Polymorphisms of the renin-angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology.
The renin-angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease. We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference. We found that AGT-235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25-fold (95% CI 1.02-1.52) in AGT-TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT-TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non-significant increased risk of silent brain infarction for AGT-TT carriers and AT1R-CC carriers, but no effect on stroke. We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin-angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology.


Altered collagen turnover in factor VIII-deficient rats with hemophilic arthropathy identifies potential novel serological biomarkers in hemophilia.
Essentials Joint bleeding in hemophilia may induce significant remodeling of the extracellular matrix. Biomarkers of collagen turnover were investigated in a F8-/- rat model of hemophilic arthropathy. Biomarkers of cartilage degradation increased significantly during development of arthropathy. Basement membrane and interstitial matrix turnover changed significantly following hemarthrosis. Background Hemophilic arthropathy is a severe complication of hemophilia. It is caused by recurrent bleeding into joint cavities, which leads to synovial inflammation, fibrosis, cartilage degradation and bone remodeling. Extracellular matrix remodeling of affected tissues is a hallmark of these pathological processes. Objectives The aim of this study was to use serological biomarkers of collagen turnover to evaluate extracellular matrix remodeling in a factor VIII-deficient rat model of hemophilic arthropathy. Methods F8-/- rats and wild-type littermate controls were subjected to repeated knee bleeds induced by needle puncture on days 0 and 14. Development of arthropathy was confirmed by histology after termination on day 28. Serum samples were collected at baseline and throughout the study and analyzed for biomarkers of collagen turnover, including collagens of the basement membrane (type IV collagen), the interstitial matrix (collagen types III, V and VI) and cartilage (type II collagen). Results In F8-/- rats, induced knee bleeding and subsequent development of arthropathy caused significant alterations in collagen turnover, measured as changes in serological biomarkers of basement membrane turnover, interstitial matrix turnover and cartilage degradation. Biomarkers of type II collagen degradation correlated significantly with cartilage degradation and degree of arthropathy. Hemophilic rats had a 50% higher turnover of the basement membrane than wild-type littermates at baseline. Conclusions Joint bleeding and hemophilic arthropathy cause changes in turnover of extracellular matrix collagens in hemophilic rats. Biomarkers of collagen turnover may be used to monitor joint bleeding and development of blood-induced joint disease in hemophilia.


Human immunodeficiency virus infection in women: report of 102 cases.
We examined surgical specimens from 19 human immunodeficiency virus (HIV) seropositive females and 83 females with acquired immunodeficiency syndrome (AIDS) to determine (a) frequency of opportunistic infections (OI) and malignancies, (b) differences or similarities between different risk groups, and (c) differences or similarities when compared with men having AIDS. A risk factor was identified in 86 patients (72 AIDS and 14 HIV seropositive), of whom the majority were intravenous drug abusers (IVDA) (74%) or had had heterosexual contact with a person with AIDS or at risk for AIDS (20%). The remaining patients were blood transfusion recipients or Haitians. All females were treated at Bellevue hospital, a large municipal inner city hospital. The conclusions of our study are as follows. (a) Women with AIDS develop the same type and incidence of OI and lymphomas as the general AIDS population. (b) The incidence of Kaposi's sarcoma in females with AIDS is similar to that seen in male heterosexuals with AIDS. A greater than expected number of epithelial malignancies were found in our population. Characteristics of these carcinomas included young age of the patients (average age of 40), unusually aggressive nature of the tumors, and tendency to occur prior to development of AIDS. We therefore suggest HIV testing in all young females (and males) who present with an unusual or particularly aggressive epithelial neoplasm. (c) The most common OI was Pneumocystis carinii pneumonia (PCP), followed by mycobacterial infections. PCP was seen in a significantly greater percentage of females with a sexual contact risk than in female IVDA (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents.
To determine whether insulin resistance or insulin deficiency is primary in the pathogenesis of type II diabetes. Cohort analytic study of persons with normal glucose tolerance but with a high risk for developing type II diabetes (average follow-up time, 13 years). Outpatients had an intravenous glucose tolerance test and were contacted periodically to ascertain diagnoses of diabetes. One hundred and fifty-five normal offspring, ranging in age from 16 to 60 years, of two parents with type II diabetes and 186 normal control subjects in the same age range who had no family history of diabetes. Two phenotypic characteristics distinguished the offspring of diabetic parents from control subjects. They had slower glucose removal rates (Kg) (P less than 0.01) and higher insulin levels (fasting and during the second phase of insulin response to intravenous glucose; P less than 0.0001) than did control subjects, even after adjustment for differences in obesity. Sixteen percent of the offspring developed type II diabetes. Mean Kg at baseline was 1.7%/min among offspring who subsequently developed diabetes, 2.2%/min among offspring who remained nondiabetic, and 2.3%/min among control subjects. Corresponding means for first-phase insulin were 498, 354, and 373 pM, respectively, whereas second-phase insulin means were 329, 117, and 87 pM, respectively. In multivariate analysis, low Kg and high serum insulin levels independently increased the risk for developing diabetes among the offspring of diabetic parents. One to two decades before type II diabetes is diagnosed, reduced glucose clearance is already present. This reduced clearance is accompanied by compensatory hyperinsulinemia, not hypoinsulinemia, suggesting that the primary defect is in peripheral tissue response to insulin and glucose, not in the pancreatic beta cell.


Biasing the brain's attentional set: II. effects of selective intersensory attentional deployments on subsequent sensory processing.
This study used high-density mapping of human event-related potentials to examine the brain activity associated with selective information processing when subjects were cued on a trial-by-trial basis to perform a discrimination in either the visual or auditory modality. On each trial, word-cues (S1) instructed subjects to attend to features within one sensory-modality of an impending compound auditory-visual stimulus (S2) that arrived approximately 1-second following the cue. Subjects made a discrimination within the cued modality of the S2 stimulus. The spatio-temporal patterns of activity in response to the compound S2 stimulus were examined as a function of the sensory modality being attended. The earliest effects of intersensory attention on visual processing were seen subsequent to the initial activation of visual cortex, beginning at 80 ms and continuing into the P1 and N1 components of the visual ERP. The scalp-topography of this earliest modulation was consistent with modulation of activity in ventral visual stream areas. Thus, the locus of effects on visual S2 processing differed from the anticipatory parieto-occipital biasing activity that preceded S2 presentation. This pattern of effects strongly suggests that the anticipatory activity (following the cue) associated with sustaining the focus of attention during intersensory attention, at least in the context of this paradigm, does not operate as a simple gain mechanism in early visual sensory areas. Rather, attentional biasing can operate through a higher-order process whereby parieto-occipital cortices influence the subsequent flow of visual processing in the ventral stream.


Pharmacological interventions for chronic pain in children: an overview of systematic reviews.
We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.


Weekly miscarriage rates in a community-based prospective cohort study in rural western Kenya.
Information on adverse pregnancy outcomes is important to monitor the impact of public health interventions. Miscarriage is a challenging end point to ascertain and there is scarce information on its rate in low-income countries. The objective was to estimate the background rate and cumulative probability of miscarriage in rural western Kenya. This was a population-based prospective cohort. Women of childbearing age were followed prospectively to identify pregnancies and ascertain their outcomes in Siaya County, western Kenya. The cohort study was carried out in 33 adjacent villages under health and demographic surveillance. Miscarriage. Between 2011 and 2013, among 5536 women of childbearing age, 1453 pregnancies were detected and 1134 were included in the analysis. The cumulative probability was 18.9%. The weekly miscarriage rate declined steadily with increasing gestation until approximately 20 weeks. Known risk factors for miscarriage such as maternal age, gravidity, occupation, household wealth and HIV infection were confirmed. This is the first report of weekly miscarriage rates in a rural African setting in the context of high HIV and malaria prevalence. Future studies should consider the involvement of community health workers to identify the pregnancy cohort of early gestation for better data on the actual number of pregnancies and the assessment of miscarriage.


Soluble glycoprotein VI is raised in the plasma of patients with acute ischemic stroke.
Ischemic stroke induced by thrombosis may be triggered by atherosclerotic plaque rupture and collagen-induced platelet activation. Collagen induces glycoprotein VI shedding. We measured plasma-soluble glycoprotein VI (sGPVI) by enzyme-linked immunosorbent assay in 159 patients with acute (<7-day) ischemic stroke and age/sex-matched community-based control subjects. sGPVI was elevated in stroke compared with controls (P=0.0168). ORs were higher in Quartile 4 for stroke cases (P=0.0121), and sGPVI was significantly elevated in stroke associated with large artery disease across Quartiles 2 to 4 and small artery disease in Quartile 4. sGPVI decreased 3 to 6 months after antiplatelet treatment, consistent with elevated sGPVI due to platelet activation during the thrombotic event. sGPVI correlated with P-selectin (P=0.0007) and was higher in individuals with the GPVIa haplotype (P=0.024). Glycoprotein VI shedding is implicated in the pathology of acute ischemic stroke.


Investigation of atypical bacteria and virus antigens in respiratory tract infections by use of an immunofluorescence method.
In this study an immunofluorescence (IF) method was used to investigate the antigens of viruses and atypical bacteria in respiratory tract infections (RTI) in pediatric and adult age groups. In this prospective study of 2 years (1998-2000), IF was used to investigate the antigens of 7 viral and 3 atypical bacteria to be used for the etiological diagnosis of RTI. Sputum (33.6%) and nasopharyngeal aspirate specimens were obtained from pediatric patients (Group I, 76 cases) and adults (Group II, 135 cases) with RTI symptoms. Antigen detection rates were found to be 44.7% in Group I and 67.4% in Group II (P < 0.05). The following rates for specific antigens in Groups I and II, respectively, were as follows: Chlamydia pneumoniae, 17.1 and 13.3% (P > 0.05); Mycoplasma pneumoniae, 0 and 9.6% (P < 0.05); influenza A virus, 3.9 and 16.3% (P < 0.05); adenovirus, 3.9 and 14.8% (P < 0.05); parainfluenza virus type 1, 5.3 and 7.4% (P > 0.05); respiratory syncytial virus, 9.2 and 1.5% (P < 0.05); parainfluenza virus type 2, 3.9 and 3%(P > 0.05); and influenza B virus, 1.3 and 1.5% (P > 0.05). Mixed agents were found at a rate of 2.6 and 3.7% (P > 0.05) in Groups I and II, respectively. Parainfluenza virus type 3 and Legionella pneumophila antigens were not found. Since detecting etiological agents provides an important guide for determining the most appropriate antibiotic therapy, this IF method could be applied in clinical practice for arriving at a correct diagnosis and administration of effective treatment.


Nursing the adopted infant.
Breast feeding is commonly accepted as the preferred method of infant nutrition for various reasons, both nutritional and emotional. For some who have become parents by adoption, there is a strong desire to induce lactation for adoptive nursing. Information regarding adoptive nursing was initially obtained for the author's personal experience from searching the internet and speaking with other adoptive mothers. The medical literature was also searched through OVID/MEDLINE using pertinent terms, including induced lactation, adoptive nursing, domperidone, and metoclopramide. Use of physiologic and pharmacologic methods can help an adoptive mother bring in a milk supply. The quantity may not be sufficient to entirely meet an infant's nutritional needs. However, for many the emotional benefits remain. There is some controversy surrounding the use of domperidone and metoclopramide for induced lactation. Herbals such as fenugreek have not been researched. Physicians can help their patients understand the current tools available to assist them with this unique endeavor.


Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice.
Crohn's disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. "Humanized" mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential.


Influence of tissue- and cell-scale extracellular matrix distribution on the mechanical properties of tissue-engineered cartilage.
The insufficient load-bearing capacity of today's tissue- engineered (TE) cartilage limits its clinical application. Generally, cartilage TE studies aim to increase the extracellular matrix (ECM) content, as this is thought to determine the load-bearing properties of the cartilage. However, there are apparent inconsistencies in the literature regarding the correlation between ECM content and mechanical properties of TE constructs. In addition to the amount of ECM, the spatial inhomogeneities in ECM distribution at the tissue scale as well as at the cell scale may affect the mechanical properties of TE cartilage. The relative importance of such structural inhomogeneities on mechanical behavior of TE cartilage is unknown. The aim of the present study was, therefore, to theoretically elucidate the influence of these inhomogeneities on the mechanical behavior of chondrocyte-agarose TE constructs. A validated non-linear fiber-reinforced poro-elastic swelling cartilage model that can accommodate for effects of collagen reinforcement and swelling by proteoglycans was used. At the tissue scale, ECM was gradually varied from predominantly localized in the periphery of the TE construct toward an ECM-rich inner core. The effect of these inhomogeneities in relation to the total amount of ECM was also evaluated. At the cell scale, ECM was gradually varied from localized in the pericellular area, toward equally distributed throughout the interterritorial area. Results from the tissue-scale model indicated that localization of ECM in either the construct periphery or in the inner core may reduce construct stiffness compared with that of constructs with homogeneous ECM. Such effects are more significant at high ECM amounts. At the cell scale, localization of ECM around the cells significantly reduced the overall stiffness, even at low ECM amounts. The compressive stiffness gradually increased when ECM distribution became more homogeneous and the osmotic swelling pressure in the interterritorial area increased. We conclude that for the same amount of ECM content in TE cartilage constructs, superior mechanical properties can be achieved with more homogeneous ECM distribution at both tissue and cell scale. Inhomogeneities at the cell scale are more important than those at the tissue scale.


Extracorporeal irradiated tumor bone: A reconstruction option in diaphyseal Ewing's sarcomas.
Limb salvage in extremity tumors is now established as an oncologically safe option without compromising long-term survival. En bloc resection followed by extracorporeal radiation and reimplantation is a biological reconstruction option in diaphyseal Ewing's sarcomas. We analyzed the results of 12 cases of diaphyseal Ewing's sarcomas treated using this modality. Between March 2006 and March 2008, 12 patients with Ewing's sarcoma underwent enbloc resection and reconstruction, with reimplantation of the sterilized tumor bone, after extracorporeal irradiation. There were eight males and four females, with a mean age of 14 years (range 2 to 22 years). The femur was the most common bone involved (n=8) followed by the tibia and the humerus (two cases each). All these patients were non-metastatic at presentation and received chemotherapy as per the existing hospital protocol. The mean length of the bone resected was 20 cm (range 11 to 25 cm). The specimen was irradiated with 50 Gy prior to reimplantation and stabilized with the host bone, using suitable internal fixation. Standard biplanar radiographs were assessed for evidence of union on the follow-up visits. The functional status was assessed using the Musculoskeletal Tumor Society Scoring system at the time of the last follow up. The mean follow up duration was 29 months (range 12 to 57 months). Two patients (17%) had early infection with graft removal, hence are excluded from any analysis of union, however they are included when analysing complications such as infection. Rest 10 cases were analyzed for bony union at the osteotomy sites. Sixteen (84%) of the 19 osteotomy sites united primarily, without any intervention. Implant failure and non-union was seen at three diaphyseal osteotomy sites. The average time for union of all osteotomy sites was 7.2 months (range 3 to 13 months).The average time for union of the metaphyseal osteotomy sites was 5.9 months (range 3 to 12 months) and of diaphyseal osteotomy sites was 8.3 months (range 4 to 13 months). The mean Musculoskeletal Tumor Society Score was 27 (range 19 to 30) with a mean of 27. Nine of the ten patients with lower limb involvement were independent ambulators without additional aids. At the time of the last review, six patients were free of disease and six patients had died from the disease. There were two recurrences around the operative site. Both were associated with disseminated disease and in both the recurrences were in the soft tissue, away from the irradiated graft. Extracorporeal irradiation is a useful, convenient technique for limb salvage in diaphyseal Ewing's sarcomas when there is reasonable residual bone stock. It is oncologically safe and has good functional results. A radiation dose of 50 Gy for sterilizing the bone ensures adequate tumor kill, while minimizing the deleterious effects on the biomechanical and biological properties of the bone. The use of appropriate implants for adequate internal fixation and supplementary bone grafting at the index surgery may help reduce the need for subsequent additional interventions to achieve union. The limitations of this procedure are that it is not applicable in tumor bones that are structurally weak and in bones with pathological fractures.


Potent bombesin receptor antagonists distinguish receptor subtypes.
To determine whether newly described bombesin (BN) receptor antagonists distinguish subtypes of BN receptors, we investigated their abilities to interact with BN receptors on esophageal muscle or pancreatic acinar tissue. For inhibition of binding of 125I-[Tyr4]BN to rat pancreatic tissue, the relative potencies were [D-Phe6]BN-(6-13)ethyl ester (5 nM) greater than Ac-gastrin-releasing peptide (GRP)-(20-26)ethyl ester (17 nM) greater than [D-Phe6,Cpa,14, psi 13-14]BN-(6-14) (40 nM) greater than [Leu14, psi 13-14]BN (0.43 microM) greater than [Tyr4,D-Phe12]BN = [D-Pro4, D-Trp7,9,10]substance P (SP)-4-11 (13 microM) greater than [Leu14, psi 9,10]BN (32 microM) greater than [D-Arg1,D-Trp7,9,Leu11]SP (70 microM). Each antagonist also inhibited binding of 125I-[Tyr4]BN or 125I-Bolton-Hunter-neuromedin B to rat esophageal tissue, and the potency of each antagonist for each tracer was similar. In comparison to rat pancreas, [D-Phe6]BN-(6-13)ethyl ester, Ac-GRP-(20-26)ethyl ester, [D-Phe6,Cpa14, psi 13-14]BN-(6-14), [Leu14, psi 13-14]BN, and [Leu14, psi 9,10]BN had a 10,000-, 2,940-, 1,425-, 122-, and 4-fold, respectively, weaker affinity for BN receptors. In contrast [Tyr4,D-Phe12]BN, [D-Pro4,D-Trp7,9,10]SP-4-11, and [D-Arg1,D-Trp7,9,Leu11]SP had a 4-, 4-, and 9-fold, respectively, higher affinity compared with pancreatic tissue. Comparison of the activity of each peptide at inhibiting the ability of equipotent concentrations of BN or neuromedin B to stimulate contraction of rat esophageal muscle demonstrated that each peptide had the same relative potencies as for inhibiting binding.(ABSTRACT TRUNCATED AT 250 WORDS)


The urgency of preparing primary care physicians to care for older people with chronic illnesses.
Population trends are driving an undeniable imperative: The United States must begin training its primary care physicians to provide higher-quality, more cost-effective care to older people with chronic conditions. Doing so will require aggressive initiatives to educate primary care physicians to apply principles of geriatrics--for example, optimizing functional autonomy and quality of life--within emerging models of chronic care. Policy options to drive such reforms include the following: providing financial support for medical schools and residency programs that adopt appropriate educational innovations; tailoring Medicare's educational subsidy to reform graduate medical education; and invoking state requirements that physicians obtain geriatric continuing education credits to maintain their licensure or to practice as Medicaid providers or medical directors of nursing homes. This paper also argues that the expertise of geriatricians could be broadened to include educational and leadership skills. These geriatrician-leaders could then become teachers in the educational programs of many disciplines. This would require changes inside and outside academic medicine.


Surgical management and its post-operative complications in congenital aural atresia.
The post-operative complications and hearing results of surgical intervention for congenital aural atresia were investigated. Seventy-five ears with congenital aural atresia were operated on for hearing loss from 1982 to 1996. Tympanoplasty was performed on 37 ears and canaloplasty on the remaining 38. Hearing improvement rates were 70.3% and 31.6%, respectively. The post-operative complications included stenosis of the created auditory canal (29.3%), deterioration of the improved hearing (21.3%) and infection (12.0%). Reoperations were performed on 6 cases for restoring hearing, 16 for stenosis and 6 for infection. Reoperative findings demonstrated that scar formation in the canal caused the stenosis of the newly formed external canal and that lateralization of the new tympanic membrane and subsequent detachment from the ossicles caused the deterioration of improved hearing. Using cartilage and pedicled skin flap prevented stenosis at the orifice of the newly formed external canal. Maintaining hearing improvement requires creating a wide ear canal using as many pedicle flaps as possible and attaching a new tympanic membrane firmly to the ossicles.


Metabolomics in chemical ecology.
Chemical ecology elucidates the nature and role of natural products as mediators of organismal interactions. The emerging techniques that can be summarized under the concept of metabolomics provide new opportunities to study such environmentally relevant signaling molecules. Especially comparative tools in metabolomics enable the identification of compounds that are regulated during interaction situations and that might play a role as e.g. pheromones, allelochemicals or in induced and activated defenses. This approach helps overcoming limitations of traditional bioassay-guided structure elucidation approaches. But the power of metabolomics is not limited to the comparison of metabolic profiles of interacting partners. Especially the link to other -omics techniques helps to unravel not only the compounds in question but the entire biosynthetic and genetic re-wiring, required for an ecological response. This review comprehensively highlights successful applications of metabolomics in chemical ecology and discusses existing limitations of these novel techniques. It focuses on recent developments in comparative metabolomics and discusses the use of metabolomics in the systems biology of organismal interactions. It also outlines the potential of large metabolomics initiatives for model organisms in the field of chemical ecology.


Assessment of Urine Proteomics in Type 1 Primary Hyperoxaluria.
Primary hyperoxaluria type 1 (PH1) and idiopathic hypercalciuria (IHC) are stone-forming diseases that may result in the formation of calcium (Ca) oxalate (Ox) stones, nephrocalcinosis, and progressive chronic kidney disease (CKD). Poorer clinical outcome in PH1 is segregated by the highest urine (Ur)-Ox (UrOx), while IHC outcomes are not predictable by UrCa. We hypothesized that differences would be found in selected Ur-protein (PRO) patterns in PH1 and IHC, compared to healthy intra-familial sibling controls (C) of PH1 patients. We also hypothesized that the PRO patterns associated with higher UrOx levels would reflect injury, inflammation, biomineralization, and abnormal tissue repair processes in PH1. Twenty four-hour Ur samples were obtained from 3 cohorts: PH1 (n = 47); IHC (n = 35) and C (n = 13) and were analyzed using targeted platform-based multi-analyte profile immunoassays and for UrOx and UrCa by biochemical measurements. Known stone matrix constituents, osteopontin, calbindin, and vitronectin were lowest in PH1 (C > IHC > PH1; p < 0.05). Ur-interleukin-10; chromogranin A; epidermal growth factor (EGF); insulin-like growth factor-1 (IGF-1), and macrophage inflammatory PRO-1α (MIP-1α) were higher in PH1 > C (p = 0.03 to p < 0.05). Fetuin A; IGF-1, MIP-1α, and vascular cell adhesion molecule-1 were highest in PH1 > IHC (p < 0.001 to p = 0.005). PH1 Ur-PROs reflected overt inflammation, chemotaxis, oxidative stress, growth factors (including EGF), and pro-angiogenic and calcification regulation/inhibition compared to the C and IHC cohorts. Many of the up- and downregulated PH1-PROs found in this study are also found in CKD, acute kidney injury, stone formers, and/or stone matrices. Further data analyses may provide evidence for PH1 unique PROs or demonstrate a poorer clinical outcome.


A mixed methods assessment of barriers to maternal, newborn and child health in gogrial west, south Sudan.
Health conditions for mothers, newborns, and children in South Sudan are among the worst worldwide. South Sudan has the highest rate of maternal mortality in the world and despite alarming statistics, few women and children in South Sudan have access to needed healthcare, especially in rural areas. The purpose of this study was to understand the barriers to maternal, newborn and child health in Gogrial West, Warrap State, South Sudan, one of the most underdeveloped states. A randomized household quantitative study and supplemental qualitative interviews were employed in 8/9 payams in Gogrial West, Warrap, South Sudan. Interviews were conducted with randomly selected female household members (n = 860) who were pregnant or had children less than 5 years of age, and men (n = 144) with a wife having these characteristics. Non-randomized qualitative interviews (n = 72) were used to nuance and add important socio-cultural context to the quantitative data. Analysis involved the estimation of weighted population means and percentages, using 95% confidence intervals and considering p-values as significant when less than 0.05, when comparisons by age, age of marriage, wife status and wealth were to be established. Most women (90.8%) and men (96.6%) did not want contraception. Only 1.2% of women aged 15-49 had met their need for family planning. On average, pregnant women presented for antenatal care (ANC) 2.3 times and by unskilled providers. Less than half of households had a mosquito net; fewer had insecticide treated nets. Recognition of maternal, newborn and child health danger signs overall was low. Only 4.6% of women had skilled birth attendants. One quarter of children had verifiable DPT3 immunization. Five percent of men and 6% of women reported forced intercourse. Overall men and women accept beatings as a norm. Barriers to care for mothers, infants and children are far more than the lack of antenatal care. Maternal, newborn and child health suffers from lack of skilled providers, resources, distance to clinics. A lack of gender equity and accepted negative social norms impedes healthy behaviors among women and children. The paucity of a peer-reviewed evidence base in the world's newest country to address the overwhelming needs of the population suggests these data will help to align health priorities to guide programmatic strategy for key stakeholders.


'I start my day by thinking about what we're going to have for dinner'--a qualitative study on approaches to food-related activities among elderly men with somatic diseases.
The aim of this study was to address the question of how older men with somatic diseases living in their own home approach the question of food-related activities (FRA). Further, any adaptations of these activities necessitated by effects of diseases and of altered life circumstances were explored. Interviews were conducted with a purposeful sample of 18 co-living and single-living men, 64-84 years old. They were diagnosed with Parkinson's disease, rheumatoid arthritis or stroke. In the analysis, a thematic framework was used. The findings revealed three food-related approaches, namely 'Cooking as a pleasure', describing joy in cooking; 'Cooking as a need', indicating no habits or skills in cooking; and 'Food is served', that is, being served meals by a partner. It was found that gender-related roles in particular, but also changed life circumstances, activity limitations, personal interests, and a wish to maintain continuity and independence, affected the men's approaches to these activities. This knowledge may be useful in attempts to facilitate and support FRA among elderly men with diseases. Health care efforts to promote FRA should preferably be individualised in respect to older men's approaches to these activities.


Nogo-B is the major form of Nogo at the floor plate and likely mediates crossing of commissural axons in the mouse spinal cord.
Using Nogo antibodies with defined binding specificity, Nogo-B, but not Nogo-A, was localized on radial glia in the floor plate of mouse embryos. The presence of Nogo-B was confirmed in Nogo-A knockout mice. In explant cultures of embryonic day (E) 11 and E12 spinal cord, blocking of NgR function with antagonist peptide NEP1-40 reduced the crossing of newly arrived commissural axons, resulting in an accumulation of growth cones in the floor plate. Analysis of growth cone morphology demonstrated an increase in size of growth cones in the floor plate after peptide treatment, which was not detected in axons growing toward the midline. In knockout embryos, midline crossing was not affected by absence of Nogo-A. In co-culture experiments using collagen gel, floor plate showed a strong inhibitory effect on the extension of post-commissural neurites from the spinal cord. This effect was abolished by NEP1-40, and was observed neither in pre-commissural neurites, nor in post-commissural neurites grown with floor plate derived from Nogo-A knockout embryo. Furthermore, western blot analysis of conditioned medium from floor plates showed a truncated form of Nogo with molecular weight of 37 kDa, which could mediate the diffusible effect to axon growth. We conclude that Nogo-B is expressed in the floor plate of mouse embryo, which probably mediates axon crossing in the spinal cord by repelling axons out of the midline when they start upregulate NgR. Nogo acts on axon growth not only through a contact-mediated mechanism, but also through a diffusible mechanism.


17β-Estradiol-Induced Synaptic Rearrangements Are Accompanied by Altered Ectonucleotidase Activities in Male Rat Hippocampal Synaptosomes.
17β-Estradiol (E2) rapidly, by binding to membrane estrogen receptors, activates cell signaling cascades which induce formation of new dendritic spines in the hippocampus of males as in females, but the interaction with other metabolic processes, such as extracellular adenine nucleotides metabolism, are currently unknown. Extracellular adenine nucleotides play significant roles, controlling excitatory glutamatergic synapses and development of neural circuits and synaptic plasticity. Their precise regulation in the synaptic cleft is tightly controlled by ecto-nucleoside triphosphate diphosphohydrolase (NTPDase)/ecto-5'-nucleotidase (eN) enzyme chain. Therefore, we sought to clarify whether a single systemic injection of E2 in male rats is accompanied by changes in the expression of the pre- and postsynaptic proteins and downstream kinases linked to E2-induced synaptic rearrangement as well as alterations in NTPDase/eN pathway in the hippocampal synaptosomes. Obtained data showed activation of mammalian target of rapamycin and upregulation of key synaptic proteins necessary for spine formation, 24 h after systemic E2 administration. In E2-mediated conditions, we found downregulation of NTPDase1 and NTPDase2 and attenuation of adenine nucleotide hydrolysis by NTPDase/eN enzyme chain, without changes in NTPDase3 properties and augmentation of synaptic tissue-nonspecific alkaline phosphatase (TNAP) activity. Despite reduced NTPDase activities, increased TNAP activity probably prevents toxic accumulation of ATP in the extracellular milieu and also hydrolyzes accumulated ADP due to unchanged NTPDase3 activity. Thus, our initial evaluation supports idea of specific roles of different ectonucleotidases and their coordinated actions in E2-mediated spine remodeling and maintenance.


Subcortical amygdala pathways enable rapid face processing.
Human faces may signal relevant information and are therefore analysed rapidly and effectively by the brain. However, the precise mechanisms and pathways involved in rapid face processing are unclear. One view posits a role for a subcortical connection between early visual sensory regions and the amygdala, while an alternative account emphasises cortical mediation. To adjudicate between these functional architectures, we recorded magnetoencephalographic (MEG) evoked fields in human subjects to presentation of faces with varying emotional valence. Early brain activity was better explained by dynamic causal models containing a direct subcortical connection to the amygdala irrespective of emotional modulation. At longer latencies, models without a subcortical connection had comparable evidence. Hence, our results support the hypothesis that a subcortical pathway to the amygdala plays a role in rapid sensory processing of faces, in particular during early stimulus processing. This finding contributes to an understanding of the amygdala as a behavioural relevance detector.


Correlates, comorbidities, and suicidal tendencies of problematic game use in a national wide sample of Korean adults.
This study aimed to investigate the prevalence, correlates, comorbidities, and suicidal tendencies of problematic game use in a nationally representative sample of Korean adults. Of the 6022 subjects who participated in the 2011 Korean Epidemiologic Catchment Area study and completed the Composite International Diagnostic Interview 2.1, 1397 game users were evaluated for problematic game use using 9-item DSM-5 proposed criteria for Internet gaming disorder. Respondents who responded "yes" to five or more of the nine DSM-5 criteria were considered as problematic game users and the reminders were considered as normal game users. 4.0% (56/1397) of game users were classified as a problematic game user. Problematic game users were more likely to be in younger age group and live in urban area compared with normal game user. Problematic game use was positively associated with several psychiatric disorders including nicotine use disorder, depressive disorder, and anxiety disorder, but not associated with alcohol use disorder and obsessive-compulsive disorder, after adjusting for age, sex, and residential area. Problematic game use was significantly and positively associated with suicide plans, after controlling for psychiatric disorders as well as socio-demographic factors. Problematic game use is relatively prevalent in Korean adult population and highly comorbid with other psychiatric disorders and suicidality. Therefore, preventive strategy for problematic game use is needed for game users who were more likely to be addicted such as young adults in urban area, and mental health screening and appropriate treatment are needed for individuals with problematic game use.


Essential Items for Structured Reporting of Rectal Cancer MRI: 2016 Consensus Recommendation from the Korean Society of Abdominal Radiology.
High-resolution rectal MRI plays a crucial role in evaluating rectal cancer by providing multiple prognostic findings and imaging features that guide proper patient management. Quality reporting is critical for accurate effective communication of the information among multiple disciplines, for which a systematic structured approach is beneficial. Existing guides on reporting of rectal MRI are divergent on some issues, largely reflecting the differences in overall management of rectal cancer patients between the United States and Europe. The Korean Society of Abdominal Radiology (KSAR) study group for rectal cancer has developed an expert consensus recommendation regarding essential items for structured reporting of rectal cancer MRI using a modified Delphi method. This recommendation aims at presenting an up-to-date, evidence-based, practical, structured reporting template that can be readily adopted in daily clinical practice. In addition, a thorough explanation of the clinical and scientific rationale underlying the reporting items and their formats is provided. This KSAR recommendation may serve as a useful tool to help achieve more standardized optimal care for rectal cancer patients using rectal MRI.


A new metrics for countries' fitness and products' complexity.
Classical economic theories prescribe specialization of countries industrial production. Inspection of the country databases of exported products shows that this is not the case: successful countries are extremely diversified, in analogy with biosystems evolving in a competitive dynamical environment. The challenge is assessing quantitatively the non-monetary competitive advantage of diversification which represents the hidden potential for development and growth. Here we develop a new statistical approach based on coupled non-linear maps, whose fixed point defines a new metrics for the country Fitness and product Complexity. We show that a non-linear iteration is necessary to bound the complexity of products by the fitness of the less competitive countries exporting them. We show that, given the paradigm of economic complexity, the correct and simplest approach to measure the competitiveness of countries is the one presented in this work. Furthermore our metrics appears to be economically well-grounded.


In vitro transport of a fluorescent nuclear protein and exclusion of non-nuclear proteins.
An in vitro system was developed that provides a quick microscopic assay for nuclear transport. The assay uses an extract of Xenopus eggs, normal or synthetic nuclei, and a fluorescently labeled nuclear protein, nucleoplasmin. This in vitro system accurately mimics in vivo nuclear transport, both in exclusivity and in the amount of accumulation observed (up to 17-fold). Selective accumulation of fluorescent nucleoplasmin is observed microscopically within 30 min with rat liver nuclei, Xenopus embryonic nuclei, regrown Xenopus sperm nuclei, or nuclei reconstituted in vitro from bacteriophage lambda DNA. This transport requires the signal domain of nucleoplasmin. Furthermore, the ability of nuclei to accumulate nucleoplasmin directly correlates with their ability to exclude the fluorescent non-nuclear proteins, FITC-immunoglobulin and phycoerythrin. An active transport model would predict that nuclear transport be temperature- and energy-dependent and that inhibition of transport by either low temperature or energy depletion would be reversible. Both predictions were confirmed in our system. Nucleoplasmin accumulation increases with temperature, while the protein is completely excluded at 0 degrees C. The effects of low temperature are reversible. As found for 125I-labeled nucleoplasmin (Newmeyer, D. D., J. M. Lucocq, T. R. Bürglin, and E. M. De Robertis, 1986, EMBO (Eur. Mol. Biol. Organ.) J., 5:501-510), transport of fluorescent nucleoplasmin is inhibited by ATP depletion. This effect is reversed by later ATP addition. Under ATP-depleted conditions non-nuclear proteins continue to be excluded. These results argue for a direct role of ATP in transport rather than for a simple role in preserving envelope integrity. In a first step towards defining the minimum requirements for a transport medium, egg extracts were depleted of membrane vesicles. Membrane-depleted extracts neither support transport nor maintain the integrity of the nuclear envelope.


Contribution of vagal pathways to the renal responses to head-out immersion in the nonhuman primate.
Studies were carried out to determine the contribution of cardiopulmonary receptors to the renal responses to head-out water immersion in the nonhuman primate. Immersion to the suprasternal notch was associated with significant increases in central venous pressure, urine flow, and sodium excretion. The increased sodium excretion was due primarily to a significant increase in the percent of the filtered sodium excreted. Deoxycorticosterone acetate (DOCA) and antiduretic hormone (ADH) had no substantial effects on these responses. The finding of a vasopressin-resistant hyposthenuria is consistent with the natriuresis of immersion being due, at least in part, to a decrease in sodium reabsorption proximal to the diluting segment, possibly the proximal tubule. Bilateral cervical vagotomy had no substantial influence on the renal responses to immersion, demonstrating that cardiopulmonary receptors whose axons traverse the vagus nerves are not necessary for the homeostatic adjustments to central hypervolemia in the primate. Since the renal and cardiovascular responses of the primate to immersion are essentially the same as those seen in man, it is probable that vagal pathways also are not necessary in man. However, it is possible that sympathetic afferents are involved in the natriuresis observed in the primate during immersion.


A national report of nursing home information technology: year 1 results.
To provide a report on year 1 results of a national study investigating nursing home information technology (IT) adoption, called IT sophistication. A reliable and valid survey was used to measure IT sophistication. The target goal was 10% from each state in the United States, 1570 nursing homes. A random sample of homes from each state was recruited from Nursing Home Compare. The team reached 2627 nursing home administrators, among whom 1799 administrators agreed to participate and were sent a survey. A total of 815 surveys were completed (45.3% response rate), which was below the goal. Facilities in the participating sample have similar demographic characteristics (ownership, total population in a location, and bed size) to the remaining homes not participating. There are greater IT capabilities in resident care and administrative activities, less in clinical support. The extent of use of these capabilities appears to be highest in administrative activities and lowest in clinical support. IT in resident care appears to be the most integrated with internal and external stakeholders. IT capabilities appear to be greater than IT extent of use in all health domains, with the greatest difference in resident care. National evaluations of nursing home IT are rare. Measuring trends in IT adoption in a nationally representative sample provides meaningful analytics that could be more useful for policy makers and nursing home leaders in the future. Discovering national baseline assessments is a first step toward recognizing nursing home trends in IT adoption.


Species heterogeneity in macrophage expression of the CD4 antigen.
The CD4 antigen is expressed on T cells of all mammalian species examined and appears to play an important role in the response of T cells to antigen. In humans, the molecule acts as a receptor for the AIDS virus. Previous studies have demonstrated that M phi in the rat and human also express the CD4 antigen, which is indistinguishable from that on T cells. In this paper we demonstrate by FACS analysis, Northern blot hybridization, and immunoperoxidase labeling that, in striking contrast to the rat and human, mouse M phi do not express the CD4 (L3T4) antigen. This species heterogeneity indicates that T cells and M phi regulate CD4 antigen expression independently and that CD4 may not be essential for M phi function.


Quantification of thermotolerant Campylobacter in Swiss water treatment plants, by real-time quantitative polymerase chain reaction.
A total of 49 wastewater samples from 23 different wastewater treatment plants (WWTPs) were analyzed using real-time quantitative polymerase chain reaction for the presence and quantity of thermotolerant campylobacters. Thermotolerant campylobacters were detected in 87.5% (21/24) and 64% (16/25) of untreated and treated wastewater samples, respectively. Their concentration was sufficiently high to be quantified in 20.4% (10/49) of the samples. In these samples, the concentration ranged from 68,000 to 2,292,000 cells/L in untreated wastewater and from 10,800 to 28,000 cells/L in treated water. We conclude that thermotolerant campylobacters present a health hazard for workers at WWTPs in Switzerland.


Stem cells primed for action: polycomb repressive complexes restrain the expression of lineage-specific regulators in embryonic stem cells.
Stem cells are characterised by a capacity to self renew and generate progeny capable of differentiating along several defined lineage paths. Embryonic Stem (ES) cells are derived from the inner cell mass (ICM) of early-stage embryos and can contribute to all tissues of the developing embryo. Discovering how ES cell pluripotency and lineage induction is achieved is important for understanding normal development and for successfully applying stem cell-based therapies. A series of recent studies have shown that the chromatin profile of ES cells is unusual and have revealed a critical role for the Polycomb Repressive Complexes (PRCs) in maintaining pluripotency. In human and mouse ES cells many genes that encode transcription factors that are required for lineage specification bind PRC2 and carry bivalent (or opposing) histone signatures, being enriched for conventional indicators of active chromatin such as acetylated H3K9 and methylated H3K4, while lying within domains of repressive trimethylated H3K27. Mutant ES cells that lack H3K27 methylation inappropriately expressed these genes showing that PRC2 represses lineage-specific gene programs in ES cells. Here we discuss the implications of these new discoveries and explore the interdependence of PRC1 and PRC2 in regulating lineage-specific gene expression in ES cells.


High performance RO membranes for desalination and wastewater reclamation and their operation results.
Reverse osmosis (RO) membrane is one of the most powerful tools for solving the global water crisis, and is used in a variety of water treatment scenes such as drinking water purification, waste-water treatment, boiler feed water production, ultra pure water production for semiconductor industry, etc. The desired performance of RO membrane varies according to quality of feed water being treated, and Toray has been developing RO membranes with suitable characteristic for each operating condition. RO membranes for seawater desalination and wastewater reclamation are especially regarded as most promising targets. Recently, high boron removal and energy saving RO membrane for seawater desalination and low fouling RO membrane for wastewater reclamation have been developed. In this paper, the prospect of attaining these renovative RO membrane, and furthermore, job references will be discussed.


Characterization of Adult Heart Rate Responses During Recreational Skateboarding at Community Skateparks.
Youth participating in recreational skating at community skate parks attain exercise intensities and durations that are comparable with the CDC's exercise recommendations for cardiovascular fitness for their age group. However, it is currently unclear if adults who skateboard in the same environment also achieve the recommended intensities and durations for cardiovascular fitness. Therefore, the purpose of this study was to test the hypothesis that skateboarding would elicit heart rates and durations consistent with the CDC's recommendations for cardiovascular fitness in adults. Fifty-five subjects between ages 18-55 were recruited from six community skateparks for this study. Subjects completed a questionnaire and were instrumented with a Polar V800 heart rate receiver on the left wrist and an H7 Bluetooth heart rate transmitter around the chest below the pectoralis major. Participants were instructed to engage in a typical skateboarding session on their own board with the duration and intensity of activity to be determined by the participant. The mean age of the participants was 27.4 ± 8.5 years, and participants reported skateboarding at a community skate park a mean of 3.1 ± 1.8 days/week. Participants had a mean heart rate of 138.2 ± 21.9 beats per minute (71.7% of age predicted maximum), skated for 65.5 ± 36.2 minutes, and traveled 4.56 ± 4.5 kilometers. Subjects spent 70% of their total duration at moderate-intensity or above and 30% within the low, and below low-intensity range. Results from this study suggest that adults participating in recreational skateboarding in community skateparks achieve the CDC's exercise recommendations for cardiovascular fitness. These findings may have implications for community skatepark design and professional training programs for adult skateboarding athletes.


Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures.
Proteopathic brain lesions are a hallmark of many age-related neurodegenerative diseases including synucleinopathies and develop at least a decade before the onset of clinical symptoms. Thus, understanding of the initiation and propagation of such lesions is key for developing therapeutics to delay or halt disease progression. Alpha-synuclein (αS) inclusions were induced in long-term murine and human slice cultures by seeded aggregation. An αS seed-recognizing human antibody was tested for blocking seeding and/or spreading of the αS lesions. Release of neurofilament light chain (NfL) into the culture medium was assessed. To study initial stages of α-synucleinopathies, we induced αS inclusions in murine hippocampal slice cultures by seeded aggregation. Induction of αS inclusions in neurons was apparent as early as 1week post-seeding, followed by the occurrence of microglial inclusions in vicinity of the neuronal lesions at 2-3 weeks. The amount of αS inclusions was dependent on the type of αS seed and on the culture's genetic background (wildtype vs A53T-αS genotype). Formation of αS inclusions could be monitored by neurofilament light chain protein release into the culture medium, a fluid biomarker of neurodegeneration commonly used in clinical settings. Local microinjection of αS seeds resulted in spreading of αS inclusions to neuronally connected hippocampal subregions, and seeding and spreading could be inhibited by an αS seed-recognizing human antibody. We then applied parameters of the murine cultures to surgical resection-derived adult human long-term neocortical slice cultures from 22 to 61-year-old donors. Similarly, in these human slice cultures, proof-of-principle induction of αS lesions was achieved at 1week post-seeding in combination with viral A53T-αS expressions. The successful translation of these brain cultures from mouse to human with the first reported induction of human αS lesions in a true adult human brain environment underlines the potential of this model to study proteopathic lesions in intact mouse and now even aged human brain environments.


Selective Oxidation of Hydrogen Sulfide to Sulfur Using Vanadium Oxide Supported on Porous Clay Heterostructures (PCHs) Formed by Pillars Silica, Silica-Zirconia or Silica-Titania.
Vanadium oxide (V₂O₅) species has been supported on different porous clay heterostructures (with silica pillars, silica-zirconia with a molar ratio Si/Zr = 5 and silica-titania with a molar ratio Si/Ti = 5) by wetness incipient method. All catalysts were characterized by X-ray diffraction (XRD), N₂ adsorption-desorption at -196 °C, NH₃ thermoprogrammed desorption (NH₃-TPD), Raman spectroscopy, diffuse reflectance UV-Vis and X-ray photoelectron spectroscopy (XPS). After that, the catalytic activity of the vanadium-based catalysts was evaluated in the selective oxidation of H₂S to elemental sulfur. The catalytic data show that both the activity and the catalytic stability increase with the vanadium content, obtaining the highest conversion values and sulfur yield for the catalysts with vanadium content of 16 wt.%. The comparison among all supports reveals that the incorporation of TiO₂ species in the pillars of the PCH improves the resistance to the deactivation, attaining as best results a H₂S conversion of 89% for SiTi-PCH-16V catalyst and elemental sulfur is the only compound detected by gas chromatography.


Scaled Subprofile Modeling and Convolutional Neural Networks for the Identification of Parkinson's Disease in 3D Nuclear Imaging Data.
Over the last years convolutional neural networks (CNNs) have shown remarkable results in different image classification tasks, including medical imaging. One area that has been less explored with CNNs is Positron Emission Tomography (PET). Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is a PET technique employed to obtain a representation of brain metabolic function. In this study we employed 3D CNNs in FDG-PET brain images with the purpose of discriminating patients diagnosed with Parkinson's disease (PD) from controls. We employed Scaled Subprofile Modeling using Principal Component Analysis as a preprocessing step to focus on specific brain regions and limit the number of voxels that are used as input for the CNNs, thereby increasing the signal-to-noise ratio in our data. We performed hyperparameter optimization on three CNN architectures to estimate the classification accuracy of the networks on new data. The best performance that we obtained was accuracy = 0.86 and area under the receiver operating characteristic curve (AUC ROC) = 0.94 on the test set. We believe that, with larger datasets, PD patients could be reliably distinguished from controls by FDG-PET scans alone and that this technique could be applied to more clinically challenging tasks, like the differential diagnosis of neurological disorders with similar symptoms, such as PD, Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA).


Estimating the total genetic diversity of a spatial field population from a sample and implications of its dependence on habitat area.
The total genetic diversity of a species is a key factor in its persistence and conservation. Because realistic sample sizes are far smaller than the total population, it is impractical to exhaustively characterize diversity of most populations. Here, we demonstrate the possibility of calculating the genetic diversity of a spatial population from a sample using genealogical models. We trace the history of a population by simulating the locations of the ancestors of a particular sample of the population backwards in time. We use this method to estimate the genetic diversity of the global population of Pseudomonas bacteria. The same results are obtained whether using a global sample or a subsample restricted to a particular geographic region (California). The results are also validated by comparing additional predictions of the model to the data. Furthermore, we use these results to show that the level of genetic diversity in a population depends strongly on the size of its habitat, much more strongly than does biodiversity as measured by the number of species. The strong dependence of diversity on habitat area has significant implications for conservation strategies.


The promise and failures of epigenetic therapies for cancer treatment.
Genetic mutations and gross structural defects in the DNA sequence permanently alter genetic loci in ways that significantly disrupt gene function. In sharp contrast, genes modified by aberrant epigenetic modifications remain structurally intact and are subject to partial or complete reversal of modifications that restore the original (i.e. non-diseased) state. Such reversibility makes epigenetic modifications ideal targets for therapeutic intervention. The epigenome of cancer cells is extensively modified by specific hypermethylation of the promoters of tumor suppressor genes relative to the extensive hypomethylation of repetitive sequences, overall loss of acetylation, and loss of repressive marks at microsatellite/repeat regions. In this review, we discuss emerging therapies targeting specific epigenetic modifications or epigenetic modifying enzymes either alone or in combination with other treatment regimens. The limitations posed by cancer treatments elicit unintended epigenetic modifications that result in exacerbation of tumor progression are also discussed. Lastly, a brief discussion of the specificity restrictions posed by epigenetic therapies and ways to address such limitations is presented.


Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.


Positive parenting approaches and their association with child eating and weight: A narrative review from infancy to adolescence.
Parents play a critical role in the development of children's eating behaviours and weight status, serving as providers, models and regulators of the food environment. Many research reviews have focused on the robust body of evidence on coercive control in feeding: how parenting practices such as restriction and pressure to eat increase children's risk for developing undesirable eating behaviours and unhealthy weight outcomes. Fewer reviews adopt a strengths-based perspective focusing on the ways that parents can actively support the development of healthy eating behaviours and weight trajectories. Emerging research on such positive parenting styles and practices offers solutions beyond the avoidance of coercive control, as well as opportunities to highlight parallels between research on food parenting and the broader, well-established developmental literature on positive parenting. The focus of this review is to summarize what is known regarding benefits of positive parenting styles and practices for child eating and weight outcomes and discuss recommendations for future research. Current evidence supports starting with responsive feeding and parenting during infancy and incorporating structure and limit setting in early childhood, with monitoring and mealtime structure remaining important during middle childhood and adolescence. Areas for future research include: (1) further examination of the implications of identified food parenting practices and styles among diverse groups and caregivers; (2) increased consideration of child factors (eg, temperament) as moderators or mediators; and (3) further clarification of the relationship between general parenting and food parenting.


Efficient luminescent solar cells based on tailored mixed-cation perovskites.
We report on a new metal halide perovskite photovoltaic cell that exhibits both very high solar-to-electric power-conversion efficiency and intense electroluminescence. We produce the perovskite films in a single step from a solution containing a mixture of FAI, PbI2, MABr, and PbBr2 (where FA stands for formamidinium cations and MA stands for methylammonium cations). Using mesoporous TiO2 and Spiro-OMeTAD as electron- and hole-specific contacts, respectively, we fabricate perovskite solar cells that achieve a maximum power-conversion efficiency of 20.8% for a PbI2/FAI molar ratio of 1.05 in the precursor solution. Rietveld analysis of x-ray diffraction data reveals that the excess PbI2 content incorporated into such a film is about 3 weight percent. Time-resolved photoluminescence decay measurements show that the small excess of PbI2 suppresses nonradiative charge carrier recombination. This in turn augments the external electroluminescence quantum efficiency to values of about 0.5%, a record for perovskite photovoltaics approaching that of the best silicon solar cells. Correspondingly, the open-circuit photovoltage reaches 1.18 V under AM 1.5 sunlight.


The effects of demographic change on disease transmission and vaccine impact in a household structured population.
The demographic structure of populations in both more developed and less developed countries is changing: increases in life expectancy and declining fertility have led to older populations and smaller households. The implications of these demographic changes for the spread and control of infectious diseases are not fully understood. Here we use an individual based model with realistic and dynamic age and household structure to demonstrate the marked effect that demographic change has on disease transmission at the population and household level. The decline in fertility is associated with a decrease in disease incidence and an increase in the age of first infection, even in the absence of vaccination or other control measures. Although large households become rarer as fertility decreases, we show that there is a proportionate increase in incidence of disease in these households as the accumulation of susceptible clusters increases the potential for explosive outbreaks. By modelling vaccination, we provide a direct comparison of the relative importance of demographic change and vaccination on incidence of disease. We highlight the increased risks associated with unvaccinated households in a low fertility setting if vaccine behaviour is correlated with household membership. We suggest that models that do not account for future demographic change, and especially its effect on household structure, may potentially overestimate the impact of vaccination.


Dynamic light scattering study of biaxial ordering in a thermotropic liquid crystal.
Dynamic light scattering from orientational order fluctuations in a liquid crystalline tetrapode reveals successive, weakly first-order isotropic to uniaxial and uniaxial to biaxial nematic phase transitions. The order parameter relaxation rates exhibit temperature dependences consistent with Landau-de Gennes mean field theory. Combined with previous evidence of a second-order uniaxial-biaxial transition in a closely related tetrapode, the present study supports the existence of a nematic-nematic tricritical point in thermotropic liquid crystals.


A Current Estimation of the Early Risk of Stroke after Transient Ischemic Attack: A Systematic Review and Meta-Analysis of Recent Intervention Studies.
Recent studies have demonstrated that there is a decrease in the risk of subsequent stroke after transient ischemic attack (TIA) when urgent care (UC) is administered. However, no meta-analysis has been developed with contemporaneous TIA studies. We perform a systematic review and a meta-analysis to establish the risk of early stroke recurrence (SR) considering data from studies that offered UC to TIA patients. We searched for studies, without language restriction, from January 2007 to January 2015 according to PRISMA guidelines. We included studies with TIA patients who underwent UC and reported the proportion of SR at 90 days. We excluded studies that were centered on less than 100 patients and cohorts including both stroke and TIA, if stroke risk after TIA was not described. For its relevance, we included the TIAregistry.org study published in 2016. We performed both fixed and random effects meta-analyses to determine SR and assess sources of heterogeneity. From 4,103 identified citations, we selected 15 papers that included 14,889 patients. There was great variation in terms of the number of patients included in each study, ranging from 115 to 4,160. Seven studies were TIA clinic based. The mean age and the percentage of men were similar among studies, ranging from 62.4 to 73.1 years and 45.1-62%, respectively. The reported risk of stroke ranged from 0 to 1.46% 2 days after TIA (9 studies included), 0-2.55% 7 days after TIA (11 studies included), 1.91-2.85% 30 days after TIA (4 studies included), and 0.62-4.76% 90 days after TIA (all studies included). The pooled stroke risk was 3.42% (95% CI 3.14-3.74) at 90 days, 2.78% (95% CI 2.47-3.12) at 30 days, 2.06% (95% CI 1.83-2.33) at 7 days and 1.36% (95% CI 1.15-1.59) at 2 days. Although we did not find statistically significant heterogeneity in SR among studies, those with a higher proportion of patients with motor weakness had a significantly higher risk of SR. No statistically significant association was observed between TIA clinic management and SR. The pooled early SR is lower than in previous meta-analyses and homogeneous for all studies with an urgent assessment and management strategy regardless of vascular risk factors and clinical characteristics. Therefore, the best setting for TIA management can be individualized for each center.


Cryptococcus neoformans variety gattii.
Cryptococcus neoformans var. gattii is emerging as a primary human pathogen which is distinct genetically and biochemically from C. neoformans var. neoformans. There is increasing evidence that it should be reclassified as a separate species within the Tremellales. In nature, C. n. var. gattii has been consistently isolated from decaying wood in hollows of species of the red gum group of eucalyptus trees (Eucalyptus ser. Exsertae Blakely). The role that trees play in the life-cycle of C. n. var. gattii is not known, but its association with decaying wood is suggestive of an endophytic existence, in common with other wood-rot fungi. Despite the demonstration in the laboratory of sexual reproduction between mating types oc and a of F. neoformans var. gattii, this has not been demonstrated in nature. Human cryptococcosis develops following environmental exposure and inhalation of the infectious propagule. Whether this is the basidiospore or dessicated yeast form is uncertain. The major risk factor for development of disease appears to be exposure, though there is indirect evidence that unidentified host factors may contribute to the relatively high incidence of cryptococcosis in Australian Aboriginals. The rarity of cryptococcosis due to C. n. var. gattii in immunocompromised patients remains unexplained. Virulence determinants of C. neoformans are currently the subject of intensive investigation, especially in C. n. var. neoformans. The best-characterized, major, virulence determinants in this variety, the polysaccharide capsule, products of the laccase enzyme pathway and ability to grow at physiological temperatures, contribute to its survival in the host. They are also present in C. n. var. gattii. A potential determinant of tissue invasion, secreted phospholipase B, is produced in vitro and in vivo by C. n. var. gattii. This enzyme has now been confirmed to play a role in the virulence of C. neoformans serotype A. Disease caused by C. n. var. gattii is distinguished from that due to C. n. var. neoformans by an increased incidence of cryptococcomas in lung and brain, increased neurological morbidity and a slower response to antifungal therapy. The difference in clinical presentation is predominantly due to the effect of underlying immunocompromise in patients infected with C. n. var. neoformans.


Bridges to excellence quality indicators in inflammatory bowel disease (IBD): differences between IBD and non-IBD gastroenterologists.
The American Gastroenterology Association (AGA) Bridges to Excellence (BTE) Inflammatory Bowel Disease (IBD) Care Recognition program encourages clinicians to develop a superior quality of care in the treatment of IBD. We evaluated adherence to BTE measures in the care of IBD patients among IBD and non-IBD gastrointestinal physicians at a tertiary care hospital. We performed a retrospective chart analysis of IBD patients who had received care at our center between January 2013 and March 2015. The patients were divided into two groups: a. care provided by an IBD-trained physician with more than 50% of their practice dedicated to IBD; and b. care provided by a non-IBD gastrointestinal physician. Data collected included baseline patient characteristics and eight BTE measures. Overall adherence to BTE measures and average scores as per the AGA 100 point scale were evaluated and compared between the two groups. A total of 325 IBD patients met the inclusion criteria and were included in the analysis. Of these, 216 patients received care from an IBD physician. Patients managed by IBD physicians were younger and had more severe disease. Both physician groups scored above the recommended score of 60. IBD physicians had a higher average score on the AGA 100 point scale (73.9 vs 66.3, P=0.001). Overall adherence to BTE quality measures was higher for IBD physicians compared to non-IBD physicians (71.8% vs. 58.8%, P value: 0.001). Both IBD and non-IBD physicians exceeded the AGA recommended score of 60 on the BTE measures at our center. IBD physicians perform better overall on BTE quality measures compared to non-IBD physicians.


Reconstruction of three-dimensional refractive index fields from multidirectional interferometric data.
Numerical and analytical techniques are presented that allow three-dimensional, asymmetric, refractive index fields to be reconstructed from optical pathlength measurements, which can be obtained using multidirectional holographic interferometry. Analytical reconstruction techniques that have been used in radioaptronomy and electron microscopy for a number of years, and recently in interferometry, are presented in the context of interferometric applications in the refractionless limit. These techniques require that optical pathlength data be collected over a 180 degrees angle of view. The required pathlength sampling rate is discussed. An efficient numerical procedure is developed for direct inversion of the data. Several numerical techniques are developed that do not require that data be collected over a full 180 degrees angle of view. All such techniques require redundant data to achieve accurate reconstructions. The required degree of redundancy increases as the angle of view decreases. Numerical simulations using six different reconstruction techniques indicate that with a 180 degrees angle of view, all are capable of providing accurate reconstructions. Four of the techniques were used to analyze simulated interferometric data recorded over an angle of view of less than 180 degrees . Examples of reasonably accurate reconstructions using data with angles of view as low as 45 degrees are presented.


Neuropeptide Y and cannabinoids interaction in the amygdala after exposure to shock and reminders model of PTSD.
Modulation of cannabinoid and neuropeptide Y (NPY) receptors may offer therapeutic benefits for post-traumatic stress disorder (PTSD). In this study, we aimed to investigate the functional interaction between these systems in the basolateral amygdala (BLA) in a rat model of PTSD. Rats were exposed to the shock and reminders model of PTSD and tested for hyper arousal/PTSD- and depression-like behaviors 3 weeks later. Immediately after shock exposure rats were microinjected into the BLA with URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH) that increases the levels of the endocannabinoid anandamide or with the NPY1 receptor agonist Leu31,Pro34-NPY (Leu). Intra-BLA URB597 prevented the shock/reminders-induced PTSD- behaviors (extinction, startle) and depression-behaviors (despair, social impairments). These preventing effects of URB597 on PTSD- and depression-like behaviors were shown to be mostly mediated by cannabinoid CB1 and NPY1 receptors, as they were blocked when URB597 was co-administered with a low dose of a CB1 or NPY1 receptor antagonist. Similarly, intra-BLA Leu prevented development of all the behaviors. Interestingly, a CB1 antagonist prevented the effects of Leu on despair and social behavior, but not the effects on extinction and startle. Moreover, exposure to shock and reminders upregulated CB1 and NPY1 receptors in the BLA and infralimbic prefrontal cortex and this upregulation was restored to normal with intra-BLA URB597 or Leu. The findings suggest that the functional interaction between the eCB and NPY1 systems is complex and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid and NPY systems for stress-related diseases.


Cigarette smoking and protection from Parkinson's disease: false association or etiologic clue?
We reviewed 46 published reports associating cigarette smoking and Parkinson's disease. Although the majority indicated an approximate halving of smoking frequency in persons with Parkinson's disease, many observers have suggested that the effect could be a spurious result. That the association may be real is suggested by at least six observations: (1) the consistency of findings between independent studies of different design, conducted by different investigators, in different nations, over 35 years; (2) the association's predominance and strength in prospective studies; (3) the apparent detection of a dose-response relation; (4) the inability to explain the association by confounding variables; (5) the flaws in certain arguments against the association's validity; and (6) the identification of a similar association, of similar magnitude, between smoking and reduced occurrence of Alzheimer's disease. A protective association of cigarette smoking for Parkinson's disease may constitute an important etiologic clue.


Antibody-resistant mutants of Borrelia burgdorferi: in vitro selection and characterization.
We used polyclonal antisera and monoclonal antibodies (mAbs) to inhibit the growth of clonal populations of two strains of Borrelia burgdorferi, the Lyme disease agent, and thereby select for antibody-resistant mutants. mAbs were directed at the outer membrane proteins, OspA or OspB. Mutants resistant to the growth-inhibiting properties of the antibodies were present in the populations at frequencies ranging from 10(-5) to 10(-2). The several escape variants that were examined were of four classes. Class I mutants were resistant to all mAbs; they lacked OspA and OspB and the linear plasmid that encodes them. Two other proteins were expressed in larger amounts in class I mutants; mAbs to these proteins inhibited the mutant but not the wild-type cells. Class II mutants were resistant to some but not all mAbs; they had truncated OspA and/or OspB proteins. Class III mutants were resistant only to the selecting mAb; they had full-length Osp proteins that were not bound by the selecting antibody in Western blots. In two class III mutants resistant to different anti-OspA mAbs, missense mutations were demonstrated in the ospA genes. Class IV mutants were likewise resistant only to selecting antibody, but in this case the selecting antibody still bound in Western blots.


Socioeconomic status and cervical cancer survival among older women: findings from the SEER-Medicare linked data cohorts.
Tumor stage, age, and cell type are well-characterized predictors for cervical cancer survival; socioeconomic factors may also play an important role. The purpose of this study is to estimate cervical cancer survival by socioeconomic indicators and race/ethnicity among elderly women diagnosed with cervical cancer. We studied 1251 women with cervical cancer aged 65 or older, identified between 1992 and 1999 from the Surveillance, Epidemiology, and End Results [SEER]-Medicare linked data. All women had similar access to care through Medicare fee-for-services insurance. A composite measure of socioeconomic status was created using census tract level data for poverty, education, and income. Cox proportional hazard modeling was used for all-cause and cervical cancer-specific survival analysis. Increased age (P < 0.0001) and advanced tumor stage (<0.0001) were associated with poorer all-cause and cervical cancer-specific survival. After adjustment for age, stage, and treatment, increased co-morbidity scores and having non-squamous cervical cancer were associated with poorer all-cause survival (P < 0.001). After adjusting for confounders, women receiving hysterectomy vs. no surgery or any treatment had significantly better all-cause and cervical cancer-specific survival. Socioeconomic factors were not associated with either all-cause (P for trend = 0.79) or cervical cancer-specific (P for trend = 0.81) survival. No racial/ethnic differences in all-cause or cervical cancer-specific survival were observed after adjusting for socioeconomic factors. Among women with similar access to care, neither minority race/ethnicity nor poorer socioeconomic status were associated with poorer survival in this large sample of older women diagnosed with invasive cervical cancer. Presence of co-morbid conditions and treatment were important predictors of cervical cancer survival.


Development and optimization of a Q-RT PCR method to quantify CYP19 mRNA expression in testis of male adult Xenopus laevis: comparisons with aromatase enzyme activity.
Due to limitations of the currently used enzymatic assays, it is difficult to determine aromatase activity in testicular tissue of amphibians. Quantitative reverse transcription polymerase chain reaction (Q-RT PCR) is a sensitive and reliable technique to detect low amounts of mRNA for specific genes. This study was designed to develop and optimize a SYBR Green I-based Q-RT PCR method to quantify CYP19 mRNA in testicular tissue from male Xenopus laevis. Four quantification methods for measuring CYP19 mRNA expression were compared. The established test system proved to be highly sensitive (detectable mRNA copies < 10), reproducible (interassay CV < 5.4%, intraassay CV < 0.9%), precise and specific for the CYP19 gene. To confirm the validity of the applied test system, an ex vivo testicular and ovarian explant study with a known inducer of aromatase, forskolin, was conducted. Forskolin induced CYP19 gene expression in both ovarian (3.7-fold) and testicular (2.6-fold) explants. Of the four quantification methods, the absolute standard curve and the comparative CT method appear to be optimal as indicated by their highly significant correlation (r2 = 0.998, p < 0.001). In conclusion, we recommend the comparative CT method over the standard curve method because it is more economical in terms of both cost and labor. Although both aromatase activity and CYP19 mRNA were clearly detectable in testes of X. laevis, both aromatase enzyme activity and CYP19 gene expression were very low. Also, no significant relationships were found between aromatase enzyme activity and gene expression. This is likely due the fact that the aromatase enzyme may have been dormant at the developmental stage the frogs were in during the experiment.


Concordance between elderly patients' understanding of and their primary healthcare physician's diagnosis of heart failure.
The objective was to study primary healthcare patients' understanding of their diagnosis of heart failure (HF), using patients treated for diabetes mellitus (DM) as a comparative group. A cross-sectional community based study. Karlskrona community situated on the Swedish south-east coast with 60,600 inhabitants. A total of 1402 subjects, aged 60-96 years in 10 age cohorts, selected randomly from the national population registry participating in the Swedish National study on Ageing and Care - Blekinge. Understanding of diagnosis of HF or DM in primary healthcare. Prevalence of cognitive impairment. In all, 39.8% of patients with a diagnosis of HF treated in primary healthcare and 97.1% of patients with DM had an understanding of their respective diagnosis. Cognitive impairment was significantly more prevalent in the groups of patients treated for HF (OR 1.9, 95% CI 1.2 to 3.0) and DM (OR 1.8, 95% CI 1.1 to 3.1), when compared with those not treated for either HF or DM. The odds ratio for understanding of diagnosis was 0.013 (95% CI 0.003 to 0.052, p < 0.001) in patients treated for HF, compared with patients treated for DM, when adjusted for the subject's age, sex, and cognitive function. In this study it was shown that patients' understanding of their diagnosis was highly dependent on diagnosis, independently of age, sex, or cognitive function. The results suggest that there is room for improvement of care in primary healthcare, to increase HF patients' understanding of their diagnosis.


Electrodiffusioosmosis-Induced Negative Differential Resistance in pH-Regulated Mesopores Containing Purely Monovalent Solutions.
Negative differential resistance (NDR) refers to a unique electrical property where current decreases with increasing voltage. Herein, we report experimental evidence showing that the NDR effect can be observed in mesopores that feature charged pore walls and are subjected to a KCl concentration gradient. NDR in our system originates from the solution and ion flows driven by the synergistic effects of electroosmosis [electroosmotic flow (EOF)] and diffusioosmosis, the so-called electrodiffusioosmosis. Experiments reveal that in addition to the ion current rectification, the mesopores considered here exhibit the NDR phenomenon that is dependent on the magnitude and direction of the salinity gradient and on pH. The NDR behavior can be observed only at conditions at which the EOF and diffusioosmosis occur in the opposite directions: diffusioosmosis fills the tip opening with a high concentration solution, while EOF brings a low concentration solution to the pore. All experimental findings are supported by our numerical model, which takes into account the interfacial site reactions of acidic and basic functional groups on the entire pore membrane surfaces. Our results provide an important insight into how liquid pH, salinity gradients, interfacial site reactions, and pore geometries can influence the current-voltage characteristics of mesopores, enriching transport modes that can be induced by voltage.


Potential blindness in children of patients with hereditary bone disease.
Mono- and bi-allelic mutations in the low-density lipoprotein receptor related protein 5 (LRP5) may cause osteopetrosis, autosomal dominant and recessive exudative vitreoretinopathy, juvenile osteoporosis, or persistent hyperplastic primary vitreous (PHPV). We report on a child affected with PHPV and carrying compound mutations. The father carried the splice mutation and suffered from severe bone fragility since childhood. The mother carried the missense mutation without any clinical manifestations. The genetic diagnosis of their child allowed for appropriate treatment in the father and for the detection of osteopenia in the mother. Mono- and bi-allelic mutations in LRP5 may cause osteopetrosis, autosomal dominant and recessive exudative vitreoretinopathy, juvenile osteoporosis, or PHPV. PHPV is a component of persistent fetal vasculature of the eye, characterized by highly variable expressivity and resulting in a wide spectrum of anterior and/or posterior congenital developmental defects, which may lead to blindness. We evaluated a family diagnosed with PHPV in their only child. The child presented photophobia during the first 3 weeks of life, followed by leukocoria at 2 months of age. Molecular resequencing of NDP, FZD4, and LRP5 was performed in the child and segregation of the observed mutations in the parents. At presentation, fundus examination of the child showed a retrolental mass in the right eye. Ultrasonography revealed retinal detachment in both eyes. Thorough familial analysis revealed that the father suffered from many fractures since childhood without specific fragility bone diagnosis, treatment, or management. The mother was asymptomatic. Molecular analysis in the proband identified two mutations: a c.[2091+2T>C] splice mutation and c.[1682C>T] missense mutation. We report the case of a child affected with PHPV and carrying compound heterozygous LRP5 mutations. This genetic diagnosis allowed the clinical diagnosis of the bone problem to be made in the father, resulting in better management of the family. It also enabled preventive treatment to be prescribed for the mother and accurate genetic counseling to be provided.


Structural determinants of food insufficiency, low dietary diversity and BMI: a cross-sectional study of HIV-infected and HIV-negative Rwandan women.
In Sub-Saharan Africa, the overlapping epidemics of undernutrition and HIV infection affect over 200 and 23 million people, respectively, and little is known about the combined prevalence and nutritional effects. The authors sought to determine which structural factors are associated with food insufficiency, low dietary diversity and low body mass index (BMI) in HIV-negative and HIV-infected Sub-Saharan women. Cross-sectional analysis of a longitudinal cohort. Community-based women's organisations. 161 HIV-negative and 514 HIV-infected Rwandan women. Primary outcomes included food insufficiency (reporting 'usually not' or 'never' to 'Do you have enough food?'), low household dietary diversity (Household Dietary Diversity Score ≤3) and BMI <18.5 (kg/m(2)). The authors also measured structural and behavioural factors including: income, household size, literacy and alcohol use. Food insufficiency was prevalent (46%) as was low dietary diversity (43%) and low BMI (15%). Food insufficiency and dietary diversity were associated with low income (adjusted odds ratio (aOR)=2.14 (95% CI 1.30 to 3.52) p<0.01), (aOR=6.51 (95% CI 3.66 to 11.57) p<0.001), respectfully and illiteracy (aOR=2.00 (95% CI 1.31 to 3.04) p<0.01), (aOR=2.10 (95% CI 1.37 to 3.23) p<0.001), respectfully and were not associated with HIV infection. Alcohol use was strongly associated with food insufficiency (aOR=3.23 (95% CI 1.99 to 5.24) p<0.001). Low BMI was inversely associated with HIV infection (aOR≈0.5) and was not correlated with food insufficiency or dietary diversity. Rwandan women experienced high rates of food insufficiency and low dietary diversity. Extreme poverty, illiteracy and alcohol use, not HIV infection alone, may contribute to food insufficiency in Rwandan women. Food insufficiency, dietary diversity and low BMI do not correlate with one another; therefore, low BMI may not be an adequate screening tool for food insufficiency. Further studies are needed to understand the health effects of not having enough food, low food diversity and low weight in both HIV-negative and HIV-infected women.


Tolerance and immunity to MUC1 in a human MUC1 transgenic murine model.
The human epithelial mucin, MUC1, is a large transmembrane glycoprotein that is expressed on most simple epithelia. It is overexpressed and aberrantly glycosylated on many human epithelial tumors, including more than 90% of human breast cancers. MUC1 is of interest as an immunotherapy target because patients with breast, ovarian, and pancreatic cancers have T lymphocytes in their tumor-draining lymph nodes that can be induced to recognize and lyse MUC1-expressing tumor cells. We have produced a transgenic mouse model that expresses the human MUC1 molecule on an inbred C57Bl/6 background to investigate the effect of endogenous expression of MUC1 on the ability of mice to generate antitumor immunity to MUC1-expressing tumors. Transgenic mice expressed the human transgene in a pattern and level consistent with that observed in humans. Transgenic mice were tolerant to stimulation by MUC1 as evidenced by the ability of MUC1-expressing tumor cells to grow in these mice, whereas MUC1-expressing cells were eliminated from wild-type mice. Moreover, transgenic mice immunized with MUC1 peptides failed to exhibit immunoglobulin class switching to the IgG subtypes. These data suggest that endogenous expression of MUC1 protein by MUC1 transgenic mice induces T-cell tolerance to stimulation by MUC1. The transgenic mice will provide a useful model to investigate the mechanisms that regulate immunological tolerance to tumor antigens and will facilitate the investigation of anti-MUC1 immunotherapy formulations.


"Enough is enough, I don't want any audience": exploring medical students' explanations of consent-related behaviours.
Medical students are often faced with an ethical dilemma within the clinical setting--to learn from as many patients as possible but to learn only with consenting patients. Although studies have examined patients' and students' views about informed consent, none have examined how medical students talk about consent-related behaviours in 'naturalistic' focus group settings. This paper aims to explore medical students' explanations of behaviours relating to patient consent. Thirty-five excerpts across eight focus group discussions were identified using what we call momentum analysis: an identification of where the impetus of the groups' discussions changed noticeably. Ten were related to consent issues, seven of which occurred in focus groups with medical students. Utilising Malle's folk conceptual theory of behavioural explanation (2004. How the mind explains behavior. Folk explanations, meaning, and social interaction. Cambridge Massachusetts: MIT Press) within a narrative framework, we identified seven types of consent-related behaviour across the seven excerpts and 101 explanations for these behaviours by students. We found that students employed less reason explanations but more causal history reason (CHR) and enabling factor explanations than is found in other studies of naturally occurring talk, suggesting that consent-related behaviours were difficult and that our students actively managed others' impressions of them and their behaviours. Although our data is generally supportive of Malle's folk conceptual theory of behavioural explanation we suggest potential developments to this theoretical framework following our analysis with naturally occurring talk. However, further research is needed with larger samples of behavioural explanations to contribute more fully to theoretical development.


Molecular, Macromolecular, and Supramolecular Glucuronide Prodrugs: Lead Identified for Anticancer Prodrug Monotherapy.
In this work, a tumor growth intervention by localized drug synthesis within the tumor volume, using the enzymatic repertoire of the tumor itself, is presented. Towards the overall success, molecular, macromolecular, and supramolecular glucuronide prodrugs were designed for a highly potent toxin, monomethyl auristatin E (MMAE). The lead candidate exhibited a fold difference in toxicity between the prodrug and the drug of 175, had an engineered mechanism to enhance the deliverable payload to tumours, and contained a highly potent toxin such that bioconversion of only a few prodrug molecules created a concentration of MMAE sufficient enough for efficient suppression of tumor growth. Each of these points is highly significant and together afford a safe, selective anticancer measure, making tumor-targeted glucuronides attractive for translational medicine.