Preliminary study on eye colour in Japanese macaques (Macaca fuscata) in their natural habitat.
Eye colour in Japanese macaques shows apparent differences between individuals, continuously ranging from orange (bright), through shades of yellow and hazel-blue to dark blue (dark). We arbitrarily classified them into either 'yellow' eyes or 'blue' eyes based on the yellow area occupying in the iris' peripupillary ring. Most Japanese macaques have yellow eyes after infant phase, whilst 19, 17, 12, and 15% of monkeys (>6 months, sexes combined) have blue-eye in studied two groups of Shodoshima and two groups of Takasakiyama, respectively. Frequency of eye colour did not differ between males and females, but significantly differed in each age class. Blue eyes significantly more frequently occurred in newborns, infants and aged monkeys than in juveniles and prime adults. Data from mother-infant pairs indicated eye colour could be inherited from their parents. A case of asymmetric eye colour in Japanese macaques was found from a sample of 1962 individuals. Eye colour variation of Japanese macaques was discussed in relation to those of humans and rhesus macaques. A possible evolutionary model of eye colour in Japanese macaques was discussed.


Design Considerations of a Fiber Optic Pressure Sensor Protective Housing for Intramuscular Pressure Measurements.
Intramuscular pressure (IMP), defined as skeletal muscle interstitial fluid pressure, reflects changes in individual muscle tension and may provide crucial insight into musculoskeletal biomechanics and pathologies. IMP may be measured using fiber-optic fluid pressure sensors, provided the sensor is adequately anchored to and shielded from surrounding muscle tissue. Ineffective anchoring enables sensor motion and inadequate shielding facilitates direct sensor-tissue interaction, which result in measurement artifacts and force-IMP dissociation. The purpose of this study was to compare the effectiveness of polyimide and nitinol protective housing designs to anchor pressure sensors to muscle tissue, prevent IMP measurement artifacts, and optimize the force-IMP correlation. Anchoring capacity was quantified as force required to dislodge sensors from muscle tissue. Force-IMP correlations and non-physiological measurement artifacts were quantified during isometric muscle activations of the rabbit tibialis anterior. Housing structural integrity was assessed after both anchoring and activation testing. Although there was no statistically significant difference in anchoring capacity, nitinol housings demonstrated greater structural integrity and superior force-IMP correlations. Further design improvements are needed to prevent tissue accumulation in the housing recess associated with artificially high IMP measurements. These findings emphasize fundamental protective housing design elements crucial for achieving reliable IMP measurements.


Altered body image: appearance-related concerns of people with visible disfigurement.
The aim of this paper is to report a study to establish the extent and type of psychosocial needs of outpatients attending for treatment of a wide range of disfiguring conditions. Visible disfigurements can be associated with extensive psychosocial difficulties. The majority of research to date has been carried out with people identified by themselves or others as experiencing difficulties. Little is known about levels of distress in the broader population of patients receiving treatment for a range of disfiguring conditions. A cross-sectional survey was conducted, with a convenience sample. Participants (n = 458) drawn from 15 outpatient clinics completed standardized measures of anxiety and depression (Hospital Anxiety and Depression Scale), social anxiety and avoidance (Derriford Appearance Scale short-form) and quality of life (World Health Organization Quality of Life Brief Scale). A semi-structured interview was used to generate further quantitative and qualitative data about individual concerns, and satisfaction with the provision of care. Staff views about levels of psychosocial distress were elicited through group discussions. The results revealed high levels of psychological distress in the sample, compared with normative values. The majority of difficulties related to problems experienced in social situations. Patient satisfaction with care was generally high; however, and 71% of participants expressed a moderate to strong desire for a health care professional with training to deal with their appearance-related concerns. Nursing staff felt unable to address patients' appearance-related difficulties because of time constraints, lack of an environment conducive to the discussion of patients' concerns, and lack of appropriate knowledge and training. A significant proportion of participants experienced psychosocial distress in relation to their visible difference. Psychosocial needs were poorly met in current outpatient care provision, and a range of options could be considered to address these more effectively.


Fungal Morphogenesis, from the Polarized Growth of Hyphae to Complex Reproduction and Infection Structures.
Filamentous fungi constitute a large group of eukaryotic microorganisms that grow by forming simple tube-like hyphae that are capable of differentiating into more-complex morphological structures and distinct cell types. Hyphae form filamentous networks by extending at their tips while branching in subapical regions. Rapid tip elongation requires massive membrane insertion and extension of the rigid chitin-containing cell wall. This process is sustained by a continuous flow of secretory vesicles that depends on the coordinated action of the microtubule and actin cytoskeletons and the corresponding motors and associated proteins. Vesicles transport cell wall-synthesizing enzymes and accumulate in a special structure, the Spitzenkörper, before traveling further and fusing with the tip membrane. The place of vesicle fusion and growth direction are enabled and defined by the position of the Spitzenkörper, the so-called cell end markers, and other proteins involved in the exocytic process. Also important for tip extension is membrane recycling by endocytosis via early endosomes, which function as multipurpose transport vehicles for mRNA, septins, ribosomes, and peroxisomes. Cell integrity, hyphal branching, and morphogenesis are all processes that are largely dependent on vesicle and cytoskeleton dynamics. When hyphae differentiate structures for asexual or sexual reproduction or to mediate interspecies interactions, the hyphal basic cellular machinery may be reprogrammed through the synthesis of new proteins and/or the modification of protein activity. Although some transcriptional networks involved in such reprogramming of hyphae are well studied in several model filamentous fungi, clear connections between these networks and known determinants of hyphal morphogenesis are yet to be established.


Sexual and reproductive health in rheumatic disease.
Family size is reduced among patients with rheumatic diseases. The causes for the low number of children are multifactorial and include impaired sexual function, decreased gonadal function, pregnancy loss, therapy and personal choices. Sexuality contributes to quality of life in patients with rheumatic disease, but is often ignored by health professionals. Both disease-related factors and psychological responses to chronic disease can impair sexual functioning. Toxic effects of anti-inflammatory and immunosuppressive drugs can induce transient or permanent gonadal failure in women and men. Furthermore, permanent infertility can be a consequence of treatment with cyclophosphamide, whereas transient infertility can be caused by NSAIDs in women and sulfasalazine in men. These adverse effects must be communicated to the patients, and measures to preserve fertility should be initiated before the start of gonadotoxic therapy. Management of patients of both genders should include regular family planning, effective treatment of high disease activity, sexual counselling, and, if necessary, infertility treatment.


Two active copies of the X-linked gene spermidine/spermine N1-acetyltransferase (SSAT) in a female lung cancer cell line are associated with an increase in sensitivity to an antitumor polyamine analogue.
The expression of the polyamine catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT), has been associated with tumor sensitivity to antitumor polyamine analogues. In the sensitive cell types the level of SSAT is greatly induced by these agents. Although SSAT expression is regulated at many levels, the initial regulation of this X-linked gene occurs at the level of transcription. Because most previous work in human cell lines has been performed in cells of male origin and because the SSAT gene is located near the pseudoautosomal region of the X chromosome, we investigated the possibility that both copies of SSAT could be expressed in normal and tumor cells in women. DNA methyl-sensitive restriction enzyme analysis of DNA from normal peripheral lymphocytes suggested that like most X-linked genes, only one copy of SSAT is actively transcribed. However, in an examination of four representative human lung tumor cell lines derived from women, two were found to have a methylation pattern identical to male-derived cells, suggesting a reactivation of the normally inactive allele or loss of the inactive allele. Microsatellite repeat polymorphism analysis indicated that one of the lines, a female carcinoid line, NCI H727, had reactivated the previously inactive copy, thus providing H727 with two active alleles, whereas a small cell lung cancer line, H889, appears to have lost the inactive allele. Most importantly, the H727 line expressed high amounts of SSAT mRNA and protein in response to treatment with the polyamine analogue, N1,N12-bis(ethyl)spermine, a compound known to increase SSAT transcription in sensitive cell types. H727 was also the only female line that responded to treatment in a cytotoxic manner. These data suggest that both copies of the SSAT allele may be expressed and that the inappropriate expression of the second copy can lead to an increase in tumor sensitivity to polyamine analogues that induce SSAT.


Prevalence of psychiatric disorders among incarcerated women. I. Pretrial jail detainees.
There are little epidemiologic data on psychiatric disorders of women in jails. Accurate data on female jail detainees are critical because of their increasing numbers and their unique treatment needs. Using the Diagnostic Interview Schedule, independent interviewers assessed a randomly selected, stratified sample of 1272 female jail detainees awaiting trial in Chicago, Ill. We tabulated lifetime and 6-month prevalence rates of disorders by race or ethnicity (African American, non-Hispanic white, Hispanic), age, and education and compared the jail rates with general population rates for women in the Epidemiologic Catchment Area program. We also examined whether or not psychiatric disorder was associated with the severity of the detainee's current arrest charges. Over 80% of the sample met criteria for one or more lifetime psychiatric disorders; 70% were symptomatic within 6 months of the interview. The most common disorders were drug abuse or dependence, alcohol abuse or dependence, and post-traumatic stress disorder. Major depressive episode was the most prevalent major mental disorder. Rates were generally highest among non-Hispanic whites and among older detainees. Rates for all disorders were significantly higher than general population rates, except for schizophrenia. Most detainees with psychiatric disorders were arrested for nonviolent crimes. These results suggest substantial psychiatric morbidity among female jail detainees.


HIV-1: a case of RT67 deletion in a multi-treated non responder patient.
The early detection of mutations in the HIV-1 polymerase is a key point in the management of anti-retroviral therapy. While nucleotide substitutions and insertions have been well and frequently desribed in literature as linked to drug resistance, deletions have been rarely observed and desribed (ART67, Imamichi et al.). The aim of this study is to describe a case of deletion of three nucleotides in the RT gene (ART67) of a multi-treated HIV-1 infected patient. As this deletion has not been detected by the oligoprobe assay, the phenotyping test was used to support therapy but without an appreciable success in terms of viral load. Then a sequencing based genotyping system was used to analyse the viral polymerase and a novel deletion was found at codon 67 of RT gene.


CHIP28 water channels are localized in constitutively water-permeable segments of the nephron.
The sites of water transport along the nephron are well characterized, but the molecular basis of renal water transport remains poorly understood. CHIP28 is a 28-kD integral protein which was proposed to mediate transmembrane water movement in red cells and kidney (Preston, G. M., T. P. Carroll, W. B. Guggino, and P. Agre. 1992. Science [Wash. DC]. 256:385-387). To determine whether CHIP28 could account for renal epithelial water transport, we used specific polyclonal antibodies to quantitate and localize CHIP28 at cellular and subcellular levels in rat kidney using light and electron microscopy. CHIP28 comprised 3.8% of isolated proximal tubule brush border protein. Except for the first few cells of the S1 segment, CHIP28 was immunolocalized throughout the convoluted and straight proximal tubules where it was observed in the microvilli of the apical brush border and in basolateral membranes. Very little CHIP28 was detected in endocytic vesicles or other intracellular structures in proximal tubules. Uninterrupted, heavy immunostaining of CHIP28 was also observed over both apical and basolateral membranes of descending thin limbs, including both short and long loops of Henle. These nephron sites have constitutively high osmotic water permeabilities. CHIP28 was not detected in ascending thin limbs, thick ascending limbs, or distal tubules, which are highly impermeable to water. Moreover, CHIP28 was not detected in collecting duct epithelia, where water permeability is regulated by antidiuretic hormone. These determinations of abundance and structural organization provide evidence that the CHIP28 water channel is the predominant pathway for constitutive transepithelial water transport in the proximal tubule and descending limb of Henle's loop.


Neurological soft signs as an endophenotype in an African schizophrenia population - a pilot study.
The use of endophenotypes, such as neurological soft signs (NSS), is advocated as one possible method to elucidate the heterogeneity of schizophrenia. Exploring the associations between NSS and specific illness symptoms has revealed some trends, although results have been conflicting. To date, such studies have been conducted largely on Caucasian populations and our pilot study represents the first attempt to gather such data in a homogenous African population. Fifty-one patients, all of Xhosa ethnicity and participating in a larger schizophrenia genetic study were recruited. NSS were evaluated using a modified Neurological Evaluation Scale. Data were analysed using SPSS with the strength of the overall relationships between NES groups and SANS and SAPS components analyzed by means of canonical correlation analysis. The canonical correlation of SANS domains (excluding asociality) with the NES conceptual groups was 0.53 (SE=0.11, p=0.024) and of the SAPS domains 0.38 (SE=0.13, p=0.943). Our results suggest a correlation between negative symptoms of schizophrenia and the presence of NSS, supporting the recruitment of a larger sample to more comprehensively evaluate a possible role for NSS as an endophenotype in the Xhosa schizophrenia population. Taking into account that NSS evaluations allow for inexpensive, relatively easy-to-do objective evaluations, this method presents us with a valuable research tool that can be used effectively within our under-resourced environment to help inform on the neurobiological substrate of schizophrenia.


Knowledge and use of antibiotics among low-income small-scale farmers of Peru.
The extensive use and misuse of antibiotics in the livestock sector is one of the main drivers of the emergence and spread of antimicrobial resistance. Although small-scale farms constitute most of the livestock production in low and middle-income countries, knowledge and use of antibiotics among these populations is sparse. We conducted 201 questionnaires to estimate the use and knowledge of antibiotics by small-scale farmers located in the coastal area of the Lima region of Peru. Our results show that farmers had a small number of livestock (e.g. average of 11 cows, 7 pigs and 19 chickens per farm) and 80 % earned less than minimum wage. More than half of farmers reported at least one episode of respiratory disease, diarrhea, mastitis, skin lesion or post-parturition infection in their animals during the previous year, and 40 % of these episodes were treated with antibiotics. Farmers reported using 14 different antibiotics, most commonly oxytetracycline (31 % of episodes treated with antibiotics), penicillin (21 %), gentamicin (19 %) and trimethoprim-sulfamethazine (18 %). The third-generation cephalosporin ceftiofur was occasionally used to treat mastitis. Most farmers relied on veterinarians to prescribe (95 % of respondents) and administer (59 %) antibiotics. Only half of farmers knew what micro-organisms can be treated with antibiotics and the degree of knowledge of antibiotics (based on a 5-question metric) was positively correlated with respondents' educational level, monthly income, knowledge of the animal health authority, farm area, number of cows and knowledge of an antiparasitic drug. In contrast, knowledge of antibiotics was not correlated with respondents' age, gender, main occupation, knowledge of a veterinarian or household size. Potential misuse of antibiotics was reported, including 21 % of framers reporting stopping the treatment when clinical signs disappear and infrequent use of antibiotics to treat parasites or animals not eating. Our study highlights poor knowledge and potential misuse of antibiotics among small-scale farmers in coastal Peru, but high reliance on veterinarians for prescription and administration. Strengthening farmers' relationships with veterinarians and improving the diagnostic capacity of the veterinary sector could result in more judicious antibiotic use on these farms.


Development of a diagnostic test set to assess agreement in breast pathology: practical application of the Guidelines for Reporting Reliability and Agreement Studies (GRRAS).
Diagnostic test sets are a valuable research tool that contributes importantly to the validity and reliability of studies that assess agreement in breast pathology. In order to fully understand the strengths and weaknesses of any agreement and reliability study, however, the methods should be fully reported. In this paper we provide a step-by-step description of the methods used to create four complex test sets for a study of diagnostic agreement among pathologists interpreting breast biopsy specimens. We use the newly developed Guidelines for Reporting Reliability and Agreement Studies (GRRAS) as a basis to report these methods. Breast tissue biopsies were selected from the National Cancer Institute-funded Breast Cancer Surveillance Consortium sites. We used a random sampling stratified according to woman's age (40-49 vs. ≥50), parenchymal breast density (low vs. high) and interpretation of the original pathologist. A 3-member panel of expert breast pathologists first independently interpreted each case using five primary diagnostic categories (non-proliferative changes, proliferative changes without atypia, atypical ductal hyperplasia, ductal carcinoma in situ, and invasive carcinoma). When the experts did not unanimously agree on a case diagnosis a modified Delphi method was used to determine the reference standard consensus diagnosis. The final test cases were stratified and randomly assigned into one of four unique test sets. We found GRRAS recommendations to be very useful in reporting diagnostic test set development and recommend inclusion of two additional criteria: 1) characterizing the study population and 2) describing the methods for reference diagnosis, when applicable.


The internal and external validity of sluggish cognitive tempo and its relation with DSM-IV ADHD.
Studies of subtypes of DSM-IV attention-deficit/hyperactivity disorder (ADHD) have provided inconsistent support for the discriminant validity of the combined type (ADHD-C) and predominantly inattentive type (ADHD-I). A large sample of children and adolescents with ADHD (N = 410) and a comparison group without ADHD (N = 311) were used to test the internal and external validity of sluggish cognitive tempo (SCT), a dimension characterized by low energy and sleepy and sluggish behavior. SCT scores were then incorporated in analyses of ADHD subtypes to test whether the discriminant validity of ADHD-C and ADHD-I could be improved by including SCT symptoms as part of the criteria for ADHD-I. Factor analyses of parent and teacher ratings indicated that six SCT items loaded on a factor separate from symptoms of ADHD and other psychopathology, providing important support for the internal validity of SCT. The external validity of SCT was supported by significant associations between SCT and measures of functional impairment and neuropsychological functioning when symptoms of ADHD and other psychopathology were controlled. However, contrary to initial predictions, high levels of SCT did not identify a subgroup of ADHD-I that was clearly distinct from ADHD-C. Instead, the current results suggest that DSM-IV inattention and SCT are separate but correlated symptom dimensions that are each independently associated with important aspects of functional impairment and neuropsychological functioning.


Impact of Medical Marijuana Legalization on Opioid Use, Chronic Opioid Use, and High-risk Opioid Use.
To determine the association of medical marijuana legalization with prescription opioid utilization. A 10% sample of a nationally representative database of commercially insured population was used to gather information on opioid use, chronic opioid use, and high-risk opioid use for the years 2006-2014. Adults with pharmacy and medical benefits for the entire calendar year were included in the population for that year. Multilevel logistic regression analysis, controlling for patient, person-year, and state-level factors, were used to determine the impact of medical marijuana legalization on the three opioid use measures. Sub-group analysis among cancer-free adults and cancer-free adults with at least one chronic non-cancer pain condition in the particular year were conducted. Alternate regression models were used to test the robustness of our results including a fixed effects model, an alternate definition for start date for medical marijuana legalization, a person-level analysis, and a falsification test. The final sample included a total of 4,840,562 persons translating into 15,705,562 person years. Medical marijuana legalization was found to be associated with a lower odds of any opioid use: OR = 0.95 (0.94-0.96), chronic opioid use: OR = 0.93 (0.91-0.95), and high-risk opioid use: OR = 0.96 (0.94-0.98). The findings were similar in both the sub-group analyses and all the sensitivity analyses. The falsification tests showed no association between medical marijuana legalization and prescriptions for antihyperlipidemics (OR = 1.00; CI 0.99-1.01) or antihypertensives (OR = 1.00; CI 0.99-1.01). In states where marijuana is available through medical channels, a modestly lower rate of opioid and high-risk opioid prescribing was observed. Policy makers could consider medical marijuana legalization as a tool that may modestly reduce chronic and high-risk opioid use. However, further research assessing risk versus benefits of medical marijuana legalization and head to head comparisons of marijuana versus opioids for pain management is required.


Myocardin enhances Smad3-mediated transforming growth factor-beta1 signaling in a CArG box-independent manner: Smad-binding element is an important cis element for SM22alpha transcription in vivo.
Transforming growth factor (TGF)-beta1 is an important cytokine involved in various diseases. However, the molecular mechanism whereby TGF-beta1 signaling modulates the regulatory network for smooth muscle gene transcription remains largely unknown. To address this question, we previously identified a Smad-binding element (SBE) in the SM22alpha promoter as one of the TGF-beta1 response elements. Here, we show that mutation of the SBE reduces the activation potential of a SM22alpha promoter in transgenic mice during embryogenesis. Chromatin immunoprecipitation assays reveal that TGF-beta1 induces Smad3 binding to the SM22alpha promoter in vivo. A multimerized SBE promoter responsive to TGF-beta1 signaling is highly activated by Smad3 but not by the closely related Smad2. Intriguingly, myocardin (Myocd), a known CArG box-dependent serum response factor coactivator, participates in Smad3-mediated TGF-beta1 signaling and synergistically stimulates Smad3-induced SBE promoter activity independent of the CArG box; no such synergy is seen with Smad2. Importantly, Myocd cooperates with Smad3 to activate the wild-type SM22alpha, SM myosin heavy chain, and SMalpha-actin promoters; they also activate the CArG box-mutated SM22alpha promoter as well as the CArG box-independent aortic carboxypeptidase-like protein promoter. Immunopreciptiation assays reveal that Myocd and Smad3 directly interact both in vitro and in vivo. Mutagenesis studies indicate that the C-terminal transactivation domains of Myocd and Smad3 are required for their functional synergy. These results reveal a novel regulatory mechanism whereby Myocd participates in TGF-beta1 signal pathway through direct interaction with Smad3, which binds to the SBEs. This is the first demonstration that Myocd can act as a transcriptional coactivator of the smooth muscle regulatory network in a CArG box-independent manner.


Estrogen-dependent regulation of neurokinin 3 receptor-mediated uterine contractility in the rat.
The receptors for neurokinin 1 (NK1-R), neurokinin 2 (NK2-R), and neurokinin 3 (NK3-R) are expressed and functionally active in the uterus, promoting strong contractions of the myometrium. Previously, we demonstrated that myometrial contractility activated by the NK-Rs is regulated by estrogen. In the current study, we furthered our investigations of the role of estrogen in the regulation of NK3-R-mediated myometrial contractility. Estrogen promotes both heterologous and homologous desensitization of NK3-R-mediated uterine contractility. In tissue obtained from estrogen-dominated rats (ovariectomized estrogen-treated rats and rats in estrus), the magnitude of uterine contractions decreased in response to consecutive additions of the NK3-R-selective agonist senktide. By addition of the fourth dose of agonist, the contractile response was routinely barely above baseline. In contrast, in tissue obtained from non-estrogen-dominated rats consecutive doses of senktide resulted in contractions of identical magnitude. The homologous desensitization was specific to the NK3-R, and the desensitization of the NK3-R-mediated response did not affect the magnitude or nature of uterine contractions in response to NK1-R or NK2-R activation. Furthermore, heterologous and homologous desensitization of NK3-R-mediated contractility is dependent upon the duration of exposure to estrogen. This complex mechanism appears to be important in intact tissue; capsaicin-mediated release of endogenous neuropeptides resulted in a desensitization of response to subsequent stimulation with senktide in estrogen-dominated uterine tissue.


Evolutionary ecology of human birth sex ratio under the compound influence of climate change, famine, economic crises and wars.
1. Human sex ratio at birth at the population level has been suggested to vary according to exogenous stressors such as wars, ambient temperature, ecological disasters and economic crises, but their relative effects on birth sex ratio have not been investigated. It also remains unclear whether such associations represent environmental forcing or adaptive parental response, as parents may produce the sex that has better survival prospects and fitness in a given environmental challenge. 2. We examined the simultaneous role of wars, famine, ambient temperature, economic development and total mortality rate on the annual variation of offspring birth sex ratio and whether this variation, in turn, was related to sex-specific infant mortality rate in Finland during 1865-2003. 3. Our findings show an increased excess of male births during the World War II and during warm years. Instead, economic development, famine, short-lasting Finnish civil war and total mortality rate were not related to birth sex ratio. Moreover, we found no association between annual birth sex ratio and sex-biased infant mortality rate among the concurrent cohort. 4. Our results propose that some exogenous challenges like ambient temperature and war can skew human birth sex ratio and that these deviations likely represent environmental forcing rather than adaptive parental response to such challenges.


Suppression of serum antibody responses by pertussis toxin after respiratory tract colonization by Bordetella pertussis and identification of an immunodominant lipoprotein.
Pertussis toxin (PT), a virulence factor secreted by Bordetella pertussis, contributes to respiratory tract infection and disease caused by this pathogen. By comparing a wild-type (WT) B. pertussis strain to a mutant strain with an in-frame deletion of the ptx genes encoding PT (DeltaPT), we recently found that the lack of PT confers a significant defect in respiratory tract colonization in mice after intranasal inoculation. In this study, we analyzed serum antibody responses in mice infected with the WT or DeltaPT strain and found that infection with the DeltaPT strain elicited greater responses to several B. pertussis antigens than did infection with the WT, despite the lower colonization level achieved by the DeltaPT strain. The same enhanced antibody response was observed after infection with a strain expressing an enzymatically inactive PT; but this response was not observed after infection with B. pertussis mutant strains lacking filamentous hemagglutinin or adenylate cyclase toxin, nor when purified PT was administered with the DeltaPT inoculum, indicating a specific role for PT activity in this immunosuppressive effect. In particular, there were consistent strong serum antibody responses to one or more low-molecular-weight antigens after infection with the DeltaPT strain. These antigens were Bvg independent, membrane localized, and also expressed by the closely related pathogens Bordetella parapertussis and Bordetella bronchiseptica. Two-dimensional gel electrophoresis and mass spectrometry were used to identify one of the immunodominant low-molecular-weight antigens as a protein with significant sequence homology to peptidoglycan-associated lipoprotein in several other gram-negative bacterial species. However, a serum antibody response to this protein alone did not protect mice against respiratory tract infection by B. pertussis.


Development of the Motor Neuron Disease Carer Questionnaire.
Our objective was to develop a validated questionnaire that can measure the extent to which dimensions of caring affect the health of carers of patients with motor neuron disease. An initial 190-item questionnaire was developed from in-depth interviews, focus groups and two pilot studies with carers. Factor analysis was applied to the data obtained from a large survey in the UK that identified the underlying dimensions of caring. The newly formed scales were tested for reliability using Cronbach's alpha, and for construct validity. The SF36-v2 was the benchmark instrument on which correlations were made to ascertain the relationship with carers' health. A 34-item instrument was developed which has demonstrated promising evidence of internal reliability and validity for six scales: emotional well-being, physical well-being, self care, disturbed sleep, carers' support needs and statutory services. High correlations were found with the Mental Component Score summary scale of the SF-36v2 (0.40-0.66). The development and testing of the MNDCQ indicates that as the carers' score on the MNDCQ increases, suggesting a higher level of burden, they are more likely to report poor health. Further longitudinal studies are needed to further test the instruments' ability to detect change over time.


Exposure to 1800 MHz radiofrequency radiation impairs neurite outgrowth of embryonic neural stem cells.
A radiofrequency electromagnetic field (RF-EMF) of 1800 MHz is widely used in mobile communications. However, the effects of RF-EMFs on cell biology are unclear. Embryonic neural stem cells (eNSCs) play a critical role in brain development. Thus, detecting the effects of RF-EMF on eNSCs is important for exploring the effects of RF-EMF on brain development. Here, we exposed eNSCs to 1800 MHz RF-EMF at specific absorption rate (SAR) values of 1, 2, and 4 W/kg for 1, 2, and 3 days. We found that 1800 MHz RF-EMF exposure did not influence eNSC apoptosis, proliferation, cell cycle or the mRNA expressions of related genes. RF-EMF exposure also did not alter the ratio of eNSC differentiated neurons and astrocytes. However, neurite outgrowth of eNSC differentiated neurons was inhibited after 4 W/kg RF-EMF exposure for 3 days. Additionally, the mRNA and protein expression of the proneural genes Ngn1 and NeuroD, which are crucial for neurite outgrowth, were decreased after RF-EMF exposure. The expression of their inhibitor Hes1 was upregulated by RF-EMF exposure. These results together suggested that 1800 MHz RF-EMF exposure impairs neurite outgrowth of eNSCs. More attention should be given to the potential adverse effects of RF-EMF exposure on brain development.


Coffee consumption and risk of heart failure in the Physicians' Health Study.
Previous studies have reported the benefits of coffee consumption on diabetes, stroke, hyperlipidemia, and coronary artery disease (CAD). However, no large-scale long-term prospective study has evaluated the relation between coffee consumption and heart failure (HF) among US population. To test the hypothesis that coffee consumption is associated with risk of HF among male physicians. We prospectively studied 20,433 middle-aged and older men from the Physicians' Health Study (PHS). Coffee consumption was assessed using a semi-quantitative food frequency questionnaire. The incidence of HF was assessed based on self-reports on annual questionnaires which were validated in a subsample using by review of medical records. We used Cox proportional hazard models to compute the hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). The mean (SD) age of men was 66.4 (9.2) years. During a mean follow-up of 9.3 years, 901 new cases of HF were reported. In a multivariable Cox model adjusting for age, alcohol, smoking, and exercise, the HR (95% CI) of HF were 1.00 (reference), 1.04 (0.84-1.28), 0.90 (0.73-1.11), and 1.09 (0.91-1.30) for coffee consumption of almost never, <1 cup/day, 1 cup/day, and ≥2 cups/day, respectively (P for linear trend - 0.47). In a secondary analysis, dietary caffeine intake was not associated with HF risk: multivariable adjusted HR (95% CI) were 1.00 (reference), 1.07 (0.87-1.31), 0.95 (0.77-1.18), 1.06 (0.86-1.31), and 1.15 (0.92-1.44) across consecutive quintiles of dietary caffeine (P for linear trend - 0.34). We found no association between either coffee consumption or dietary caffeine intake with HF risk among US male physicians.


Corneal endothelial modulation: bFGF as direct mediator and corneal endothelium modulation factor as inducer.
Previously reported from this laboratory are two distinct factors responsible for corneal endothelium modulation: basic fibroblast growth factor (bFGF) and the corneal endothelium modulation factor (CEMF) that is released by inflammatory cells. The altered phenotypes mediated by these two distinct factors--marked increase in cell proliferation, cell shape changes, and synthesis of fibrillar collagens--are identical. The current study sought to determine if bFGF is the direct mediator for corneal endothelium modulation and if CEMF plays a role in inducing bFGF production. bFGF synthesis mediated by CEMF was analyzed by immunoblot assay; cycloheximide was used to block protein synthesis. bFGF-Specific antisense oligonucleotide primer was used to inhibit CEMF-mediated bFGF synthesis and to block further the autocrine activity of bFGF. Cell proliferation was measured by cell counting. The steady-state levels of RNA were determined by Northern blot analysis. CEMF was further purified to homogeneity by sequential electrophoresis, elution, and renaturation of protein. The synergistic effect of CEMF and bFGF on corneal endothelial cells was measured by their growth-promoting activity on quiescent corneal endothelial cells. There was a dose-dependent cell proliferation mediated by bFGF at any given CEMF concentration. Thus, bFGF at 10 ng/ml with CEMF at 2.5 micrograms/ml demonstrated saturable synergistic activity on endothelial cell proliferation. When the steady-state levels of collagen RNA were measured under these conditions, the untreated cells showed the doublets of 5.6 and 5.0 kb of alpha 2(I) collagen RNA. The cells treated simultaneously with bFGF and CEMF contained mostly lower transcript, compared to the significant level of upper transcript in control cells. However, there was no significant change in the level of 6.9-kb type IV collagen RNA qualitatively or quantitatively; nonetheless, the level of alpha 2(IV) collagen RNA was lowest in cells treated with bFGF plus CEMF. Neither exogenous bFGF nor CEMF caused induction of bFGF messenger RNA in corneal endothelial cells, whereas simultaneous treatment with bFGF and CEMF selectively enhanced the 4.9-kb transcript. When protein synthesis was inhibited by cycloheximide, bFGF synthesis was blocked in the presence of CEMF, leading to inhibition of corneal endothelium modulation. The effect on endothelial cell growth of bFGF antisense primer was analyzed. Antisense primer blocked by 50% the enhanced growth potential mediated by bFGF induced with CEMF. Finally, CEMF was purified to homogeneity: the purified protein is approximately 17 kD and assumes the modulating activities. These findings suggest that de novo synthesis of bFGF induced by CEMF is required for corneal endothelium modulation.


Intergenerational wealth transmission and the dynamics of inequality in small-scale societies.
Small-scale human societies range from foraging bands with a strong egalitarian ethos to more economically stratified agrarian and pastoral societies. We explain this variation in inequality using a dynamic model in which a population's long-run steady-state level of inequality depends on the extent to which its most important forms of wealth are transmitted within families across generations. We estimate the degree of intergenerational transmission of three different types of wealth (material, embodied, and relational), as well as the extent of wealth inequality in 21 historical and contemporary populations. We show that intergenerational transmission of wealth and wealth inequality are substantial among pastoral and small-scale agricultural societies (on a par with or even exceeding the most unequal modern industrial economies) but are limited among horticultural and foraging peoples (equivalent to the most egalitarian of modern industrial populations). Differences in the technology by which a people derive their livelihood and in the institutions and norms making up the economic system jointly contribute to this pattern.


Curcumin-induced Aurora-A suppression not only causes mitotic defect and cell cycle arrest but also alters chemosensitivity to anticancer drugs.
Overexpression of oncoprotein Aurora-A increases drug resistance and promotes lung metastasis of breast cancer cells. Curcumin is an active anticancer compound in turmeric and curry. Here we observed that Aurora-A protein and kinase activity were reduced in curcumin-treated human breast chemoresistant nonmetastatic MCF-7 and highly metastatic cancer MDA-MB-231 cells. Curcumin acts in a similar manner to Aurora-A small interfering RNA (siRNA), resulting in monopolar spindle formation, S and G2/M arrest, and cell division reduction. Ectopic Aurora-A extinguished the curcumin effects. The anticancer effects of curcumin were enhanced by Aurora-A siRNA and produced additivity and synergism effects in cell division and monopolar phenotype, respectively. Combination treatment with curcumin overrode the chemoresistance to four Food and Drug Administration (FDA)-approved anticancer drugs (ixabepilone, cisplatin, vinorelbine, or everolimus) in MDA-MB-231 cells, which was characterized by a decrease in cell viability and the occurrence of an additivity or synergy effect. Ectopic expression of Aurora-A attenuated curcumin-enhanced chemosensitivity to these four tested drugs. A similar benefit of curcumin was observed in MCF-7 cells treated with ixabepilone, the primary systemic therapy to patients with invasive breast cancer (stages IIA-IIIB) before surgery. Antagonism effect was observed when MCF-7 cells were treated with curcumin plus cisplatin, vinorelbine or everolimus. Curcumin-induced enhancement in chemosensitivity was paralleled by significant increases (additivity or synergy effect) in apoptosis and cell cycle arrest at S and G2/M phases, the consequences of Aurora-A inhibition. These results suggest that a combination of curcumin with FDA-approved anticancer drugs warrants further assessment with a view to developing a novel clinical treatment for breast cancer.


White Light Emission by Simultaneous One Pot Encapsulation of Dyes into One-Dimensional Channelled Aluminophosphate.
By simultaneous occlusion of rationally chosen dyes, emitting in the blue, green and red region of the electromagnetic spectrum, into the one-dimensional channels of a magnesium-aluminophosphate with AEL-zeolitic type structure, MgAPO-11, a solid-state system with efficient white light emission under UV excitation, was achieved. The dyes herein selected-acridine (AC), pyronin Y (PY), and hemicyanine LDS722-ensure overall a good match between their molecular sizes and the MgAPO-11 channel dimensions. The occlusion was carried out via the crystallization inclusion method, in a suitable proportion of the three dyes to render efficient white fluorescence systems by means of fine-tuned FRET (fluorescence resonance energy transfer) energy transfer processes. The FRET processes are thoroughly examined by the analysis of fluorescence decay traces using the femtosecond fluorescence up-conversion technique.


Volumetric Optoacoustic Temperature Mapping in Photothermal Therapy.
Photothermal therapy and ablation are commonplace medical procedures employed for treatment of tumors, vascular and brain abnormalities as well as other disorders that require selective destruction of tissues. Yet, accurate mapping of the dynamic temperature field distribution in the treated region represents an unmet clinical need, strongly affecting the clinical outcome of these interventions. We introduce a fast three-dimensional temperature mapping method based on real-time optoacoustic sensing of the treated region coupled with a thermal-diffusion-based model of heat distribution in tissues. Deviations of the optoacoustic temperature readings provided at 40 ms intervals remained below 10% in tissue-mimicking phantom experiments for temperature elevations above 3 °C, as validated by simultaneous thermocouple measurements. Performance of the new method to dynamically estimate the volumetric temperature distribution was further showcased in post-mortem mouse imaging experiments. The newly discovered capacity to non-invasively measure the temperature map in an entire treated volume with both high spatial and temporal resolutions holds potential for improving safety and efficacy of light-based therapeutic interventions.


Joint histogram-based cost aggregation for stereo matching.
This paper presents a novel method for performing efficient cost aggregation in stereo matching. The cost aggregation problem is reformulated from the perspective of a histogram, giving us the potential to reduce the complexity of the cost aggregation in stereo matching significantly. Differently from previous methods which have tried to reduce the complexity in terms of the size of an image and a matching window, our approach focuses on reducing the computational redundancy that exists among the search range, caused by a repeated filtering for all the hypotheses. Moreover, we also reduce the complexity of the window-based filtering through an efficient sampling scheme inside the matching window. The tradeoff between accuracy and complexity is extensively investigated by varying the parameters used in the proposed method. Experimental results show that the proposed method provides high-quality disparity maps with low complexity and outperforms existing local methods. This paper also provides new insights into complexity-constrained stereo-matching algorithm design.


P53 and ploidy assessed by flow cytometry in bladder washings.
To determine p53 expression in cells in bladder washings and to relate this to DNA content and clinical outcome. Washings from 102 patients (41 with newly diagnosed superficial tumours [pTa and pT1], 49 with recurrent superficial tumours and 12 with carcinoma invading bladder muscle) were studied. In 39 cases, the primary bladder tumour was also analysed. The rates of tumour recurrence and progression were determined for the new superficial tumours and related to both p53 expression and DNA content. Cells positive for p53 were detected in 22 of 90 (24%) washings from patients with superficial bladder cancer. P53 expression correlated with tumour stage (P < 0.05), grade (P < 0.05) and abnormal DNA content (P < 0.05). The analysis of pure urothelial (cyto-keratin-positive) cells improved the detection of DNA abnormalities (P < 0.001). In 74% of cases where both washings and tumour were analysed, the results for DNA content agreed. Of 41 new superficial tumours, 27 (66%) recurred (11 were p53-positive, 16 were p53-negative, P = 0.221; 17 had abnormal DNA content, 10 were diploid, P = 0.069). Four patients progressed (one was p53-positive, P = 0.315 and all had abnormal DNA content, P = 0.072). P53-positive cells can be detected in washings using flow cytometry and were more commonly detected in association with aneuploid tumours. At short-term follow-up, flow cytometric analysis of DNA content in washings had greater predictive value than had p53 expression. Few washings contained aneuploid cells when the primary tumour contained diploid cells, although the collection of washings is a convenient way of sampling tumour cells.


Multiple routes for glutamate receptor trafficking: surface diffusion and membrane traffic cooperate to bring receptors to synapses.
Trafficking of glutamate receptors into and out of synapses is critically involved in the plasticity of excitatory synaptic transmission. Endocytosis and exocytosis of receptors have initially been thought to account alone for this trafficking. However, membrane proteins also traffic through surface lateral diffusion in the plasma membrane. We describe developments in electrophysiological and optical approaches that have allowed for the real-time measurement of glutamate receptor surface trafficking in live neurons. These include (i) specific imaging of surface receptors using a pH-sensitive fluorescent protein; (ii) design of a photoactivable drug to locally inactivate surface receptors and monitor electrophysiologically their recovery; and (iii) application of single-molecule fluorescence microscopy to directly track the movement of individual surface receptors with nanometer resolution inside and outside synapses. Together, these approaches have demonstrated that glutamate receptors diffuse at high rates in the neuronal membrane and suggest a key role for surface diffusion in the regulation of receptor numbers at synapses.


Comparison of different vascular risk engines in the identification of type 2 diabetes patients with high cardiovascular risk.
Some authors consider that secondary prevention should be conducted for all DM2 patients, while others suggest that the drug preventive treatment should start or be increased depending on each patient's individual CVR, estimated using cardiovascular or coronary risk functions to identify the patients with a higher CVR. The principal objective of this study was to assess three different cardiovascular risk prediction models in type 2 diabetes patients. Multicentre, cross-sectional descriptive study of 3,041 patients with type 2 diabetes and no history of cardiovascular disease. The demographic, clinical, analytical, and cardiovascular risk factor variables associated with type 2 diabetes were analysed. The risk function and probability that a cardiovascular disease could occur were estimated using three risk engines: REGICOR, UKPDS and ADVANCE. A patient was considered to have a high cardiovascular risk when REGICOR ≥ 10 % or UKPDS ≥ 15 % in 10 years or when ADVANCE ≥ 8 % in 4 years. The ADVANCE and UKPDS risk engines identified a higher number of diabetic patients with a high cardiovascular risk (24.2 % and 22.7 %, respectively) compared to the REGICOR risk engine (10.2 %). The correlation using the REGICOR risk engine was low compared to UKPDS and ADVANCE (r = 0.288 and r = 0.153, respectively; p < 0.0001). The agreement values in the allocation of a particular patient to the high risk group was low between the REGICOR engine and the UKPDS and ADVANCE engines (k = 0.205 and k = 0.123, respectively; p < 0.0001) and acceptable between the ADVANCE and UKPDS risk engines (k = 0.608). There are discrepancies between the general population and the type 2 diabetic patient-specific risk engines. The results of this study indicate the need for a prospective study which validates specific equations for diabetic patients in the Spanish population, as well as research on new models for cardiovascular risk prediction in these patients.


What Is the Optimal Management of Patients With Prior Septic Arthritis of the Ankle Who Are Undergoing Total Ankle Arthroplasty (TAA)?
There is a paucity of data regarding total ankle arthroplasty (TAA) in patients with prior infection involving the ankle, whether it be septic arthritis, osteomyelitis, or infection of the surrounding soft tissues. We recommend that patients with prior infections in the affected ankle be worked up for infection, including a thorough history and physical examination, as well as ordering serologic tests and possible aspiration of the joint. During ankle arthroplasty in patients with prior infection, antibiotics should be added to the cement (if used), and the joint should be thoroughly cleansed. Intraoperative cultures of bone and soft tissue should also be obtained. Consensus. Agree: 100%, Disagree: 0%, Abstain: 0% (Unanimous, Strongest Consensus).


Unique [Mn6Bi5]- Nanowires in KMn6Bi5: A Quasi-One-Dimensional Antiferromagnetic Metal.
We report a new quasi-one-dimensional compound KMn6Bi5 composed of parallel nanowires crystallizing in a monoclinic space group C2/ m with a = 22.994(2) Å, b = 4.6128(3) Å, c = 13.3830(13) Å and β = 124.578(6)°. The nanowires are infinite [Mn6Bi5]- columns each of which is composed of a nanotube of Bi atoms acting as the cladding with a nanorod of Mn atoms located in the central axis of the nanotubes. The nanorods of Mn atoms inside the Bi cladding are stabilized by Mn-Mn bonding and are defined by distorted Mn-centered cluster icosahedra of Mn13 sharing their vertices along the b axis. The [Mn6Bi5]- nanowires are linked with weak internanowire Bi-Bi bonds and charge balanced with K+ ions. The [Mn6Bi5]- nanowires were directly imaged by high-resolution transmission electron microscopy and scanning transmission electron microscopy. Magnetic susceptibility studies show one-dimensional characteristics with an antiferromagnetic transition at ∼75 K and a small average effective magnetic moment (1.56 μB/Mn for H ∥ b and 1.37 μB/Mn for H ⊥ b) of Mn from Curie-Weiss fits above 150 K. Specific heat measurements reveal an electronic specific heat coefficient γ of 6.5(2) mJ K-2(mol-Mn)-1 and a small magnetic entropy change Δ Smag ≈ 1.6 J K-1 (mol-Mn)-1 across the antiferromagnetic transition. In contrast to a metallic resistivity along the column, the resistivity perpendicular to the column shows a change from a semiconducting behavior at high temperatures to a metallic one at low temperatures, indicating an incoherent-to-coherent crossover of the intercolumn tunneling of electrons.


Omega-3 and Omega-6 Polyunsaturated Fatty Acids in Bipolar Disorder: A Review of Biomarker and Treatment Studies.
There is growing evidence that inflammation is an important mediator of pathophysiology in bipolar disorder. The omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) metabolic pathways participate in several inflammatory processes and have been linked through epidemiologic and clinical studies to bipolar disorder and its response to treatment. We review the data on PUFAs as biomarkers in bipolar disorder and n-3 PUFA used as treatment for bipolar disorder. PubMed and CINAHL were searched for articles on PUFA and bipolar disorder published in the English language through November 6, 2013, with an updated search conducted on August 20, 2015. Keywords searched included omega 3 fatty acids and bipolar disorder, omega 3 fatty acids and bipolar mania, omega 3 fatty acids and bipolar depression, omega 3 fatty acids and mania, omega 3 fatty acids and cyclothymia, omega 3 fatty acids and hypomania, fatty acids and bipolar disorder, essential fatty acids and bipolar disorder, polyunsaturated fatty acids and bipolar disorder, DHA and bipolar disorder, and EPA and bipolar disorder. Studies selected measured PUFAs as biomarkers or introduced n-3 PUFA as treatment. We identified 17 relevant human clinical articles that either compared PUFA levels between a bipolar disorder group and a control group or used a PUFA intervention to treat depression or mania in bipolar disorder. Human studies suggest low n-3 red blood cell PUFA concentrations and correlations with clinical severity in studies of plasma concentrations in symptomatic bipolar disorder. Results of published n-3 PUFA dietary supplementation trials for bipolar disorder indicate efficacy in treatment for mania or depression in 5 of 5 open-label trials, efficacy in treatment of depression in 1 of 7 randomized controlled trials, and a signal for treatment of depression in 1 meta-analysis. Biomarker studies of PUFA and treatment studies of n-3 PUFA in bipolar disorder show promise for indicating a way forward in the study of PUFA in bipolar disorder. Investigation of the intake and metabolism of the n-3 and n-6 PUFA when supplementation is provided in treatment trials might offer clues for identification of when and how PUFA may be important for treatment in bipolar disorder.


Culture-Positive Pulmonary Aspergillosis Infection: Clinical and Laboratory Features of Solid-Organ Transplant Recipients.
Aspergillosis is a common fungal infection among solid-organ transplant recipients. Even after awareness of this infection occurs, there are still gaps in nonculture diagnostic tests, which can delay treatment initiation. Here, we aimed to define the common traits of pulmonary aspergillosis infection among solid-organ transplant recipients, thus shedding light on prevention and early diagnosis. We conducted a database search of patients at Baskent University who had a positive aspergillosis culture between January 2010 and March 2016. Among 20 patients identified, 15 (mean age of 50.93 ± 11.17 y, 2 female and 13 male patients) with solid-organ transplant were included in the study. Of the 15 study patients, 7 were heart transplant, 6 were kidney transplant, and 2 were liver transplant recipients. Three patients had positive aspergillosis cultures from extrapulmonary specimens (1 brain biopsy and 2 wound swap cultures). Other patients with positive cultures were from bronchoalveolar lavage (6 patients), sputum (4 patients), both bronchoalveolar lavage and sputum (1 patient), and deep tracheal aspiration specimen (1 patient). Aspergillus fumigatus was the most common species. Mean hospitalization duration was 31.53 days (range, 2-135 d). Although all patients had positive culture results, 7 patients (46.7%) had negative galactomannan test results at the time of culture specimen collection. Positive galactomannan test results were statistically higher in 6 heart transplant patients (P = .045). All patients had fever at presentation, and 13 patients had been referred to the pulmonary disease department before positive culture results were obtained. Risk factors for pulmonary aspergillosis and its clinical presentation in solid-organ transplant recipients are still unclear. Although the expected time for aspergillosis infection in solid-organ transplant recipients is 6 months after transplant, clinicians must remember the nonspecific presentation of infections in these patients and be aware of the reliability of diagnostic tools.


Early sac shrinkage is a good surrogate marker of durable success after endovascular aneurysm repair in Japanese patients.
The applicability of early sac shrinkage as a predictor of a low risk of late complications after endovascular aneurysm repair (EVAR) in Asian populations has not been validated. This study aimed to analyze early sac shrinkage and its relationship with late complications in Asian people using a Japanese multicenter database. We also assessed the impact of endoleaks. A retrospective analysis of 697 patients who had undergone EVAR of abdominal aortic aneurysms from 2008 to 2015 and were followed up for at least 1 year was conducted. Late complications were defined as any aneurysm-related events occurring >1 year after EVAR, including >5-mm aneurysm sac enlargements and any reinterventions performed. Endoleaks without any evidence of sac enlargement or a requirement for additional treatment were not considered late complications. Early sac shrinkage, defined as a >5-mm-diameter decrease within 1 year of EVAR, occurred in 335 patients (48.1%); type I endoleaks (T1ELs) and isolated type II endoleaks (iT2ELs; type II endoleaks without evidence of other endoleaks) were observed in 4.0% and 29.4%, respectively. During the mean follow-up period of 45.5 months, 93 late complications (13.3%) occurred. Kaplan-Meier curve and log-rank analyses showed that early sac shrinkage was a significant predictor for a lower risk of late complications (P < .001). Multivariate analysis revealed that early sac shrinkage was independently associated with a lower risk of late complications (adjusted hazard ratio, 0.425; P = .004). Conversely, T1ELs and iT2ELs were positively associated with late complication (adjusted hazard ratio, 11.774 and 5.137, respectively; both P < .001). Subsequent multivariate analysis demonstrated that T1ELs and iT2ELs were negatively associated with early sac shrinkage (adjusted odds ratio, 0.102 and 0.285, respectively; both P < .001). Early sac shrinkage was associated with a low risk of late complications in Asian people and may be a good surrogate marker of durable success after EVAR. T1ELs and iT2ELs were negatively associated with early sac shrinkage and positively associated with late complications. Along with the high incidence of iT2ELs observed, T2ELs may be an important condition to consider after EVAR in the Asian population.


Systematically reviewing qualitative studies complements survey design: an exploratory study of barriers to paediatric immunisations.
Designing survey questions requires content expertise, awareness of previous qualitative literature, and piloting. We examined surveys addressing parental barriers to vaccinating children to determine if they comprehensively included themes identified in published qualitative studies. We performed a systematic literature search of 12 electronic databases and compared questions asked in eligible surveys identified to issues raised in qualitative studies. Issues included nine themes related to harm, six related to distrust, eight to issues of access, and three other issues. The 29 eligible surveys failed to adequately address several important themes identified in qualitative studies. The number that failed to address the following themes were as follows: beliefs that vaccines cause diseases (n = 26); painful (n = 25); distrust of medical community (n = 28); communication problems with staff (n = 25); memories of their own or others adverse experiences (n = 28); fear of long-term effects (n = 26); belief the medical community does not understand adverse events associated with vaccines (n = 28); and parent's own lack of knowledge about diseases (n = 29). Many surveys of parental barriers to immunization failed to address a number of important themes identified in qualitative studies. To the extent this is true in other areas, ensuring that investigators have conducted an adequate number and variety of qualitative studies, and systematically reviewing those studies, will improve surveys' content validity.


Relationship between muscle stress and intramuscular pressure during dynamic muscle contractions.
Intramuscular pressure (IMP) has been used to estimate muscle stress indirectly. However, the ability of this technique to estimate muscle stress under dynamic conditions is poorly characterized. Therefore, the purpose of this study was to determine the extent to which IMP is a valid surrogate for muscle stress during dynamic contractions. IMP and muscle stress were compared under steady-state isotonic conditions and during complex dynamic length changes. During concentric contractions the shape of the IMP-velocity curve mimicked the basic shape of the force-velocity curve but with much higher variability. For eccentric contractions, a precipitous drop in IMP was observed despite increased muscle stress. The dissociation between muscle stress and IMP during dynamic contractions was partially explained by sensor movement. When the muscle was not moving, IMP explained 89% +/- 5% of the variance in muscle force. However, when transducer movement occurred the linear relationship between IMP and stress was no longer observed. These findings demonstrate the difficulty in interpreting IMP under dynamic conditions when sensor movement occurs. They also illustrate the need to control transducer movement if muscle stress is to be inferred from IMP measurements such as might be desired during clinical gait testing.


Anterior Colporrhaphy With and Without Dermal Allograft: A Randomized Control Trial With Long-Term Follow-Up.
The objective of this study was to determine whether anterior colporrhaphy plus insertion of anterior dermal allograft reduces anterior prolapse recurrence at 1 and 7 to 10 years postoperatively compared with anterior colporrhaphy alone. We present a nonblinded randomized controlled trial with 1- and 7- to 10-year follow-up. Subjects were randomized between 2005 and 2008 to anterior colporrhaphy or ultralateral anterior colporrhaphy plus insertion of a dermal allograft spanning the anterior compartment between the arcus tendineus fascia pelvis on each side. Eligible subjects had anterior prolapse to the hymen or beyond, were bothered by their prolapse, and were planning to undergo surgical correction. Subjects completed a pelvic organ prolapse quantification system (POPQ) examination and Pelvic Floor Distress Inventory (PFDI)/PFDI-20 before surgery; a POPQ, PFDI, and Pelvic Organ Prolapse/Incontinence Sexual Questionnaire at 1 year postoperatively; and a POPQ, PFDI-20, Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, Revised, and Patient-reported Global Impression of Improvement Inventory at 7 to 10 years postoperatively. Our primary outcome was anatomic anterior prolapse recurrence at 1 or 7 to 10 years defined as Aa or Ba greater than or equal to -1. Our secondary outcome was a composite score of anterior prolapse recurrence at 1 or 7 to 10 years defined as anatomic recurrence (Aa or Ba ≥ 0), retreatment for cystocele, or answering yes to PFDI-20 question 3 (subjective report of vaginal bulge). A total of 114 subjects were randomized, 70 to anterior colporrhaphy and 44 to anterior colporrhaphy plus dermal allograft. About 92% of subjects underwent concomitant apical suspension, 98% in the graft group and 89% in the nongraft group. Eighty-nine subjects (32 graft [73%], 57 nongraft [81%]) returned for 1-year follow-up. Fifty-three patients (19 graft [48%], 34 nongraft [49%]) returned for 7- to 10-year follow-up. The primary outcome was met by 8 (18%) graft and 22 (31%) nongraft subjects at 1 year postoperatively (P = 0.26) and by 10 (23%) graft and 24 (34%) nongraft subjects at 7 to 10 years postoperatively (P = 0.37). The secondary outcome was met by 8 (18%) graft and 15 (21%) nongraft subjects at 1 year postoperatively (P = 0.74) and by 13 (30%) graft and 21 (30.0%) nongraft subjects at 7 to 10 years postoperatively (P = 0.99). We cannot conclude whether there is a difference in anterior recurrence for anterior colporrhaphy with and without dermal allograft and do not recommend changes in clinical practice based on these results.


Factors Associated With Large Improvements in Health-Related Quality of Life in Patients With Atrial Fibrillation: Results From ORBIT-AF.
Atrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described. We assessed factors associated with a 1-year increase in the Atrial Fibrillation Effect on Quality-of-Life score of 1 SD (≥18 points; 3× clinically important difference), among outpatients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I registry. Overall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 versus 74, P=0.3), equally likely to be female (44% versus 48%, P=0.3), but more likely to have newly diagnosed AF at baseline (18% versus 8%; P=0.0004), prior antiarrhythmic drug use (52% versus 40%, P=0.005), baseline antiarrhythmic drug use (34.8% versus 26.8%, P=0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% versus 2.0%, P=0.003; cardioversion: 12.2% versus 5.9%, P=0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR, 2.41; P=0.01) and increased baseline diastolic blood pressure (adjusted OR, 1.23 per 10-point increase and >65 mm Hg; P=0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/transient ischemic attack, chronic obstructive pulmonary disease, and peripheral arterial disease were less likely to improve (P<0.05 for each). In this national registry of patients with AF, potentially treatable AF risk factors are associated with large hrQoL improvement, whereas less reversible conditions appeared negatively associated with hrQoL improvement. Understanding which patients are most likely to have large hrQoL improvement may facilitate targeting interventions for high-value care that optimizes patient-reported outcomes in AF. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01165710.


Identification and biochemical characterization of p70TRK, product of the human TRK oncogene.
TRK is a human transforming gene generated in a colon carcinoma by a somatic rearrangement that fused a nonmuscle tropomyosin gene to sequences that shared extensive homology with members of the tyrosine-protein kinase supergene family. These sequences are likely to be derived from a transmembrane receptor gene whose putative ligand binding domain has been replaced by tropomyosin. In the present studies, we have expressed the entire coding sequences of the TRK oncogene as well as its protein kinase-related carboxyl-terminal domain in Escherichia coli. Antisera raised against these bacteria-synthesized TRK polypeptides has allowed us to identify the gene product of the TRK oncogene as a 70-kDa protein. Immunoprecipitates containing p70TRK have an associated protein kinase activity specific for tyrosine residues. Moreover, p70TRK is phosphorylated in vivo in serine (75%), threonine (20%), and tyrosine (5%) residues. Finally, immunofluorescence and cellular fractionation studies indicate that p70TRK is preferentially located in the cytoplasmic fraction.


Response of the Anaerobic Methanotroph "Candidatus Methanoperedens nitroreducens" to Oxygen Stress.
"Candidatus Methanoperedens nitroreducens" is an archaeon that couples the anaerobic oxidation of methane to nitrate reduction. In natural and man-made ecosystems, this archaeon is often found at oxic-anoxic interfaces where nitrate, the product of aerobic nitrification, cooccurs with methane produced by methanogens. As such, populations of "Ca Methanoperedens nitroreducens" could be prone to regular oxygen exposure. Here, we investigated the effect of 5% (vol/vol) oxygen exposure in batch activity assays on a "Ca Methanoperedens nitroreducens" culture, enriched from an Italian paddy field. Metagenome sequencing of the DNA extracted from the enrichment culture revealed that 83% of 16S rRNA gene reads were assigned to a novel strain, "Candidatus Methanoperedens nitroreducens Verserenetto." RNA was extracted, and metatranscriptome sequencing upon oxygen exposure revealed that the active community changed, most notably in the appearance of aerobic methanotrophs. The gene expression of "Ca Methanoperedens nitroreducens" revealed that the key genes encoding enzymes of the methane oxidation and nitrate reduction pathways were downregulated. In contrast to this, we identified upregulation of glutaredoxin, thioredoxin family/like proteins, rubrerythrins, peroxiredoxins, peroxidase, alkyl hydroperoxidase, type A flavoproteins, FeS cluster assembly protein, and cysteine desulfurases, indicating the genomic potential of "Ca Methanoperedens nitroreducens Verserenetto" to counteract the oxidative damage and adapt in environments where they might be exposed to regular oxygen intrusion.IMPORTANCE "Candidatus Methanoperedens nitroreducens" is an anaerobic archaeon which couples the reduction of nitrate to the oxidation of methane. This microorganism is present in a wide range of aquatic environments and man-made ecosystems, such as paddy fields and wastewater treatment systems. In such environments, these archaea may experience regular oxygen exposure. However, "Ca Methanoperedens nitroreducens" is able to thrive under such conditions and could be applied for the simultaneous removal of dissolved methane and nitrogenous pollutants in oxygen-limited systems. To understand what machinery "Ca Methanoperedens nitroreducens" possesses to counteract the oxidative stress and survive, we characterized the response to oxygen exposure using a multi-omics approach.


Regulation of Proliferation and Epithelial-to-Mesenchymal Transition (EMT) of Gastric Cancer by ZEB1 via Modulating Wnt5a and Related Mechanisms.
BACKGROUND As a member of the zinc-finger E-box binding protein (ZEB) family, ZEB1 can modulate onset and progression of various tumors, but its regulatory effect or mechanism in GC has not been defined. MATERIAL AND METHODS GC tumor tissues and adjacent tissues were collected from GC patients across different TNM stages. Real-time PCR was used to measure ZEB1 expression to analyze its correlation with pathological features of tumors. Cultured GC cell lines SGC-7901 and MGC-803 were randomly assigned into control group, scramble group, and ZEB1 siRNA group. Real-time PCR was employed to analyze ZEB1 expression, and MTT approach was used to measure cell proliferation. Cell apoptosis was evaluated by flow cytometry. Wound healing assay was used to detect its effect on cell migration. Expression of E-cadherin and Vimentin involved in epithelial-to-mesenchymal transition (EMT) was measured by Western blot analysis, along with Wnt5a proteins. RESULTS GC tissues had upregulation of ZEB1 (P<0.05 compared to adjacent tissues), whose expression level was correlated with differentiation grade, lymph node metastasis, and tumor pathological stage (P<0.05). Transfection of ZEB1 siRNA into SGC-7901 or MGC-803 cells can suppress ZEB1 expression, inhibit tumor cell proliferation, enhance apoptosis, and inhibit cell migration. Transfected GC cells had higher E-cadherin expression and decreased Vimentin expression or Wnt5a expression (P<0.05 compared to the control group). CONCLUSIONS ZEB1 expression is increased in GC tumor tissues and is associated with pathological features. The downregulation of ZEB1 can facilitate cell apoptosis via mediating Wnt5a, further suppressing GC cell proliferation and migration, and reducing EMT occurrence.


Female Physicians and the Work-Family Conflict.
There has been a dramatic increase in the number of female physicians in all fields and specializations of medicine, but this increase has not resulted in a redistribution of domestic tasks and responsibilities. Reviewing the literature of the last two decades (April 1994 to April 2014) on how female physicians cope with the challenge of balancing their family and professional lives for the duration of their professional careers revealed that they suffer from the work-family conflict more than other professionals and that it has a more negative effect on women than on men. Women physicians consider work-family balance significantly when making career choices. These considerations affect their career success, their productivity as faculty members, their marital life, and parenthood. Having a supportive spouse at home and a facilitating mentor at work are important for a positive work-family balance among female physicians. Special career-supporting measures, such as flexible work schedules and expanded support for childcare over the course of work and when taking part in academic activities, are critical for female physicians.


Cross-spectrally coherent ~10.5- and 21-year biological and physical cycles, magnetic storms and myocardial infarctions*
Magnetic storms trigger myocardial infarctions with mechanisms relating to heart rate variability. Solar cycle-to-solar cycle differences and solar cycle stage dependence shown herein may resolve prior controversy and serve to advocate coordinated worldwide systematically aligned biological and physical monitoring. * This paper was originally invited by the historian-geophysicist Wilfried SCHRöDER of Bremen, Germany, for his biographical "Encounters," and is to serve as an update on the project on the BIOsphere and the Cosmos (BIOCOS) and its offspring ICEHRV (Dr. Kuniaki Otsuka's International Chronome Ecologic Study of Heart Rate Variability). It is intended for distribution at a NATO conference on space weather hazards, organized by Dr. Ioannis Daglis, June 18-29, 2000.


Acupuncture, chiropractic and osteopathy use in Australia: a national population survey.
There have been no published national studies on the use in Australia of the manipulative therapies, acupuncture, chiropractic or osteopathy, or on matters including the purposes for which these therapies are used, treatment outcomes and the socio-demographic characteristics of users. This study on the three manipulative therapies was a component of a broader investigation on the use of complementary and alternative therapies. For this we conducted a cross-sectional, population survey on a representative sample of 1,067 adults from the six states and two territories of Australia in 2005 by computer-assisted telephone interviews. The sample was recruited by random digit dialling. Over a 12-month period, approximately one in four adult Australians used either acupuncture (9.2%), chiropractic (16.1%) or osteopathy (4.6%) at least once. It is estimated that, adult Australians made 32.3 million visits to acupuncturists, chiropractors and osteopaths, incurring personal expenditure estimated to be A$1.58 billion in total. The most common conditions treated were back pain and related problems and over 90% of the users of each therapy considered their treatment to be very or somewhat helpful. Adverse events are reported. Nearly one fifth of users were referred to manipulative therapy practitioners by medical practitioners. There is substantial use of manipulative therapies by adult Australians, especially for back-related problems. Treatments incur considerable personal expenditure. In general, patient experience is positive. Referral by medical practitioners is a major determinant of use of these manipulative therapies.


Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.
Classification of rare missense substitutions observed during genetic testing for patient management is a considerable problem in clinical genetics. The Bayesian integrated evaluation of unclassified variants is a solution originally developed for BRCA1/2. Here, we take a step toward an analogous system for the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that confer colon cancer susceptibility in Lynch syndrome by calibrating in silico tools to estimate prior probabilities of pathogenicity for MMR gene missense substitutions. A qualitative five-class classification system was developed and applied to 143 MMR missense variants. This identified 74 missense substitutions suitable for calibration. These substitutions were scored using six different in silico tools (Align-Grantham Variation Grantham Deviation, multivariate analysis of protein polymorphisms [MAPP], MutPred, PolyPhen-2.1, Sorting Intolerant From Tolerant, and Xvar), using curated MMR multiple sequence alignments where possible. The output from each tool was calibrated by regression against the classifications of the 74 missense substitutions; these calibrated outputs are interpretable as prior probabilities of pathogenicity. MAPP was the most accurate tool and MAPP + PolyPhen-2.1 provided the best-combined model (R(2) = 0.62 and area under receiver operating characteristic = 0.93). The MAPP + PolyPhen-2.1 output is sufficiently predictive to feed as a continuous variable into the quantitative Bayesian integrated evaluation for clinical classification of MMR gene missense substitutions.


Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR.
Diversification of RNA-targeted scaffolds offers great promise in the search for selective ligands of therapeutically relevant RNA such as HIV-1 TAR. We herein report the establishment of amiloride as a novel RNA-binding scaffold along with synthetic routes for combinatorial C(5)- and C(6)-diversification. Iterative modifications at the C(5)- and C(6)- positions yielded derivative 24, which demonstrated a 100-fold increase in activity over the parent dimethylamiloride in peptide displacement assays. NMR chemical shift mapping was performed using the 2D SOFAST- [1H-13C] HMQC NMR method, which allowed for facile and rapid evaluation of binding modes for all library members. Cheminformatic analysis revealed distinct differences between selective and non-selective ligands. In this study, we evolved dimethylamiloride from a weak TAR ligand to one of the tightest binding selective TAR ligands reported to date through a novel combination of synthetic methods and analytical techniques. We expect these methods to allow for rapid library expansion and tuning of the amiloride scaffold for a range of RNA targets and for SOFAST NMR to allow unprecedented evaluation of small molecule:RNA interactions.


Integration for coexistence? Implementation of intercultural health care policy in Ghana from the perspective of service users and providers.
In spite of the World Health Organization's recommendations over the past decades, Ghana features pluralistic rather than truly integrated medical system. Policies about the integration of complementary medicine into the national health care delivery system need to account for individual-level involvement and cultural acceptability of care rendered by health care providers. Studies in Ghana, however, have glossed over the standpoint of the persons of the illness episode about the intercultural health care policy framework. This paper explores the health care users, and providers' experiences and attitudes towards the implementation of intercultural health care policy in Ghana. In-depth interviews, augmented with informal conversations, were conducted with 16 health service users, 7 traditional healers and 6 health professionals in the Sekyere South District and Kumasi Metropolis in the Ashanti Region of Ghana. Data were thematically analysed and presented based on the a posteriori inductive reduction approach. Findings reveal a widespread positive attitude to, and support for integrative medical care in Ghana. However, inter-provider communication in a form of cross-referrals and collaborative mechanisms between healers and health professionals seldom occurs and remains unofficially sanctioned. Traditional healers and health care professionals are skeptical about intercultural health care policy mainly due to inadequate political commitment for provider education. The medical practitioners have limited opportunity to undergo training for integrative medical practice. We also find a serious mistrust between the practitioners due to the "diversity of healing approaches and techniques." Weak institutional support, lack of training to meet standards of practice, poor registration and regulatory measures as well as negative perception of the integrative medical policy inhibit its implementation in Ghana. In order to advance any useful intercultural health care policy in Ghana, the government's total commitment in informed training and provider education, enforcement of regulatory instrument and improved community engagement is needed. Evidence-based incorporation of traditional medical therapies into clinical practice will provide safer, faster and more effective health care for the underserved and resource-poor, particularly in the rural areas.


Medical and surgical co-management - A strategy of improving the quality and outcomes of perioperative care.
With the increase of ageing population, rates of chronic diseases and complex medical conditions, the management of high-risk surgical patients is likely to become a great concern in most countries. Considering all these factors, it is certainly rational and intuitive that internists should be included into a collaborative model of medical and surgical co-management, where their multi-potentiality and synthesis capacity require them to coordinate the multidisciplinary team and to be the leading agent of change. In this regard, our aim was to present the official position and approach of the Working Group on Professional Issues and Quality of Care of the European Federation of Internal Medicine (EFIM), for implementation of this strategy of care, encouraging internists to assume an important role and to provide continuity of multidisciplinary care, from the decision to operate through to rehabilitation and recovery. Moving from the traditional model of medical care of the surgical patients to the co-management model, from a reactive simple consultation to a new pro-active continued service, may optimize the quality and perioperative care, improving the survival, shortening hospital stays, replacing the old strategy of late and complication treatment to an early and preventive one.


What does the literature say about using electronic pillboxes for older adults? A systematic literature review.
Purpose: The purpose of this study is to answer two research questions: (1) What is the clinical evidence for the reported outcomes in studies on electronic pillboxes for older adults? and (2) What is the technology readiness level (TRL) of the electronic pillboxes used, or intended to be used, for older adults?Methods: The scholarly literature was systematically searched and analyzed. Articles were included if they reported results about electronic pillboxes that were used or intended to be used for older adults' medication.Results: Clinical studies used commercially well-established electronic pillboxes with a high TRL. New electronic pillboxes in development had a low TRL. The discovered outcome was mainly adherence to medication. The overall mean adherence to medication regimens for all the studies using an electronic pillbox was higher than the gold standard of a good adherence level cut-off point (mean adherence 88.8%>80%). However, we found a large variation in this variable (SD = 10.7). With regard to an older adult population's adherence to medication regimens, for the outcome variable of those who had undergone a kidney transplant, the clinical evidence that electronic pillboxes have a positive impact was strong (1b); for those with a chronic hepatitis C medical condition, the clinical evidence was medium (3), and for those with arterial hypertension and multiple chronic (diabetes and hypertension) medical conditions, the clinical evidence was weak (5).Conclusion: More research is needed in this area using designs that provide greater validity.Implications for RehabilitationElectronic pillboxes with multiple reminders such as the "voice of a friend" or relative, which implies that electronic pillboxes which adopt "a social role" are advisable.An unequal level of clinical evidence that electronic pillboxes have a positive impact on the adherence outcome variable was found.For new electronic pillboxes still in development that specifically take into account older adults' needs, the TRL is still low; as a result, they could not be tested in real settings.


Diversity of nitrogen cycling genes at a Midwest long-term ecological research site with different management practices.
Nitrogen fertilizer results in the release of nitrous oxide (N2O), a concern because N2O is an ozone-depleting substance and a greenhouse gas. Although the reduction of N2O to nitrogen gas can control emissions, the factors impacting the enzymes involved have not been fully explored. The current study investigated the abundance and diversity of genes involved in nitrogen cycling (primarily denitrification) under four agricultural management practices (no tillage [NT], conventional tillage [CT], reduced input, biologically-based). The work involved examining soil shotgun sequencing data for nine genes (napA, narG, nirK, nirS, norB, nosZ, nirA, nirB, nifH). For each gene, relative abundance values, diversity and richness indices, and taxonomic classification were determined. Additionally, the genes associated with nitrogen metabolism (defined by the KEGG hierarchy) were examined. The data generated were statistically compared between the four management practices. The relative abundance of four genes (nifH, nirK, nirS, and norB) were significantly lower in the NT treatment compared to one or more of the other soils. The abundance values of napA, narG, nifH, nirA, and nirB were not significantly different between NT and CT. The relative abundance of nirS was significantly higher in the CT treatment compared to the others. Diversity and richness values were higher for four of the nine genes (napA, narG, nirA, nirB). Based on nirS/nirK ratios, CT represents the highest N2O consumption potential in four soils. In conclusion, the microbial communities involved in nitrogen metabolism were sensitive to different agricultural practices, which in turn, likely has implications for N2O emissions. KEY POINTS: • Four genes were less abundant in NT compared to one or more of the others soils (nifH, nirK, nirS, norB). • The most abundant sequences for many of the genes classified within the Proteobacteria. • Higher diversity and richness indices were observed for four genes (napA, narG, nirA, nirB). • Based on nirS/nirK ratios, CT represents the highest N2O consumption potential.


Serum feline trypsin-like immunoreactivity following administration of ceruletide to healthy cats.
To determine changes in serum feline trypsin-like immunoreactivity (fTLI) in response to administration of ceruletide to healthy cats. 11 healthy cats. Serum fTLI was determined, using a radioimmunoassay, before and 10, 20, 30, 40, and 50 minutes after IM administration of ceruletide (0.3 mg/kg [0.14 mg/lb]). Mean +/- SD baseline serum fTLI was 23.1 +/- 4.1 mg/L. There was a statistically significant, but clinically unimportant, increase in serum fTLI 10 and 30 minutes after ceruletide administration. In healthy cats, administration of ceruletide induced a statistically significant, but clinically unimportant, increase in serum fTLI. Whether responses in cats with exocrine pancreatic disorders would be different is unknown, but results suggest that a ceruletide stimulation test would likely not be useful for differentiating between healthy cats and cats with subclinical chronic exocrine pancreatic disorders.


Development of social behavior in young zebrafish.
Adult zebrafish are robustly social animals whereas larva is not. We designed an assay to determine at what stage of development zebrafish begin to interact with and prefer other fish. One week old zebrafish do not show significant social preference whereas most 3 weeks old zebrafish strongly prefer to remain in a compartment where they can view conspecifics. However, for some individuals, the presence of conspecifics drives avoidance instead of attraction. Social preference is dependent on vision and requires viewing fish of a similar age/size. In addition, over the same 1-3 weeks period larval zebrafish increasingly tend to coordinate their movements, a simple form of social interaction. Finally, social preference and coupled interactions are differentially modified by an NMDAR antagonist and acute exposure to ethanol, both of which are known to alter social behavior in adult zebrafish.


Duration of therapeutic coma and outcome of refractory status epilepticus.
Examine the association of duration of therapeutic coma (TC) with seizure recurrence, morbidity, and mortality in refractory status epilepticus (RSE). Define an optimal window for TC that provides sustained seizure control and minimizes complications. Retrospective, observational cohort study involving patients who presented with RSE to the University of Alabama at Birmingham or the University of California at San Francisco from 2010 to 2016. Relationship of duration of TC with primary and secondary outcomes was evaluated using two-sample t tests, simple linear regression, and chi-square tests. Multivariable linear and logistic regression models were used to identify independent predictors. Predictive ability of TC for seizure recurrence was quantified using a receiver-operating characteristic curve. Youden index was used to determine an optimal cutoff value. Multivariable analysis of clinical and treatment characteristics of 182 patients who were treated predominantly with propofol as anesthetic agent showed that longer duration of the first trial of TC (27.2 vs 15.6 hours) was independently associated with a higher chance of seizure recurrence following the first weaning attempt (P = 0.038) but not with poor functional neurologic outcome upon discharge, in-hospital complications, or mortality. Furthermore, higher doses of anesthetic utilized during the first trial of TC were independently associated with fewer in-hospital complications (P = 0.003) and associated with a shorter duration of mechanical ventilation and total length of stay. Duration of TC was identified as an independent predictor of seizure recurrence with an optimal cutoff point at 35 hours. This study suggests that a shorter duration yet deeper TC as treatment for RSE may be more effective and safer than the currently recommended TC duration of 24-48 hours. Prospective and randomized trials should be conducted to validate these assertions.


A central role for epidermal segment border cells in the induction of muscle patterning in the Drosophila embryo.
The correct patterning of muscles in the Drosophila embryo depends on the migration of developing muscles over the ectoderm and on the attachment of these muscles to specific attachment sites. We investigate the mechanisms that are involved in this process and describe experiments that allow a genetic dissection of the role of the ectoderm in muscle migration and attachment. We show that cells along the segmental border in the ectoderm are used by the developing muscles to reach their attachment sites. These segment border cells are recognized by dissociated myotubes in single suspensions in culture. Thus, developing muscles have properties that allow the specific recognition of the segment border cells and migrate to attach to these cells. The segment border cells are absent in the mutant wingless and naked. In these mutants, the muscles are severely disorganized. We show that this is not a mere consequence of disruption of the epidermis, since, in the mutant patched, where segmental patterning is affected, the segment border cells are present near their normal position; the muscles in this mutant are relatively organized. Similarly, in the mutant lines where ectopic segment border cells are present, the observed muscle derangement correlates well with the ectopic attachment sites that are present. Finally, we have analyzed mutants at the stripe locus and have shown that lethal alleles disrupt muscle organization during embryogenesis. Enhancer-trap alleles of stripe that we have analyzed show reporter gene expression in the segment border cells. Our results indicate a role for the segment border cells in guidance of migrating muscle fibers to their attachment sites.


The pathophysiology of the intervertebral disc.
After a review of disk structure, the pivotal role of disk cells in producing and renewing the extracellular disk matrix is emphasized. Disk cells rely on nutrients that diffuse through the vertebral endplates. Microelectrode methods have been developed to study nutrient diffusion and endplate permeability. Mechanical stimuli modify disk cell activity. Scoliosis is associated with decreased endplate permeability, a factor that may play a role in disk degeneration and scoliosis progression.


Routine diagnostic laparoscopy reduces the rate of unnecessary appendicectomies in young women.
The reported negative appendicectomy rate for young women remains high. This high rate of unnecessary appendicectomies has morbidity and high cost. Consensus European Association of Endoscopic Surgeons (EAES) guidelines have emphasised the value of routine laparoscopy as a diagnostic tool in young women. The objective of this study is to investigate the role of routine laparoscopy in the diagnosis of suspected appendicitis in young women. The details of young female patients who have had an appendicectomy with or without laparoscopy between 1980 and 2005 were obtained. The histopathological reports pertaining to the episode of appendicectomy were manually searched. Three periods were identified for comparison. The first period was between 1980 and 1990 when diagnostic laparoscopy was not practised in the emergency setting. The second period was between 1991 and 1999 when diagnostic laparoscopy was used selectively. The third period was between 2000 and 2005 when diagnostic laparoscopy was used routinely to investigate female patients presenting with acute right iliac fossa pain. Selective laparoscopy reduced the rate of negative appendicectomy rate from 37% to 31% (ns). By contrast, routine laparoscopy reduced the negative appendicectomy rate to 5% (p < 0.005). Additionally, considering the ratios of all appendectomies to normal appendices, an average of one in three appendices excised was normal before the era of laparoscopy. The selective use of laparoscopy did not significantly alter this ratio (ns). By contrast routine use of laparoscopy has altered the ratio to 1 in 20 appendices removed to be normal (p < 0.001). In young females, diagnostic laparoscopy used selectively reduces the rate of negative appendicectomy but not significantly. However, when used routinely, laparoscopy significantly reduces the rate of negative appendicectomy. Diagnostic laparoscopy should be used routinely for all young females presenting with right iliac fossa pain sufficiently severe to warrant surgical exploration.