Does the efficacy of neurodynamic treatments depend on the presence and type of criteria used to define neural mechanosensitivity in spinally-referred leg pain? A systematic review and meta-analysis.
It remains unclear whether definite neural mechanosensitivity (NM) is required for neural mobilisations to be beneficial in people with spinally referred leg pain. To determine whether the efficacy of neural mobilisations in patients with spinally referred leg pain depends on the presence and type of criteria used to define NM. PubMed, CINAHL, Cochrane Central Register of Controlled Trials, PEDro and Science Direct were searched from 1980 to March 2020. Randomised controlled trials evaluating the efficacy of neural mobilisations on pain and disability in spinally referred leg pain were included. Studies were grouped according to the certainty of NM into NMdefinite, NMunclear, NMuntested and NMabsent. Effects on pain and disability and subgroup differences were examined. We identified 21 studies in 914 patients (3 NMdefinite, 16 NMunclear, 2 NMuntested, 0 NMabsent). Meta-analysis revealed medium to large effect sizes on pain for neurodynamic compared to control interventions in NMdefinite and NMunclear groups. For disability, neurodynamic interventions had medium to large effects in NMunclear but not NMdefinite groups. NMuntested studies could not be pooled. The nonexistence of studies in patients with negative neurodynamic tests prevents inferences whether neural mobilisations are effective in the absence of NM. The criteria used to define NM may not impact substantially on the efficacy of neural mobilisations. The mostly high risk of bias and heterogeneity prevents firm conclusions. Neural mobilisations seem beneficial to reduce pain and disability in spinally referred leg pain independent of the criteria used to interpret neurodynamic tests.


Historical Milestones in the Management of Stable Coronary Artery Disease over the Last Half Century.
Coronary revascularization for coronary artery disease dates back to the introduction of coronary bypass by Favaloro in 1967 and coronary angioplasty by Gruentzig in 1977 (first published in 1968 and 1978, respectively). There have been many technical improvements over the ensuing 5 decades, studied in clinical trials. This article reviews the history of coronary revascularization (the development of optimal medical therapy) and points the way to the future of stable coronary artery disease management.


A game of Chinese whispers in Malaysia: contextual analysis of child road safety education.
In 2006, the Malaysian government began implementing road safety education (RSE) programs in primary schools, involving numerous stakeholders. We interviewed 19 stakeholders. Thematic analysis led to the identification of four themes: road traffic injuries (RTIs) among children in Malaysia, the role of RSE, factors affecting successful implementation, and intersectoral involvement. The latter was identified as a significant strength of the overall approach to implementation, and is one of the first examples in Malaysia and in the region of such an approach. Lack of official documentation surrounding ownership, funding responsibilities, and roles among the various sectors led to resistance from some groups. Although we know from scientific studies what works in terms of reducing RTIs, the more important question is how such interventions can be successfully and sustainably implemented, particularly in low- and middle-income countries (LMIC). The results of this study permit stronger understanding of issues surrounding the implementation of RTI interventions in LMIC.


GPR30 does not mediate estrogenic responses in reproductive organs in mice.
The G protein-coupled receptor Gpr30 (Gper) was recently claimed to bind to estradiol and to activate cytoplasmic signal transduction pathways in response to estradiol. However, there are conflicting data regarding the role of Gpr30 as an estrogen receptor (ER): several laboratories were unable to demonstrate estradiol binding to GPR30 or estradiol-activated signal transduction in Gpr30-expressing cells. To clarify the potential role of Gpr30 as an ER, we generated Gpr30-deficient mice. Although Gpr30 was expressed in all reproductive organs, histopathological analysis did not reveal any abnormalities in these organs in Gpr30-deficient mice. Mutant male and female mice were as fertile as their wild-type littermates, indicating normal function of the hypothalamic-pituitary-gonadal axis. Moreover, we analyzed estrogenic responses in two major estradiol target organs, the uterus and the mammary gland. For that purpose, we examined different readout paradigms such as morphological measures, cellular proliferation, and target gene expression. Our data demonstrate that in vivo Gpr30 is dispensable for the mediation of estradiol effects in reproductive organs. These results are in clear contrast to the phenotype of mice lacking the classic ER alpha (Esr1) or aromatase (Cyp19a1). We conclude that the perception of Gpr30 (based on homology related to peptide receptors) as an ER might be premature and has to be reconsidered.


Attenuated Semliki Forest virus for cancer treatment in dogs: safety assessment in two laboratory Beagles.
Dogs suffer from spontaneous tumors which may be amenable to therapies developed for human cancer patients, and dogs may serve as large-animal cancer models. A non-pathogenic Semliki Forest virus vector VA7-EGFP previously showed promise in targeting human tumor xenografts in mice, but the oncolytic capacity of the virus in canine cancer cells and the safety of the virus in higher mammals such as dogs, are not known. We therefore assessed the oncolytic potency of VA7-EGFP against canine cancer cells by infectivity and viability assays in two dog solid tumor cell lines. Furthermore we performed a 3-week safety study in two adult Beagles which received a single intravenous injection of ~2 × 10(5) plaque forming units of parental A7(74) strain. VA7-EGFP was able to replicate in and kill both canine cancer cell lines tested. No adverse events were observed in either of the two virus-injected adult Beagles and no infective virus could be recovered from any of the biological samples collected over the course of the study. Neutralizing antibodies to Semliki Forest virus became detectable in the dogs at 5 days post infection and remained elevated until study termination. Based on these results, testing of the oncolytic potential of attenuated Semliki Forest virus in canine cancer patients appears feasible.


Diagnostic performance of 18F-FDG-PET/CT in DTC patients with thyroglobulin elevation and negative iodine scintigraphy: a meta-analysis.
To evaluate the accuracy of 18F-FDG-PET/CT for the detection of recurrent and/or metastatic diseases in differentiated thyroid cancer (DTC) patients with thyroglobulin elevation and negative iodine scintigraphy. Whether PET/CT with TSH stimulation (sPET/CT) had better diagnostic performance than PET/CT without TSH stimulation (nsPET/CT) in this scenario was also evaluated. PubMed and Embase databases were searched for eligible studies from January 2001 to December 2018. Only studies with clearly stated reference standard (histopathology confirmation and/or clinical/imaging follow-up) were included. Publication bias was assessed by Deeks funnel plot. The pooled sensitivity, specificity, diagnostic odds ratio (DOR) and the area under the summary receiver-operating characteristics curve (AUC) for PET/CT was determined by random-effect analysis, respectively. sPET/CT and nsPET/CT were compared pairwise for all diagnostic estimate indexes using Z-test. We included 17 studies with 1195 patients in this meta-analysis. The pooled sensitivity, specificity, DOR and AUC for PET/CT on patient-based data were 0.86 (95% CI: 0.79-0.91), 0.84 (95% CI: 0.72-0.91), 31.00 (95% CI: 12.00-80.00) and 0.91 (95% CI: 0.88-0.93), respectively. There was high heterogeneity (I 2 = 80% for sensitivity, I 2 = 82% for specificity) and possible publication bias (P = 0.01). Z test did not detect statistically significant difference between sPET/CT and nsPET/CT for all the diagnostic estimate indexes (all P > 0.05). On patient-based analysis, 18F-FDG-PET/CT has high diagnostic accuracy for the detection of recurrent and/or metastatic diseases in DTC patients with thyroglobulin elevation and negative iodine scintigraphy, but existing studies were limited by high heterogeneity and possible publication bias. The diagnostic performance of sPET/CT may be not superior to nsPET/CT.


CYP2D6 increases toxicity of the designer drug 4-methylthioamphetamine (4-MTA).
4-Methylthioamphetamine (4-MTA) belongs to a group of new amphetamine derivatives that is usually sold as "ecstasy" or "flatliners" on the illicit drug market. Large interindividual differences in 4-MTA mediated toxicity have been reported in humans. Therefore, we tested whether CYP2D6 or its variant alleles as well as CYP3A4 influence the susceptibility to 4-MTA. For this purpose, we used the colony formation assay with Chinese hamster lung fibroblast V79 cells expressing human wild-type CYP2D6 (CYP2D6*1), the low activity alleles CYP2D6*2, CYP2D6*9, as well as human CYP3A4. The obtained results showed that the expression of wild type CYP2D6*1 clearly enhanced the susceptibility to the cytotoxic effects of 4-MTA compared with the parental cells devoid of CYP-dependent enzymatic activity. Toxicity in V79 CYP2D6*1 was also higher compared to the V79 cell lines expressing the low activity alleles CYP2D6*2 and CYP2D6*9. In contrast to CYP2D6, the CYP3A4 isoenzyme did not enhance 4-MTA toxicity. In conclusion, our results suggest that CYP2D6 rapid metabolizers may be more susceptible to 4-MTA toxicity than CYP2D6 poor metabolizers.


Biological, chemical, and immunological studies of Rauscher ecotropic and mink cell focus-forming viruses from JLS-V9 cells.
Two murine leukemia viruses were isolated from JLS-V9 cells which had been infected with Rauscher plasma virus. One virus was XC positive and failed to grow on mink or cat cells and thus was an ecotropic virus. The other virus formed cytopathic foci on mink cells, was XC negative, and fell into the mink cell focus-forming (MCF) viral interference group and was thus an MCF virus. The glycoproteins of the two viruses could be distinguished immunologically, by peptide mapping, and by size in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The MCF virus produced gp69, and the ecotropic virus produced gp71, explaining the origin of the heterogeneous glycoprotein (gp69 and gp71) of Rauscher leukemia virus. Amino-terminal sequences of gp69 and gp71 were determined. The MCF sequence was distinct from the ecotropic sequence, but retained partial homology to it. The data show that the glycoproteins are encoded by related yet distinct genes. The protein structural data support the proposal that MCF virus gp70 molecules have nonecotropic sequences at the amino terminus, with ecotropic sequences occurring at the 3' end of the gene. The Rauscher MCF virus glycoprotein lacks a glycosylation site found at position 12 of the ecotropic sequence.


Indications and associated factors for prescribing intravenous iron supplementation in Swiss general practice: a retrospective observational study.
Intravenous iron supplementation (IVIS) is increasing in Swiss general practice. This is controversial because of higher costs and risks compared with oral iron supplementation (OIS). In this study, we aimed to investigate indications for OIS and IVIS in Swiss general practice and test which factors are associated with prescribing IVIS instead of OIS. This was a retrospective observational study using data from electronic medical records of 279 Swiss general practitioners (GPs), including all their patients at their first OIS and IVIS administration who were at least 14 years old and with available pretreatment serum ferritin and haemoglobin measurements. We also collected data about the following comorbidities: chronic kidney disease (CKD) stage 3b or higher, inflammatory bowel disease (IBD), chronic heart failure and restless legs syndrome. Outcomes were proportions of cases treated with IVIS or OIS by assumed indication (anaemic or non-anaemic iron deficiency [NAID]) or the abovementioned comorbidities. We evaluated associations with IVIS prescription using regression models adjusting for patient and GP variables. We assessed 1282 IVIS and 3003 OIS cases (median age 44 and 40 years, female in 86.7 and 88.6%, respectively). The most important indication for both IVIS and OIS was NAID (59.4 and 74.7%, respectively). Significant associations with prescribing IVIS instead of OIS were the severity of iron deficiency (reflected by serum ferritin levels and the presence of anaemia), the presence of advanced CKD, IBD and male sex of the GP. There was a time trend towards increasing serum ferritin levels associated with initiation of IVIS in NAID. When preferring IVIS to OIS, Swiss GPs seem to consider severity of iron deficiency and comorbid conditions. However, pretreatment serum ferritin levels in IVIS for NAID are increasing, suggesting an ongoing indication extension and potential overuse.


Clerodendranoic acid, a new phenolic acid from Clerodendranthus spicatus.
Phenolic acid derivatives are typical constituents of Clerodendranthus spicatus which were considered to the active principles of this medicinal plant. These chemical constituents with their interesting frameworks and biological significance attracted our attention. As part of our ongoing chemical investigation of C. spicatus using various column chromatography techniques, a new phenolic compound, named clerodendranoic acid (1), was isolated from the aerial parts of C. spicatus together with five known ones, including rosmarinic acid (2), methyl rosmarinate (3), caffeic acid (4), methyl caffeate (5), ethyl caffeate (6). Their structures, including stereochemical configurations, were completely established by extensive spectroscopic methods, mainly inclvolving 1D, 2D NMR, as well as HRESIMS.


Disposable flow cytometer with high efficiency in particle counting and sizing using an optofluidic lens.
Flow cytometers are widely applied to environmental monitoring, industrial testing, and biochemical studies. Integrating a flow cytometer into microfluidic networks helps to miniaturize the system and make it portable for field use. The integration of optical components, such as lenses, further improves the compactness and thus has been intensively studied recently. However, the current designs suffer from severe light scattering due to the roughness of the solid-based lens interface. In this Letter, we propose a flow cytometer using an optofluidic lens to focus the light beam. Benefiting from the smooth liquid-liquid lens interface and the refractive-index matching liquid as cladding streams, a light beam can be well focused without scattering. The variations of the signal peak values are reduced, owing to the small beam width at the beam waist. The device presents an efficient and accurate performance on both the counting and sizing of particles.


Trends in elective labor induction for six United States health plans, 2001-2007.
To describe trends in labor induction, including elective induction, from 2001 to 2007 for six U.S. health plans and to examine the validity of induction measures derived from birth certificate and health plan data. This retrospective cohort study included 339,123 deliveries at 35 weeks' gestation or greater. Linked health plan and birth certificate data provided information about induction, maternal medical conditions, and pregnancy complications. Induction was defined from diagnosis and procedure codes and birth certificate data and considered elective if no accepted indication was coded. We calculated induction prevalence across health plans and years. At four health plans, we reviewed medical records to validate induction measures. Based on electronic data, induction prevalence rose from 28% in 2001 to 32% in 2005, then declined to 29% in 2007. The trend was driven by changes in the prevalence of apparent elective induction, which rose from 11% in 2001 to 14% in 2005 and then declined to 11% in 2007. The trend was similar for subgroups by parity and gestational age. Elective induction prevalence varied considerably across plans. On review of 86 records, 36% of apparent elective inductions identified from electronic data were confirmed as valid. Elective induction appeared to peak in 2005 and then decline. The decrease may reflect quality improvement initiatives or changes in policies, patient or provider attitudes, or coding practices. The low validation rate for measures of elective induction defined from electronic data has important implications for existing quality measures and for research studies examining induction's outcomes.


The chianti zebrafish mutant provides a model for erythroid-specific disruption of transferrin receptor 1.
Iron is a crucial metal for normal development, being required for the production of heme, which is incorporated into cytochromes and hemoglobin. The zebrafish chianti (cia) mutant manifests a hypochromic, microcytic anemia after the onset of embryonic circulation, indicative of a perturbation in red blood cell hemoglobin production. We show that cia encodes tfr1a, which is specifically expressed in the developing blood and requisite only for iron uptake in erythroid precursors. In the process of isolating zebrafish tfr1, we discovered two tfr1-like genes (tfr1a and tfr1b) and a single tfr2 ortholog. Abrogation of tfr1b function using antisense morpholinos revealed that this paralog was dispensable for hemoglobin production in red cells. tfr1b morphants exhibited growth retardation and brain necrosis, similar to the central nervous system defects observed in the Tfr1 null mouse, indicating that tfr1b is probably used by non-erythroid tissues for iron acquisition. Overexpression of mouse Tfr1, mouse Tfr2, and zebrafish tfr1b partially rescued hypochromia in cia embryos, establishing that each of these transferrin receptors are capable of supporting iron uptake for hemoglobin production in vivo. Taken together, these data show that zebrafish tfr1a and tfr1b share biochemical function but have restricted domains of tissue expression, and establish a genetic model to study the specific function of Tfr1 in erythroid cells.


The N-terminal transactivation domain of the glucocorticoid receptor mediates apoptosis of human small cell lung cancer cells.
Small cell lung cancer (SCLC) is an aggressive disease with a poor prognosis. These cancers are deficient in glucocorticoid receptor (GR) expression, and therefore, resistant to glucocorticoids. Overexpression of the GR both in vivo and in vitro leads to apoptotic cell death suggesting that loss of GR is favorable for cancer growth. Indeed, the GR promoter is silenced in SCLC cells by methylation. We now show that treatment of the SCLC cell line (DMS79) cells with the demethylating agent, 5-aza-2'-deoxycytidine (5-aza), results in significant endogenous re-expression of both GRα and the ligand-independent GR-P. The GR gene has a complex promoter region comprising nine alternative promoters, the proximal seven of which lie within a CpG island. The endogenous re-expression seen is attributed to the constitutive promoters 1B and 1C and 1J but predominantly 1F, which we show to be heavily methylated in SCLC cells. Flow cytometric analysis using the apoptotic marker, Annexin V, shows that this endogenous re-expression is sufficient to drive the SCLC cells to apoptosis. Apoptotic induction is specific to GR re-expression as cotreatment with 5-aza and the GR antagonist, RU486 prevented apoptosis. Of the three functional GR domains (the DNA binding domain, ligand binding domain, and transactivation domain), we identified that the transactivation domain is essential for apoptosis in SCLC. The discovery that endogenous re-expression of the GR in SCLC cells is sufficient to induce apoptotic cell death by reversing a cancer-driven DNA methylation effect may lead to the development of novel adjunct therapies.


A long-lasting measles epidemic in Maroua, Cameroon 2008-2009: mass vaccination as response to the epidemic.
A measles outbreak occurred in Maroua, Cameroon, from January 2008 to April 2009. In accordance with recent World Health Organization guidelines, an outbreak-response immunization (ORI) was conducted in January 2009. The aim of this study was to investigate the causes of the epidemic in order to guide vaccination strategies. We performed a stratified household-based survey using cluster sampling to determine measles vaccination coverage in children aged 9 months to 15 years. We defined 3 strata based on measles incidence. Next, we performed a case-control study to measure vaccine effectiveness (VE). Cases were obtained from health center registries. Controls were selected among respondents to the coverage survey. The vaccination-coverage survey included 2963 children in total. The overall routine vaccination coverage was 74.1% (95% confidence interval [CI]: 70.0%-78.3%). Measles incidence was inversely proportional to routine vaccination coverage, with high incidence associated with coverage of 71% and low incidence associated with coverage of 84%. The overall VE was 94% (95% CI, 86.7%-97.4%). After the ORI in January 2009, the coverage was >90% in all strata and measles incidence declined rapidly. Our results confirm that insufficient vaccination coverage was the main reason for this epidemic. The ORI conducted in January 2009 contributed both to control the epidemic and to increase the vaccination coverage to desirable levels.


Disease and psychological status in ankylosing spondylitis.
Psychological factors may be important in the assessment and management of ankylosing spondylitis (AS). Our primary objective was to describe associations between disease and psychological status in AS, using AS-specific assessment tools and questionnaires. Our secondary objectives were to identify patient subgroups based on such associations and to determine the stability of the measures over time. A total of 110 patients were assessed at 6-monthly intervals up to four times using tools to measure disease [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI)], psychological [Hospital Anxiety and Depression Questionnaire (HADS), Health Locus of Control-Form C Questionnaire (HLC-C)] and generic health [Short form (SF)-36] status. Eighty-nine participants completed all four assessments. Throughout the study, BASDAI, BASFI and BASMI scores correlated significantly with anxiety, depression, internality and health status, but not with levels of belief in chance or powerful others. Clinically anxious or depressed subgroups had significantly worse BASDAI and BASFI, but not BASMI, scores. BASMI scores were the least closely linked to psychological status. Mean scores for disease, psychological and health status were clinically stable over the 18 months period. Disease status scores in AS correlated significantly with anxiety, depression, internality and health status. Interpretation of AS disease scores should take an account of psychological status and the choice of measures used. These findings have important potential applications in AS management and monitoring, including the identification of patients for biological therapies.


LSD experiments by the United States Army.
Extensive LSD testing was conducted by the US Army at Edgewood Arsenal and other locations from 1955 to 1967. A number of different reports have been produced describing the health effects of this testing, including the Veterans Health Initiative Report in 2003. By and large, these reports gloss over and minimize the short and long-term side effects and complications of this testing. However, the reports themselves document frequent, severe complications of the LSD. These side effects were regarded by the Army as having been directly caused by the LSD exposure. In view of the current resurgence of interest in hallucinogens within psychiatry, the sanitized version of the effects of LSD exposure on US soldiers needs to be replaced with a more accurate account.


Sonic hedgehog from pharyngeal arch 1 epithelium is necessary for early mandibular arch cell survival and later cartilage condensation differentiation.
Morphogenesis of vertebrate craniofacial skeletal elements is dependent on a key cell population, the cranial neural crest cells (NCC). Cranial NCC are formed dorsally in the cranial neural tube and migrate ventrally to form craniofacial skeletal elements as well as other tissues. Multiple extracellular signaling pathways regulate the migration, survival, proliferation, and differentiation of NCC. In this study, we demonstrate that Shh expression in the oral ectoderm and pharyngeal endoderm is essential for mandibular development. We show that a loss of Shh in these domains results in increased mesenchymal cell death in pharyngeal arch 1 (PA1) after NCC migration. This increased cell death can be rescued in utero by pharmacological inhibition of p53. Furthermore, we show that epithelial SHH is necessary for the early differentiation of mandibular cartilage condensations and, therefore, the subsequent development of Meckel's cartilage, around which the dentary bone forms. Nonetheless, a rescue of the cell death phenotype does not rescue the defect in cartilage condensation formation. Our results show that SHH produced by the PA1 epithelium is necessary for the survival of post-migratory NCC, and suggests a key role in the subsequent differentiation of chondrocytes to form Meckel's cartilage.


Army Cardiac Unit -- cardiac catheter patients, 1991--a review.
Ninety three cardiac catheterisations were carried out at St Thomas' Hospital on behalf of the Queen Elizabeth Military Hospital in 1991. Fifty-nine (63.4%) of procedures resulted in the patient's being recommended for further intervention. Sixteen (20%) of the 79 patients, thought to have ischaemic heart disease, had normal coronary arteries, but on further analysis of this group none could reasonably have been excluded from further investigation with angiography. Fewer military patients than civilians were recommended for active intervention. This probably reflects the fact that most of the military patients were under 50 years old, had had a myocardial infarction or angina and therefore warranted catheterisation because of their young age.


Clinicopathologic significance of nuclear grooves and inclusions in renal cell carcinoma: image database construction and quantitative scoring.
Nuclear grooves and inclusions are major features of cancer. However, the nuclear irregularities in renal cell carcinoma (RCC) have not yet been well characterized. To determine the clinicopathologic significance of nuclear grooves and inclusions in RCC. The frequencies or scores of nuclear grooves and inclusions were compared with the histologic subtype, nuclear grade, and TNM stage, as well as overall survival of RCC patients. For objective counting of nuclear irregularities, a relational image database was constructed and used for quantitative assessment. Nuclear grooves and inclusions were seen in 96% and 65% of 110 RCC cases, respectively. The intranuclear inclusions were found more frequently in chromophobe and papillary types than in clear cell carcinoma (P < .001). The nuclear scores, the sum of grooves or inclusions per 5000 tumor cells, were highly related to the histologic subtype (P < .001). Clear cell RCCs with high inclusion scores (2 or more) were correlated with poorer overall survival in comparison to clear cell carcinomas with low inclusion scores (P = .04). The groove scores were highly associated with Fuhrman grade (P = .003) but not with overall survival of clear cell RCC patients (P = .65). In multivariate analysis, higher inclusion scores and advanced tumor stages (III/IV) were correlated with worse outcomes of clear cell RCC. Nuclear grooves and inclusions are histologic components of RCCs, especially chromophobe and papillary carcinomas. Furthermore, nuclear inclusions might be an independent prognostic factor for clear cell RCC.


Localization of ventral giant interneuron connections to the ventral median branch of thoracic interneurons in the cockroach.
A detailed morphological study was performed to localize the probable sites of connections between two identified populations of interneurons (ventral giant interneurons and type-A thoracic interneurons) in the cockroach. Type-A thoracic interneurons (TIAS) appear to play an important role in orienting the cockroach during wind-mediated escape. However, their large number, approximately 100 neurons, precludes analyzing each cell's role electrophysiologically. The TIAS are characterized by a prominent branch located on one or both sides of the ventral median (VM) region of the thoracic ganglion in which their soma resides. The presence of this ventral median branch can be used to predict connectivity with left or right ventral giant interneurons (vGIs) (Ritzmann and Pollack, 1988) and is correlated with the TIA's directional response to wind (Westin, Ritzmann, and Goddard, 1988), suggesting that this is the locus of synaptic connection. Two approaches were employed to address this hypothesis. Morphological overlap of differentially labelled cells (ethidium bromide, Lucifer Yellow) was examined at the light microscopic level to locate areas of possible synaptic contact. Experiments were also performed in which one-half of the vGI input to the TIAs was surgically removed early in postembryonic development. Although no changes in the overall branching pattern were observed, the VM branches on the operated side were significantly shorter than were those on the unoperated side. Thoracic interneurons that do not receive inputs from vGIs were unaffected by this surgery. The data reported here thereby confirm previous observations by localizing the vGI inputs specifically to the VM branch, and provide a morphological cue for predicting connectivity and function.


Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency.
Interleukin 10 receptor (IL10R)-deficient mice develop spontaneous colitis and, similarly, patients with loss-of-function mutations in IL10R develop severe infant-onset inflammatory bowel disease. Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1β. We demonstrated that innate immune production of IL1β mediates colitis in IL10R-deficient mice. Transfer of Il1r1-/- CD4+ T cells into Rag1-/-/Il10rb-/- mice reduced the severity of their colitis (compared to mice that received CD4+ T cells that express IL1R), accompanied by decreased production of interferon gamma, tumor necrosis factor-α, and IL17A. In macrophages from mice without disruption of IL10R signaling or from healthy humans (controls), incubation with IL10 reduced canonical activation of the inflammasome and production of IL1β through transcriptional and post-translational regulation of NLRP3. Lipopolysaccharide and adenosine triphosphate stimulation of macrophages from Il10rb-/- mice or IL10R-deficient patients resulted in increased production of IL1β. Moreover, in human IL10R-deficient macrophages, lipopolysaccharide stimulation alone triggered IL1β secretion via non-canonical, caspase 8-dependent activation of the inflammasome. We treated 2 IL10R-deficient patients with severe and treatment-refractory infant-onset inflammatory bowel disease with the IL1-receptor antagonist anakinra. Both patients had marked clinical, endoscopic, and histologic responses after 4-7 weeks. This treatment served as successful bridge to allogeneic hematopoietic stem cell transplantation in 1 patient. Our findings indicate that loss of IL10 signaling leads to intestinal inflammation, at least in part, through increased production of IL1 by innate immune cells, leading to activation of CD4+ T cells. Agents that block IL1 signaling might be used to treat patients with inflammatory bowel disease resulting from IL10R deficiency.


A novel outer membrane protein, Wzi, is involved in surface assembly of the Escherichia coli K30 group 1 capsule.
Escherichia coli group 1 K antigens form a tightly associated capsule structure on the cell surface. Although the general features of the early steps in capsular polysaccharide biosynthesis have been described, little is known about the later stages that culminate in assembly of a capsular structure on the cell surface. Group 1 capsule biosynthesis gene clusters (cps) in E. coli and Klebsiella pneumoniae include a conserved open reading frame, wzi. The wzi gene is the first of a block of four conserved genes (wzi-wza-wzb-wzc) found in all group 1 K-antigen serotypes. Unlike wza, wzb, and wzc homologs that are found in gene clusters responsible for production of exopolysaccharides (i.e., predominantly cell-free polymer) in a range of bacteria, wzi is found only in systems that assemble capsular polysaccharides. The predicted Wzi protein shows no similarity to any other known proteins in the databases, but computer analysis of Wzi predicted a cleavable signal sequence. Wzi was expressed with a C-terminal hexahistidine tag, purified, and used for the production of specific antibodies that facilitated localization of Wzi to the outer membrane. Circular dichroism spectroscopy indicates that Wzi consists primarily of a beta-barrel structure, and dynamic light scattering studies established that the protein behaves as a monomer in solution. A nonpolar wzi chromosomal mutant retained a mucoid phenotype and remained sensitive to lysis by a K30-specific bacteriophage. However, the mutant showed a significant reduction in cell-bound polymer, with a corresponding increase in cell-free material. Furthermore, examination of the mutant by electron microscopy showed that it lacked a coherent capsule structure. It is proposed that the Wzi protein plays a late role in capsule assembly, perhaps in the process that links high-molecular-weight capsule to the cell surface.


Evaluation of a new fiber-grating vision sensor for assessing pulmonary functions in healthy and COPD subjects.
Spirometry is practically the only tool to evaluate pulmonary functions. Other automatic systems comparable to spirometry are expected. A fiber-grating (FG) vision sensor is a non-contact respiratory monitoring system to detect changes in volumes by measuring the movement of laser spots on the body surface. We examined the contributions of the FG sensor to evaluating pulmonary functions. The FG sensor showed a linear correlation with spirometry in tidal volumes (TV) obtained from five controls (R = 0.98, P < 0.0001). We also showed agreement of TV between the two devices using Bland-Altman analysis. TV measured by the FG sensor were reproducible and applicable to distinct subjects. To detect airway obstruction, we performed forced expiration in controls (n = 16) and chronic obstructive pulmonary disease (COPD) patients (n = 18) with the FG sensor and spirometry. Forced expiratory volume in 1 s (FEV(1)) and FEV(1)/forced vital capacity in COPD patients were lower than those in controls by the FG sensor. In addition, prolonged expiration in natural breathing by the FG sensor was related to airflow limitation by spirometry. The FG sensor was helpful to measure volume changes and to evaluate pulmonary functions in controls and patients with COPD. Its upcoming clinical applications are promising for simplicity and feasibility.


IMpact of Platelet Rich plasma OVer alternative therapies in patients with lateral Epicondylitis (IMPROVE): protocol for a multicenter randomized controlled study: a multicenter, randomized trial comparing autologous platelet-rich plasma, autologous whole blood, dry needle tendon fenestration, and physical therapy exercises alone on pain and quality of life in patients with lateral epicondylitis.
Lateral epicondylitis, commonly known as tennis elbow, is the most common cause of lateral elbow pain and the second most frequently diagnosed musculoskeletal disorder in the neck and upper limb in a primary care setting. Many therapeutic options, including conservative, surgical, and minimally invasive procedures, have been advocated for the treatment of lateral epicondylitis. Although numerous small studies have been performed to assess the efficacy of various treatments, there are conflicting results with no clear consensus on the optimal treatment. In an economic environment with limited health care resources, it is paramount that optimal cost-effective therapies with favorable patient-important outcomes be identified. This is a protocol paper which outlines a multicenter, multidisciplinary, single-blinded, four-arm randomized controlled trial, comparing platelet-rich plasma (PRP), whole blood injection, dry needle tendon fenestration, and sham injection with physical therapy alone for the treatment of lateral epicondylitis. Patients are screened based on pre-established eligibility criteria and randomized to one of the four study groups using an Internet-based system. The patients are followed at 6-week, 12-week, 24-week, and 52-week time points to assess the primary and secondary outcomes of the study. The primary outcome is pain. Secondary outcomes include health-related quality of life and ultrasound appearance of the common extensor tendon. Two university centers (McMaster University and the University of Michigan) are currently recruiting patients. We have planned a sample size of 100 patients (25 patients per arm) to ensure over 80% power to detect a three-point difference in pain scores at 52 weeks of follow-up. This study has ethics approval from the McMaster University Research Ethics Board (REB# 12-146) and the University of Michigan Institutional Review Board (IRB# HUM00067750). Successful completion of this proposed study will significantly impact clinical practice and enhance patients' lives. More broadly, this trial will develop a network of collaboration from which further high-quality trials in ultrasound-guided interventions will follow.


Value acceleration: lessons from private-equity masters.
The most successful private-equity firms regularly spearhead dramatic business transformations, creating exceptional returns for their investors. To understand how those firms do it, the authors studied more than 2,000 PE transactions over the past ten years and discovered that the top performers' success stems from the rigor with which they manage their businesses. This article describes the four management disciplines vital to the success of the best PE firms. First, for each business, they define an investment thesis: a brief, clear statement of how to make the business more valuable within three to five years. The thesis, which guides all actions by the company, usually focuses on growth. PE firms know that the demonstration of a path to strong growth produces the big returns on investment. Second, they don't measure too much. They zero in on a few financial indicators that most clearly reveal the business's progress in increasing its value. They watch cash more closely than earnings and tailor performance measures to each business, rather than imposing one set of measures across their entire portfolio. Third, they work their balance sheets, mining undervalued assets, turning fixed assets into sources of financing, and aggressively managing their physical capital. Last, they make the center the shareholder. Corporate staffs in PE firms make unsentimental investment decisions, buying and selling businesses when the price is right and bringing in new management when performance falters. These firms also keep their corporate centers extremely lean. By adopting these four disciplines, executives at public companies should be able to reap significantly greater returns from their own business units.


An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke.
Stroke is an age-related disease. Recovery after stroke is associated with axonal sprouting in cortex adjacent to the infarct. The molecular program that induces a mature cortical neuron to sprout a new connection after stroke is not known. We selectively isolated neurons that sprout a new connection in cortex after stroke and compared their whole-genome expression profile to that of adjacent, non-sprouting neurons. This 'sprouting transcriptome' identified a neuronal growth program that consists of growth factor, cell adhesion, axonal guidance and cytoskeletal modifying molecules that differed by age and time point. Gain and loss of function in three distinct functional classes showed new roles for these proteins in epigenetic regulation of axonal sprouting, growth factor-dependent survival of neurons and, in the aged mouse, paradoxical upregulation of myelin and ephrin receptors in sprouting neurons. This neuronal growth program may provide new therapeutic targets and suggest mechanisms for age-related differences in functional recovery.


Supramolecular metallogels with bulk self-healing properties prepared by in situ metal complexation.
In this feature article, we discuss a series of contributions dealing with the in situ fabrication of supramolecular metallogels (i.e. using low molecular weight ligands and metal ions) that show self-healing properties of the bulk gel phase after complete physical segregation. Most of the advances in this area have taken place during the last three years and are mainly represented by organogels, whereas examples of hydrogels and organic-aqueous gels are still a minority. In situ gelation via metal-coordination of low molecular weight compounds is conceptually different from the use of premade (e.g. in solution) coordination polymers and polymeric structures as gelators and ligands, respectively. In the case of in situ gelation, the cooperative effects of all components of the mixture (i.e. ligand, metal ion, counterions and solvent molecules) in an appropriate ratio under well-defined experimental conditions play a crucial role in the gelation phenomenon and self-healing properties of the material.


Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency.
Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is caused by mutations in the MTHFR gene and results in hyperhomocysteinemia and varying severity of disease, ranging from neonatal lethal to adult onset. Including those described here, 109 MTHFR mutations have been reported in 171 families, consisting of 70 missense mutations, 17 that primarily affect splicing, 11 nonsense mutations, seven small deletions, two no-stop mutations, one small duplication, and one large duplication. Only 36% of mutations recur in unrelated families, indicating that most are "private." The most common mutation is c.1530A>G (numbered from NM_005957.4, p.Lys510 = ) causing a splicing defect, found in 13 families; the most common missense mutation is c.1129C>T (p.Arg377Cys) identified in 10 families. To increase disease understanding, we report enzymatic activity, detected mutations, and clinical onset information (early, <1 year; or late, >1 year) for all published patients available, demonstrating that patients with early onset have less residual enzyme activity than those presenting later. We also review animal models, diagnostic approaches, clinical presentations, and treatment options. This is the first large review of mutations in MTHFR, highlighting the wide spectrum of disease-causing mutations.


Aberrant functional connectivity in dissociable hippocampal networks is associated with deficits in memory.
In the healthy human brain, evidence for dissociable memory networks along the anterior-posterior axis of the hippocampus suggests that this structure may not function as a unitary entity. Failure to consider these functional divisions may explain diverging results among studies of memory adaptation in disease. Using task-based and resting functional MRI, we show that chronic seizures disrupting the anterior medial temporal lobe (MTL) preserve anterior and posterior hippocampal-cortical dissociations, but alter signaling between these and other key brain regions. During performance of a memory encoding task, we found reduced neural activity in human patients with unilateral temporal lobe epilepsy relative to age-matched healthy controls, but no upregulation of fMRI signal in unaffected hippocampal subregions. Instead, patients showed aberrant resting fMRI connectivity within anterior and posterior hippocampal-cortical networks, which was associated with memory decline, distinguishing memory-intact from memory-impaired patients. Our results highlight a critical role for intact hippocampo-cortical functional communication in memory and provide evidence that chronic injury-induced functional reorganization in the diseased MTL is behavioral inefficient.


DNase I hypersensitive site maps to the HBV enhancer.
Two lines of HBV transgenic mice (derived from G7 and G26) have been produced, each of which contains a unique locus of HBV DNA and expresses 2.1-kb HBsAg transcripts preferentially in liver and kidney tissues. To investigate the regulation of HBV expression in these mice, we have examined the state of methylation and the chromatin structure in and around the HBV sequences in tissues with and without HBV gene expression. Hypomethylation of HpaII and HhaI sites in and around the HBV sequences strongly correlated with HBV gene expression, although it was clearly not sufficient for HBV expression. Alterations in chromatin configuration were detected by DNase I digestion which identified a major hypersensitive site (HS) in liver and kidney tissue. By restriction enzyme mapping and indirect end-labeling, the HS was localized to the region of the HBV enhancer in both lines of HBV transgenics. The presence of this DNase I hypersensitive site was necessary but not sufficient for HBV expression, since it was also detected in tissues not expressing HBV. An additional DNase I hypersensitive site was mapped to the core promoter region of the G7 transgene in liver and kidney tissue but not in G26 tissues. The identification of a DNase I hypersensitive site mapping to the HBV enhancer region supports the notion that this region can interact with cellular proteins and is involved in the regulation of viral gene transcription in vivo.


Cardiac effects of lead in drinking water of rats.
1. There is no known cause for the increased mortality due to ischaemic heart disease in soft water areas. Since the lead concentration of soft water is elevated in houses with lead plumbing, studies have been carried out to determine the effects of lead on the heart of rats. 2. Rats were given drinking water containing lead for 1 year at concentrations similar to those found previously in Glasgow, which has a soft water supply. 3. There was increasing deposition of lead in the heart and a fall in the cardiac levels of the enzymes ferrochelatase and delta-aminolaevulinic acid dehydratase. These changes are maximal after 6 months, when there were marked electron-microscopic changes in the myocardium and myocardial mitochondria. 4. Further studies are needed to determine whether lead is a cause of the increased mortality from ischaemic heart disease in soft water areas.


Transfer of stimulus control from a TFT to CRT screen.
The use of television and computer screens for presenting stimuli to animals is increasing as it is non-invasive and can provide precise control over stimuli. Past studies have used cathode ray tube (CRT) screens; however, there is some evidence that these give different results to non-flickering thin film transistor (TFT) screens. Hens' critical flicker fusion frequency ranges between 80 and 90 Hz--above standard CRT screens. Thus, stimuli presented on CRT screens may appear distorted to hens. This study aimed to investigate whether changing the flicker rate of CRT screens altered hens' discrimination. Hens were trained (in a conditional discrimination) to discriminate between two stimuli on a TFT (flickerless) screen, and tested with the stimuli on a CRT screen at four flicker rates (60, 75, 85, and 100 Hz). The hens' accuracy generally decreased as the refresh rate of the CRT screen decreased. These results imply that the change in flicker rate changed the appearance of the stimuli enough to affect the hens' discrimination and stimulus control is disrupted when the stimuli appear to flicker.


Teaching core competencies of reconstructive microsurgery with the use of standardized patients.
The Accreditation Council of Graduate Medical Education has defined 6 core competencies that residents must master before completing their training. Objective structured clinical examinations (OSCEs) using standardized patients are effective educational tools to assess and teach core competencies. We developed an OSCE specific for microsurgical head and neck reconstruction. Fifteen plastic surgery residents participated in the OSCE simulating a typical new patient consultation, which involved a patient with oral cancer. Residents were scored in all 6 core competencies by the standardized patients and faculty experts. Analysis of participant performance showed that although residents performed well overall, many lacked proficiency in systems-based practice. Junior residents were also more likely to omit critical elements of the physical examination compared to senior residents. We have modified our educational curriculum to specifically address these deficiencies. Our study demonstrates that the OSCE is an effective assessment tool for teaching and assessing all core competencies in microsurgery.


Cost-effectiveness of malaria intermittent preventive treatment in infants (IPTi) in Mozambique and the United Republic of Tanzania.
To estimate the cost-effectiveness of malaria intermittent preventive treatment in infants (IPTi) using sulfadoxine-pyrimethamine (SP). In two previous IPTi trials in Ifakara (United Republic of Tanzania) and Manhiça (Mozambique), SP was administered three times to infants before 9 months of age through the Expanded Programme on Immunization. Based on the efficacy results of the intervention and on malaria incidence in the target population, an estimate was made of the number of clinical malaria episodes prevented. This number and an assumed case-fatality rate of 1.57% were used, in turn, to estimate the number of disability-adjusted life years (DALY) averted and the number of deaths averted. The cost of the intervention, including start-up and recurrent costs, was then assessed on the basis of these figures. The cost per clinical episode of malaria averted was US$ 1.57 (range: US$ 0.8-4.0) in Ifakara and US$ 4.73 (range: US$ 1.7-30.3) in Manhiça; the cost per DALY averted was US$ 3.7 (range: US$ 1.6-12.2) in Ifakara and US$ 11.2 (range: US$ 3.6-92.0) in Manhiça; and the cost per death averted was US$ 100.2 (range: US$ 43.0-330.9) in Ifakara and US$ 301.1 (range: US$ 95.6-2498.4) in Manhiça. From the health system and societal perspectives, IPTi with SP is expected to produce health improvements in a cost-effective way. From an economic perspective, it offers good value for money for public health programmes.


Use of short tandem repeats loci to study the genetic structure of several populations from Zulia State, Venezuela.
Genetic relationships between populations can be studied by comparing genotypic and allelic similarities. This investigation aims to demonstrate that selected autosomal microsatellite markers could be used to study the genetic structures of different populations living in northwest Venezuela, in Zulia State. Seven autosomal systems (CSF1PO, TPOX, TH01, vWA, D7S820, D13S317, and D5S818) were tested by PCR in a multiplex format on 688 different chromosomes from unrelated individuals living in Maracaibo, "Isla de Toas," and "San José de Heras," and from two Amerindian populations from the "Sierra de Perijá," Barí' and Yukpa. Allele frequencies, Hardy-Weinberg equilibria, genetic distances, phylogenetic trees, and ethnic admixtures were estimated. The study shows the existence of a clear genetic difference among these populations in accordance with their historic evolution. The populations of Maracaibo and "Isla de Toas" showed a triracial origin, with a large European contribution, followed by an Amerindian component and a small African component. The indigenous groups, Barí' and Yukpa, showed exclusively an Amerindian component, and "San José de Heras" showed only an African component. These results indicate that microsatellite markers are useful for molecular anthropology in a regional and worldwide context and provide important genetic information about contemporary populations of Venezuela.


Biological Integrity: A Long-Neglected Aspect of Water Resource Management.
Water of sufficient quality and quantity is critical to all life. Increasing human population and growth of technology require human society to devote more and more attention to protection of adequate supplies of water. Although perception of biological degradation stimulated current state and federal legislation on the quality of water resources, that biological focus was lost in the search for easily measured physical and chemical surrogates. The "fishable and swimmable" goal of the Water Pollution Control Act of 1972 (PL 92-500) and its charge to "restore and maintain" biotic integrity illustrate that law's biological underpinning. Further, the need for operational definitions of terms like "biological integrity" and "unreasonable degradation" and for ecologically sound tools to measure divergence from societal goals have increased interest in biological monitoring. Assessment of water resource quality by sampling biological communities in the field (ambient biological monitoring) is a promising approach that requires expanded use of ecological expertise. One such approach, the Index of Biotic Integrity (IBI), provides a broadly based, multiparameter tool for the assessment of biotic integrity in running waters. IBI based on fish community attributes has now been applied widely in North America. The success of IBI has stimulated the development of similar approaches using other aquatic taxa. Expanded use of ecological expertise in ambient biological monitoring is essential to the protection of water resources. Ecologists have the expertise to contribute significantly to those programs.


The transporter SynPAM71 is located in the plasma membrane and thylakoids, and mediates manganese tolerance in Synechocystis PCC6803.
Manganese (Mn) is an essential constituent of photosystem II (PSII) and therefore indispensable for oxygenic photosynthesis. Very little is known about how Mn is transported, delivered and retained in photosynthetic cells. Recently, the thylakoid-localized transporter PAM71 has been linked to chloroplast Mn homeostasis in Arabidopsis thaliana. Here, we characterize the function of its homolog in Synechocystis (SynPAM71). We used a loss-of-function line (ΔSynPAM71), wild-type (WT) cells exposed to Mn stress and strains expressing a tagged variant of SynPAM71 to characterize the role of SynPAM71 in cyanobacterial Mn homeostasis. The ΔSynPAM71 strain displays an Mn-sensitive phenotype with reduced levels of chlorophyll and PSI accumulation, defects in PSII photochemistry and intracellular Mn enrichment, particularly in the thylakoid membranes. These effects are attributable to Mn toxicity, as very similar symptoms were observed in WT cells exposed to excess Mn. Moreover, CyanoP, which is involved in the early steps of PSII assembly, is massively upregulated in ΔSynPAM71. SynPAM71 was detected in both the plasma membrane and, to a lesser extent, the thylakoid membranes. Our results suggest that SynPAM71 is involved in the maintenance of Mn homeostasis through the export of Mn from the cytoplasm into the periplasmic and luminal compartments, where it can be stored without interfering with cytoplasmic metabolic processes.


Costs of preparing to implement a virtual reality job interview training programme in a community mental health agency: A budget impact analysis.
Individual Placement and Support (IPS) is an evidence based strategy for facilitating employment among adults with severe mental illness (SMI) where staff may lead mock job interviews to prepare clients for real-world interviews (a method with limited scalability and cost effectiveness). A virtual reality job interview training program (VR-JIT)-delivered via the internet-has demonstrated efficacy for increasing employment among adults with SMI. Now, VR-JIT is being implemented with a community mental health agency (CMHA) and evaluated for its effectiveness within IPS. This study is a budget impact analysis, evaluating the costs of preparing a CMHA to implement VR-JIT. Implementation preparation occurred over 7 months from October 1, 2016 to April 30, 2017. CMHA staff (n = 15) and external research partners (n = 3) tracked their hours completing implementation preparation activities. Salaries plus a 28% fringe benefit rate were used to derive a per-hour salary amount for each individual and applied to each activity. Non-labor equipment costs were obtained from purchase receipts. A budget impact analysis evaluated the expenditures associated with preparing the CMHA to implement VRJIT. The total implementation preparation costs equaled $25,482. Labor costs equaled $22,882 and non-labor costs equaled $2,600. In total, 655 person-hours were spent preparing for VR-JIT implementation (e.g., preparing lab space, training, and supervising operations). This study presents an initial evaluation of the budget impact of preparing to implement VR-JIT in a CMHA. Cost considerations for future implementation preparation will be discussed. Given that the cost to prepare to implement an intervention can hinder its adoption, results provide an important analysis for decision-makers that may enhance uptake. Future work will determine the cost-effectiveness of VR-JIT implemented within IPS. This study is registered at http://clinicaltrials.gov, NCT = 03049813, "Virtual Reality Job Interview Training: An Enhancement to Supported Employment in Severe Mental Illness."


Saccadic disinhibition in patients with acute and remitted schizophrenia and their first-degree biological relatives.
Performance on measures of saccadic inhibition and control was investigated in a large family study of schizophrenia to evaluate the utility of using antisaccade task performance as an endophenotypic marker of genetic liability for schizophrenia. Ninety-five patients with acute schizophrenia and 116 of their first-degree biological relatives, 13 schizophrenia patients whose illness was in full remission, 35 patients with acute psychotic affective disorder, and 109 nonpsychiatric comparison subjects were administered antisaccade and prosaccade tasks. Both schizophrenia patient groups had a greater number of errors on the antisaccade task than did the first-degree relatives and the affective disorder group, which both had more errors than the comparison subjects. Among the first-degree relatives of the probands with acute schizophrenia, relatives of poor-performing patients performed worse on the antisaccade task than relatives of patients with good performance. Reflexive errors were not likely the result of interfering psychotic symptoms, medication, or medication side effects. Although the schizophrenia patients demonstrated other signs of saccadic abnormalities, these problems, which were not observed in their relatives even though they had high antisaccade error rates, seem unlikely to account for the higher antisaccade error rate of the schizophrenia patients. These findings suggest that saccadic disinhibition is strongly associated with the genetic liability for schizophrenia.


From screening to postpartum follow-up - the determinants and barriers for gestational diabetes mellitus (GDM) services, a systematic review.
Gestational diabetes mellitus (GDM) - a transitory form of diabetes first recognised during pregnancy complicates between < 1% and 28% of all pregnancies. GDM has important short and long-term health consequences for both the mother and her offspring. To prevent adverse pregnancy outcomes and to prevent or delay future onset of type 2 diabetes in mother and offspring, timely detection, optimum treatment, and preventive postpartum care and follow-up is necessary. However the area remains grossly under-prioritised. To investigate determinants and barriers to GDM care from initial screening and diagnosis to prenatal treatment and postpartum follow-up, a PubMed database search to identify quantitative and qualitative studies on the subject was done in September 2012. Fifty-eight relevant studies were reviewed. Adherence to prevailing GDM screening guidelines and compliance to screening tests seems sub-optimal at best and arbitrary at worst, with no clear or consistent correlation to health care provider, health system or client characteristics. Studies indicate that most women express commitment and motivation for behaviour change to protect the health of their unborn baby, but compliance to recommended treatment and advice is fraught with challenges, and precious little is known about health system or societal factors that hinder compliance and what can be done to improve it. A number of barriers related to health care provider/system and client characteristics have been identified by qualitative studies. Immediately following a GDM pregnancy many women, when properly informed, desire and intend to maintain healthy lifestyles to prevent future diabetes, but find the effort challenging. Adherence to recommended postpartum screening and continued lifestyle modifications seems even lower. Here too, health care provider, health system and client related determinants and barriers were identified. Studies reveal that sense of self-efficacy and social support are key determinants. The paper identifies and discusses determinants and barriers for GDM care, fully recognising that these are highly dependent on the context.


Asymptomatic ratio for seasonal H1N1 influenza infection among schoolchildren in Taiwan.
Studies indicate that asymptomatic infections do indeed occur frequently for both seasonal and pandemic influenza, accounting for about one-third of influenza infections. Studies carried out during the 2009 pH1N1 pandemic have found significant antibody response against seasonal H1N1 and H3N2 vaccine strains in schoolchildren receiving only pandemic H1N1 monovalent vaccine, yet reported either no symptoms or only mild symptoms. Serum samples of 255 schoolchildren, who had not received vaccination and had pre-season HI Ab serotiters <40, were collected from urban, rural areas and an isolated island in Taiwan during the 2005-2006 influenza season. Their hemagglutination inhibition antibody (HI Ab) serotiters against the 2005 A/New Caledonia/20/99 (H1N1) vaccine strain at pre-season and post-season were measured to determine the symptoms with the highest correlation with infection, as defined by 4-fold rise in HI titer. We estimate the asymptomatic ratio, or the proportion of asymptomatic infections, for schoolchildren during the 2005-6 influenza season when this vaccine strain was found to be antigenically related to the circulating H1N1 strain. Fever has the highest correlation with the 2005-06 seasonal influenza A(H1N1) infection, followed by headache, cough, vomiting, and sore throat. Asymptomatic ratio for the schoolchildren is found to range between 55.6% (95% CI: 44.7-66.4)-77.9% (68.8-87.0) using different sets of predictive symptoms. Moreover, the asymptomatic ratio was 66.9% (56.6-77.2) when using US-CDC criterion of fever + (cough/sore throat), and 73.0 (63.3-82.8) when under Taiwan CDC definition of Fever + (cough or sore throat or nose) + ( headache or pain or fatigue). Asymptomatic ratio for children is found to be substantially higher than that of the general population in literature. In providing reasonable quantification of the asymptomatic infected children spreading pathogens to others in a seasonal epidemic or a pandemic, our estimates of symptomatic ratio of infected children has important clinical and public health implications.


Retrospective evaluation of natural course in mild cases of Mycobacterium avium complex pulmonary disease.
There is no proven management for mild cases of Mycobacterium avium complex (MAC) pulmonary disease, who do not immediately receive treatment and are managed with observation alone, because its long term-natural course, factors predictive of deterioration, and the effect of treating the disease remain unclear. Thus, we sought to investigate the natural course of mild cases of MAC pulmonary disease. We conducted a multicenter retrospective study. Sixty-five patients with mild MAC pulmonary disease in whom treatment was withheld for at least 6 months after diagnosis were retrospectively recruited after a review of 747 medical records. Longitudinal changes in clinical features were evaluated by using a mixed effects model. Mean follow-up was 6.9 ± 5.7 years. During the follow-up period, 15 patients (23%) required treatment and 50 (77%) were managed with observation alone. At diagnosis, 65 patients had nodular bronchiectatic disease without fibrocavitary lesions. Among clinical features, mean body mass index (BMI), forced expiratory volume in 1 second as percent of forced vital capacity (%FEV1), nodular lung lesions, and bronchiectasis worsened significantly in the observation group during follow-up. In the treatment group, BMI, and %FEV1 were stable, but bronchiectasis significantly worsened. At diagnosis, the polyclonal MAC infection rate in the treatment group was higher than that in the observation group. Other microbiological factors, such as insertion sequences, did not differ significantly between the groups. Mild MAC pulmonary disease progresses slowly but substantially without treatment. Treatment prevents the deterioration of the disease but not the progression of bronchiectasis. Polyclonal MAC infection is a predictor of disease progression.


Lessons from the Fourth Metronomic and Anti-angiogenic Therapy Meeting, 24-25 June 2014, Milan.
The Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24-25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well understood and that the field would learn a lot from ancillary studies performed during the clinical trials of metronomic chemotherapies. From the pre-clinical side, new research findings indicate additional possible mechanisms of actions of metronomic schedule on the immune and blood vessel compartments of the tumour micro-environment. New clinical results of metronomic chemotherapy were presented in particular in paediatric cancers [especially neuroblastoma and central nervous system (CNS) tumours], in angiosarcoma (together with beta-blockers), in hepatocellular carcinoma, in prostate cancer, and in breast cancer. The use of repurposed drugs such as metformin, celecoxib, or valproic acid in the metronomic regimen was reported and highlighted the potential of other candidate drugs to be repurposed. The clinical experiences from low- and middle-income countries with affordable regimens gave very encouraging results which will allow more patients to be effectively treated in economies where new drugs are not accessible. Looking at the impact of metronomic approaches that have been shown to be effective, it was admitted that those approaches were rarely used in clinical practice, in part because of the absence of commercial interest for companies. However, performing well-designed clinical trials of metronomic and repurposing approaches demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing the financial issue. Metronomics should always be seen as a chance to come up with new innovative affordable approaches and not as a cheap rescue strategy.


[Atherosclerosis in rheumatoid arthritis: the role of high-resolution B mode ultrasound in the measurement of the arterial intima-media thickness].
Patients with rheumatoid arthritis (RA) have a reduced life expectancy and high cardiovascular morbidity and mortality as compared to the general population. A number of possible factors for the atherogenesis in this disease have been described, such as homocysteine, altered serum levels of selected lipoproteins and treatment. Recent findings indicate that the systemic inflammation may contribute to the development of atherosclerosis and confer an additional risk for cardiovascular death among patients with RA. The aim of our study was to evaluate the ability of high resolution Bmode ultrasound and color Doppler to assess the existence of subclinical atherosclerosis in RA patients, measuring the intima-media thickness (IMT) and resistance index of the common carotid arteries. Carotid IMT and carotid plaque were measured using high-resolution B-mode ultrasound in 40 patients with RA and 40 age- and sex-matched healthy persons. We used color Doppler ultrasound to assess vascular damage of the common carotid arteries and the resistance index (RI) was determined by analysis of the spectral waveforms. Serum total cholesterol, triglycerides-density lipoprotein cholesterol, low-density lipoprotein cholesterol, rheumatoid factor, body mass index (BMI), visual analogue scale (VAS) were determined in patients and controls. C-reactive protein (CRP) and the DAS28 were used to measure systemic inflammation. Common carotid IMT were significantly higher (p=0.0009) in RA patients (0.83 +/- 0.23) compared with controls (0.66 +/- 0.22). In RA patients common carotid IMT was significantly correlated with serum total cholesterol (p=0.0008), low-density lipoprotein cholesterol (p=0.006), triglycerides (p=0.042), age (p=0.031) and disease duration (p=0.019). No significant correlation was found with clinical and laboratory parameters reflecting disease activity. The prevalence of plaques was higher in RA patients compared with controls (25% vs 12.5%). There was no significant difference in color Doppler findings, and in particular in RI, between patients and controls. Our results confirm an accelerated atherosclerosis, as shown by increased common carotid IMT, in patients with RA compared with controls and it is related mainly to lipid levels. High-resolution B-mode ultrasound may be considered a promising, sensitive and non invasive tool for assessing the existence of subclinical atherosclerosis in RA patients.


Kinetics of rouleaux formation using TV image analyzer. II. Rat erythrocytes.
With the use of a rheoscope combined with a TV image analyzer, the kinetics of specific pathogen-free rat erythrocyte aggregation was studied. Under certain conditions (gamma 7.5 s-1, hematocrit 0.36%, in own plasma, at 25 degrees C) one-dimensional aggregates (rouleaux) were formed without the development of three-dimensional aggregates, perhaps because of very low concentration of gamma-globulin. The observed phenomena could be explained by 1) the erythrocyte sedimentation and 2) the rouleaux formation. The time courses, of the biphasic change in erythrocyte count and of the increments in total area and in the area/count, were successfully simulated by a kinetic model of linear polymerization, assuming a sedimentation rate constant and an association rate constant. Further, a Poissonlike distribution of the length of rouleaux was shown, as predicted theoretically on the basis of the same kinetic model.


Millimeter spatial resolution in vivo sodium MRI of the human eye at 7 T using a dedicated radiofrequency transceiver array.
The aim of this study was to achieve millimeter spatial resolution sodium in vivo MRI of the human eye at 7 T using a dedicated six-channel transceiver array. We present a detailed description of the radiofrequency coil design, along with electromagnetic field and specific absorption ratio simulations, data validation, and in vivo application. Electromagnetic field and specific absorption ratio simulations were performed. Transmit field uniformity was optimized by using a multi-objective genetic algorithm. Transmit field mapping was conducted using a phase-sensitive method. An in vivo feasibility study was carried out with 3-dimensional density-adapted projection reconstruction imaging technique. Measured transmit field distribution agrees well with the one obtained from simulations. The specific absorption ratio simulations confirm that the radiofrequency coil is safe for clinical use. Our radiofrequency coil is light and conforms to an average human head. High spatial resolution (nominal 1.4 and 1.0 mm isotropic) sodium in vivo images of the human eye were acquired within scan times suitable for clinical applications (∼ 10 min). Three most important eye compartments in the context of sodium physiology were clearly delineated in all of the images: the vitreous humor, the aqueous humor, and the lens. Our results provide encouragement for further clinical studies. The implications for research into eye diseases including ocular melanoma, cataract, and glaucoma are discussed. Magn Reson Med 80:672-684, 2018. © 2018 International Society for Magnetic Resonance in Medicine.


Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis.
Thrombotic diseases are among the leading causes of morbidity and mortality in the world. To add insights into the genetic regulation of thrombotic disease, we conducted a genome-wide association study (GWAS) of 6135 self-reported blood clots events and 252 827 controls of European ancestry belonging to the 23andMe cohort of research participants. Eight loci exceeded genome-wide significance. Among the genome-wide significant results, our study replicated previously known venous thromboembolism (VTE) loci near the F5, FGA-FGG, F11, F2, PROCR and ABO genes, and the more recently discovered locus near SLC44A2 In addition, our study reports for the first time a genome-wide significant association between rs114209171, located upstream of the F8 structural gene, and thrombosis risk. Analyses of expression profiles and expression quantitative trait loci across different tissues suggested SLC44A2, ILF3 and AP1M2 as the three most plausible candidate genes for the chromosome 19 locus, our only genome-wide significant thrombosis-related locus that does not harbor likely coagulation-related genes. In addition, we present data showing that this locus also acts as a novel risk factor for stroke and coronary artery disease (CAD). In conclusion, our study reveals novel common genetic risk factors for VTE, stroke and CAD and provides evidence that self-reported data on blood clots used in a GWAS yield results that are comparable with those obtained using clinically diagnosed VTE. This observation opens up the potential for larger meta-analyses, which will enable elucidation of the genetics of thrombotic diseases, and serves as an example for the genetic study of other diseases.


Arrested phase separation in a short-ranged attractive colloidal system: a numerical study.
We numerically investigate the competition between phase separation and dynamical arrest in a colloidal system interacting via a short-ranged attractive potential. Equilibrium fluid configurations are quenched at two different temperatures below the critical temperature and followed during their time evolution. At the lowest studied T, the phase-separation process is interrupted by the formation of an attractive glass in the dense phase. At the higher T, no arrest is observed and the phase-separation process proceeds endlessly in the simulated time window. The final structure of the glass retains memory of the interrupted phase-separation process in the form of a frozen spinodal decomposition peak, whose location and amplitude is controlled by the average packing fraction. We also discuss the time evolution of the nonergodicity parameter, providing evidence of a progressively decreasing localization length on increasing the packing fraction. Finally, we confirm that the reported results are independent of the microscopic dynamics.


Pappa2 deletion in mice affects male but not female fertility.
Recent studies have found associations between the gene encoding pregnancy associated plasma protein-A2 (PAPP-A2), a protease of insulin-like growth factor binding protein -5 (IGFBP-5), and measures of female reproductive performance in cattle. The purpose of the present study was to test the effects of Pappa2 deletion on reproduction in mice. We measured the fertility and offspring growth of Pappa2 deletion females, and also performed reciprocal matings (i.e., deletion males mated to control females) to control for the effects of offspring genotype. Ovarian and testicular IGFBP-5 levels were measured by Western blotting. As expected, deletion of Pappa2 increased ovarian IGFBP-5 levels. However, Pappa2 deletion in females had no effect on the interval between pairing and the birth of the first litter, the interval between the births of the first and second litters, or litter size. Offspring weight was lower in the offspring of Pappa2 deletion females, but effects of similar magnitude were observed in the offspring of Pappa2 deletion males, suggesting that the effects were due to heterozygosity for the deletion in the offspring. Pappa2 deletion in males had no effect on litter size or the interval between pairing and the birth of the first litter. However, the interval between the births of the first and second litters was significantly longer in deletion males. Pappa2 deletion had no effect on female reproductive performance. In contrast, Pappa2 deletion had subtle effects on male fertility, although the underlying mechanism remains to be elucidated.


Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort.
Irritable bowel syndrome (IBS) is a common disorder that affects 10-15% of the population. Although characterised by a lack of reliable biological markers, the disease state is increasingly viewed as a disorder of the brain-gut axis. In particular, accumulating evidence points to the involvement of both the central and peripheral serotonergic systems in disease symptomatology. Furthermore, altered tryptophan metabolism and indoleamine 2,3-dioxygenase (IDO) activity are hallmarks of many stress-related disorders. The kynurenine pathway of tryptophan degradation may serve to link these findings to the low level immune activation recently described in IBS. In this study, we investigated tryptophan degradation in a male IBS cohort (n = 10) and control subjects (n = 26). Plasma samples were obtained from patients and healthy controls. Tryptophan and its metabolites were measured by high performance liquid chromatography (HPLC) and neopterin, a sensitive marker of immune activation, was measured using a commercially available ELISA assay. Both kynurenine levels and the kynurenine:tryptophan ratio were significantly increased in the IBS cohort compared with healthy controls. Neopterin was also increased in the IBS subjects and the concentration of the neuroprotective metabolite kynurenic acid was decreased, as was the kynurenic acid:kynurenine ratio. These findings suggest that the activity of IDO, the immunoresponsive enzyme which is responsible for the degradation of tryptophan along this pathway, is enhanced in IBS patients relative to controls. This study provides novel evidence for an immune-mediated degradation of tryptophan in a male IBS population and identifies the kynurenine pathway as a potential source of biomarkers in this debilitating condition.


Variation in Surgeons' Requests for General Anesthesia When Scheduling Carpal Tunnel Release.
Background: Carpal tunnel release (CTR) can be performed with a variety of anesthesia techniques. General anesthesia is associated with higher risk profile and increased resource utilization, suggesting it should not be routinely used for CTR. The purpose of this study was to examine the patient factors associated with surgeons' requests for general anesthesia for CTR and the frequency of routine use of general anesthesia by Veterans Health Administration (VHA) surgeons and facilities. Methods: National VHA data for fiscal years 2015 and 2017 were used to identify patients receiving CTR. Mixed-effects logistic regression was used to evaluate patient, procedure, and surgeon factors associated with requests by the surgeon for general anesthesia versus other anesthesia techniques. Results: In all, 18 145 patients underwent CTR performed by 780 surgeons in 113 VHA facilities. Overall, there were 2218 (12.2%) requests for general anesthesia. Although some patient (eg, older age, obesity), procedure (eg, open vs endoscopic), and surgeon (eg, higher volume) factors were associated with lower odds of requests for general anesthesia, there was substantial facility- and surgeon-level variability. The percentage of patients with general anesthesia requested ranged from 0% to 100% across surgeons. Three facilities and 28 surgeons who performed at least 5 CTRs requested general anesthesia for more than 75% of patients. Conclusions: Where CTR is performed and by whom appear to influence requests for general anesthesia more than patient factors in this study. Avoidance of routine use of general anesthesia for CTR should be considered in future clinical practice guidelines and quality measures.


Three-Year Improvements in Weight Status and Weight-Related Behaviors in Middle School Students: The Healthy Choices Study.
Few dissemination evaluations exist to document the effectiveness of evidence-based childhood obesity interventions outside the research setting. Evaluate Healthy Choices (HC), a multi-component obesity prevention program, by examining school-level changes in weight-related behaviors and weight status and the association of implementation components with odds of overweight/obesity. We compared baseline and Year 3 school-level behavioral and weight status outcomes with paired t-tests adjusted for schools' socio-demographic characteristics. We used generalized estimating equations to examine the odds of overweight/obesity associated with program components. Consecutive sample of 45 of 51 middle schools participating in the HC program with complete baseline and follow-up survey data including a subsample of 35 schools with measured anthropomentry for 5,665 7th grade students. Schools developed a multi-disciplinary team and implemented an obesity prevention curriculum, before and after school activities, environmental and policy changes and health promotions targeting a 5-2-1 theme: eat ≥ 5 servings/day of fruits and vegetables (FV), watch ≤ 2 hours of television (TV) and participate in ≥ 1 hours/day of physical activity (PA) on most days. 1) School-level percent of students achieving targeted behaviors and percent overweight/obese; and 2) individual odds of overweight/obesity. The percent achieving behavioral goals over three years increased significantly for FV: 16.4 to 19.4 (p = 0.001), TV: 53.4 to 58.2 (p = 0.003) and PA: 37.1 to 39.9 (p = 0.02), adjusting for school size, baseline mean age and percent female, non-Hispanic White, and eligible for free and reduced price lunch. In 35 schools with anthropometry, the percent of overweight/obese 7th grade students decreased from 42.1 to 38.4 (p = 0.016). Having a team that met the HC definition was associated with lower odds of overweight/obesity (OR = 0.83, CI: 0.71-0.98). The HC multi-component intervention demonstrated three-year improvements in weight-related behaviors and weight status across diverse middle schools. Team building appears important to the program's effectiveness.


Investigation of the role of a beta(1-4) agarase produced by Pseudoalteromonas gracilis B9 in eliciting disease symptoms in the red alga Gracilaria gracilis.
Gracilaria species are an important source of agar. The South African Gracilaria industry has experienced a number of setbacks over the last decade in the form of complete or partial die-offs of the agarophyte growing in Saldanha Bay, which may be attributed to bacterial infection. Since a positive correlation was observed between the presence of agarolytic epiphytes and bacterial pathogenicity, we investigated the role of an agarase in the virulence mechanism employed by a bacterium that elicits disease in Gracilaria gracilis. The recombinant plasmid pDA1, isolated from a Pseudoalteromonas gracilis B9 genomic library, was responsible for the agarolytic activity exhibited by Escherichia coli transformants when grown on solid medium. A BLAST search of the GenBank database showed that an 873 bp ORF (aagA) located on pDA1 had 85 % identity to the beta-agarase (dagA) from Pseudoalteromonas atlantica ATCC 19262(T) (or IAM 12927(T)) at the amino acid level. AagA was purified from the extracellular medium of an E. coli transformant harbouring pDA1 by using a combination of gel filtration and ion-exchange chromatography. AagA has an M(r) of 30 000 on SDS-PAGE. TLC of the digestion products of AagA showed that the enzyme cleaves the beta-(1,4) linkages of agarose to yield predominately neoagarotetraose. Western hybridization confirmed that the cloned agarase was in fact the extracellular beta-agarase of P. gracilis B9. The observed relationship between disease symptoms of G. gracilis and the agarolytic phenotype of P. gracilis B9 was confirmed. Transmission electron microscope examination of cross sections of both healthy G. gracilis and G. gracilis infected with P. gracilis, revealed a weakening of the cell structure in the latter plants. Immunogold-labelled antibodies localized the agarase in situ to the cell walls of bleached G. gracilis. Thus, the weakening observed in the cell structure of G. gracilis infected with P. gracilis can be attributed to degradation of the mucilaginous component of the cell wall of the bleached thalli.


Assessing the lipid requirements of the Torpedo californica nicotinic acetylcholine receptor.
The lipid requirements of the Torpedo californica nicotinic acetylcholine receptor (nAChR) were assessed by reconstituting purified receptors into lipid vesicles of defined composition and by using photolabeling with 3-trifluoromethyl-3-(m-[125I]iodophenyl)diazirine ([125I]TID) to determine functionality. Earlier studies demonstrated that nAChRs reconstituted into membranes containing phosphatidylcholine (PC), the anionic lipid phosphatidic acid (PA), and cholesterol (CH) are particularly effective at stabilizing the nAChR in the resting (closed) state that is capable of undergoing agonist-induced conformational transitions (i.e., functionality). The present studies demonstrate that (1) there is no obligatory requirement for PC, (2) increasing the CH content serves to increase the degree to which nAChRs are stabilized in the resting state, and this effect saturates at approximately 35 mol % (molar lipid percentage), and (3) the effect of increasing levels of PA saturates at approximately 12 mol % and in the absence of PA nAChRs are stabilized in the desensitized state (i.e., nonfunctional). Native Torpedo membranes contain approximately 35 mol % CH but less than 1 mol % PA, suggesting that other anionic lipids may substitute for PA. We report that (1) phosphatidylserine (PS) and phosphatidylinositol (PI), anionic lipids that are abundant in native Torpedo membranes, also stabilize the receptor in the resting state although with reduced efficacy (approximately 50-60%) compared to PA, and (2) for nAChRs reconstituted into PA/CH membranes at different lipid-protein molar ratios, receptor functionality decreases rapidly below approximately 65 lipids per receptor. Collectively, these results are consistent with a functional requirement of a single shell of lipids surrounding the nAChR and specific anionic lipid- and sterol (CH)-protein interactions.


Overexpression of uncoupling protein 2 inhibits glucose-stimulated insulin secretion from rat islets.
Uncoupling protein 2 (UCP-2) mRNA expression has been shown to be altered by metabolic conditions such as obesity in humans, but its functional significance is unknown. The expression of UCP-2 mRNA and protein in normal rat islets was established by reverse transcriptase-polymerase chain reaction and immunocytochemistry in pancreatic islets and tissue, respectively. Intense immunostaining of UCP-2 correlated with insulin-positive ,-cells. Overexpression of UCP-2 in normal rat islets was accomplished by infection with an adenovirus (AdEGI-UCP-2) containing the full-length human UCP-2 coding sequence. Induction of the AdEGI-UCP-2 gene resulted in severe blunting of glucose-stimulated insulin secretion (GSIS) without affecting islet insulin content or the ability of the calcium ionophore A23187 to increase insulin secretion from AdEGI-UCP-2-expressing islets. Therefore, UCP-2 overexpression affects signal transduction proximal to Ca2+-mediated steps, including exocytosis. Insulin secretion from single beta-cells to 16.5 mmol/l glucose examined by reverse hemolytic plaque assay was nearly ablated if UCP-2 was overexpressed. Thus, a direct, causal relationship between overexpression of UCP-2 and inhibition of GSIS in normal islets has been established. These data suggest that increased expression of UCP-2 has the potential to cause the lack of a glucose effect on insulin secretion in type 2 diabetes.


On the flow topology inside droplets moving in rectangular microchannels.
The flow topology in moving microdroplets has a significant impact on the behaviour of encapsulated objects and hence on applications of the technology. This study reports on a systematic investigation of the flow field inside droplets moving in a rectangular microchannel, by means of micro-particle image velocimetry (μPIV). Various water/oil (w/o) fluid mixtures were studied in order to elucidate the effects of a number of parameters such as capillary number (Ca), droplet geometry, viscosity ratio and interfacial tension. A distinct change in flow topology was observed at intermediate Ca ranging from 10(-3) to 10(-1), in surfactant-laden droplets, which was attributed primarily to the viscosity ratio of the two phases rather than the Marangoni effect expected in such systems. W/o droplet systems of lower inner-to-outer viscosity ratios tend to exhibit the well-known flow pattern characterised by a parabola-like profile in the droplet bulk-volume, surrounded by two counter rotating recirculation zones on either side of the droplet axis. As the viscosity ratio between the two phases is increased, the flow pattern becomes more uniform, exhibiting low velocities in the droplet bulk-volume and higher-reversed velocities along the w/o interface. The Ca and droplet geometry had no effect on the observed flow topology change. The study highlights the complex, three-dimensional (3D) nature of the flow inside droplets in rectangular microchannels and demonstrates the ability to control the droplet flow environment by adjusting the viscosity ratio between the two phases.


Biopsy and treatment decisions in the initial management of prostate cancer and the role of PCA3; a systematic analysis of expert opinion.
The Prostate CAncer gene 3 (PCA3) assay may guide prostate biopsy decisions and predict prostate cancer (PCa) aggressiveness. This study explored the appropriateness of (1) PCA3 testing; (2) biopsy; (3) active surveillance (AS) and the value of the PCA3 Score for biopsy and AS decisions. Using the RAND/UCLA appropriateness method, 12 urologists assessed the appropriateness of PCA3, biopsy and AS for theoretical patient profiles, constructed by combining clinical variables. They individually scored the appropriateness for all profiles using a 9-point scale. Based on the median score and extent of agreement, the appropriateness for each profile was calculated. The PCA3 Assay was mainly considered appropriate in men with ≥1 negative biopsy, PSA ≥ 3 ng/mL and life expectancy (LE) ≥10 years. A LE < 10 years, ≥2 negative biopsies and PCA3 Score <20 decreased biopsy appropriateness, while PSA ≥ 3 ng/mL and PCA3 Score >50 increased it. In men without a prior biopsy, LE ≥ 10 years and a suspicious DRE, PCA3 did not affect biopsy appropriateness. In other men, a PCA3 Score <20 discouraged biopsy, while a value ≥35 supported biopsy. AS was mainly considered appropriate if LE < 10 years, T1c PCa, ≤20% positive cores and PSA < 3 ng/mL. A PCA3 Score <20 pleads for and higher scores (particularly >50) against AS. These findings illustrate in which men PCA3 can be of additional value when taking biopsy and treatment decisions in clinical practice.


Assailant identity and self-reported nondisclosure of military sexual trauma in partnered women veterans.
Department of Veterans Affairs estimates of military sexual trauma (MST) suggest 27% of female veterans have experienced MST. However, Department of Defense data (Department of Defense, 2014) show that a subgroup of active-duty women do not report sexual assaults to a military authority, suggesting barriers to disclosure exist among military samples. No study of female veterans has examined rates of nondisclosure among those with previous screens for MST; these data could inform screening efforts and establishment of safe havens for candid disclosures. Using an explanatory sequential mixed-methods survey, a history of MST, and postservice MST disclosures during screening and their associations with demographic, assault, and screening-setting characteristics were evaluated in 359 female veterans. Open-ended responses regarding barriers to disclosure were analyzed using editing analysis style. Eighty-one percent (n = 289) reported MST. Of these, 50% (n = 143) reported a prior screening and 25% (n = 35) reported they did not disclose their true MST status. Veterans who experienced MST by a unit-member assailant were significantly less likely to disclose (adjusted odds ratio = 4.75, 95% confidence interval = 1.20-18.30). Disclosure barriers included stigma, experiential avoidance, and discomfort with the screening setting. Creative interventions to reduce nondisclosure among female veterans, with specific attention to those assaulted by a unit member, are urgently needed. (PsycINFO Database Record


The age-specific relationships of abnormal cytology and human papillomavirus DNA results to the risk of cervical precancer and cancer.
To estimate the relationship of human papillomavirus (HPV) detection and abnormal cytology with histologic diagnoses of cervical precancer and cancer. From 2003 to 2008 we examined the HPV, cytology, and diagnostic results from almost one million cervical cancer screenings done on women aged 30 and older who were members in Kaiser Permanente Northern California, a large health maintenance organization that introduced cotesting in 2003. Women were screened using conventional Pap tests and a DNA test for a pool of 13 high-risk HPV genotypes. Women with HPV-positive atypical squamous cells of undetermined significance and other abnormal cervical cytology, independent of their HPV results, routinely underwent colposcopy. Results were stratified by 5-year age groups from 30 to 64. High-grade squamous intraepithelial lesions (HSIL), atypical squamous cells, cannot exclude HSIL (ASC-H), and atypical glandular cells were more strongly associated with cervical intraepithelial neoplasia grade 3 while low-grade squamous intraepithelial lesions (LSIL) and HPV-positive atypical squamous cells of undetermined significance were more strongly associated with cervical intraepithelial neoplasia grade 2 (CIN2). Cervical cancer was most commonly found in women with HSIL and atypical glandular cells cytology. Human papillomavirus-negative women with ASC-H cytology were at a reduced but significant risk of CIN2 or more severe (CIN2+) (10.6%) compared with HPV-positive women with ASC-H cytology. Human papillomavirus-negative women with LSIL were at a 4.0% risk of CIN2+, and among women 50 and older, at a 0.5% risk of CIN2+ with no cancers were diagnosed. Human papillomavirus testing may be useful for triage for colposcopic referral for LSIL cytology in older women but not for ASC-H cytology at any age. II.


Design and characterization of anionic PEGylated liposomal formulation loaded with paclitax for ovarian cancer.
Despite its strong antitumor activity, paclitaxel (Taxol(®)) has limited clinical applications due to its low aqueous solubility and hypersensitivity caused by cremophor EL and ethanol which is the vehicle used in the current commercial product. In an attempt to develop a pharmaceutically acceptable formulation that could replace Taxol(®), we have prepared PEGylated liposomes containing paclitaxel to improve its solubility and physicochemical stability. Its percent drug entrapment (PDE), mean particle size, zeta potential and in vitro release profile were determined. The optimized PEGylated liposomes provided high percent entrapment efficiency (64.29%) and mean particle size of 228.6 nm. The electroflocculation method showed 5 mol% of DSPE-mPEG2000 was required to obtain maximum stability for PEGylated liposome. In vitro release data showed its long circulating characteristic. Paclitaxel loaded PEGylated liposomes can be considered a promising long circulating paclitaxel delivery with absence of side effects related to Taxol(®).


Neural network analysis of sleep stages enables efficient diagnosis of narcolepsy.
Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph-a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies.