Molecular Characterization of a cDNA Encoding Vitellogenin and Its Expression in the Hepatopancreas and Ovary during Vitellogenesis in the Kuruma Prawn, Penaeus japonicus.
In Crustacea, reproductive function and mechanisms regulating vitellogenesis have not been fully elucidated. This is due in great part to a lack of information concerning the biochemical nature of the vitellogenin molecule, the hemolymph precursor of yolk protein, vitellin, as well as the functional expression of the vitellogenin-encoding gene. We have therefore cloned a cDNA encoding vitellogenin in the kuruma prawn, Penaeus japonicus based on the N-terminal amino acid sequence of the 91 kDa subunit of vitellin. The open reading frame of this cDNA encoded 2,587 amino acid residues. This is the first investigation reporting a full-length cDNA and its corresponding amino acid sequence for vitellogenin in any crustacean species.Northern blot analysis and in situ hybridization have revealed that mRNA encoding vitellogenin was expressed in both the follicle cells in the ovary and the parenchymal cells in the hepatopancreas. In nonvitellogenic females, vitellogenin mRNA levels were negligible in both the ovary and hepatopancreas, but in vitellogenic females, levels were dramatically increased in both tissues. In the ovary, highest levels were observed during the early exogenous vitellogenic stage, and thereafter rapidly decreased, whereas in the hepatopancreas, high levels were maintained until the onset of the late vitellogenic stage. Differing profiles of vitellogenin mRNA levels in the ovary and hepatopancreas suggest that the contribution of these tissues to vitellogenin synthesis harbor separate and complementary roles during vitellogenesis.


First Community-Wide, Comparative Cross-Linking Mass Spectrometry Study.
The number of publications in the field of chemical cross-linking combined with mass spectrometry (XL-MS) to derive constraints for protein three-dimensional structure modeling and to probe protein-protein interactions has increased during the last years. As the technique is now becoming routine for in vitro and in vivo applications in proteomics and structural biology there is a pressing need to define protocols as well as data analysis and reporting formats. Such consensus formats should become accepted in the field and be shown to lead to reproducible results. This first, community-based harmonization study on XL-MS is based on the results of 32 groups participating worldwide. The aim of this paper is to summarize the status quo of XL-MS and to compare and evaluate existing cross-linking strategies. Our study therefore builds the framework for establishing best practice guidelines to conduct cross-linking experiments, perform data analysis, and define reporting formats with the ultimate goal of assisting scientists to generate accurate and reproducible XL-MS results.


High mortality of Red Sea zooplankton under ambient solar radiation.
High solar radiation along with extreme transparency leads to high penetration of solar radiation in the Red Sea, potentially harmful to biota inhabiting the upper water column, including zooplankton. Here we show, based on experimental assessments of solar radiation dose-mortality curves on eight common taxa, the mortality of zooplankton in the oligotrophic waters of the Red Sea to increase steeply with ambient levels of solar radiation in the Red Sea. Responses curves linking solar radiation doses with zooplankton mortality were evaluated by exposing organisms, enclosed in quartz bottles, allowing all the wavelengths of solar radiation to penetrate, to five different levels of ambient solar radiation (100%, 21.6%, 7.2%, 3.2% and 0% of solar radiation). The maximum mortality rates under ambient solar radiation levels averaged (±standard error of the mean, SEM) 18.4±5.8% h(-1), five-fold greater than the average mortality in the dark for the eight taxa tested. The UV-B radiation required for mortality rates to reach ½ of maximum values averaged (±SEM) 12±5.6 h(-1)% of incident UVB radiation, equivalent to the UV-B dose at 19.2±2.7 m depth in open coastal Red Sea waters. These results confirm that Red Sea zooplankton are highly vulnerable to ambient solar radiation, as a consequence of the combination of high incident radiation and high water transparency allowing deep penetration of damaging UV-B radiation. These results provide evidence of the significance of ambient solar radiation levels as a stressor of marine zooplankton communities in tropical, oligotrophic waters. Because the oligotrophic ocean extends across 70% of the ocean surface, solar radiation can be a globally-significant stressor for the ocean ecosystem, by constraining zooplankton use of the upper levels of the water column and, therefore, the efficiency of food transfer up the food web in the oligotrophic ocean.


Poor Linkage to Care Despite Significant Improvement in Access to Early cART in Central Poland - Data from Test and Keep in Care (TAK) Project.
The main objective of the TAK project is investigating barriers in accessing HIV care after HIV-diagnosis at the CBVCTs of central Poland. Here we describe factors associated with and changes over time in linkage to care and access to cART. Data collected in 2010-2013 in CBVCTs were linked with HIV clinics records using unique identifiers. Individuals were followed from the day of CBVCTs visit until first clinical visit or 4/06/2014. Cox-proportional hazard models were used to identify factors associated with being linked to care and starting cART. In total 232 persons were diagnosed HIV-positive and 144 (62.1% 95%CI: 55.5-68.3) persons were linked to care. There was no change over time in linkage to care (p = 0.48), while time to starting cART decreased (p = 0.02). Multivariate factors associated with a lower rate of linkage to care were hetero/bisexual sexual orientation, lower education, not having an HIV-positive partner and not using condoms in a stable relationship. Multivariate factors associated with starting cART were lower education, recent year of linked to care, and first HIV RNA and CD4 cell count. Benefits of linkage to care, measured by access to early treatment, steadily improved in recent years. However at least 1 in 3 persons aware of their HIV status in central Poland remained outside professional healthcare. Persons at higher risk of remaining outside care, thus target population for future interventions, are bi/heterosexuals and those with lower levels of education.


Expression of LIF in transgenic mice results in altered thymic epithelium and apparent interconversion of thymic and lymph node morphologies.
Leukemia inhibitory factor (LIF) is a cytokine involved in embryonic and hematopoietic development. To investigate the effects of LIF on the lymphoid system, we generated a line of transgenic mice that expresses diffusible LIF protein specifically in T cells. These mice display two categories of phenotype that were not previously attributed to LIF overexpression. First, they display B cell hyperplasia, polyclonal hypergammaglobulinemia and mesangial proliferative glomerulonephritis, defects similar to those described for transgenic mice overexpressing the functionally related cytokine, interleukin-6. Secondly, the LIF transgenic mice display novel thymic and lymph node abnormalities. In the thymus, cortical CD4+CD8+ lymphocytes are lost, while numerous B cell follicles develop. Peripheral lymph nodes contain a vastly expanded CD4+CD8+ lymphocyte population. Furthermore, the thymic epithelium is profoundly disorganized, suggesting that disruption of stroma-lymphocyte interactions is responsible for many observed defects. Transplantation of transgenic bone marrow into wild type recipients transfers both the thymic and lymph node defects. However, transplantation of wild type marrow into transgenic recipients rescues the lymph node abnormality, but not the thymic defect, indicating the thymic epithelium is irreversibly altered. Our observations are consistent with a role for LIF in maintaining a functional thymic epithelium that will support proper T cell maturation.


Losses at chromosome 4q are associated with poor survival in operable ductal pancreatic adenocarcinoma.
Here we tested the prognostic impact of genomic alterations in operable localized pancreatic ductal adenocarcinoma (PDAC). Fifty-two formalin-fixed and paraffin-embedded primary PDAC were laser micro-dissected and were investigated by comparative genomic hybridization after whole genome amplification using an adapter-linker PCR. Chromosomal gains and losses were correlated to clinico-pathological parameters and clinical follow-up data. The most frequent aberration was loss on chromosome 17p (65%) while the most frequent gains were detected at 2q (41%) and 8q (41%), respectively. The concomitant occurrence of losses at 9p and 17p was found to be statistically significant. Higher rates of chromosomal losses were associated with a more advanced primary tumor stage and losses at 9p and 18q were significantly associated with presence of lymphatic metastasis (chi-square: p = 0.03, p = 0.05, respectively). Deletions on chromosome 4 were of prognostic significance for overall survival and tumor recurrence (Cox-multivariate analysis: p = 0.026 and p = 0.021, respectively). In conclusion our data suggest the common alterations at chromosome 8q, 9p, 17p and 18q as well as the prognostic relevant deletions on chromosome 4q as relevant for PDAC progression. Our comprehensive data from 52 PDAC should provide a basis for future studies with a higher resolution to discover the relevant genes located within the chromosomal aberrations identified.


Studying the genetics of participation using footprints left on the ascertained genotypes.
The trait of participating in a genetic study probably has a genetic component. Identifying this component is difficult as we cannot compare genetic information of participants with nonparticipants directly, the latter being unavailable. Here, we show that alleles that are more common in participants than nonparticipants would be further enriched in genetic segments shared by two related participants. Genome-wide analysis was performed by comparing allele frequencies in shared and not-shared genetic segments of first-degree relative pairs of the UK Biobank. In nonoverlapping samples, a polygenic score constructed from that analysis is significantly associated with educational attainment, body mass index and being invited to a dietary study. The estimated correlation between the genetic components underlying participation in UK Biobank and educational attainment is estimated to be 36.6%-substantial but far from total. Taking participation behaviour into account would improve the analyses of the study data, including those of health traits.


Inter-professional perspectives of dementia services and care in England: Outcomes of a focus group study.
Many people living with dementia are supported at home using a variety of health and social care services. This paper reports the findings from a focus group study undertaken with staff in community mental health teams to explore areas for improvement in relation to national policies and recommendations for dementia care. Two focus groups were held with staff (n = 23) in 2011 to discuss topics including service delivery, information and communication, and provision of health and community care for people with dementia. Respondents identified problems with information sharing and incompatible electronic systems; inflexibility in home care services; and poor recognition of dementia in hospital settings. General practitioners had developed a greater awareness of the disease and some community services worked well. They felt that budgetary constraints and a focus on quality indicators impeded good dementia care. Key areas suggested by staff for improvements in dementia care included the implementation of more flexible services, dementia training for health and social care staff, and better quality care in acute hospital settings.


The business of academic plastic surgery.
Given the changes in health care economics and the changes in increasing rates of uninsured and undercovered patients in the United States, the revenue stream for all physicians, and particularly those in academic medical centers, is subject to fluctuations that make it difficult to fund the missions of education and research. Often, academic plastic surgeons are required to use clinical revenue to supplement efforts in research and education. A large margin on clinical revenue that was present perhaps 10 or 20 years ago has been eroded by many socioeconomic factors, making it difficult to provide optimal training in academic environments for our residents. In an attempt to ascertain "best in show," a survey was sent to 89 plastic surgery programs that requested information regarding faculty salaries, relative value units, National Institutes of Health support, ancillary revenue support for taking call, and the number of faculty within individual programs. Fifty-three programs responded with completed data. The following practices directly contribute to stable financial environments: external support for call coverage, recruitment support, and gain sharing associated with health system profitability. Coverage agreements with outside facilities can be lucrative if properly negotiated. Paid medical directorships for administrative/clinical oversight are helpful. Payor mixes with high percentages of commercial, managed care, and self-pay (aesthetic) and low percentages of Medicaid are beneficial. Practices with a healthy mix of aesthetic surgery add strength.


Preparation and Characterization of Polyhedral Oligomeric Silsesquioxane-Containing, Titania-Thiol-Ene Composite Photocatalytic Coatings, Emphasizing the Hydrophobic-Hydrophilic Transition.
Coatings prepared from titania-thiol-ene compositions were found to be both self-cleaning, as measured by changes in water contact angle, and photocatalytic toward the degradation of an organic dye. Stable titania-thiol-ene dispersions at approximately 2 wt % solids were prepared using a combination of high-shear mixing and sonication in acetone solvent from photocatalytic titania, trisilanol isobutyl polyhedral oligomeric silsesquioxane (POSS) dispersant, and select thiol-ene monomers, i.e., trimethylolpropane tris(3-mercaptopropionate) (TMPMP), pentaerythritol allyl ether (APE), and 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (TTT). The dispersed particle compositions were characterized by DLS and TEM. The synthetic methods employed yield a strongly bound particle/POSS complex, supported by IR, 29Si NMR, and TGA. The factors of spray techniques, carrier solvent volatility, and particle size and size distributions, in combination, likely all contribute to the highly textured but uniform surfaces observed via SEM and AFM. Polymer composites possessed thermal transitions (e.g., Tg) consistent with composition. In general, the presence of polymer matrix provided mechanical integrity, without significantly compromising or prohibiting other critical performance characteristics, such as film processing, photocatalytic degradation of adsorbed contaminants, and the hydrophobic-hydrophilic transition. In all cases, coatings containing photocatalytic titania were converted from superhydrophobic to superhydrophilic, as defined by changes in the water contact angle. The superhydrophilic state of samples was considered persistent, since long time durations in complete darkness were required to observe any significant hydrophobic return. In a preliminary demonstration, the photocatalytic activity of prepared coatings was confirmed through the degradation of crystal violet dye. This work demonstrates that a scalable process can be found to prepare titania-thiol-ene coatings having improved coating properties which also exhibit photocatalytic and self-cleaning attributes.


Improved Outcomes Associated with the Liberal Use of Thoracic Epidural Analgesia in Patients with Rib Fractures.
Each year, more than 150,000 patients with rib fractures are admitted to US trauma centers; as many as 10% die. Effective pain control is critical to survival. One way to manage pain is thoracic epidural analgesia. If this treatment reduces mortality, more frequent use may be indicated. We analyzed the patient registry of a level II trauma center. All patients admitted with one or more rib fractures (N = 1,347) were considered. Patients who were not candidates for epidural analgesia (N = 382) were eliminated. Mortality was assessed with binary logistic regressions. Across the total population, mortality was 6.7%; incidence of pneumonia was 11.1%; mechanical ventilation was required in 23.8% of patients, for an average duration of 10.0 days; average stay in the hospital was 7.7 nights; and 49.7% of patients were admitted to the ICU for an average of 7.2 nights. Epidural analgesia was administered to 18.4% of patients. After matching samples for candidacy, patients who received epidurals were 3.7 years older, fractured 2.6 more ribs, had higher injury severity scores, and were more likely to present with bilateral fractures, flail segments, pulmonary contusions, hemothoraces, and pneumothoraces. Despite greater injury severity, mortality among these patients was lower (0.5%) than those who received alternative care (1.9%). Controlling for age, injury severity, and use of mechanical ventilation, epidural analgesia predicted a 97% reduction in mortality. Thoracic epidural analgesia associates with reduced mortality in rib fracture patients. Better care of this population is likely to be facilitated by more frequent reliance on this treatment.


[Molecular pathways in aseptic loosening of orthopaedic endoprosthesis].
Operative joint replacement to treat disabling joint conditions secondary to degenerative and inflammatory arthritides has become one of the most efficacious and cost-effective procedures to relieve pain and restore joint function. However, prosthetic implants are not built to last forever and osteolysis and aseptic loosening has been associated with prosthetic arthroplasties since their introduction. The functional life of a synthetic joint is influenced by many factors including the material of the implant, operation procedures and the surgeon involved, as well as patient-related factors. Although promising developments have been achieved in this field, more than 10% of all implants still have to undergo operative revision within 15 years after the initial operation. Failure due to sepsis, fractures and dislocations has become rare; premature loosening of implants on the other hand is becoming much more important. Prosthetic loosening without concurrent infection or trauma is called aseptic loosening. It is generally accepted that small particles ("wear debris") and activated macrophages play a key role in aseptic loosening. The pathophysiology of this condition, however, is still not very well characterized. In this article, we review the molecular mechanisms and signal pathways that were unravelled as responsible factors for loosening orthopaedic implants. Finally, we discuss possible novel strategies for future therapeutic approaches.


Hospital readmission in persons with dementia: A systematic review.
Hospital readmission in persons with dementia is becoming a critical safety and cost issue. The purpose of this review is to systematically assess published evidence on hospital readmissions in persons with dementia, including rate, clinical reasons, risk factors, and prevention programs. A systematic review of relevant literature was conducted. Literature were searched in PubMed, CINAHL, PsycINFO, and Embase as well as hand searching. Quality of reviewed studies were assessed independently by reviewers using quality assessment checklists. Nineteen studies met the inclusion criteria and were reviewed. In persons with dementia, all-cause 30-day readmission rate was most frequently reported and ranged from 7% to 35%. Compared with those without dementia, persons with dementia had significantly higher rate of readmission. Reported risk factors of readmission varied across studies from patient sociodemographic and clinical status, history of health care utilization, to family caregivers. Reasons for readmission were rarely documented. Programs of home-based individualized care and interdisciplinary team care were used for preventing readmissions. Findings from some of the studies were limited by small sample sizes, single data source, and other methodologic flaws. Persons with dementia are at high risk for hospital readmission, but many of the readmissions are potentially preventable. Multiple strategies such like identifying high-risk individuals and the clinical reasons for index admission and readmission and implementing home-based individualized care by interdisciplinary team can reduce preventable hospital readmissions. Future studies should use multiple national data sources and advanced methodology to identify risk factors and clinical reasons of hospital readmissions.


Ageing, testicular tumours and the pituitary-testis axis in dogs.
Dogs of different ages without testicular diseases were evaluated to study possible age-related changes in hormone concentrations in serum. Dogs with testicular tumours were also investigated to study the relation between tumour type and hormone concentrations; in this study, dogs with Sertoli cell tumours, Leydig cell tumours and seminomas were included. We measured testosterone, oestradiol, LH, FSH and inhibin-like immunoreactivity concentrations in peripheral venous and testicular venous blood of these animals. In normal dogs there appeared to be no age-related changes in the concentrations of the investigated hormones, except for a significant age-related decrease in oestradiol concentrations in testicular venous blood (P<0.02). Dogs with a Sertoli cell tumour had greater oestradiol concentrations and inhibin-like immunoreactivity in both peripheral and testicular venous blood than did dogs without a neoplasm (P<0. 05). Testosterone concentrations were reduced in dogs with Sertoli cell tumours, as were FSH and LH. Feminisation occurred in eight of 13 dogs with a Sertoli cell tumour and in two of 14 dogs with a Leydig cell tumour; it was accompanied by a significantly greater oestradiol concentration than in normal dogs and in dogs with Sertoli cell tumours without signs of feminisation. Dogs with a Leydig cell tumour had greater concentrations of oestradiol and inhibin-like immunoreactivity in both peripheral venous and testicular venous blood than did dogs without a neoplasm (P<0.05). The testosterone concentration in testicular venous blood of these dogs was lower than that in dogs with normal testes. The concentration of LH in peripheral venous blood was also reduced (P<0. 05). Hormone concentrations in dogs with a seminoma were not different from those in normal dogs. It was concluded that seminomas are not endocrinologically active. In contrast, both Sertoli cell tumours and Leydig cell tumours can cause increased oestrogen production leading to signs of feminisation. These tumours also have considerable amounts of inhibin-like immunoreactivity, but only in Sertoli cell tumours does this result in a reduction in FSH concentrations, suggesting that Sertoli cell tumours secrete dimeric inhibin, whereas Leydig cell tumours presumably produce loose alpha-subunits that cross-react in the inhibin assay but are not biologically active.


DDX3, a DEAD box RNA helicase with tumor growth-suppressive property and transcriptional regulation activity of the p21waf1/cip1 promoter, is a candidate tumor suppressor.
DDX3 is a DEAD box RNA helicase with diverse biological functions. Using colony formation assay, our results revealed that DDX3 inhibited the colony formation ability of various tumor cells, and this inhibition might be due to a reduced growth rate caused by DDX3. Additionally, we identified p21(waf1/cip1), a cyclin-dependent kinase inhibitor, as a target gene of DDX3, and the up-regulation of p21(waf1/cip1) expression accounted for the colony-suppressing activity of DDX3. Moreover, DDX3 exerted its transactivation function on p21(waf1/cip1) promoter through an ATPase-dependent but helicase-independent mechanism, and the four Sp1 sites located within the -123 to -63 region, relative to the transcription start site of p21(waf1/cip1) promoter, were essential for the response to DDX3. Furthermore, DDX3 interacted and cooperated with Sp1 to up-regulate the promoter activity of p21(waf1/cip1). To determine the relevance of DDX3 in clinical cancers, the expression profile of DDX3 in various tumors was also examined. A declined expression of DDX3 mRNA and protein was found in approximately 58% to 73% of hepatoma specimens, which led to the reduction of p21(waf1/cip1) expression in a manner independent of p53 status. Additionally, an alteration of subcellular localization from nuclei to cytoplasm was also observed in >70% of cutaneous squamous cell carcinoma samples. Because DDX3 exhibits tumor suppressor functions, such as a growth-suppressive property and transcriptional activation of the p21(waf1/cip1) promoter, and is inactivated through down-regulation of gene expression or alteration of subcellular localization in tumor cells, all these features together suggest that DDX3 might be a candidate tumor suppressor.


Loss of heterozygosity at 11q13: analysis of pituitary tumors, lung carcinoids, lipomas, and other uncommon tumors in subjects with familial multiple endocrine neoplasia type 1.
Loss of heterozygosity (LOH) for polymorphic markers flanking the multiple endocrine neoplasia type 1 (MEN-1) gene in parathyroid and pancreatic islet tumors from subjects with familial MEN-1 (FMEN-1) has been well documented and has led to the hypothesis that the MEN-1 gene functions as a tumor suppressor. To assess the role of the MEN-1 gene in the pathogenesis of tumors less commonly associated with MEN-1, we employed a large number of highly informative polymorphic markers closely linked to the MEN-1 gene to study a series of 13 such tumors from subjects with FMEN-1 for LOH at 11q13. We were able to identify LOH for 1 or more 11q13 markers in 2 of 3 pituitary tumors, 3 lung carcinoids, and 1 of 2 lipomas. In every case studied, the allele lost represented the normal allele inherited from the unaffected parent. No LOH was detected in 3 skin angiofibromas, an esophageal leiomyoma, or a renal angiomyolipoma despite the presence of at least 2 informative markers for each tumor. Our results suggest that, like that for parathyroid and pancreatic islet tumors, the pathogenesis of pituitary tumors, lung carcinoids, and lipomas occurring in subjects with FMEN-1 probably involves loss of the normal tumor suppressor function of the MEN-1 gene. Our inability to detect 11q13 LOH in skin angiofibromas, leiomyoma, and angiomyolipoma from subjects with FMEN-1 is consistent with the possibility that these neoplasms arose independently by a mechanism unrelated to the MEN-1 gene, but a role for the MEN-1 gene in the pathogenesis of these tumors cannot be definitively excluded until the gene itself is identified and evaluated for small intragenic deletions or point mutations in such tumors.


Economic growth, income inequality and life expectancy in China.
China had made dramatic health gains before its economic reform that began in 1978 produced rapid economic growth in the ensuing years. Since the economic reform, China's income inequality has substantially increased, and health gains have stagnated. This article investigates the extent to which China's health stagnation may be attributable to the rise in income inequality in China. By simulating the improvement in life expectancy that could have resulted if, ceteris paribus, income inequality had stayed constant at the lowest level after the founding of the People's Republic of China in 1949, we find that the sharply increasing income inequality in China has contributed to life loss in China's population, about 0.6 years for men and 0.4 years for women. These findings suggest that redistribution of income from rich to poor may be one of the most important policy levers for improving population health in China.


Introduction to Homeostatic Migration.
Immune cell development and function occur in specialized immunological tissues, the function of which requires active cell migration and interactions between hematopoietic cells and underlying networks of stromal cells. These cells provide a scaffold on which immune cell migrate, provide microenvironments for efficient antigen presentation, and provide signals required for immune cell recruitment and survival. Technical advances in imaging technologies including multiphoton microscopy and 3D tissue reconstructions are being combined with computational approaches to provide new insights into the process of cell migration and function in immunological tissues.


Hemoglobin parameters from diffuse reflectance data.
Tissue vasculature is altered when cancer develops. Consequently, noninvasive methods of monitoring blood vessel size, density, and oxygenation would be valuable. Simple spectroscopy employing fiber optic probes to measure backscattering can potentially determine hemoglobin parameters. However, heterogeneity of blood distribution, the dependence of the tissue-volume-sampled on scattering and absorption, and the potential compression of tissue all hinder the accurate determination of hemoglobin parameters. We address each of these issues. A simple derivation of a correction factor for the absorption coefficient, μa, is presented. This correction factor depends not only on the vessel size, as others have shown, but also on the density of blood vessels. Monte Carlo simulations were used to determine the dependence of an effective pathlength of light through tissue which is parameterized as a ninth-order polynomial function of μa. The hemoglobin bands of backscattering spectra of cervical tissue are fit using these expressions to obtain effective blood vessel size and density, tissue hemoglobin concentration, and oxygenation. Hemoglobin concentration and vessel density were found to depend on the pressure applied during in vivo acquisition of the spectra. It is also shown that determined vessel size depends on the blood hemoglobin concentration used.


Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: our case series and literature review.
Recently, nonalcoholic steatohepatitis (NASH) has been considered to be another cause of liver cirrhosis and hepatocellular carcinoma (HCC). The natural history and prognosis of NASH are controversial. Accordingly, we assessed the clinicopathological features of NASH-associated HCC in our experience and reviewed the literature of NASH-associated HCC. We experienced 11 patients with NASH-associated HCC (6 male, 5 female; mean age 73.8 +/- 4.9 years) who received curative treatments. Most (91%) patients had been diagnosed with obesity, diabetes, hypertension, or dyslipidemia. Seven patients (64%) also had a non-cirrhotic liver. The recurrence-free survival rates at 1, 3 and 5 years were 72%, 60%, and 60%. We also summarized and reviewed 94 cases of NASH-associated HCC which were reported in the literature (64 male; mean age 66 years). The majority of patients (68%) were obese, 66% of patients had diabetes, and 24% had dyslipidemia. Furthermore, 26% of the HCCs arose from the non-cirrhotic liver. In conclusion, patients with non-cirrhotic NASH may be a high-risk group for HCC, and regular surveillance for HCC is necessary in non-cirrhotic NASH patients as well as cirrhotic patients.


Group B streptococcus infection, not birth asphyxia.
This case illustrates 2 main points. Firstly, fetal infection can mimic exactly both the immediate and delayed signs of perinatal asphyxia. Secondly, the placenta may hold the key to the diagnosis of sepsis which may be made difficult in the neonate by labour ward practices such as the use of intrapartum and immediate newborn antibiotics. We strongly support the recommendation that newborn blood and fetal membrane cultures should always be obtained in babies with a diagnosis of 'intrapartum asphyxia and fetal distress' (1). To this we would add the recommendation that placental histology be performed in these circumstances.


Ion-mediated conformational switches.
Molecular switches are ubiquitous in Nature and provide the basis of many forms of transport and signalling. Single synthetic molecules that change conformation, and thus function, reversibly in a stimulus-dependent manner are of great interest not only to chemists but society in general; myriad applications exist in storage, display, sensing and medicine. Here we describe recent developments in the area of ion-mediated switching.


Antipsychotic medication prescribing in children enrolled in Medicaid.
Although the increase in treatment of children and adolescents with antipsychotic medications has been well documented, much less is known about the factors related to the use of these agents and how closely the treatment follows best practice recommendations. Prescribers of each antipsychotic medication prescription issued for a Medicaid-insured child in Vermont aged <18 years were sent a prior authorization survey that assessed several domains including the clinical indication, other treatments, metabolic monitoring, prescriber specialty, and prescription origin. These variables were combined to categorize prescriptions as following indications approved by the US Food and Drug Administration (FDA) and best practice guidelines. The response rate of the survey was 80%, with 677 surveys from 147 prescribers available for analysis; more than one-half of the respondents were primary care clinicians. Overall, the clinical indication for an antipsychotic prescription followed best practice guidelines 91.7% of the time, with overall best practice guidelines followed at a rate of 50.1%. An FDA indication was followed in 27.2% of cases. Psychiatrists were significantly more likely to follow best practice guidelines than nonpsychiatrists. Antipsychotic medications were typically used only after other pharmacologic and nonpharmacologic treatments were ineffective, although previous treatment with cognitive-behavioral therapy was uncommon (15.5%). Metabolic monitoring that included serial laboratory tests was reported in 57.2% of cases. Current prescribing patterns of antipsychotic medications for children and adolescents follow best practice guidelines approximately one-half of the time, with nonadherence often related to lack of metabolic monitoring.


Genetic and molecular functional characterization of variants within TNFSF13B, a positional candidate preeclampsia susceptibility gene on 13q.
Preeclampsia is a serious pregnancy complication, demonstrating a complex pattern of inheritance. The elucidation of genetic liability to preeclampsia remains a major challenge in obstetric medicine. We have adopted a positional cloning approach to identify maternal genetic components, with linkages previously demonstrated to chromosomes 2q, 5q and 13q in an Australian/New Zealand familial cohort. The current study aimed to identify potential functional and structural variants in the positional candidate gene TNFSF13B under the 13q linkage peak and assess their association status with maternal preeclampsia genetic susceptibility. The proximal promoter and coding regions of the positional candidate gene TNFSF13B residing within the 13q linkage region was sequenced using 48 proband or founder individuals from Australian/New Zealand families. Ten sequence variants (nine SNPs and one single base insertion) were identified and seven SNPs were successfully genotyped in the total Australian/New Zealand family cohort (74 families/480 individuals). Borderline association to preeclampsia (p = 0.0153) was observed for three rare SNPs (rs16972194, rs16972197 and rs56124946) in strong linkage disequilibrium with each other. Functional evaluation by electrophoretic mobility shift assays showed differential nuclear factor binding to the minor allele of the rs16972194 SNP, residing upstream of the translation start site, making this a putative functional variant. The observed genetic associations were not replicated in a Norwegian case/control cohort (The Nord-Trøndelag Health Study (HUNT2), 851 preeclamptic and 1,440 non-preeclamptic women). TNFSF13B has previously been suggested to contribute to the normal immunological adaption crucial for a successful pregnancy. Our observations support TNFSF13B as a potential novel preeclampsia susceptibility gene. We discuss a possible role for TNFSF13B in preeclampsia pathogenesis, and propose the rs16972194 variant as a candidate for further functional evaluation.


RAS mutations contribute to evolution of chronic myelomonocytic leukemia to the proliferative variant.
The biological and clinical heterogeneity of chronic myelomonocytic leukemia features renders its classification difficult. Moreover, because of the limited knowledge of the mechanisms involved in malignant evolution, chronic myelomonocytic leukemia remains a diagnostic and therapeutic challenge and a poor prognosis disease. We aimed to verify the biological and clinical significance of the discrimination, based on the leukocyte count, between myelodysplastic chronic myelomonocytic leukemia (MD-CMML) and myeloproliferative chronic myelomonocytic leukemia (MP-CMML). Peripheral blood samples from 22 patients classified as MD-CMML and 18 as MP-CMML were collected at different time points during disease course, and patients' clinical characteristics were examined. RAS mutational screening was done by sequencing and, for each substitution identified, a highly selective allele-specific PCR was set up to screen all specimens. MP-CMML patients showed a significantly poorer survival (P = 0.003) and a higher frequency of RAS mutations (P = 0.033) by sequencing compared with MD-CMML. Overall, five MD-CMML patients progressed to myeloproliferative disease: in two, allele-specific PCR unveiled low levels of the RAS mutations predominating in the myeloproliferative phase at the time of myelodysplastic disease, documenting for the first time the expansion of a RAS mutated clone in concomitance with chronic myelomonocytic leukemia evolution. Moreover, one of the progressed patients harbored the FLT3-ITD and two MP-CMML patients presented with the JAK2 V617F substitution. All these lesions were mutually exclusive. Our results strongly suggest RAS mutations to function as a secondary event that contributes to development of the chronic myelomonocytic leukemia variant with the poorer prognosis (MP-CMML) and therefore advise their detection to be implemented in chronic myelomonocytic leukemia diagnostics and monitoring.


Collectivizing rescue obligations in bioethics.
Bioethicists invoke a duty to rescue in a wide range of cases. Indeed, arguably, there exists an entire medical paradigm whereby vast numbers of medical encounters are treated as rescue cases. The intuitive power of the rescue paradigm is considerable, but much of this power stems from the problematic way that rescue cases are conceptualized-namely, as random, unanticipated, unavoidable, interpersonal events for which context is irrelevant and beneficence is the paramount value. In this article, I critique the basic assumptions of the rescue paradigm, reframe the ethical landscape in which rescue obligations are understood, and defend the necessity and value of a wider social and institutional view. Along the way, I move back and forth between ethical theory and a concrete case where the duty to rescue has been problematically applied: the purported duty to regularly return incidental findings and individual research results in genomic and genetic research.


Clinicopathologic relationships, survival, and therapy in 59 patients with observations on occupation as a new prognostic factor.
Clinicopathologic relationships, survival and therapy were reviewed in 59 patients with mycosis fungoides (MF). An analysis of patient survival disclosed that stage of disease was a significant prognostic variable only if both cutaneous and visceral manifestations were considered in the staging design. The classical three-stage format, based solely on findings of eczema (I), plaques (II), or skin tumors (III), was not a significant factor in predicting survival. However, the inclusion of lymphadenopathy (IV) and organomegaly (V) or circulation Sézary cells (VI) in an expanded model revealed a significant decline in the probability of survival with increasing stage of disease. Regarding cases where the original histopathologic material was available for review, there was no association between the histologic stage of the specimen and the morphology of skin lesions. These data militate against the use of a staging scheme based on histologic criteria. Among 30 different types of treatment employed during the course of this study, highdose electron beam was superior to all other physical and chemotherapeutic modalities. In a case-control study considering occupational factors, patients with MF who were employed in manufacturing or construction industries were at significantly increased risk (relative risk = 4.3). Patient survival was reduced considerably for those with industrial backgrounds, suggesting that this subgroup was inclined to have severe disease. The concept that occupational factors may be implicated in the etiology of mycosis fungoides provides a new dimension to previous pathogenic hypotheses that needs further evaluation.


A meta-analysis on the effect of telemedicine on the management of attention deficit and hyperactivity disorder in children and adolescents.
This study aims to report the effect sizes of telemedicine treatments on the symptom domains of paediatric ADHD. In this systematic review and meta-analysis, electronic databases, i.e. PubMed, Scopus, Web of Science and Embase, were searched for articles published up to December 2020. The inclusion criteria were as follows: children or adolescents diagnosed for ADHD or other hyperkinetic disorders; randomized controlled trials (RCTs); efficacy established with parents and teachers or self-rating scales at least for one of the following domains: inattention, cognitive function, hyperactivity, hyperactivity/impulsivity or oppositional behaviours. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs. From 310 records reduced to 228 after removing duplicates, overall 12 studies were fulfilled our inclusion criteria. They consisted of 708 participants (358 with telemedicine intervention and 350 controls). The telemedicine interventions varied from computerized training programmes with phone calls to videoconferencing programmes, virtual reality classrooms or games. The most applicable method consisted of computerized training programmes with phone calls. Pooling results of all studies with available data on each subscale showed a significant effect of telemedicine on inattention/cognitive function (standardized mean difference (SMD) = 0.26, 95% CI: 0.16, 0.36), hyperactivity/impulsivity (SMD = 0.29, 95% CI: 0.06, 0.52), and oppositional behaviours (SMD = 0.72, 95% CI: 0.24, 1.20) subscales in ADHD. Almost all studies had an overall unclear risk of bias. The source of outcome assessment (parents, teachers or self-report questionnaire) was addressed as a potential confounding factor. In almost all symptom domains, the satisfaction from the treatment was higher in parents than in teachers. The clinical effects of telemedicine on the treatment of ADHD showed a small effect size for inattention/cognitive function, hyperactivity/impulsivity and oppositional behaviours.


Development of glaucoma after cataract surgery in dogs: 220 cases (1987-1998).
To examine postoperative ocular hypertension (POH) and other variables as predictors of the risk of developing glaucoma after cataract surgery in dogs. Retrospective study. 220 dogs that had cataract surgery. Medical records of 220 dogs (346 eyes) that had extracapsular cataract removal or phacoemulsification of cataracts were reviewed. With respect to glaucoma development, 8 variables were analyzed, which included development of POH, breed, sex, age at time of surgery, eye (right vs left), phacoemulsification time, intraocular lens (IOL) placement (yes or no), and stage of cataract development. Eyes developed glaucoma within 6 or 12 months of surgery or did not have signs of glaucoma at least 6 or 12 months after cataract surgery. Of 346 eyes, 58 (16.8%) developed glaucoma after surgery. At 6 months, 32 of 206 (15.5%) eyes examined had glaucoma; at 12 months, 44 of 153 (28.8%) eyes examined had glaucoma. Median follow-up time was 5.8 months (range, 0.1 to 48 months). Mixed-breed dogs were at a significantly lower risk for glaucoma, compared with other breeds. Eyes with IOL placement were at a significantly lower risk for glaucoma, compared with eyes without IOL placement. Eyes with hypermature cataracts were at a significantly higher risk for glaucoma, compared with eyes with mature or immature cataracts. Multiple factors appear to contribute to the onset of glaucoma in dogs after cataract surgery. Complications prohibiting IOL placement during cataract surgery may lead to a high risk of glaucoma development.


Scrotal reconstruction and testicular prosthetics.
Scrotal surgery encompasses a wide-variety of surgical techniques for an even wider variety of indications. In this manuscript, we review our indications, techniques, and pit-falls for various reconstructive scrotal surgeries as-well-as surgical tips for placement of testicular prostheses. Penoscrotal webbing (PSW) is an abnormal, often-problematic distal insertion of scrotal skin onto the ventral penile shaft. There are several effective and straightforward techniques used to revise this condition, which include simple scrotoplasty, single- or double-Z-plasty, or the VY-flap scrotoplasty. Reconstruction is also commonly indicated following scrotal skin loss caused by infection, trauma, lymphedema, hidradenitis, and cancer. Although initial management of these conditions often involves scrotal skin removal, repair of expansive scrotal skin loss can be technically difficult and can be accomplished by using one of several skin flaps or skin grafting. Split-thickness skin grafting of scrotal defects can be accomplished easily, and provides durable results.


Inoculation dose of Mycobacterium tuberculosis does not influence priming of T cell responses in lymph nodes.
The effect of Mycobacterium tuberculosis inocula size on T cell priming in the lymph node and effector T cells in the lung remains controversial. In this study, we used a naive mouse model, without the transfer of transgenic T cells, in conjunction with mathematical model to test whether infection with higher aerosolized inocula would lead to increased priming of M. tuberculosis-specific T cells in the lung-draining lymph node. Our data do not support that inoculum size has a measurable influence on T cell priming in the lymph nodes but is associated with more cells overall in the lung, including T cells. To account for increased T cells in the lungs, we tested several possible mechanisms, and recruitment of T cells to the lungs was most influenced by inoculum dose. We also identified IL-10 as a possible mechanism to explain the lack of influence of inoculum dose on priming of T cells in the lymph node.


Functional characterization of TtnD and TtnF, unveiling new insights into tautomycetin biosynthesis.
The biosynthetic gene cluster for tautomycetin (TTN), a highly potent and selective protein phosphatase (PP) inhibitor isolated from Streptomyces griseochromogenes, has recently been cloned and sequenced. To better understand the transformations responsible for converting the post-polyketide synthase product into the exciting anticancer and immunosuppressive chemotherapeutic candidate TTN, we produced and characterized new analogues resulting from inactivation of two genes, ttnD and ttnF, in S. griseochromogenes. Inactivation of ttnD and ttnF, which encode for putative decarboxylase and dehydratase enzymes, respectively, afforded mutant strains SB13013 and SB13014. The DeltattnD mutant SB13013 accumulated four new TTN analogues, TTN D-1, TTN D-2, TTN D-3, and TTN D-4, whereas the DeltattnF mutant accumulated only one new TTN analogue, TTN F-1. The accumulation of these new TTN analogues defines the function of TtnD and TtnF and the timing of their chemistries in relation to installation of the C5 ketone moiety within TTN. Notably, all new analogues possess a structurally distinguishing carboxylic acid moiety, revealing that TtnD apparently cannot catalyze decarboxylation in the absence of TtnF. Additionally, cytotoxicity and PP inhibition assays reveal the importance of the functional groups installed by TtnDF and, consistent with earlier proposals, the C2''-C5 fragment of TTN to be a critical structural determinant behind the important and unique PP-1 selectivity displayed by TTN.


Self-reported use of evidence-based medicine and smoking cessation 6 - 9 months after acute coronary syndrome: a single-centre perspective.
Good evidence exists to support the use of secondary prevention medications (aspirin, statins, beta-blockers and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs)) and smoking cessation in patients after acute coronary syndromes (ACSs). Little is currently known about adherence to medication and smoking behaviour after discharge in South Africa. We conducted a cross-sectional analysis of all patients with a diagnosis of ACS discharged from the Coronary Care Unit at Groote Schuur Hospital, Cape Town, between 15 November 2011 and 15 April 2012. Patients were telephoned 6 - 9 months after discharge and completed a standardised questionnaire detailing current medication use, reasons for non-adherence and smoking status. Prescribing of secondary prevention medications at discharge was high (aspirin 94.5%, statins 95.7%, beta-blockers 85.4%, ACEIs/ARBs 85.9%), and 70.7% of patients were discharged on a combination of all four drugs. At 6 - 9-month follow-up, the proportion using these medications had dropped by 8.9% for aspirin, 10.1% for statins, 6.2% for beta-blockers and 17.9% for ACEIs/ARBs. Only 47.2% remained on all four drugs, a reduction of 23.5%. Of the 56.0% of patients who were smokers, 31.4% had stopped smoking. A significant decline in adherence to recommended therapy 6 - 9 months after discharge and a poor rate of smoking cessation suggest that efforts to educate patients about the importance of long-term adherence need to be improved. Furthermore, more effective interventions than in-hospital reminders about the hazards of smoking are needed to improve smoking cessation.


The combined action of Esrrb and Nr5a2 is essential for murine naïve pluripotency.
The maintenance of pluripotency in mouse embryonic stem cells (ESCs) is governed by the action of an interconnected network of transcription factors. Among them, only Oct4 and Sox2 have been shown to be strictly required for the self-renewal of ESCs and pluripotency, particularly in culture conditions in which differentiation cues are chemically inhibited. Here, we report that the conjunct activity of two orphan nuclear receptors, Esrrb and Nr5a2, parallels the importance of that of Oct4 and Sox2 in naïve mouse ESCs. By occupying a large common set of regulatory elements, these two factors control the binding of Oct4, Sox2 and Nanog to DNA. Consequently, in their absence the pluripotency network collapses and the transcriptome is substantially deregulated, leading to the differentiation of ESCs. Altogether, this work identifies orphan nuclear receptors, previously thought to be performing supportive functions, as a set of core regulators of naïve pluripotency.


Tennis injuries: epidemiology, pathophysiology, and treatment.
Tennis places high loads on the joints of players, with supraphysiologic forces being generated at the shoulder and elbow hundreds of times per match. Acute injuries tend to affect the lower extremity; chronic injuries usually involve the upper extremity. Commonly encountered upper extremity conditions include rotator cuff injury, internal impingement, superior labral tears, and epicondylitis of the elbow. Serving is the most strenuous stroke in tennis, with the highest peak muscle activity in the shoulder and forearm occurring during this stroke. The kinetic chain links upper extremity, lower extremity, and core muscle segments by transmitting coordinated activation and motion; in this regard, any pathologic process that disturbs the groin, hip, and abdominal musculature can further result in an increased risk of injury to the shoulder and upper extremity. Evolution in equipment and in play surfaces has also affected the type and frequency of injuries. Prevention programs that address the muscular imbalances throughout the kinetic chain may help reduce the incidence of both acute and chronic injuries experienced by tennis athletes.


Protocol for a systematic review of health promotion interventions for African Americans delivered in US barbershops and hair salons.
African American adults are disproportionately burdened by chronic diseases, particularly at younger ages. Developing culturally appropriate interventions is paramount to closing the gap in these health inequities. The purpose of this systematic review is to critically evaluate health promotion interventions for African Americans delivered in two environments that are frequented by this population: barbershops and hair salons. Characteristics of effective interventions will be identified and evidence for the effectiveness of these interventions will be provided. Results of this review will inform future health promotion efforts for African Americans particularly focused on the leading health inequities in obesity-related chronic diseases: cardiovascular disease, cancer and type 2 diabetes. Subject headings and keywords will be used to search for synonyms of 'barbershops,' 'hair salons' and 'African Americans' to identify all relevant articles (from inception onwards) in the following databases: Academic Search Ultimate, Cumulative Index of Nursing and Allied Health Literature, Embase, PsycINFO, PubMed, Web of Science (Science Citation Index and Social Sciences Citation Index) and ProQuest Dissertations. Experimental and quasi-experimental studies for adult (>18 years) African Americans delivered in barbershops and hair salons will be included. Eligible interventions will include risk reduction/management of obesity-related chronic disease: cardiovascular disease, cancer and type 2 diabetes. Two reviewers will independently screen, select and extract data and a third will mediate disagreements. The methodological quality (or risk of bias) of individual studies will be appraised using the Effective Public Health Practice Project Quality Assessment Tool. Quality and content of the evidence will be narratively synthesised. Since this is a protocol for a systematic review, ethical approval is not required. Findings from the review will be widely disseminated through conference presentations, peer-reviewed publications and traditional and social media outlets.


Evolution of the muscles of facial expression in a monogamous ape: evaluating the relative influences of ecological and phylogenetic factors in hylobatids.
Facial expression is a communication mode produced by facial (mimetic) musculature. Hylobatids (gibbons and siamangs) have a poorly documented facial display repertoire and little is known about their facial musculature. These lesser apes represent an opportunity to test hypotheses related to the evolution of primate facial musculature as they are the only hominoid with a monogamous social structure, and thus live in very small groups. Primate species living in large groups with numerous social relationships, such as chimpanzees and rhesus macaques, have been shown to have a complex facial display repertoire and a high number of discrete facial muscles. The present study was designed to examine the relative influence of social structure and phylogeny on facial musculature evolution by comparing facial musculature complexity among hylobatids, chimpanzees, and rhesus macaques. Four faces were dissected from four hylobatid species. Morphology, attachments, three-dimensional relationships, and variation among specimens were noted and compared to rhesus macaques and chimpanzees. Microanatomical characteristics of the orbicularis oris muscle were also compared. Facial muscles of hylobatids were generally gracile and less complex than both the rhesus macaque and chimpanzee. Microanatomically, the orbicularis oris muscle of hylobatids was relatively loosely packed with muscle fibers. These results indicate that environmental and social factors may have been important in determining morphology and complexity of facial musculature in the less social hylobatids and that they may not have experienced as strong selection pressure for mimetic muscle complexity as other, more social primates.


Increased plasma levels of the APC-interacting protein MAPRE1, LRG1, and IGFBP2 preceding a diagnosis of colorectal cancer in women.
Longitudinal blood collections from cohort studies provide the means to search for proteins associated with disease before clinical diagnosis. We investigated plasma samples from the Women's Health Initiative (WHI) cohort to determine quantitative differences in plasma proteins between subjects subsequently diagnosed with colorectal cancer (CRC) and matched controls that remained cancer-free during the period of follow-up. Proteomic analysis of WHI samples collected before diagnosis of CRC resulted in the identification of six proteins with significantly (P < 0.05) elevated concentrations in cases compared with controls. Proteomic analysis of two CRC cell lines showed that five of the six proteins were produced by cancer cells. Microtubule-associated protein RP/EB family member 1 (MAPRE1), insulin-like growth factor-binding protein 2 (IGFBP2), leucine-rich alpha-2-glycoprotein (LRG1), and carcinoembryonic antigen (CEA) were individually assayed by enzyme linked immunosorbent assay (ELISA) in 58 pairs of newly diagnosed CRC samples and controls and yielded significant elevations (P < 0.05) among cases relative to controls. A combination of these four markers resulted in a receiver operating characteristics curve with an area under the curve value of 0.841 and 57% sensitivity at 95% specificity. This combination rule was tested in an independent set of WHI samples collected within 7 months before diagnosis from cases and matched controls resulting in 41% sensitivity at 95% specificity. A panel consisting of CEA, MAPRE1, IGFBP2, and LRG1 has predictive value in prediagnostic CRC plasmas.


Effects of hyperglycemia and iron deficiency on kidney and heart function in type 2 diabetes disease.
Untreated anemia can caused significant cardiac and kidney damage. The aim of this study was to investigate the efficiency of anemia and hyperglycemia treatment in type 2 diabetes and their impact on kidney and heart impairment. The study is clinical retrospective and prospective and it was conducted in Clinic of Endocrinology, Diabetes Mellitus and Metabolic Diseases, University Clinical Center of Sarajevo. Prior to the study all patients were taking oral hypoglycemic drugs included sulfonylureas and biguanides. These subjects were put on 2 times daily fix mix insulin and biguanides after lunch. Each day, subjects received Iron tab 1 x 100 mg/ day, and C vitamin 1 x 100 mg/day. The results of our study are showing that effective treatment of glycaemia and anemia in patients with diabetes, reduces blood pressure, urine albumin secretion and pulse rate, diminishing cardiovascular damage and improving kidney function.


The Streptococcus mutans serine/threonine kinase, PknB, regulates competence development, bacteriocin production, and cell wall metabolism.
Bacteria can detect, transmit, and react to signals from the outside world by using two-component systems (TCS) and serine-threonine kinases and phosphatases. Streptococcus mutans contains one serine-threonine kinase, encoded by pknB. A gene encoding a serine-threonine phosphatase, pppL, is located upstream of pknB. In this study, the phenotypes of pknB and pppL single mutants and a pknB pppL double mutant were characterized. All mutants exhibited a reduction in genetic transformability and biofilm formation, showed abnormal cell shapes, grew slower than the wild-type strain in several complex media, and exhibited reduced acid tolerance. The mutants had reduced cariogenic capacity but no significant defects in colonization in a rat caries model. Whole-genome transcriptome analysis revealed that a pknB mutant showed reduced expression of genes involved in bacteriocin production and genetic competence. Among the genes that were differentially regulated in the pknB mutant, several were likely to be involved in cell wall metabolism. One such gene, SMU.2146c, and two genes encoding bacteriocins were shown to also be downregulated in a vicK mutant, which encodes a sensor kinase involved in the response to oxidative stress. Collectively, the results lead us to speculate that PknB may modulate the activity of the two-component signal transduction systems VicKR and ComDE. Real-time reverse transcriptase PCR (RT-PCR) showed that genes downregulated in the pknB mutant were upregulated in the pppL mutant, indicating that PppL serves to counteract PknB.


A Residue Quartet in the Extracellular Domain of the Prolactin Receptor Selectively Controls Mitogen-activated Protein Kinase Signaling.
Cytokine receptors elicit several signaling pathways, but it is poorly understood how they select and discriminate between them. We have scrutinized the prolactin receptor as an archetype model of homodimeric cytokine receptors to address the role of the extracellular membrane proximal domain in signal transfer and pathway selection. Structure-guided manipulation of residues involved in the receptor dimerization interface identified one residue (position 170) that in cell-based assays profoundly altered pathway selectivity and species-specific bio-characteristics. Subsequent in vitro spectroscopic and nuclear magnetic resonance analyses revealed that this residue was part of a residue quartet responsible for specific local structural changes underlying these effects. This included alteration of a novel aromatic T-stack within the membrane proximal domain, which promoted selective signaling affecting primarily the MAPK (ERK1/2) pathway. Importantly, activation of the MAPK pathway correlated with in vitro stabilities of ternary ligand·receptor complexes, suggesting a threshold mean lifetime of the complex necessary to achieve maximal activation. No such dependence was observed for STAT5 signaling. Thus, this study establishes a residue quartet in the extracellular membrane proximal domain of homodimeric cytokine receptors as a key regulator of intracellular signaling discrimination.


A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies.
Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive--many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders.


Spatial organization of the Nim1-Wee1-Cdc2 mitotic control network in Schizosaccharomyces pombe.
In Schizosaccharomyces pombe the onset of mitosis is regulated by a network of protein kinases and phosphatases. The M-phase inducing Cdc2-Cdc13 cyclin-dependent kinase is inhibited by Wee1 tyrosine kinase and activated by Cdc25 phosphatase. Wee1 is negatively regulated by Nim1 protein kinase. Here, we describe investigations aimed at better understanding the role of Nim1 in the mitotic control. The most important finding to emerge from these studies is that Wee1 and Nim1 have different patterns of intracellular localization. Immunofluorescence confocal microscopy has revealed that Nim1 is localized in the cytoplasm, whereas it substrate Wee1 is predominantly localized in the nucleus. Previous studies showed that the Cdc2-Cdc13 complex is located in the nucleus. Diversion of Nim1 to the nucleus, accomplished by addition of the SV40 nuclear localization signal, caused the advancement of M, confirming that Nim1 has restricted access to Wee1 in vivo. We propose that the intracellular distribution of Nim1 and Wee1 may serve to coordinate the regulation of nuclear Cdc2-Cdc13 with cytoplasmic growth.


Physical education for deaf students.
An ideal physical education program would be one that focuses on aspects leading to lifelong participation in and enjoyment of physical activity accompanied by appropriate fitness levels. Often, physical education classes are the only physical activity that many children receive throughout the day, and without them, an even greater number of children, including those who are deaf, would be prone to aspects associated with sedentary lifestyles. Schools need to involve their students in daily physical education classes. The emphasis of such a program should be placed on promoting physical fitness and developing skills that lead to a lifelong enjoyment of physical activity and healthy lifestyles. This paper reviews the literature on the state of physical fitness among deaf students and describes an exemplary physical education program that was implemented at a school for deaf children.


Role of stereotactic radiosurgery in the treatment of acromegaly.
Acromegaly is a rare, indolent disease due to overproduction of growth hormone. Surgery is identified as primary treatment, but has its limitation, thus frequently requiring alternate treatment options as adjunct to surgery. Stereotactic radiosurgery (SRS) has been used as adjuvant and alternate therapy in patients with inoperable or residual disease; or those not fit for surgery. It has shown reasonable results for treating macroadenoma and tumours invading cavernous sinuses with significant reduction in tumour size and durable endocrinological remission. Factors favouring better outcomes include time from last resection to SRS, older age, peri-procedural withdrawal of medication, higher margin and maximum dose.Hypopituitarism is the most common side effects and requires yearly screening. With the new advances in the field Fractionated-stereotactic radiosurgery and cyber-knife robotic radiosurgery have been introduced with promising preliminary results..


Baseline factors predicting placebo response to treatment in children and adolescents with autism spectrum disorders: a multisite randomized clinical trial.
The finding of factors that differentially predict the likelihood of response to placebo over that of an active drug could have a significant impact on study design in this population. To identify possible nonspecific, baseline predictors of response to intervention in a large randomized clinical trial of children and adolescents with autism spectrum disorders. Randomized clinical trial of citalopram hydrobromide for children and adolescents with autism spectrum disorders and prominent repetitive behavior. Baseline data at study entry were examined with respect to final outcome to determine if response predictors could be identified. A total of 149 children and adolescents 5 to 17 years of age (mean [SD] age, 9.4 [3.1] years) from 6 academic centers were randomly assigned to citalopram (n = 73) or placebo (n = 76). Participants had autistic disorder, Asperger syndrome, or pervasive developmental disorder, not otherwise specified; had illness severity ratings that were moderate or more than moderate on the Clinical Global Impression-Severity scale; and scored moderate or more than moderate on compulsive behaviors measured with the modified Children's Yale-Brown Obsessive-Compulsive Scale. Twelve weeks of treatment with citalopram (10 mg/5 mL) or placebo. The mean (SD) maximum dose of citalopram was 16.5 (6.5) mg by mouth daily (maximum dose, 20 mg/d). A positive response was defined as having a score of at least much improved on the Clinical Global Impression-Improvement scale at week 12. Baseline measures included demographic (sex, age, weight, and pubertal status), clinical, and family measures. Clinical variables included baseline illness severity ratings (the Aberrant Behavior Checklist, the Child and Adolescent Symptom Inventory, the Vineland Adaptive Behavior Scales, the Repetitive Behavior Scale-Revised, and the Children's Yale-Brown Obsessive-Compulsive Scale). Family measures included the Caregiver Strain Questionnaire. Several baseline predictors of response were identified, and a principal component analysis yielded 3 composite measures (disruptive behavior, autism/mood, and caregiver strain) that significantly predicted response at week 12. Specifically, participants in the placebo group were significantly less likely than participants in the citalopram group to respond at week 12 if they entered the study more symptomatic on each of the 3 composite measures, and they were at least 2 times less likely to be responders. This analysis suggests strategies that may be useful in anticipating and potentially mitigating the nonspecific response in randomized clinical trials of children and adolescents with autism spectrum disorders. clinicaltrials.gov Identifier: NCT00086645.


Capture stress and post-release mortality of blacktip sharks in recreational charter fisheries of the Gulf of Mexico.
Understanding the stress responses of sharks to recreational catch and release fishing has important management and conservation implications. The blacktip shark Carcharhinus limbatus is a popular recreational species targeted throughout the western, central and eastern Gulf of Mexico (Gulf) yet it is unclear what levels of physiological stress result from catch-release fishing practices with hook and line gear and if the stress levels result in post-release mortality. This study correlates physiological response to stress through blood chemistry analysis and examines post-release behaviour of adult blacktip sharks caught to determine post-release mortality rates. Release behaviour was determined by pop-up satellite archival transmitting (PSAT) tags that record temperature, depth and light level data. To quantify physiological stress levels, blood samples were collected from 52 blacktip sharks and a suite of metabolic and osmotic markers were measured. Thirty-six of those blacktip sharks were also outfitted with a PSAT tag yielding time-at-large from 3 to 180 days. Of the 36 tags, 22 (61%) provided sufficient data to confirm post-release fate and 11 (31%) were recovered providing high-resolution data. Tag data suggests a post-release morality rate of 22.7% (95% confidence interval 7.8-45.4%), with mortality occurring within minutes (immediate mortality) to over 12 h post-release (delayed mortality). Compared to survivors, immediate mortalities exhibited significantly higher lactate (median 2.8 mmol/Lsurvivor vs 5.9 mmol/Limmediate mortality) and significantly lower hematocrit (median 24.4% survivor vs 14% immediate mortality) levels, but no difference was detected between survivors and delayed mortalities. Higher mortality in the western (30%) compared to the central (20%) Gulf may be due to shark handling. All PSATs from mortalities (N = 5) were recovered, and archived data revealed evidence of tag ingestion by predators. Results suggest reduced fight time, decreased handling time and limited air exposure provide blacktip sharks the best survival chances after release by recreational anglers.


Paternal occupation and retinoblastoma: a case-control study based on data for Great Britain 1962-1999.
To examine the association between paternal occupational exposures and retinoblastoma using birth registration data for cases from the National Registry of Childhood Tumours (NRCT) and controls from the general population of Great Britain. A case-control study of paternal occupational data for 1318 cases of retinoblastoma, born and diagnosed in Great Britain between 1962 and 1999, and 1318 controls matched on sex, date of birth and birth registration sub-district. Paternal occupations at birth were grouped according to inferred exposure using an occupational exposure classification scheme. A conditional (matched) case-control analysis was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for each paternal occupational exposure group. For non-heritable retinoblastoma, a statistically significant increased risk was found with father's definite occupational exposure to oil mists in metal working (OR = 1.85 (95% CI 1.05 to 3.36)). Together with a (non-significant) risk (OR = 1.64 (0.73 to 3.83)) amongst the heritable cases, this occupational exposure was also associated with a significant increased risk when all retinoblastoma cases were considered together (OR = 1.77 (1.12 to 2.85)). No statistically significant associations were observed for other exposure groups. Our finding for exposure to oil mists in metal working (a subset of metal workers) is not directly comparable to those for metal working previously reported in the literature. Overall, our findings do not support the hypothesis that paternal occupational exposure is an important aetiological factor for retinoblastoma, however, the study has low power and other methodological limitations.


A Narrative Review of the Lesser Known Medications for Treatment of Restless Legs Syndrome and Pathogenetic Implications for Their Use.
There are several well-known treatments for Restless Legs Syndrome (RLS), including dopamine agonists (pramipexole, ropinirole, rotigotine), anticonvulsants (gabapentin and its analogs, pregabalin), oral or intravenous iron, opioids and benzodiazepines. However, in clinical practice, treatment is sometimes limited due to incomplete response or side effects and it is necessary to be aware of other treatment options for RLS, which is the purpose of this review. We performed a narrative review detailing all of the lesser known pharmacological treatment literature on RLS. The review purposefully excludes well-established, well-known treatments for RLS which are widely accepted as treatments for RLS in evidence-based reviews. We also have emphasized the pathogenetic implications for RLS of the successful use of these lesser known agents. Alternative pharmacological agents include clonidine which reduces adrenergic transmission, adenosinergic agents such as dipyridamole, glutamate AMPA receptor blocking agents such as perampanel, glutamate NMDA receptor blocking agents such as amantadine and ketamine, various anticonvulsants (carbamazepine/oxcarbazepine, lamotrigine, topiramate, valproic acid, levetiracetam), anti-inflammatory agents such as steroids, as well as cannabis. Bupropion is also a good choice for the treatment of co-existent depression in RLS because of its pro-dopaminergic properties. Clinicians should first follow evidence-based review recommendations for the treatment of RLS but when the clinical response is either incomplete or side effects are intolerable other options can be considered. We neither recommend nor discourage the use of these options, but leave it up to the clinician to make their own choices based upon the benefit and side effect profiles of each medication.


Neuroprotective potential of Linezolid: a quantitative and distribution study via mass spectrometry.
A study was undertaken to determine the neuroprotective potential of Linezolid (LIN) in an animal model. Female Sprague-Dawley rats were either given a single (100 mg/kg) dose or treated daily for 4 weeks. A validated LC-MS/MS method was used to measure LIN levels in plasma and brain, this was paired with mass spectrometry imaging to determine the tissue spatial distribution of the drug. The results showed that after a single dose there was poor penetration of the drug into the brain. With multiple doses there were high tissue levels, with the drug reaching steady state in subsequent weeks. LIN displayed a promising distribution pattern with localisation in the brainstem. Systemic circulation is fed into the brain by the carotid and vertebral arteries which enter through the brain stem, therefore high drug concentrations is this area may protect against infectious agents entering via this route.


[Diagnostic accuracy research of needle puncture biopsy during operation for pulmonary single nodules].
To investigate the diagnostic accuracy of needle puncture biopsy and pathological examination of frozen during operation for pulmonary nodules, and whether this diagnostic method can replace tumor resection examination. Totally 50 patients (28 males and 22 females, average age was 59 years) who had the single nodule after imaging examination without any pathological diagnostic from January to October 2010 were selected in this research work. During open operation or video assisted thoracic surgery, needle (14 G model) was used to puncture biopsy for pathological examination of frozen. All the adverse events during puncture biopsy would be recorded. The resection specimens would be accepted paraffin pathological examination. The relationship between puncture frozen pathological and paraffin pathological examination was analyzed. All tumor sizes were ranged from 1.0 cm × 0.6 cm to 5.6 cm × 9.0 cm. The paraffin pathological examination after operation as the golden standard, there were 7 cases of benign tumor and 43 cases of malignant tumor. The diagnostic sensitivity of puncture biopsy was 90.7%, the specificity was 100%, the positive predictive value was 100% and the negative predictive value was 63.6%. There were 11 cases of benign tumor diagnosed by needle puncture biopsy, among which 4 cases were proved as malignant tumor by paraffin pathology, and the false negative rate was 9.3%. The main risk of puncture biopsy was bleeding after puncture immediately, and the rate was 4.0% (2/50). The puncture biopsy during operation had a high specificity for malignant lung tumor, and there was a certain false negative rate for benign tumor. Puncture biopsy and pathological examination of frozen tissue can replace tumor section biopsy in a way.


Population Dynamics and Community Composition of Ammonia Oxidizers in Salt Marshes after the Deepwater Horizon Oil Spill.
The recent oil spill in the Gulf of Mexico had significant effects on microbial communities in the Gulf, but impacts on nitrifying communities in adjacent salt marshes have not been investigated. We studied persistent effects of oil on ammonia-oxidizing archaeal (AOA) and bacterial (AOB) communities and their relationship to nitrification rates and soil properties in Louisiana marshes impacted by the Deepwater Horizon oil spill. Soils were collected at oiled and unoiled sites from Louisiana coastal marshes in July 2012, 2 years after the spill, and analyzed for community differences based on ammonia monooxygenase genes (amoA). Terminal Restriction Fragment Polymorphism and DNA sequence analyses revealed significantly different AOA and AOB communities between the three regions, but few differences were found between oiled and unoiled sites. Community composition of nitrifiers was best explained by differences in soil moisture and nitrogen content. Despite the lack of significant oil effects on overall community composition, we identified differences in correlations of individual populations with potential nitrification rates between oiled and unoiled sites that help explain previously published correlation patterns. Our results suggest that exposure to oil, even 2 years post-spill, led to subtle changes in population dynamics. How, or if, these changes may impact ecosystem function in the marshes, however, remains uncertain.


Infants' brain responses to speech suggest analysis by synthesis.
Historic theories of speech perception (Motor Theory and Analysis by Synthesis) invoked listeners' knowledge of speech production to explain speech perception. Neuroimaging data show that adult listeners activate motor brain areas during speech perception. In two experiments using magnetoencephalography (MEG), we investigated motor brain activation, as well as auditory brain activation, during discrimination of native and nonnative syllables in infants at two ages that straddle the developmental transition from language-universal to language-specific speech perception. Adults are also tested in Exp. 1. MEG data revealed that 7-mo-old infants activate auditory (superior temporal) as well as motor brain areas (Broca's area, cerebellum) in response to speech, and equivalently for native and nonnative syllables. However, in 11- and 12-mo-old infants, native speech activates auditory brain areas to a greater degree than nonnative, whereas nonnative speech activates motor brain areas to a greater degree than native speech. This double dissociation in 11- to 12-mo-old infants matches the pattern of results obtained in adult listeners. Our infant data are consistent with Analysis by Synthesis: auditory analysis of speech is coupled with synthesis of the motor plans necessary to produce the speech signal. The findings have implications for: (i) perception-action theories of speech perception, (ii) the impact of "motherese" on early language learning, and (iii) the "social-gating" hypothesis and humans' development of social understanding.


Inventory of oncologists' unmet needs for tools to support decision-making about palliative treatment for metastatic colorectal cancer.
Decision-making about palliative care for metastatic colorectal cancer (mCRC) consists of many different treatment-related decisions, and there generally is no best treatment option. Decision support systems (DSS), e.g., prognostic calculators, can aid oncologists' decision-making. DSS that contain features tailored to the needs of oncologists are more likely to be implemented in clinical practice. Therefore, our aim is to inventory colorectal cancer specialists' unmet decision support needs. We asked oncologists from the Dutch colorectal cancer group (DCCG), to participate in an online inventory questionnaire on their unmet decision support needs. To get more in-depth insight in required features of the DSS they need, we also conducted semi-structured telephone interviews. Forty-one oncologists started the inventory questionnaire, and 27 of them completed all items. Of all respondents, 18 were surgeons (44%), 22 were medical oncologists (54%), and 28 (68%) had more than 10 years of experience treating mCRC. In both the inventory questionnaire and interviews, respondents expressed a need for an overarching DSS incorporating multiple treatment options, and presenting both the treatment benefits and harms. Respondents found it relevant for other outcomes, such as cost-effectiveness of treatment or quality of life, to be incorporated in DSS. There was also a wish for DSS incorporating an up-to-date "personalized" overview of the ongoing trials for which a specific patient is eligible. Experienced oncologists indicate that their treatment advice is currently almost solely based on the available clinical guidelines. They experience a lack of good quality DSS to help them personalize their treatment advice. New tools integrating multiple treatment options and providing a broad range of clinically relevant outcomes are urgently needed to stimulate and safeguard more personalized treatment decision-making.


Reverse engineering cellular networks with information theoretic methods.
Building mathematical models of cellular networks lies at the core of systems biology. It involves, among other tasks, the reconstruction of the structure of interactions between molecular components, which is known as network inference or reverse engineering. Information theory can help in the goal of extracting as much information as possible from the available data. A large number of methods founded on these concepts have been proposed in the literature, not only in biology journals, but in a wide range of areas. Their critical comparison is difficult due to the different focuses and the adoption of different terminologies. Here we attempt to review some of the existing information theoretic methodologies for network inference, and clarify their differences. While some of these methods have achieved notable success, many challenges remain, among which we can mention dealing with incomplete measurements, noisy data, counterintuitive behaviour emerging from nonlinear relations or feedback loops, and computational burden of dealing with large data sets.


Can we estimate the critical micelle concentration of amphiphilic drug bases from molecular connectivity indices?
Self-aggregation of drugs is since many years an important topic in the pharmaceutical sciences. Drugs can aggregate similar to surfactants and thereby exhibit a critical micelle concentration (CMC). The present work focused on amphiphilic drug bases and it was aimed to predict log(CMC) based on chemical structure alone. A dataset of 35 compounds was gathered mostly form the literature and complemented with own measurements based on ultrasonic resonator technology. The hydrophilic-lipophilic balance (HLB) values of the protonated bases were calculated and provided a range of 22.9-27.4. Based on a hypothesis from surfactant sciences, it was tried to predict log(CMC) with connectivity and shape indices as well as molecular dipole moment. A fairly good model was obtained using the Randix index (RI), 3 D Wiener number (WN) and molecular dipole moment (DM) (R2 = 0.824). Interestingly, a simple linear regression of log(CMC) with the Randic index alone, resulted in an acceptable model (R2 = 0.755). The present work should help with early identification of drug bases that exhibit surfactant-like behavior and an estimation of log(CMC) values is proposed. An improved understanding of drug aggregation and prediction of log(CMC) helps to better cope with physical consequences like, for example, "anomalous" drug solubility in drug discovery and development.


The global distribution of risk factors by poverty level.
To estimate the individual-level association of income poverty with being underweight, using tobacco, drinking alcohol, having access only to unsafe water and sanitation, being exposed to indoor air pollution and being obese. Using survey data for as many countries as possible, we estimated the relative risk association between income or assets and risk factors at the individual level within 11 medium- and low-income subregions of WHO. WHO and The World Bank data on the prevalence of risk factors and income poverty (defined as living on < US$ 1.00 per day, US$ 1-2.00 per day and > US$ 2.00 per day) were analysed to impute the association between poverty and risk factors for each subregion. The possible effect of poverty reduction on the prevalence of risk factors was estimated using population-attributable risk percentages. There were strong associations between poverty and malnutrition among children, having access only to unsafe water and sanitation, and being exposed to indoor air pollution within each subregion (relative risks were twofold to threefold greater for those living on < US$ 1.00 per day compared with those living on > US$ 2.00 per day). Associations between poverty and obesity, tobacco use and alcohol use varied across subregions. If everyone living on < US$ 2.00 per day had the risk factor profile of those living on > US$ 2.00 per day, 51% of exposures to unimproved water and sanitation could be avoided as could 37% of malnutrition among children and 38% of exposure to indoor air pollution. The more realistic, but still challenging, Millennium Development Goal of halving the number of people living on < US$ 1.00 per day would achieve much smaller reductions. To achieve large gains in global health requires both poverty eradication and public health action. The methods used in this study may be useful for monitoring pro-equity progress towards Millennium Development Goals.


MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.
The histone 3 lysine 79 (H3K79) methyltransferase Dot1l has been implicated in the development of leukemias bearing translocations of the Mixed Lineage Leukemia (MLL) gene. We identified the MLL-fusion targets in an MLL-AF9 leukemia model, and conducted epigenetic profiling for H3K79me2, H3K4me3, H3K27me3, and H3K36me3 in hematopoietic progenitor and leukemia stem cells (LSCs). We found abnormal profiles only for H3K79me2 on MLL-AF9 fusion target loci in LSCs. Inactivation of Dot1l led to downregulation of direct MLL-AF9 targets and an MLL translocation-associated gene expression signature, whereas global gene expression remained largely unaffected. Suppression of MLL translocation-associated gene expression corresponded with dependence of MLL-AF9 leukemia on Dot1l in vivo. These data point to DOT1L as a potential therapeutic target in MLL-rearranged leukemia.


Regenerative proliferation in inner ear sensory epithelia from adult guinea pigs and humans.
Supporting cells in the vestibular sensory epithelia from the ears of mature guinea pigs and adult humans proliferate in vitro after treatments with aminoglycoside antibiotics that cause sensory hair cells to die. After 4 weeks in culture, the epithelia contained new cells with some characteristics of immature hair cells. These findings are in contrast to expectations based on previous studies, which had suggested that hair cell loss is irreversible in mammals. The loss of hair cells is responsible for hearing and balance deficits that affect millions of people.


Repeatability of Choroidal Thickness Measurements on Enhanced Depth Imaging Optical Coherence Tomography Using Different Posterior Boundaries.
To assess the reliability of manual choroidal thickness measurements by comparing different posterior boundary definitions of the choroidal-scleral junction on enhanced depth imaging optical coherence tomography (EDI-OCT). Reliability analysis. Two graders marked the choroidal-scleral junction with segmentation software using different posterior boundaries: (1) the outer border of the choroidal vessel lumen, (2) the outer border of the choroid stroma, and (3) the inner border of the sclera, to measure the vascular choroidal thickness (VCT), stromal choroidal thickness (SCT), and total choroidal thickness (TCT), respectively. Measurements were taken at 0.5-mm intervals from 1.5 mm nasal to 1.5 mm temporal to the fovea, and averaged continuously across the central 3 mm of the macula. Intraclass correlation coefficient (ICC) and coefficient of reliability (CR) were compared to assess intergrader and intragrader reliability. Choroidal thickness measurements varied significantly with different posterior boundaries (P < .001 for all). Intergrader ICCs were greater for SCT (0.959-0.980) than for TCT (0.928-0.963) and VCT (0.750-0.869), even in eyes where choroidal-scleral junction visibility was <75%. Intergrader CRs were lower for SCT (41.40-62.31) than for TCT (61.13-74.24) or VCT (72.44-115.11). ICCs and CRs showed greater reliability for averaged VCT, SCT, or TCT measurements than at individual locations. Intragrader ICCs and CRs were comparable to intergrader values. Choroidal thickness measurements are more reproducible when measured to the border of the choroid stroma (SCT) than the vascular lumen (VCT) or sclera (TCT).


Regulatory aspects on the use of fish embryos in environmental toxicology.
Animal alternative tests are gaining serious consideration in an array of environmental sciences, particularly as they relate to sound management of chemicals and wastewater discharges. The ILSI Health and Environmental Sciences Institute and the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) held an International Workshop on the Application of the Fish Embryo Test in March, 2008. This relatively young discipline is following advances in animal alternatives for human safety sciences, and it is advisable to develop a broad comparison of how animal alternative tests involving fish are viewed in a regulatory context over a wide array of authorities or advising bodies. These include OECD, Western Europe, North America, and Japan. This paper summarizes representative practices from these regions. Presently, the global regulatory environment has varying stances regarding the protection of fish for use as an experimental animal. Such differences have a long-term potential to lead to a lack of harmony in approaches to fish toxicity testing, especially for chemicals in commerce across multiple geographic regions. Implementation of alternative methods and approaches will be most successful if accepted globally, including methods of fish toxicity testing. An important area for harmonization would be in the interpretation of protected and nonprotected life stages of fish. Use of fish embryos represent a promising alternative and allow bridging to more technically challenging alternatives with longer prospective timelines, including cell-based assays, ecotoxicogenomics, and QSARs.


Diseases of the pancreas and suicide mortality: A nationwide nested case-control study among patients with mental health disorders in Taiwan.
Diseases of the pancreas, especially pancreatitis, have been implicated as possible risk factors for psychiatric illnesses, such as depression and anxiety disorder. This nested case-control study aimed to investigate the association between diseases of the pancreas and completed suicide in a psychiatric population-based study. The case group comprised 6568 completed suicides (ICD-9: E950-E959, E980-989) patients from the national mortality database between January 1, 2002 and December 1, 2010. These cases were compared with 6568 gender-, age-, residence-, and insurance premium-matched controls. Both suicide and non-suicide study patients were drawn from a group with previous psychiatric diagnoses. The risk of suicide among patients with diseases of the pancreas was analyzed using a conditional logistic regression model that controlled for alcohol-related disorder, drug dependence, schizophrenia, depressive disorder, bipolar disorder, anxiety disorder, Charlson comorbidity score, and outpatient visits. Disease of the pancreas was an independent risk factor for psychiatric patients who had completed suicide when adjusted for clinical and other comorbid factors. Among these covariates, alcohol-related disorders partially mediate the suicide risk among patients with disease of the pancreas, and mental disorders may not mediate this suicide risk. Diseases of the pancreas were associated with increased risk of completed suicide after controlling for potential confounding factors.


The meaning of close relationships and sexuality: women's well-being following a myocardial infarction.
Relationships and sexuality following heart attack (MI) have been studied; nevertheless, little is known about the meaning of social support and relationships to health and well-being after an MI. To our knowledge, no qualitative studies have further investigated the phenomenon. In this study we explore the meaning of close relationships and sexuality to women's health and well-being following MI. Ten women were interviewed using a reflective lifeworld approach and phenomenological epistemology. The meaning of women's close relationships following an MI appears to be closely intertwined with their long-term health process; both health processes and the relationships are affected. Suffering after an MI can be compared to taking a fall in that close relationships can become a safety net. Close relationships and sexuality are integrated into their lived bodies, and in that way have profound influence in their lifeworld experiences. Not all close relationships are intimate; however, all close and meaningful relationships can provide power and strength to the women's health processes. At the same time, these relationships also appear to drain energy and cause suffering.


Alpha adrenoceptors and autonomic mechanisms in perinephritis hypertension in the rabbit.
Increased pressor responses to norepinephrine and other pressor agents have been reported to occur in human essential hypertension and in several animal models of experimental hypertension. These increased responses might be related to the development of hypertension or could be a secondary consequence of the elevation in blood pressure. We have examined pressor responses to alpha-adrenoceptor agonists and to angiotensin II in male New Zealand White rabbits with perinephritic hypertension. Increased pressor responses were observed for the alpha 1 adrenoceptor agonist phenylephrine and the mixed alpha 1/alpha 2-adrenoceptor agonist norepinephrine but not for the alpha 2 adrenoceptor selective agonist guanabenz or angiotensin II. The increase occurred within 7 days of surgery and in some animals was observed when mean arterial pressure was not significantly elevated. It could not readily be attributed to intimal thickening or hypertrophy of the arterial wall, altered basal levels of norepinephrine or epinephrine, changes in norepinephrine clearance, beta-adrenoceptor interactions, or decreased baroreceptor sensitivity. However, the possibility that vascular hypertrophy and decreased baroreflex sensitivity may contribute to the increase at later times cannot be excluded. In all tissues examined, specific prazosin binding was decreased in the older animals and specific clonidine binding was decreased in forebrain. However, these changes were observed in both hypertensive and sham-operated animals and were probably age-related. We believe the increased response to alpha 1-adrenoceptor agonists may be related to changes at a postreceptor site in the coupling of receptor activation to smooth muscle contraction.