrafish overexpressing SPX1 in the dHb had anxiolytic behaviors compared with their wildtype siblings. Furthermore, quantitative PCR revealed that mRNA expression of galr2a and galr2b in the IPN and serotonin-related genes in the raphe was upregulated in the brains of transgenic zebrafish. Taken together, our data suggest that SPX1 function in the dHb-IPN neural circuits is implicated in the regulation of anxiety behaviors via modulation of the serotoninergic system in zebrafish.


Effects of aromatase inhibitor on sex differentiation and levels of P450 (17 alpha) and P450 arom messenger ribonucleic acid of gonads in chicken embryos.
On Day 5 of incubation fertilized eggs of single-comb White Leghorn hens were injected with an aromatase inhibitor (AI) and the sex reversal effect and levels of mRNA of P450(17alpha-hydroxylase) (P450(17alpha)) and 450(aromatase) (P450(arom)) were evaluated by observation of gonadal phenotype and by Northern and slot blot analysis. Individual genetic sex was evaluated by Southern blot analysis of red blood cells using a female sex chromosomal W-specific DNA probe. Saline injection had no sex reversal effect, whereas AI injection resulted in 50% sex reversal from genetic female but no effect on male. Levels of P450(17-alpha) mRNA were high in both ovary and testis in the control group but these levels were lowered significantly in ovary, testis, and sex-reversed gonad (testis) in the AI-treated group. On the other hand, levels of P450(arom) mRNA in the ovary were higher than those in the testis of the control group. AI treatment significantly suppressed ovarian levels of P450(arom) mRNA. Although estradiol alone failed to prevent the phenotypic male to female change, coadministration of estrogen suppressed the sex-reversal effect of AI and restored mRNA levels of P450(arom) in the ovary to control levels. These results suggest that expression of P450(arom) mRNA and estrogen plays an important role in sex differentiation of the female gonad of the chicken.


Vascular malformations: an update.
Vascular malformations occur as a result of an arrest in the development of the vascular system. The modified Hamburg classification distinguishes arterial, venous, arteriovenous, capillary, lymphatic, and mixed vascular malformations. Each malformation is further subdivided based on anatomy and on the time when arrest in development of the embryogenesis occurred; malformations can be truncular or extratruncular. Progress in the last decade in management has been significant because of improvements in open surgical procedures and perfection of percutaneous and hybrid endovascular interventions and devices, such as balloons, stents, and stent-grafts. There has been increasing use of embolization for the treatment of malformations with coils, other particles, glue, or with endovascular placement of occlusive plugs. Absolute alcohol, detergent liquids, or foam have been used for sclerotherapy with improved efficacy. The agents are delivered percutaneously or through a catheter placed either into the feeding arteries or the draining veins. This review aims to aid vascular and endovascular specialists in staying familiar with vascular malformations. These specialists need to be able to evaluate the patients, perform treatment if appropriate, or refer complex cases to multidisciplinary vascular malformation clinics and vascular centers.


Genetic analysis of somatic cell score in danish holsteins using a liability-normal mixture model.
Mixture models are appealing for identifying hidden structures affecting somatic cell score (SCS) data, such as unrecorded cases of subclinical mastitis. Thus, liability-normal mixture (LNM) models were used for genetic analysis of SCS data, with the aim of predicting breeding values for such cases of mastitis. Here, putative mastitis statuses and breeding values for liability to putative mastitis were inferred solely from SCS observations. In total, there were 395,906 test-day records for SCS from 50,607 Danish Holstein cows. Four different statistical models were fitted: A) a classical (nonmixture) random regression model for test-day SCS; B1) an LNM test-day model assuming homogeneous (co)variance components for SCS from healthy (IMI-) and infected (IMI+) udders; B2) an LNM model identical to B1, but assuming heterogeneous residual variances for SCS from IMI- and IMI+ udders; and C) an LNM model assuming fully heterogeneous (co)variance components of SCS from IMI- and IMI+ udders. For the LNM models, parameters were estimated with Gibbs sampling. For model C, variance components for SCS were lower, and the corresponding heritabilities and repeatabilities were substantially greater for SCS from IMI- udders relative to SCS from IMI+ udders. Further, the genetic correlation between SCS of IMI- and SCS of IMI+ was 0.61, and heritability for liability to putative mastitis was 0.07. Models B2 and C allocated approximately 30% of SCS records to IMI+, but for model B1 this fraction was only 10%. The correlation between estimated breeding values for liability to putative mastitis based on the model (SCS for model A) and estimated breeding values for liability to clinical mastitis from the national evaluation was greatest for model B1, followed by models A, C, and B2. This may be explained by model B1 categorizing only the most extreme SCS observations as mastitic, and such cases of subclinical infections may be the most closely related to clinical (treated) mastitis.


What do service users with bipolar disorder want from a web-based self-management intervention? A qualitative focus group study.
Bipolar disorder (BD) is a chronic and recurrent severe mental health problem. A web-based self-management intervention provides the opportunity to widen access to psychological interventions. This qualitative study aims to identify what an ideal web-based intervention would look like for service users with BD. Twelve service users with BD were recruited in the UK and took part in a series of focus groups to inform and refine the development of a web-based self-management intervention. Reported here is a subset analysis of data gathered with the primary aim of identifying the needs and desires of service users for such an intervention for BD. We analysed service users' responses to questions about content, outcomes, format, barriers and support. Focus groups were transcribed verbatim, and thematic analysis was employed. The data were ordered into four key themes: (1) gaining an awareness of and managing mood swings; (2) not just about managing mood swings: the importance of practical and interpersonal issues; (3) managing living within mood swings without losing the experience; (4) internet is the only format: freely accessible, instant and interactive; (5) professional and peer support to overcome low motivation and procrastination difficulties. The small group of participants are not representative of those living with BD. These findings have significantly enhanced our understanding of what service users with BD want from a web-based self-management intervention and have clear implications for the future development of such approaches. Service users desire a web-based self-management approach that gives them the techniques they need to not only manage their moods but also manage their lives alongside the disorder, including interpersonal and practical issues. Service users describe their primary outcome, not as a cure or reduction in their symptoms, but instead being able to live a fulfilling life alongside their condition. Service users see the internet as their preferred format because of the increased accessibility to evidence-based intervention. Service users discussed the potential barriers to web-based interventions including motivation and procrastination. Effective and acceptable content and low-level support provide potential solutions to these issues.


Prevalence and risk factors of late presentation for HIV diagnosis and care in a tertiary referral centre in Switzerland.
We sought to identify reasons for late human immunodeficiency virus (HIV) testing or late presentation for care. A structured chart review was performed to obtain data on test- and health-seeking behaviour of patients presenting late with CD4 cell counts below 350 cells/µl or with acquired immunodeficiency syndrome (AIDS), at the Zurich centre of the Swiss HIV Cohort Study between January 2009 and December 2011. Logistic regression analyses were used to compare demographic characteristics of persons presenting late with not late presenters. Of 281 patients, 45% presented late, 48% were chronically HIV-infected non-late presenters, and an additional 7% fulfilled the <350 CD4 cells/µl criterion for late presentation but a chart review revealed that lymphopenia was caused by acute HIV infection. Among the late presenters, 60% were first tested HIV positive in a private practice. More than half of the tests (60%) were suggested by a physician, only 7% following a specific risk situation. The majority (88%) of patients entered medical care within 1 month of testing HIV positive. Risk factors for late presentation were older age (odds ratio [OR] for ≥ 50 vs <30 years: 3.16, p = 0.017), Asian versus Caucasian ethnicity (OR 3.5, p = 0.021). Compared with men who have sex with men (MSM) without stable partnership, MSM in a stable partnership appeared less likely to present late (OR 0.50, p = 0.034), whereas heterosexual men in a stable partnership had a 2.72-fold increased odds to present late (p = 0.049). The frequency of late testing could be reduced by promoting awareness, particularly among older individuals and heterosexual men in stable partnerships.


Structured assessment of violence risk in schizophrenia and other psychiatric disorders: a systematic review of the validity, reliability, and item content of 10 available instruments.
To undertake a systematic review on structured violence risk assessment tools in individuals with schizophrenia. A systematic search was conducted from 1990 to 2011 to identify violence risk assessment tools and studies examining their predictive validity. Item content of the identified instruments was analyzed, and areas under the curve (AUC) from the studies were extracted. In addition, an 11-item checklist was developed to assess the utility and psychometric properties of these tools. Ten risk assessment tools designed to predict community violence in psychiatric patients were identified, but only 2 studies reporting predictive validity estimates in patients with schizophrenia were found (median AUC = 0.69; interquartile range = 0.60-0.77). When inclusion criteria was broadened to include studies measuring accuracy for any diagnostic group, mixed evidence of predictive validity was found, with median AUCs ranging from 0.62 to 0.85 depending on the population. Item content included mostly clinical, sociodemographic, and criminal history factors. As only 1 tool included a neurobiological item, a structured review of brain-based and cognitive risk factors for violence was included, and 3 clusters (neurocognitive ability, neurocognitive awareness, and attitudinal cognition) were identified. While a number of violence risk assessment tools exist that can be used to predict the likelihood of community violence in psychiatric patients, there is currently little direct evidence for their utility in individuals with schizophrenia. In addition, there is large variation in item content between instruments, and further research is necessary to determine whether the inclusion of alternative factors could improve risk assessment.


Ferrocenyl Phthalocyanine as Donor in Non-Poly(3-hexylthiophen-2,5-diyl) Bulk Heterojunction Solar Cell.
Bulk heterojunction (BHJ) solar cells might one day play a vital role in realizing low-cost and environmentally benign photovoltaic devices. In this work, a BHJ solar cell was designed, based on a hexadeca-substituted phthalocyanine (FcPc) with ferrocenyl linked to the phthalocyanine ring. Next, we sought to obtain more quantitative information about the usability of this newly synthesized compound as a donor material in BHJ solar cells. Thus, BHJs with the structure of indium tin oxide/poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate)/FcPc:[6,6]-phenyl-C61-butyric acid methyl ester (PCBM) blend/LiF/Al were fabricated and characterized. The effect of blend ratio (0.5-2.0) on the BHJ solar cell parameters was also investigated. Interesting results were obtained in FcPc and the PCBM blend-based BHJ solar cell under optimized conditions. Our results presented here demonstrate that BHJ devices employing FcPc as a donor has great potential for the development of highly efficient non-poly(3-hexylthiophen-2,5-diyl) photovoltaic devices.


Transcalvarial brain herniation volume after decompressive craniectomy is the difference between two spherical caps.
Decompressive craniectomy (DC) is a surgical procedure used to relieve severely increased intracranial pressure (ICP) by removing a portion of the skull. Following DC, the brain expands through the skull defect created by DC, resulting in transcalvarial herniation (TCH). Traditionally, people measure only changes in the ICP but not in the intracranial volume (ICV), which is equivalent to the volume of TCH (V(TCH)), in patients undergoing DC. We constructed a simple model of the cerebral hemispheres, assuming the shape of the upper half of a sphere with a radius of 8 cm. We hypothesized that the herniated brain following DC also conforms to the shape of a spherical cap. Considering that a circular piece of the skull with a radius of a was removed, V(TCH) is the volume difference between 2 spherical caps at the operated side and the corresponding non-operated side, which represents the pre-DC volume underneath the removed skull due to the bilateral symmetry of the skull and the brain. Subsequently, we hypothesized that the maximal extent of TCH depends on a because of the biomechanical limitations imposed by the inelastic scalp. The maximum value of V(TCH) is 365.0 mL when a is 7.05 cm and the height difference between the spherical caps (Δh) at its maximum is 2.83 cm. To facilitate rapid calculation of V(TCH), we proposed a simplified estimation formula, Vˆ(TCH)=1/2A(2)Δh, where A=2a. With the a value ranging between 0 and 7 cm, the ratio between Vˆ(TCH) and V(TCH) ranges between 0.77 and 1.27, with different Δh values. For elliptical skull defects with base diameters of A and C, the formula changes to Vˆ(TCH)=1/2ACΔh. If our hypothesis is correct, surgeons can accurately calculate V(TCH) after DC. Furthermore, this can facilitate volumetric comparisons between the effects of DCs in skulls of varying sizes, allowing quantitative comparisons between ICVs in addition to ICPs.


High throughput determination of TGFβ1/SMAD3 targets in A549 lung epithelial cells.
Transforming growth factor beta 1 (TGFβ1) plays a major role in many lung diseases including lung cancer, pulmonary hypertension, and pulmonary fibrosis. TGFβ1 activates a signal transduction cascade that results in the transcriptional regulation of genes in the nucleus, primarily through the DNA-binding transcription factor SMAD3. The objective of this study is to identify genome-wide scale map of SMAD3 binding targets and the molecular pathways and networks affected by the TGFβ1/SMAD3 signaling in lung epithelial cells. We combined chromatin immunoprecipitation with human promoter region microarrays (ChIP-on-chip) along with gene expression microarrays to study global transcriptional regulation of the TGFβ1/SMAD3 pathway in human A549 alveolar epithelial cells. The molecular pathways and networks associated with TGFβ1/SMAD3 signaling were identified using computational approaches. Validation of selected target gene expression and direct binding of SMAD3 to promoters were performed by quantitative real time RT-PCR and electrophoretic mobility shift assay on A549 and human primary lung epithelial cells. Known TGFβ1 target genes such as SERPINE1, SMAD6, SMAD7, TGFB1 and LTBP3, were found in both ChIP-on-chip and gene expression analyses as well as some previously unrecognized targets such as FOXA2. SMAD3 binding of FOXA2 promoter and changed expression were confirmed. Computational approaches combining ChIP-on-chip and gene expression microarray revealed multiple target molecular pathways affected by the TGFβ1/SMAD3 signaling. Identification of global targets and molecular pathways and networks associated with TGFβ1/SMAD3 signaling allow for a better understanding of the mechanisms that determine epithelial cell phenotypes in fibrogenesis and carcinogenesis as does the discovery of the direct effect of TGFβ1 on FOXA2.


Dopamine D1 receptor antagonist inhibits swallowing reflex in guinea pigs.
To determine whether dopamine D1 receptor antagonist impairs the swallowing reflex and reduces substance P (SP) in the peripheral organs, the swallowing reflex in terms of the number of swallows elicited by injections of three different volumes (0.2, 0.4, and 0.6 ml) of distilled water into the pharynx through a catheter was examined in anesthetized guinea pigs pretreated with Sch-23390. Animals were pretreated with either subcutaneous Sch-23390 (200 micrograms/kg) or a vehicle of Sch-23390 every 12 h for 7 days. The number of swallows was counted by submental electromyographic activity and visual observation of characteristic laryngeal movement. Injections of distilled water caused a volume-dependent increase in the number of swallows in animals without Sch-23390 treatment. Sch-23390 significantly decreased and exogenously administered SP increased the number of swallows elicited by all volumes of distilled water. FK-888 (10(-5) M, 1 ml), a specific inhibitor of the NK1 receptor, reduced the number of swallows to a greater degree than Sch-23390. Sch-23390 significantly reduced SP content in the laryngeal and pharyngeal mucosa compared with control. These results suggest that inhibition of the dopamine D1 receptor may impair the swallowing reflex and reduce SP content in the peripheral organs.


Voice rehabilitation after laryngectomy with the Provox voice prosthesis in South Africa.
A study was undertaken to determine whether the Provox voice prosthesis provides good voice rehabilitation following a total laryngectomy in the urban, suburban and rural populations served by a tertiary referral hospital in South Africa. Between 1995 and 1999, a cohort of 128 patients at Tygerberg Hospital was rehabilitated with the Provox voice prosthesis after laryngectomy. In 104 patients primary placement of the prosthesis was done at the time of the laryngectomy. Mean device life and adverse events were determined. Voice quality was assessed subjectively in 104 patients and objectively in 26 patients. The mean device life was 303 days and adverse events occurred in 16 patients. Subjectively, 77 of 104 patients had a good voice, and objectively 22 of 26 patients had good voice intelligibility. The Provox voice prosthesis provides good voice rehabilitation following total laryngectomy, with minimal complications, in the population served by Tygerberg Hospital.


Macroevolutionary inferences from primate phylogeny.
We apply new statistical methods to a recent estimate of the phylogeny of all living primate species to test a range of models of cladogenesis. Null models in which probabilities of speciation and extinction do not differ among contemporaneous lineages are not consistent with the phylogeny. We present evidence that the net rate of cladogenesis (speciation rate minus extinction rate) increased in the lineage leading to the Cercopithecidae (Old World monkeys), and that there have been further increases in some lineages within that family. Such increases suggest the occurrence of clade selection, although we have not identified the selected trait or traits. There is no evidence that the net rate of cladogenesis is a function either of how many primate lineages are already present or of time. Intriguingly, three other clades--Strepsirhini, Platyrrhini and Hominoidea--appear to have had very similar rates of clade growth, in spite of their great biological differences.


Multifaceted SOX2-chromatin interaction underpins pluripotency progression in early embryos.
Pioneer transcription factors (TFs), such as OCT4 and SOX2, play crucial roles in pluripotency regulation. However, the master TF-governed pluripotency regulatory circuitry was largely inferred from cultured cells. In this work, we investigated SOX2 binding from embryonic day 3.5 (E3.5) to E7.5 in the mouse. In E3.5 inner cell mass (ICM), SOX2 regulates the ICM-trophectoderm program but is dispensable for opening global enhancers. Instead, SOX2 occupies preaccessible enhancers in part opened by early-stage expressing TFs TFAP2C and NR5A2. SOX2 then widely redistributes when cells adopt naive and formative pluripotency by opening enhancers or poising them for rapid future activation. Hence, multifaceted pioneer TF-enhancer interaction underpins pluripotency progression in embryos, including a distinctive state in E3.5 ICM that bridges totipotency and pluripotency.


Topologically protected surface states in a centrosymmetric superconductor β-PdBi2.
The topological aspects of electrons in solids can emerge in real materials, as represented by topological insulators. In theory, they show a variety of new magneto-electric phenomena, and especially the ones hosting superconductivity are strongly desired as candidates for topological superconductors. While efforts have been made to develop possible topological superconductors by introducing carriers into topological insulators, those exhibiting indisputable superconductivity free from inhomogeneity are very few. Here we report on the observation of topologically protected surface states in a centrosymmetric layered superconductor, β-PdBi2, by utilizing spin- and angle-resolved photoemission spectroscopy. Besides the bulk bands, several surface bands are clearly observed with symmetrically allowed in-plane spin polarizations, some of which crossing the Fermi level. These surface states are precisely evaluated to be topological, based on the Z2 invariant analysis in analogy to three-dimensional strong topological insulators. β-PdBi2 may offer a solid stage to investigate the topological aspect in the superconducting condensate.