Differences in quality of life of patients undergoing total pelvic exenteration compared with standard rectal cancer surgery: a scoping review.
Rectal cancer is often treated surgically with an anterior resection (AR) or abdominoperineal excision (APE). However, for patients with locally advanced disease or local recurrence total pelvic exenteration (TPE) surgery can be performed. The magnitude of surgery varies, and little research has been done to consider how quality of life (QoL) may vary according to the extent of surgery. A search was conducted on MEDLINE and PubMed for papers published from 2010 to 2021. Inclusion criteria consisted of observational studies comparing adult populations with rectal cancer undergoing APE, AR or TPE, reporting QoL using validated tools. Risk of bias was assessed using the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool. Outcomes of interest were global QoL, gastrointestinal (GI) symptoms (nausea and vomiting, diarrhoea, and constipation) and pain. Seven studies including 1402 patients were analysed. QoL following TPE generally improves over time, back to baseline or better. AR and APE groups have similar patterns of improvement between baseline and 12 months after surgery, although scores declined in some studies at 12 months. TPE scores are lower overall, and the pattern of improvement differs, with patients tending to have worse nausea and vomiting symptoms. AR and APE patients tend to experience more lower GI symptoms. It is not possible to draw firm conclusions based on the studies analysed. However, QoL returns to baseline following TPE, APE and AR. Preoperative QoL appears to be an indication of postoperative outcomes. Further observational studies are required.


Establishment of left/right asymmetry in neuroblast migration by UNC-40/DCC, UNC-73/Trio and DPY-19 proteins in C. elegans.
The bilateral C. elegans neuroblasts QL and QR are born in the same anterior/posterior (A/P) position, but polarize and migrate left/right asymmetrically: QL migrates toward the posterior and QR migrates toward the anterior. After their migrations, QL but not QR switches on the Hox gene mab-5. We find that the UNC-40/netrin receptor and a novel transmembrane protein DPY-19 are required to orient these cells correctly. In unc-40 or dpy-19 mutants, the Q cells polarize randomly; in fact, an individual Q cell polarizes in multiple directions over time. In addition, either cell can express MAB-5. Both UNC-40 and DPY-19, as well as the Trio/GTPase exchange factor homolog UNC-73, are required for full polarization and migration. Thus, these proteins appear to participate in a signaling system that orients and polarizes these migrating cells in a left/right asymmetrical fashion during development. The C. elegans netrin UNC-6, which guides many cells and axons along the dorsoventral axis, is not involved in Q cell polarization, suggesting that a different netrin-like ligand serves to polarize these cells along the anteroposterior axis.


Simultaneous transfer of one good-quality and one poor-quality cleavage stage embryo does not improve pregnancy outcomes.
Embryo quality and quantity are key factors that determine the success of IVF-ET. Yet it is still unclear if, for those patients with only one good-quality embryo in an IVF cycle, the inclusion of a poor-quality embryo increases the procedure's success rate. This is a common question for both clinicians and patients in determining their course of treatment. The purpose of this work was to answer this intriguing question in the context of prognosis of patients undergoing fresh cycles with only one good-quality and more than one poor-quality cleavage-stage embryos. To control for confounding effects, we only included patients at similar age, body mass index (BMI), level of basal follicle stimulating hormone (FSH) and endometrial thickness from January 2015 to June 2021. A propensity score-matched analysis was performed to extract the matched pairs. Then we evaluated pregnancy outcome, including the rate of clinical pregnancy, live birth, embryo implantation, early miscarriage, and ectopic pregnancy. We found that the clinical pregnancy rate (34.8 vs. 38.0%, p = 0.553), live birth rate (27.1 vs. 29.9%, p = 0.598), early miscarriage rate (18.1 vs. 9.5%, p = 0.171) and ectopic pregnancy rate (1.3 vs. 1.2%, p = 1.000) did not significantly differ between those two groups, notwithstanding significant difference of the implantation rate (34.8 vs. 21.3%, p <0.001). Our work indicates that, for prognosis patients at approximately 34 years old with only one good-quality embryo, having additional poor-quality embryos does not seem to help to improve ART success rates per intended embryo transfer. In conclusion, we found that simultaneous transfer of one good-quality and one poor-quality cleavage stage embryo does not improve pregnancy outcomes.


Effects of short-term endurance exercise on gut microbiota in elderly men.
Regular exercise reduces the risks for cardiovascular diseases. Although the gut microbiota has been associated with fitness level and cardiometabolic risk factors, the effects of exercise-induced gut microbiota changes in elderly individuals are unclear. This study evaluated whether endurance exercise modulates the gut microbiota in elderly subjects, and whether these changes are associated with host cardiometabolic phenotypes. In a randomized crossover trial, 33 elderly Japanese men participated in a 5-week endurance exercise program. 16S rRNA gene-based metagenomic analyses revealed that the effect of endurance exercise on gut microbiota diversity was not greater than interindividual differences, whereas changes in α-diversity indices during intervention were negatively correlated with changes in systolic and diastolic blood pressure, especially during exercise. Microbial composition analyses showed that the relative abundance of Clostridium difficile significantly decreased, whereas that of Oscillospira significantly increased during exercise as compared to the control period. The changes in these taxa were correlated with the changes in several cardiometabolic risk factors. The findings indicate that short-term endurance exercise has little effect on gut microbiota in elderly individuals, and that the changes in gut microbiota were associated with cardiometabolic risk factors, such as systolic and diastolic blood pressure, providing preliminary insight into the associations between the gut microbiota and cardiometabolic phenotypes.


Selective inhibition by epinephrine of parathyroid hormone-stimulated adenylate cyclase in rat renal cortex.
Parathyroid hormone- (PTH) stimulated adenylate cyclase activity in homogenates of rat renal cortex was inhibited by l-epinephrine. The specificity of the inhibition indicated that it was mediated by alpha 2-receptors. The inhibition of PTH-stimulated activity was greater than the inhibition of basal activity. The absolute decrease in adenylate cyclase activity produced by 10-4 M l-epinephrine was from 16.3 +/-0.6 (SE) to 11.2 +/- 0.6 pmol.min-1.mg-1 for activity stimulated by 10 microgram/ml PTH. Basal activity was decreased from 2.3 +/- 0.07 to 1.7 +/- 0.04. A similar inhibition of PTH-stimulated adenylate cyclase by l-epinephrine was demonstrated in preparations of renal cortical tubules. In contrast, the quantitative decrease in vasopressin-or calcitonin-stimulated activity by 10-4 M l-epinephrine was the same as the decrease in basal activity. These results demonstrate that PTH receptors that stimulated adenylate cyclase and alpha 2-adrenergic receptors that inhibit adenylate cyclase are present on the same cells in the renal tubules. Thus, a mechanism exists whereby alpha-adrenergic agonists can oppose the tubular actions of PTH via a direct inhibition of adenylate cyclase activity.


Purification and characterization of 3-dehydroquinase from Escherichia coli.
A procedure has been developed for the purification of 3-dehydroquinase from Escherichia coli. Homogeneous enzyme with specific activity 163 units/mg of protein was obtained in 19% overall yield. The subunit Mr estimated from polyacrylamide-gel electrophoresis in the presence of sodium dodecyl sulphate was 29,000. The native Mr, estimated by gel permeation chromatography on Sephacryl S-200 (superfine) and on TSK G3000SW, was in the range 52,000-58,000, indicating that the enzyme is dimeric. The catalytic properties of the enzyme have been determined and shown to be very similar to those of the biosynthetic 3-dehydroquinase component of the arom multifunctional enzyme of Neurospora crassa.


Myb-related Schizosaccharomyces pombe cdc5p is structurally and functionally conserved in eukaryotes.
Schizosaccharomyces pombe cdc5p is a Myb-related protein that is essential for G2/M progression. To explore the structural and functional conservation of Cdc5 throughout evolution, we isolated Cdc5-related genes and cDNAs from Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and Homo sapiens. Supporting the notion that these Cdc5 gene family members are functionally homologous to S. pombe cdc5(+), human and fly Cdc5 cDNAs are capable of complementing the temperature-sensitive lethality of the S. pombe cdc5-120 mutant. Furthermore, S. cerevisiae CEF1 (S. cerevisiae homolog of cdc5(+)), like S. pombe cdc5(+), is essential during G2/M. The location of the cdc5-120 mutation, as well as mutational analyses of Cef1p, indicate that the Myb repeats of cdc5p and Cef1p are important for their function in vivo. However, we found that unlike in c-Myb, single residue substitutions of glycines for hydrophobic residues within the Myb repeats of Cef1p, which are essential for maintaining structure of the Myb domain, did not impair Cef1p function in vivo. Rather, multiple W-to-G substitutions were required to inactivate Cef1p, and many of the substitution mutants were found to confer temperature sensitivity. Although it is possible that Cef1p acts as a transcriptional activator, we have demonstrated that Cef1p is not involved in transcriptional activation of a class of G2/M-regulated genes typified by SWI5. Collectively, these results suggest that Cdc5 family members participate in a novel pathway to regulate G2/M progression.


Spatial neglect during electrocortical stimulation mapping in the right hemisphere.
Spatial processing was assessed following implantation of subdural electrodes in the nondominant hemisphere with electrocortical stimulation mapping (ESM) in two patients before epilepsy surgery. The first patient had mild hemispatial neglect/extinction during ESM of posterior temporal and inferior parietal areas. These areas were resected, and the patient had postoperative deficits that were similar to those occurring with ESM. The second patient was found to have marked hemispatial neglect during stimulation of parietal areas. These areas were not resected, and the patient had no neglect following surgery. These results suggest that ESM can help predict spatial processing deficits associated with cortical resection, and may help prevent postoperative impairments following resection in right parietal or temporal regions.


[Morphological features of Bundleia spp. (Ciliophora: Entodiniomorphida: Buetschliidae) and ontogenesis in Bundleia Cunha and Muniz 1928].
The aim of this study was to investigate the morphological features of 7 endocommensal ciliates, B. (s. str.) postciliata, B. (s. str.) piriformis, B. (s. str.) nana, B. (C.) elongata, B. (C.) triangularis, B. (F.) dolichosoma, and B. (F.) inflata belonging to the genus Bundleia, which exist in the hindgut of 15 Rahvan horses and 15 racing horses living in the vicinity of Izmir and to investigate the ontogenesis in the Bundleia genus. Specimens were obtained from 30 horses and were fixed with 10% formalin. The morphological features of the species were investigated with the pyridinated silver carbonate impregnation and silver nitrate impregnation techniques at the level of light microscopy. The morphological features of Bundleia spp. were found to be similar to the original descriptions, and it was detected that ontogenesis in the Bundleia genus exhibited suitability with other ciliate species in the Entodiniomorphida order. We conclude that the geographical variation and feeding habits of host animals are important for evaluating the biometric data of species.


[Improvement in treatment of patients with gonorrheal epididymo-orchitis].
Examinations of 46 patients with gonorrheal orchiepididymitis have revealed reduced IgA, IgG and IgM levels, a rise of circulating immune complexes level, and depressed lysozyme activity. Addition of proteolytic enzymes to combined therapy has improved the treatment efficacy and normalized the humoral immunity and nonspecific defense parameters.


Molecular pathology via IR and Raman spectral imaging.
During the last 15 years, vibrational spectroscopic methods have been developed that can be viewed as molecular pathology methods that depend on sampling the entire genome, proteome and metabolome of cells and tissues, rather than probing for the presence of selected markers. First, this review introduces the background and fundamentals of the spectroscopies underlying the new methodologies, namely infrared and Raman spectroscopy. Then, results are presented in the context of spectral histopathology of tissues for detection of metastases in lymph nodes, squamous cell carcinoma, adenocarcinomas, brain tumors and brain metastases. Results from spectral cytopathology of cells are discussed for screening of oral and cervical mucosa, and circulating tumor cells. It is concluded that infrared and Raman spectroscopy can complement histopathology and reveal information that is available in classical methods only by costly and time-consuming steps such as immunohistochemistry, polymerase chain reaction or gene arrays. Due to the inherent sensitivity toward changes in the bio-molecular composition of different cell and tissue types, vibrational spectroscopy can even provide information that is in some cases superior to that of any one of the conventional techniques.


Synthesis and transistor application of the extremely extended phenacene molecule, [9]phenacene.
Many chemists have attempted syntheses of extended π-electron network molecules because of the widespread interest in the chemistry, physics and materials science of such molecules and their potential applications. In particular, extended phenacene molecules, consisting of coplanar fused benzene rings in a repeating W-shaped pattern have attracted much attention because field-effect transistors (FETs) using phenacene molecules show promisingly high performance. Until now, the most extended phenacene molecule available for transistors was [8]phenacene, with eight benzene rings, which showed very high FET performance. Here, we report the synthesis of a more extended phenacene molecule, [9]phenacene, with nine benzene rings. Our synthesis produced enough [9]phenacene to allow the characterization of its crystal and electronic structures, as well as the fabrication of FETs using thin-film and single-crystal [9]phenacene. The latter showed a field-effect mobility as high as 18 cm(2) V(-1) s(-1), which is the highest mobility realized so far in organic single-crystal FETs.


Brachioradial pruritus: cervical spine disease and neurogenic/neuropathic [corrected] pruritus.
The main cause of brachioradial pruritus (BRP) is not known but there is evidence to suggest that BRP may arise in the nervous system. Cervical spine disease may be an important contributing factor. Our aim was to determine whether spine pathology is associated with BRP. Medical charts of patients with BRP seen in the Division of Dermatology of the University of Massachusetts Medical Center between the years of 1993 and 2000 were retrospectively analyzed. On the basis of clinical index of suspicion, some patients had undergone radiography of the spine. Of 22 patients with BRP, 11 had cervical spine radiographs. The radiographs showed cervical nnspine disease that could be correlated with the location of pruritus in each of these 11 patients. Patients with BRP may have underlying cervical spine pathology. Whether this association is causal or coincidental remains to be determined.


Chronically stressed female rats show increased anxiety but no behavioral alterations in object recognition or placement memory: a preliminary examination.
Stress, depending on intensity and duration, elicits adaptive or maladaptive physiological effects. Increasing evidence shows those patterns of advantageous versus deleterious physiologic stress effects also exist for some brain functions, including learning and memory. For example, short stress enhances, while chronic stress impairs, performance on numerous cognitive tasks in male rats. In contrast, performance of female rats is enhanced, or not altered, following both short-term and long-term stress exposure on the same behavioral tasks. The current study was designed to better characterize the behavioral effects of sustained chronic restraint stress in female rats. Female Sprague Dawley rats were assigned to a stress (restraint, 6 h/day, 35 days) or control (no stress) condition, weighed weekly, and then tested on open field (OF), object recognition (OR) and object placement (OP) tasks. Stressed females gained less weight during stress than controls. On the OF, there were no group differences in locomotor activity, but stressed females made fewer inner visits than controls, indicating increased anxiety. Both groups successfully performed the OP and OR tasks across all inter-trial delays, indicating intact non-spatial and spatial memory in both control and stress females. The current results provide preliminary evidence that the commonly used chronic restraint stress model may not be an efficient stressor to female rats.


Amphotericin B as antiviral drug: Possible efficacy against COVID-19.
Since its discovery, amphotericin B (AmB) is still one of the most common first-line choices in treatment pulmonary mycoses for over seventh decades from discovery. AmB which is belonged to the polyene group has a wide spectrum in vitro and in vivo antimicrobial activity against fungi and parasites, resistance to AmB is rare despite extensive use. Recently, some studies focused on the potential antimicrobial action of AmB against some enveloped viruses such as human immunodeficiency virus, Japanese encephalitis virus, and rubella virus. Coronaviruses are enveloped positive-sense RNA nucleic acid viruses that have club-like spikes, characterized by a distinctive replication strategy; they are round and sometimes pleomorphic shapes. COVID-19 is regarding the new genera of coronaviridae that appear the first time in Wuhan, China, in early December 2019. Due to the continuous spreading of the novel COVID-19 with the exponential rise in death numbers, new therapeutic development is urgent, in general, there are no specific antiviral drugs or vaccines for 2019-novel coronavirus. Hence, this review may serve as an impetus for researchers working in the field of medical microbiology, vaccination, and antiviral drug design by discussion the most recent information about the antiviral action of AmB against COVID-19 infection as well as trying to a deep understanding of major properties, mechanisms of action, immune system responses, and antimicrobial efficiency of AmB. Since AmB is expected to alter the structure of the viral envelope, membrane integrity of cells, and internal cellular organelles, besides its other unique properties such as host immunomodulatory effects, so this review suggested that AmB as an effective anti-fungi drug thus may hold the promise of formulating a novel therapeutic option to treat COVID-19.


Mental health services then and now.
Over the past twenty-five years, psychiatric services have shifted from hospital to community. Managed care reinforces this trend. Mental illness is better understood and less stigmatized, and services are more commonly used. But many in need do not receive care consistent with evidence-based standards, or at all. Challenges are greatest for people with serious and persistent mental illnesses who depend on generic health and welfare programs and integrated services. Evidence-based rehabilitative care is often unavailable. Failures in community care lead to arrest; jail diversion and treatment are required. Despite progress, implementing an effective, patient-centered care system remains a formidable challenge.


Molecular and morphological evidence for type B retrovirus (oncornavirus) expression in human mammary carcinoma. An overview using scanning electron microscopy, immunoperoxidase staining, and transmission electron microscopy.
Approximately 45% of human mammary carcinoma cases express an antigen which cross reacts in formalin fixed tissues with antiserum prepared against the purified 52,000 molecular weight structural glycoprotein (gp52) of mouse mammary tumor virus (MMTV). Breast carcinoma immunoperoxidase marking is abolished by antiserum adsorption with MMTV. Adsorption with murine leukemia virus failed to block immunoperoxidase marking. No correlation was seen in the cases analyzed between gp52-like antigen expression and family history of mammary carcinoma, age, or pathological classification. The evidence linking an oncornaviral agent in human mammary carcinoma is reviewed with respect to the structure and biology of a known etiological agent, MMTV, in murine mammary cancer. The potential role of SEM in amplifying the surface area available for analysis in malignant and premalignant human breast epithelia is considered.


The moral economy of selfhood and caring: negotiating boundaries of personal care as embodied moral practice.
This paper engages with the dichotomous notions of caring underpinning social policy and practice in Britain, that splits up the 'carer' and 'cared for' into autonomous, unitary subjects, by locating personal care as an embodied, moral practice within a theoretical framework of relational ontology. Drawing on empirical accounts and narratives related to personal care within the context of advanced cancer, we argue that personal care involves negotiation of boundaries between notions of relatedness and legitimate dependence on one hand, and independence and integrity of the embodied self on the other; and we analyse how these boundaries are informed by particular cultural or religious scripts on gender, relatedness, conjugality and filial obligations. The paper draws on data and analysis based on observations and in-depth interviews with White and South Asian participants between 19 and 89 years of age receiving treatment for cancer, and family members closely involved in their personal care. In using a comparative method for analysis and understanding caring as an embodied moral practice and site of subjectivity across cultural/religious groups, it is suggested that ethnicity is not necessarily the only useful analytical concept to explore the illness and caring experiences of research participants from minority ethnic backgrounds.


Mental health care utilisation among internally displaced persons in Ukraine: results from a nation-wide survey.
AimsThere are an estimated 1.5 million internally displaced persons (IDPs) in Ukraine because of the armed conflict in the east of the country. The aim of this paper is to examine utilisation patterns of mental health and psychosocial support (MHPSS) care among IDPs in Ukraine. A cross-sectional survey design was used. Data were collected from 2203 adult IDPs throughout Ukraine between March and May 2016. Data on mental health care utilisation were collected, along with outcomes including post-traumatic stress disorder (PTSD), depression and anxiety. Descriptive and multivariate regression analyses were used. PTSD prevalence was 32%, depression prevalence was 22%, and anxiety prevalence was 17%. Among those that likely required care (screened positive with one of the three disorders, and also self-reporting a problem) there was a large treatment gap, with 74% of respondents who likely required MHPSS care over the past 12 months not receiving it. For the 26% (N = 180) that had sought care, the most common sources of services/support were pharmacies, family or district doctor/paramedic (feldsher), neurologist at a polyclinic, internist/neurologist at a general hospital, psychologists visiting communities, and non-governmental organisations/volunteer mental health/psychosocial centres. Of the 180 respondents who did seek care, 163 could recall whether they had to pay for their care. Of these 163 respondents, 72 (44%) recalled paying for the care they received despite government care officially being free in Ukraine. The average costs they paid for care was US$107 over the previous 12 months. All 180 respondents reported having to pay for medicines and the average costs for medicines was US$109 over the previous 12 months. Among the 74% had not sought care despite likely needing it; the principal reasons for not seeking care were: thought that they would get better by using their own medications, could not afford to pay for health services or medications, no awareness of where to receive help, poor understanding by health care providers, poor quality of services, and stigma/embarrassment. The findings from multivariate regression analysis show the significant influence of a poor household economic situation on not accessing care. The study highlights a high burden of mental disorders and large MHPSS treatment gap among IDPs in Ukraine. The findings support the need for a scaled-up, comprehensive and trauma-informed response to provision of MHPSS care of IDPs in Ukraine alongside broader health system strengthening.


Histologic Response and Toxicity following Interval-Compressed Four-Drug Therapy Given Preoperatively in Children and Young Adults with Osteosarcoma: A Retrospective Study.
The histologic response to chemotherapy is an important prognostic factor in osteosarcoma. Thus, we attempted to develop an effective neoadjuvant regimen to achieve an improvement in histologic response. Twenty-nine patients with a high-grade osteosarcoma received 2 courses of neoadjuvant chemotherapy non-randomly with either the MAP regimen (methotrexate 12 g/m2, cisplatin 120 mg/m2, and doxorubicin 75 mg/m2) or MAPI regimen (MAP plus ifosfamide 9 g/m2). We applied interval compression to MAPI by shortening the preoperative period to be aligned with that of MAP. Adjuvant chemotherapy was tailored according to the necrosis rate of resected tumor specimens. Necrosis rate, toxicity, and survival outcome were compared retrospectively between the 2 groups. The median interval between the beginning of neoadjuvant chemotherapy and surgery was 97.0 days in the MAPI group (17 patients) and 90.5 days in the MAP group (12 patients; p = 0.19). The good histologic response (>90% of necrosis) was observed in 71% of MAPI and in 42% of MAP (p = 0.12). Major toxicities of grade 3 or worse were not different between the 2 groups. The probability of 5-year progression-free survival and overall survival of the MAPI group were 74 and 83%, and those in the MAP group were 50 and 75%, showing no difference. Interval-compressed MAPI therapy given in a similar duration of the preoperative phase to that of conventional MAP therapy showed a marginal trend toward a better histologic response without a significant increase in major toxicities. Regarding the proportion of good histologic response, 71% is one of the highest values ever reported in the literature. The results warrant further testing in a prospective way in a larger cohort.


[A 73 year-old patient with thrombocytopenia and a giant cerebral vascular malformation].
We report the case of a patient who was seen by purpura and thrombocytopenia. The differential diagnosis in this patient included the presence of cerebral giant vascular malformation, the intake antiepileptic drugs and the presence of a chronic liver disease caused by viral hepatitis C infection. However the final diagnoses of Idiopathic Thrombocytopenia Purpura was made because of the presence of antiplatelets antibodies, the fluctuate evolution, and the increase of platelet count after costicosteroid therapy.


The Role of Social Mobilization in Controlling Ebola Virus in Lofa County, Liberia.
The West Africa Ebola virus epidemic now appears to be coming to an end. In the proposed model, we simulate changes in population behavior that help to explain the observed transmission dynamics. We introduce an EVD transmission model accompanied by a model of social mobilization. The model was fit to Lofa County, Liberia through October 2014, using weekly counts of new cases reported by the US CDC. In simulation studies, we analyze the dynamics of the disease transmission with and without population behavior change, given the availability of beds in Ebola treatment units (ETUs) estimated from observed data. Only the model scenario that included individuals' behavioral change achieved a good fit to the observed case counts. Although the capacity of the Lofa County ETUs greatly increased in mid-August, our simulations show that the expansion was insufficient to alone control the outbreak. Modeling the entire outbreak without considering behavior change fit the data poorly, and extrapolating from early data without taking behavioral changes into account led to a prediction of exponential outbreak growth, contrary to the observed decline. Education and awareness-induced behavior change in the population was instrumental in curtailing the Ebola outbreak in Lofa County and is likely playing an important role in stopping the West Africa epidemic altogether.


Bone loss, weight loss, and weight fluctuation predict mortality risk in elderly men and women.
Low baseline BMD, rate of BMD loss, weight loss, and weight fluctuation are significant predictors of all-cause mortality in elderly men and women, independent of each other and of age, incident fracture, and concomitant diseases. Although low BMD has been shown to be associated with mortality in women, the effect of BMD is affected by weight and weight change and the contribution of these factors to mortality risk, particularly in men, is not known. This study examined the association between baseline BMD, rate of bone loss, weight loss, and weight fluctuation and all-cause mortality risk in elderly men and women. Data from 1059 women and 644 men, >or=60 years of age (as of 1989), of white background who participated in the Dubbo Osteoporosis Epidemiology Study were analyzed. All-cause mortality was recorded annually between 1989 and 2004. BMD at the femoral neck was measured by DXA (GE-LUNAR) at baseline and at approximately every 2 yr afterward. Data on incident osteoporotic fractures and concomitant diseases, including cardiovascular diseases, all types of cancer, and type I/II diabetes mellitus, was also recorded. In the multivariable Cox's proportional hazards model with adjustment for age, incident fractures, and concomitant diseases, the following variables were independent risk factors of all-cause mortality in men: rate of BMD loss of at least 1%/yr, rate of weight loss of at least 1%/yr, and weight fluctuation (defined by the CV) of at least 3%. In women, in addition to the significant factors observed in men, lower baseline BMD was also an independent risk factor of mortality. In both sexes, baseline weight was not an independent and significant predictor of mortality risk. Approximately 36% and 22% of deaths in women and men, respectively, were attributable to the four risk factors. These data suggest that, although low BMD was a risk factor of mortality in women, it was not a risk factor of mortality in men. However, high rates of BMD loss, weight loss, and weight fluctuation were also independent predictors of all-cause mortality in elderly men and women, independent of age, incident fracture, and concomitant diseases.


Techno-Economic Prospects and Desirability of 3D Food Printing: Perspectives of Industrial Experts, Researchers and Consumers.
3D food printing is an emerging food technology innovation that enables the personalization and on-demand production of edible products. While its academic and industrial relevance has increased over the past decade, the functional value of the technology remains largely unrealized on a commercial scale. This study aimed at updating the business outlook of 3D food printing so as to help entrepreneurs and researchers in the field to channel their research and development (R&D) activities. A three-phase mixed methods approach was utilized to gain perspectives of industrial experts, researchers, and potential consumers. Data were collected from two sets of interviews with experts, a survey with experts, and consumer focus group discussions. The results gave insights into key attributes and use cases for a 3D food printer system, including the techno-economic feasibility and consumer desirability of identified use cases. A business modelling workshop was then organized to translate these results into three refined value propositions for 3D food printing. Both the experts and consumers found personalized nutrition and convenience to be the most desirable aspects of 3D food printing. Accordingly, business models related to 3D printed snacks/meals in semi-public spaces such as fitness centers and hospitals were found to offer the highest business potential. While the technology might be mature enough at component level, the successful realization of such high-reward models however would require risk-taking during the developmental phase.


Affinity capillary electrophoretic DNA separation using PEG-oligodeoxyribonucleotide block copolymers: relationship between peak resolution and affinity strength.
Capillary electrophoretic separation of chemically synthesized ssDNA and a single-base-substituted one (normal and mutant ssDNA, respectively) was demonstrated using a PEG-oligodeoxyribonucleotide block copolymer (PEG-b-ODN) as an affinity ligand. When the base sequence of PEG-b-ODN was designed to be complementary to part of normal ssDNA including the base-substituted site, the electrophoretic mobility of normal ssDNA significantly decreased whereas that of mutant ssDNA slightly changed. Resolution of the separation strongly depended on the ODN length of the copolymer, the capillary temperature, and the Mg2+ concentration in the running buffer, indicating that the retardation of migration of normal ssDNA was induced by the reversible hybridization with PEG-b-ODN. It was found that the dissociation constant (K(d)) of the duplex between normal ssDNA and the affinity probe ODN should be smaller than 10(-6) M to achieve the good peak separation. In addition, we calculated the mobility of the complex (mu(C)) between normal ssDNA and PEG-b-ODN using a two-state model. The base sequence of affinity probe ODN appropriate to achieve the sufficient resolution will be predicted on the basis of the mu(C) and K(d )values.


CD4 down-modulation during infection of human T cells with human immunodeficiency virus type 1 involves independent activities of vpu, env, and nef.
The human immunodeficiency virus type 1 (HIV-1) genes vpu, env, and nef have all been implicated in modulating the levels of cell surface CD4 on infected cells. To quantitatively assess the relative contribution of each gene product to the regulation of CD4 during HIV infection of Jurkat T cells and peripheral blood mononuclear cells, we have developed an infectious HIV reporter system which expresses different combinations of these genes. To distinguish infected cells in the early or late stages of infection from uninfected cells, these viruses were designed to express human placental alkaline phosphatase with the kinetics of either early or late viral genes. Flow cytometry to detect placental alkaline phosphatase and CD4 in infected cells showed that vpu, env, and nef are independently capable of down-modulation of CD4. As predicted by their respective expression patterns, nef down-modulated CD4 rapidly during the early phase of virus infection whereas vpu and env functioned late in the infection. In both Jurkat cells and peripheral blood mononuclear cells, a combination of the three genes was more efficient than any one or two genes, demonstrating that all three genes are required to achieve maximal CD4 down-modulation. In primary cells, down-modulation of CD4 was less efficient than in Jurkat cells and there was a stronger dependence on nef function for reducing cell surface CD4. HIV therefore has three genes that are able to independently down-modulate CD4; together, they can eliminate the bulk of cell surface CD4.


Isolation and characterization of unusual multinuclear Schiff base complexes: rearrangements reactions and octanuclear cluster formation.
The isolation and full characterization of multinuclear Schiff base complexes is reported, and their relevance as precursors for octanuclear Zn(8) salen cluster complex formation is discussed. Starting from simple precursors, three tetranuclear Zn(4) complexes were accessed that incorporate typical half-salen units and comprise of bridging acetates. The use of alternative reaction conditions or a step-wise approach smoothly leads to Zn(8) cluster formation. In addition, the tetranuclear Zn(4) complexes themselves may also serve as precursors toward Zn(8) cluster formation when treated under appropriate reaction conditions. The influence of the solvent medium in the latter Zn(4) → Zn(8) conversion was separately studied and revealed the formation of unusual pyridine-ligated multinuclear structures with fully condensed salen coordination pockets, providing a possible prelude to octanuclear cluster formation.


Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™).
Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME™ trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes. Patients who were drug-naïve (HbA1c ≥7.0% and ≤9.0%), or on background glucose-lowering therapy (HbA1c ≥7.0% and ≤10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until ≥691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided α of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved. Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63 ± 9 years, BMI 30.6 ± 5.3 kg/m2, HbA1c 8.1 ± 0.8%, and eGFR 74 ± 21 ml/min/1.73 m2. The study is expected to report in 2015. EMPA-REG OUTCOME™ will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection. Clinicaltrials.gov NCT01131676.


Cross-modal transfer of shape is difficult to demonstrate in one-month-olds.
We tested 1-month-olds for cross-modal transfer of shape between touch and vision using a procedure described by Meltzoff and Borton, but including controls for side bias and stimulus preference. In Experiment 1 (N = 48), infants' looking times to smooth and nubby visual stimuli were not influenced by previous oral exposure to one of the shapes during the preceding 90 s, except for an effect on the first test trial in one group; this effect could have been due to limited cross-modal transfer, to Type 1 error, or to side bias, possibly interacting with a small stimulus preference. The failure of that effect to replicate in a group (N = 16) with less side bias (Experiment 2) suggests that it was not due to cross-modal transfer. Experiment 3 (N = 32), an exact replication of Meltzoff and Borton's experiment, also failed to yield evidence of cross-modal transfer. Overall, there is not good evidence that 1-month-olds can transfer information about these shapes from touch to vision. Future studies exploring the ability to transfer information about other shapes will be easier to interpret if they include controls for side bias and stimulus preference.


Neural plasticity of development and learning.
Development and learning are powerful agents of change across the lifespan that induce robust structural and functional plasticity in neural systems. An unresolved question in developmental cognitive neuroscience is whether development and learning share the same neural mechanisms associated with experience-related neural plasticity. In this article, I outline the conceptual and practical challenges of this question, review insights gleaned from adult studies, and describe recent strides toward examining this topic across development using neuroimaging methods. I suggest that development and learning are not two completely separate constructs and instead, that they exist on a continuum. While progressive and regressive changes are central to both, the behavioral consequences associated with these changes are closely tied to the existing neural architecture of maturity of the system. Eventually, a deeper, more mechanistic understanding of neural plasticity will shed light on behavioral changes across development and, more broadly, about the underlying neural basis of cognition.


A treatment algorithm for stable slipped capital femoral epiphysis deformity.
The authors' current experience in the surgical treatment strategy of stable slipped capital femoral epiphysis deformities was reviewed. From this, a treatment algorithm was developed that could be utilized as a guide in the evaluation and treatment of future patients with slipped capital femoral epiphysis. The clinical parameters of patients' histories of symptoms, physical examinations, and radiographic assessments of slip severity were used in formulating the algorithm. The intent was to prepare a comprehensive algorithm providing necessary alternate treatment pathways for the variable slip deformity in accordance with the surgical experience/expertise of the treating surgeon.


Patterns of service provision in child and adolescent mental health care in Australia.
Standard description of local care provision is essential for evidence-informed planning. This study aimed to map and compare the availability and diversity of current mental health service provision for children and adolescents in Australia. We used a standardised service classification instrument, the Description and Evaluation of Services and DirectoriEs (DESDE) tool, to describe service availability in eight urban and two rural health districts in Australia. The pattern of care was compared with that available for other age groups in Australia. Outpatient care was found to be the most common type of service provision, comprising 212 (81.2%) of all services identified. Hospital care (acute and non-acute) was more available in urban than in rural areas (20 services [9.7%] vs 1 [1.8%]). The level of diversity in the types of care available for children and adolescents was lower than that for the general adult population, but slightly higher than that for older people in the same areas. Standardised comparison of the pattern of care across regions reduces ambiguity in service description and classification, enables gap analysis and can inform policy and planning.


Detection of u-serrated patterns in direct immunofluorescence images of autoimmune bullous diseases by inhibition-augmented COSFIRE filters.
Direct immunofluorescence (DIF) microscopy of a skin biopsy is used by physicians and pathologists to diagnose autoimmune bullous dermatoses (AIBD). This technique is the reference standard for diagnosis of AIBD, which is used worldwide in medical laboratories. For diagnosis of subepidermal AIBD (sAIBD), two different types of serrated pattern of immunodepositions can be recognized from DIF images, namely n- and u-serrated patterns. The n-serrated pattern is typically found in the most common sAIBD bullous pemphigoid. Presence of the u-serrated pattern indicates the sAIBD subtype epidermolysis bullosa acquisita (EBA), which has a different prognosis and requires a different treatment. The manual identification of these serrated patterns is learnable but challenging. We propose an automatic technique that is able to localize u-serrated patterns for automated computer-assisted diagnosis of EBA. The distinctive feature of u-serrated patterns as compared to n-serrated patterns is the presence of ridge-endings. We introduce a novel ridge-ending detector which uses inhibition-augmented trainable COSFIRE filters. Then, we apply a hierarchical clustering approach to detect the suspicious u-serrated patterns from the detected ridge-endings. For each detected u-serrated pattern we provide a score that indicates the reliability of its detection. In order to evaluate the proposed approach, we created a data set with 180 DIF images for serration pattern analysis. This data set consists of seven subsets which were obtained from various biopsy samples under different conditions. We achieve an average recognition rate of 82.2% of the u-serrated pattern on these 180 DIF images, which is comparable to the recognition rate achieved by experienced medical doctors and pathologists.


Boron Nitride Based Nanobiocomposites: Design by 3D Printing for Bone Tissue Engineering.
Here, we produced a synthetic polymer having adequate biocompatibility, biodegradability, and bioresorbability, as well as mechanical properties for applications in bone tissue engineering. We used the fused deposition modeling (FDM) based 3D printing approach in order to produce biomimetic biodegradable scaffolds made of polylactic acid (PLA). We strengthened these scaffolds by addition of exfoliated boron nitride (EBN) as filler. We demonstrated the presence of EBN by physicochemical analysis using Raman spectroscopy and X-ray diffraction (XRD). Using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), we found that EBN incorporation did not influence the transition temperature, but reduced the polymer crystallinity. Scanning electron microscopy for morphology evaluation showed a mean scaffold pore size of 500 μm. EBN incorporation did not affect the scaffold mechanical properties (tensile test), but modified the surface roughness. Moreover, contact angle quantification indicated that the surface of PLA/EBN scaffolds was hydrophilic and that of PLA scaffolds hydrophobic. Finally, the results of the cytotoxicity, cell attachment, and proliferation experiments using MG-63 and MC3T3 cells indicated that PLA scaffolds filled with EBN were nontoxic and compatible with osteoblastic cells and also promoted the scaffold mineralization by MG-63 cells. Altogether, our results suggest that this 3D printed nanocomposite scaffold is suitable for tissue engineering.


Effect of proton pump inhibitors on mortality of cirrhotic patients with pneumonia.
Pneumonia is life-threatening in patients with liver cirrhosis. Proton pump inhibitors (PPIs) may increase the risk of these patients developing pneumonia. However, whether PPIs increase mortality in patients with cirrhosis and pneumonia remain unknown. We used the Taiwan National Health Insurance Database to enroll 1,201 cirrhotic patients with pneumonia without active gastrointestinal bleeding who were receiving PPIs and were hospitalized between January 1, 2010 and December 31, 2013. A one-to-three propensity score match was performed to select a comparison group based on age, gender, and comorbid disorders. The overall 30-day and 90-day all-cause mortality rates were 13.7% and 26.9% in the PPI group, and 14.3% and 25.1% in the non-PPI group, respectively. After Cox regression model adjusting for age, gender, and comorbid disorders, the hazard ratios of the effect of PPIs on 30-day and 30 to 90-day mortality were 0.94 (95% Confidence Interval [CI], 0.79-1.12, P = 0.468) and 1.26 (95% CI, 1.05-1.52; P = 0.013), respectively. PPIs were not associated with 30-day mortality among cirrhotic patients with pneumonia but not active gastrointestinal bleeding. However, prolonged PPI therapy may be associated with higher mortality.


Statistical assessment of the global regulatory role of histone acetylation in Saccharomyces cerevisiae.
Histone acetylation plays important but incompletely understood roles in gene regulation. A comprehensive understanding of the regulatory role of histone acetylation is difficult because many different histone acetylation patterns exist and their effects are confounded by other factors, such as the transcription factor binding sequence motif information and nucleosome occupancy. We analyzed recent genomewide histone acetylation data using a few complementary statistical models and tested the validity of a cumulative model in approximating the global regulatory effect of histone acetylation. Confounding effects due to transcription factor binding sequence information were estimated by using two independent motif-based algorithms followed by a variable selection method. We found that the sequence information has a significant role in regulating transcription, and we also found a clear additional histone acetylation effect. Our model fits well with observed genome-wide data. Strikingly, including more complicated combinatorial effects does not improve the model's performance. Through a statistical analysis of conditional independence, we found that H4 acetylation may not have significant direct impact on global gene expression. Decoding the combinatorial complexity of histone modification requires not only new data but also new methods to analyze the data. Our statistical analysis confirms that histone acetylation has a significant effect on gene transcription rates in addition to that attributable to upstream sequence motifs. Our analysis also suggests that a cumulative effect model for global histone acetylation is justified, although a more complex histone code may be important at specific gene loci. We also found that the regulatory roles among different histone acetylation sites have important differences.


[Raman spectra and IR spectra of 3-triphenylgermyl-1,1-diphenyl-1-butanol and its derivatives].
The Raman spectra and FTIR spectra of 3-triphenylgermyl-1,1-diphenyl-1-propanol (A), 3-triphenylgermyl-1,1-diphenyl-1-butanol (B) and 3-triphenylgermyl-2-methyl-1,1-diphenyl-1-propanol (C) have been measured and analyzed. In Raman spectra of these compounds, the Ge--Ph stretching vibrations are near 1,000 cm-1, and the Ge--C stretching vibrations are 594.1 (for A), 578.7 (for B), 599.2 cm-1 (for C). The spectra show that the three compounds have similar molecular vibration characteristics.


Comparing Perceived Social Support and Perceived Stress in Healthy Pregnant Women and Pregnant Women with Preeclampsia.
Preeclampsia is a prevalent side effect of pregnancy. Different studies have reported different results about the relationship between mental stress and blood pressure disorders. In addition, social support is highly important to help women who experience risky pregnancy in adapting to the stressors they experience. This study aimed to compare perceived social support and perceived stress in women with and without preeclampsia. Fifty pregnant women definitely diagnosed with preeclampsia and 50 healthy pregnant women visiting public hospitals including Hazrat Masoumeh, Motazedi, and Imam Reza in Kermanshah-Iran took part in a descriptiveanalytical study from June 2017 to January 2018. Data gathering tools included demographics questionnaire, social support appraisals scale and perceived stress scale. The collected data was analyzed with SPSS (v.20) using independent t-test. The mean score of perceived social support in the preeclampsia and non-preeclampsia groups were 69.88±7.3 and 76.80±7.6 respectively (P<0.01). The mean score of perceived stress in the preeclampsia and non-preeclampsia groups were 35.6±8.7 and 26.01±5.56 respectively (P<0.01). This means that compared with healthy women, women with preeclampsia perceived more stress and less social support. In comparison with healthy pregnant women, women with preeclampsia perceived more stress and less social support. Healthcare providers should recommended to pay more attention to improving social support and attenuating stress in pregnant women.


Prognostic Gene Discovery in Glioblastoma Patients using Deep Learning.
This study aims to discover genes with prognostic potential for glioblastoma (GBM) patients' survival in a patient group that has gone through standard of care treatments including surgeries and chemotherapies, using tumor gene expression at initial diagnosis before treatment. The Cancer Genome Atlas (TCGA) GBM gene expression data are used as inputs to build a deep multilayer perceptron network to predict patient survival risk using partial likelihood as loss function. Genes that are important to the model are identified by the input permutation method. Univariate and multivariate Cox survival models are used to assess the predictive value of deep learned features in addition to clinical, mutation, and methylation factors. The prediction performance of the deep learning method was compared to other machine learning methods including the ridge, adaptive Lasso, and elastic net Cox regression models. Twenty-seven deep-learned features are extracted through deep learning to predict overall survival. The top 10 ranked genes with the highest impact on these features are related to glioblastoma stem cells, stem cell niche environment, and treatment resistance mechanisms, including POSTN, TNR, BCAN, GAD1, TMSB15B, SCG3, PLA2G2A, NNMT, CHI3L1 and ELAVL4.


Fibroblast growth factors share binding sites in heparan sulphate.
HS (heparan sulphate) proteoglycans bind secreted signalling proteins, including FGFs (fibroblast growth factors) through their HS side chains. Such chains contain a wealth of differentially sulphated saccharide epitopes. Whereas specific HS structures are commonly believed to modulate FGF-binding and activity, selective binding of defined HS epitopes to FGFs has generally not been demonstrated. In the present paper, we have identified a series of sulphated HS octasaccharide epitopes, derived from authentic HS or from biosynthetic libraries that bind with graded affinities to FGF4, FGF7 and FGF8b. These HS species, along with previously identified oligosaccharides that interact with FGF1 and FGF2, constitute the first comprehensive survey of FGF-binding HS epitopes based on carbohydrate sequence analysis. Unexpectedly, our results demonstrate that selective modulation of FGF activity cannot be explained in terms of binding of individual FGFs to specific HS target epitopes. Instead, different FGFs bind to identical HS epitopes with similar relative affinities and low selectivity, such that the strength of these interactions increases with increasing saccharide charge density. We conclude that FGFs show extensive sharing of binding sites in HS. This conclusion challenges the current notion of specificity in HS-FGF interactions, and instead suggests that a set of common HS motifs mediates cellular targeting of different FGFs.


The flow of forage particles and solutes through segments of the digestive tracts of cattle.
An experiment was conducted to investigate the compartmental mean residence time, (CMRT) of feed residues in segments of gastrointestinal digesta of mature Holstein steers. The objective was to evaluate assumptions that feed residues flow through ruminal digesta as sequential mixing pools having age-dependent (GN) and age-independent (G1) distributed residence times respectively (GN-->G1 flow). The basal diet was a semi-tropical hay containing 98 g crude protein and 503 g apparently digestible DM per kg DM. The hay was consumed and feed residues of different size and/or previous digestion from the hay were inserted into the reticulo-rumen (rumen) and abomasum. Marker profiles appearing at the duodenum and faeces were fitted to various compartment models to estimate CMRT. Post-abomasal CMRT did not differ among solutes or feed residues of different size and previous digestion and constituted only 5.8% of the CMRT for the entire gastrointestinal tract. Markers initially applied to orally or ruminally dosed feed residues exhibited profiles in duodenal digesta and faeces conforming to GN-->G1 flow. Previously undigested, masticated feed residues inserted into the dorsal rumen digesta had longer ruminal CMRT in the GN pool but not the G1 pool than did similarly inserted faecal small particles or normally ingested hay. These results support model assumptions of GN-->G1 flow within rumen digesta. The results support mechanisms proposed for the GN pool as the 'lag-rumination pool' and the G1 pool as the 'mass action turnover pool'. If further validated, rumen CMRT in cattle could be estimated from marker profiles in more easily obtained faeces to estimate ruminal CMRT required for feed evaluation systems.


Gender issues in the pharmacotherapy of opioid-addicted women: buprenorphine.
Gender, a biological determinant of mental health and illness, plays a critical role in determining patients' susceptibility, exposure to mental health risks, and related outcomes. Regarding sex differences in the epidemiology of opioid dependence, one third of the patients are women of childbearing age. Women have an earlier age of initiation of substance use and a more rapid progression to drug involvement and dependence than men. Generally few studies exist which focus on the special needs of women in opioid maintenance therapy. The aim of this paper is to provide an overview of treatment options for opioid-dependent women, with a special focus on buprenorphine, and to look at recent findings related to other factors that should be taken into consideration in optimizing the treatment of opioid-dependent women. Issues addressed include the role of gender in the choice of medication assisted treatment, sex differences in pharmacodynamics and pharmacokinetics of buprenorphine drug interactions, cardiac interactions, induction of buprenorphine in pregnant patients, the neonatal abstinence syndrome and breastfeeding. This paper aims to heighten the awareness for the need to take gender into consideration when making treatment decisions in an effort to optimize services and enhance the quality of life of women suffering from substance abuse.


[Effect of hypothyroidism on the solid form of Ehrlich tumor in intact or castrated adult female mice].
The effect of hypothyroidism on the solid form of the Ehrlich tumor in intact or castrated adult female mice was studied. Hypothyroidism was induced by treatment with propylthiouracil (PTU). Forty mice were divided into four groups: castrated hypothyroid, intact hypothyroid, castrated euthyroid, and intact euthyroid. The mice were inoculated with suspension cells into the left footpad. The tumor growth curve was determined by measuring the inoculated footpad during 12 days. At the end of the experimental period the mice were sacrificed. Hypothyroidism was associated with a reduction in size of the tumor only in the castrated animals. Although the neoplastic growth was lower, mean nuclear diameter, number of nucleolar organizer regions (NORs), and area of mitosis were higher. In conclusion, hypothyroidism resulted in a delayed growth of the tumor, but it did not affect the malignant features of the neoplastic cells. In addition, the isolated effect of castration caused only mild alterations, whereas hypothyroidism associated with castration resulted in a more prominent delay in the growth rate of the Ehrlich tumor.


Community paramedicine-cost-benefit analysis and safety with paramedical emergency services in rural areas: scoping review protocol.
Community paramedicine models have been developed around the world in response to demographic changes, healthcare system needs and reforms. The traditional role of the paramedic has primarily been to provide emergency medical response and transportation of patients to nearby medical facilities. As a response to healthcare service gaps in underserved communities and the growing professionalisation of the workforce, the role of community paramedicine has evolved as a new model of care. A community paramedicine model in one region might address other healthcare needs than a model in another region. Various terms are also in use for community paramedicine providers, with no consensus on the definition for community paramedics, although the definition used by the International Roundtable on Community Paramedicine has been widely accepted. We aimed to examine the current knowledge and possibly identify gaps in the research/knowledge base for cost-benefit analysis and safety concerning community paramedicine in rural areas using a scoping review methodology. This scoping review will follow the methodology developed by Arksey and O'Malley and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. In October 2020, we will search electronic databases (MEDLINE via PubMed, CINAHL, Cochrane and Embase) and the reference lists of key studies to identify studies for inclusion. The selection process is in two steps. First, two reviewers will independently screen identified articles for title and abstracts and, second, perform a full-text review of eligible studies for inclusion. Studies focusing on community paramedicine in rural areas, which include cost-benefit analysis or safety evaluation, will be included. The data used are available from publicly secondary sources, therefore this study will not require ethical review. The results will be disseminated through peer-reviewed publication.


LESIONS IN THE MEDIAL FOREBRAIN BUNDLE: DELAYED EFFECTS ON SENSITIVITY TO ELECTRIC SHOCK.
Rats with bilateral lesions in the medial forebrain bundle demonstrate both an increased sensitivity to electric shock, as reflected by a lowered jump threshold, and a decrease in the concentration of serotonin in the brain. Both effects of the lesion are characterized by a delayed time of onset and gradual development, which approximates the time required for progressive nerve degeneration in the central nervous system. It is suggested that this behavioral effect of bilateral lesions in the medial forebrain bundle may be due to a central denervation supersensitivity.


Serum iron concentrations, lipid peroxidation and superoxide dismutase activity in Turkish iron miners.
The effects of iron exposure, on serum iron, serum superoxide dismutase (SOD), a free radical scavenger, and plasma malondialdehyde (MDA), a lipid peroxidation parameter, were investigated in Turkish iron miners, office workers and healthy control subjects. Serum iron levels in both miner and office workers groups were higher than those of healthy controls (p < 0.05). There were higher mean values of plasma MDA levels in both iron miners and office workers compared to controls (p < 0.05). Serum SOD activity in the miner group was lower than that of controls (p < 0.05). These results suggested that elevated MDA levels in both miners and office workers were the result of an increased production and/or decreased catabolism of MDA in chronic iron exposure. These changes in MDA metabolism may be due to iron-induced lipid peroxidation in the blood and related body compartments.


Association of Parental Screen Addiction with Young Children's Screen Addiction: A Chain-Mediating Model.
Preschool children are immersed in screen media, yet little study has been conducted on screen addiction among them. This study aimed to investigate the relationship between parental screen addiction and young children's screen addiction and to verify factors that mediate this relationship. A total of 477 parents of kindergarteners (3-6 years old) were recruited via six kindergartens in Henan province, China. They completed the Problematic Media Use Measure Short Form of Children, the Self-Rating Anxiety Scale, the Child-Parent Relationship Scale, and the Parental Screen Addiction Scale. The results showed that the relationships between each pair of parental screen addiction, parental anxiety, and children's screen addiction were significantly positive, but the parent-child relationship was negatively correlated with the other variables. Parental screen addiction can directly and indirectly affect children's screen addiction through parental anxiety and the parent-child relationship. The findings contribute to the development of family protection mechanisms against screen addiction in children.


Patellofemoral osteoarthritis coexistent with tibiofemoral osteoarthritis in a meniscectomy population.
To evaluate the frequency of patellofemoral osteoarthritis and its relevance to symptoms and function in a meniscectomy population. 317 patients with no cruciate ligament injury were evaluated (mean (SD) age, 54 (11) years). They had undergone meniscal resection 15 to 22 years earlier (follow up rate 70%). Standing tibiofemoral and skyline patellofemoral radiographs were graded according to the OARSI atlas. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was used to quantify symptoms and function. Controls were 68 unoperated subjects identified from national population records. Patellofemoral osteoarthritis (isolated or coexisting with tibiofemoral osteoarthritis) was present in 66 of 317 index knees (21%) and 21 of 263 unoperated contralateral knees (8%, p<0.001). In 57/66 (86%) of these index knees, tibiofemoral osteoarthritis was present (mixed osteoarthritis). In a model adjusted for age, sex, and body mass index, the odds ratio for patellofemoral osteoarthritis (alone or in combination with tibiofemoral osteoarthritis) was 2.6 (95% confidence interval, 1.1 to 6.6) after medial meniscectomy and 5.3 (1.9 to 15.0) after lateral meniscectomy, using controls as the reference. Individuals with a mixed knee osteoarthritis pattern had more symptoms, lower function in sports and recreation, and worse knee related quality of life than subjects with isolated tibiofemoral osteoarthritis. Mixed patellofemoral and tibiofemoral osteoarthritis is common in a meniscectomy population. Patellofemoral osteoarthritis is a contributing cause of knee symptoms and reduced knee related quality of life and is relevant to the management of knee complaints of this group of patients.


Strict blood pressure control following thrombectomy is associated with neuronal injury and poor functional outcome.
Mechanical thrombectomy (MT) has become standard treatment in acute ischemic stroke due to large vessel occlusion (LVO). However, optimal blood pressure (BP) management following successful recanalization remains unclear. We aim to investigate the association of strictly achieving BP targets of ≤160/90 mmHg with the extent of neuronal loss and functional outcome. In patients prospectively enrolled in the Gutenberg-Stroke-Study (May 2018-November 2019), BP was measured half-hourly for 24 h following MT. Based on achieving BP target of ≤160/90 mmHg, patients with successful recanalization of LVO were divided into "low-BP" group (BP ≤ 160/90 mmHg) or "high-BP" group (BP > 160/90 mmHg). Neuronal loss was quantified by serum-based measurement of neurofilament light chain (sNfL) after three days. BP groups and association of BP parameters with sNfL were investigated by correlation analyses and multiple regression modeling. Of 253 enrolled patients (mean age 73.1 ± 12.9 years, 53.4% female), 165 met inclusion criteria. 21.2% (n = 35) strictly achieved "low-BP" target. "low-BP" was associated with unfavorable functional outcome at 90-day follow-up (aOR [95%CI]: 5.88 [1.88-18.32], p = 0.002) and decreased health-related quality of life (mean EQ-5D-index 0.45 ± 0.28 vs 0.63 ± 0.31, p = 0.009). sNfL levels were increased in "low-BP" patients (median [IQR] 239.7 [168.4-303.4] vs 118.8 [52.5-220.5] pg/mL, p = 0.026). Hypotensive episodes were more frequent in the "low-BP" group (48.6% vs 29.2%, p = 0.031). sNfL level could identify patients who had experienced hypotensive episodes with high discriminative ability (AUC [95%CI]: 0.68 [0.56-0.78], p = 0.007). Strict BP control (≤160/90 mmHg) within 24 h following successful recanalization of LVO by MT is associated with increased neuronal injury, displayed by higher sNfL levels, and poorer functional outcome, potentially indicating hypotension-induced neuronal loss during post-MT phase.


Transcatheter aortic valve implantation for severe aortic stenosis-a new paradigm for multidisciplinary intervention: a prospective cohort study.
Transcatheter aortic valve implantation (TAVI) is an alternative treatment option for patients with aortic stenosis deemed high risk or unsuitable for aortic valve replacement. The aim of this study was to assess the feasibility of TAVI in elderly patients, the delivery of this technology with a multidisciplinary approach, and the use of traditional surgical scoring systems. One hundred fifty-one consecutive patients (mean age 82.6 +/- 7.3 years) with severe aortic stenosis underwent TAVI with the Edwards Lifesciences (Irvine, CA) Sapien bioprosthesis using the transapical (n = 84; 56%) or transfemoral (n = 67; 44%) approach from August 2007 to September 2009 at King's Health Partners, London, United Kingdom. We analyzed procedural outcome, complications, functional status, and midterm outcome of patients. The multidisciplinary team comprised interventional cardiologists, cardiothoracic surgeons, imaging specialists, cardiac anesthetists, and specialist nurses. Seventy percent of patients were in New York Heart Association class III/IV, and logistic EuroSCORE was 21.6 +/- 11.9. Procedural success was achieved in 98%. Postoperative complications included stroke (6%), complete atrioventricular block (5.3%), renal failure requiring hemofiltration (9.3%), and vascular injury (8.6%). Overall 30-day mortality was 9.9% (n = 15). The logistic EuroSCORE was a predictor of short-term mortality (logistic regression model, P < .05). Thirty-day mortality post-TAVI for patients with logistic EuroSCORE <20, 20 to 40, and >40 was 5.4%, 13.2%, and 22.2%, respectively. Transcatheter aortic valve implantation is a feasible treatment option in this patient group with promising short/medium-term results. Renal failure is the commonest short-term complication, and the incidence of vascular complications remains high. Risk prediction/case selection remains challenging, and a multidisciplinary team approach appears to be helpful in appropriate patient selection.


Contralateral hearing loss following inner ear injury: sympathetic cochleolabyrinthitis?
Acoustic tumor surgery provided an ideal model in which to study possible contralateral hearing loss following a destructive surgical procedure on the inner ear. Follow-up audiometric studies were performed on patients with unilateral acoustic tumors who had undergone resection of their tumors. Patients who had obvious causes for contralateral hearing loss, such as chronic otitis media, unrelated otologic surgery, and noise-induced hearing loss, were excluded from this patient population. A total of 380 patients had available pre- and postoperative audiograms. A mean air-conduction threshold (500, 1000, 2000 Hz) of greater than or equal to 20 dB was considered a significant hearing loss. After adjusting these losses for presbycusis, 1.3% of these patients still had a significant contralateral hearing loss. We discuss the possible causes for the development of contralateral hearing loss and examine the possibility that, following surgical manipulation and injury to the inner ear, immunocompetent cells become sensitized to previously unseen inner ear antigens, setting the stage for contralateral inner ear dysfunction. The similarities of this condition to sympathetic ophthalmia are discussed.


Assistance from Automated ASPECTS Software Improves Reader Performance.
To compare physicians' ability to read Alberta Stroke Program Early CT Score (ASPECTS) in patients with a large vessel occlusion within 6 hours of symptom onset when assisted by a machine learning-based automatic software tool, compared with their unassisted score. 50 baseline CT scans selected from two prior studies (CRISP and GAMES-RP) were read by 3 experienced neuroradiologists who were provided access to a follow-up MRI. The average ASPECT score of these reads was used as the reference standard. Two additional neuroradiologists and 6 non-neuroradiologist readers then read the scans both with and without assistance from the software reader-augmentation program and reader improvement was determined. The primary hypothesis was that the agreement between typical readers and the consensus of 3 expert neuroradiologists would be improved with software augmented vs. unassisted reads. Agreement was based on the percentage of the individual ASPECT regions (50 cases, 10 regions each; N=500) where agreement was achieved. Typical non-neuroradiologist readers agreed with the expert consensus read in 72% of the 500 ASPECTS regions, evaluated without software assistance. The automated software alone agreed in 77%. When the typical readers read the scan in conjunction with the software, agreement improved to 78% (P<0.0001, test of proportions). The software program alone achieved correlations for total ASPECT scores that were similar to the expert readers who had access to the follow-up MRI scan to help enhance the quality of their reads. Typical readers had statistically significant improvement in their scoring of scans when the scan was read in conjunction with the automated software, achieving agreement rates that were comparable to neuroradiologists.


Bioimpedance technology for detection of thoracic injury.
Thoracic trauma is one of the most common and lethal types of injury, causing over a quarter of traumatic deaths. Severe thoracic injuries are often occult and difficult to diagnose in the field. There is a need for a point-of-care diagnostic device for severe thoracic injuries in the prehospital setting. Electrical bioimpedance (EBI) is non-invasive, portable, rapid and easy to use technology that can provide objective and quantitative diagnostic information for the prehospital environment. Here, we evaluated the performance of EBI to detect thoracic injuries. In this open study, EBI resistance (R), reactance (X) and phase angle (PA) of both sides of the thorax were measured at 50 kHz on patients suffering from thoracic injuries (n = 20). In parallel, a control group consisting of healthy subjects (n = 20) was recruited. A diagnostic mathematical algorithm, fed with input parameters derived from EBI data, was designed to differentiate patients from healthy controls. Ratios between the X and PA measurements of both sides of the thorax were significantly different (p < 0.05) between healthy volunteers and patients with left- and right-sided injuries. The diagnostic algorithm achieved a performance evaluated by leave-one-out cross-validation analysis and derived area under the receiver operating characteristic curve of 0.88. A diagnostic algorithm that accurately discriminates between patients suffering thoracic injuries and healthy subjects was designed using EBI technology. A larger, prospective and blinded study is thus warranted to validate the feasibility of EBI technology as a prehospital tool.


Elevation of extracellular adenosine mobilizes haematopoietic progenitor cells and granulocytes into peripheral blood and enhances the mobilizing effects of granulocyte colony-stimulating factor.
We tested the capabilities of drugs elevating extracellular adenosine and of granulocyte colony-stimulating factor (G-CSF), given alone or in combination, to mobilize haematopoietic progenitor cells for granulocytes and macrophages (GM-CFC) and granulocytes into peripheral blood. Elevation of extracellular adenosine was induced by joint administration of dipyridamole (DP), a drug inhibiting the cellular uptake of adenosine, and adenosine monophosphate (AMP) serving as an adenosine prodrug. DP + AMP, G-CSF or all these drugs in combination were administered either singly or repeatedly in a 4-d treatment regimen. Elevation of extracellular adenosine was found to mobilize significantly both GM-CFC and granulocytes after both single and repeated administration of DP + AMP. These results show that the elevation of extracellular adenosine presents a potent mechanism for mobilization of GM-CFC and granulocytes into the blood. When the combination of DP + AMP + G-CSF was given under the 4-d regimen, the mobilizing effects of its administration were additive when compared with those of DP + AMP alone or G-CSF alone. The observed ability of the drugs elevating extracellular adenosine to enhance the mobilizing action of G-CSF points out possible practical utilization of the findings presented here. This conclusion is further supported by the results of an additional experiment which indicate that blocking of haemodynamic side effects of drugs elevating extracellular adenosine by noradrenaline does not suppress their mobilizing effects.


Arteriolar reactivity in conscious diabetic rats: influence of aminoguanidine treatment.
The effect of 6 weeks' streptozotocin (STZ)-induced (70 mg/kg) diabetes and aminoguanidine (AG) treatment (50 mg/kg s.c. or 250-750 mg/l given in drinking water) on arteriolar reactivity to vasoactive substances was investigated in conscious rats. Studies were performed in untreated control rats (n = 13), STZ-induced diabetic rats (n = 11), AG-treated control rats (n = 12), and AG-treated diabetic rats (n = 12). Rats were provided with a dorsal microcirculatory chamber that allowed intravital microscopy of striated muscle arterioles of varying diameter (A1, large; A2, intermediate; and A3, small arterioles) in conscious animals. The mean arterial pressure (MAP) and arteriolar diameter responses to intravenous infusion of the following drugs were examined: the endothelium-dependent vasodilator acetylcholine (ACh; 3, 10, and 30 microg x kg(-1) x min(-1)), the potassium-channel opener levcromakalim (LC; 30 microg/kg), and the vasoconstrictor agents ANG II (0.1 and 0.3 microg x kg(-1) x min(-1)) and norepinephrine (NE; 0.2, 0.6, and 2.0 microg x kg(-1) x min(-1)). Baseline MAP was lower in both diabetic groups versus the nondiabetic groups (P < 0.05). AG treatment had no influence on baseline MAP. The absolute change in MAP after drug infusion tended to be lower in the diabetic rats than in their nondiabetic littermates. Arteriolar vasodilatory responses to ACh and LC were attenuated in the diabetic animals (1 +/- 7 vs. 19 +/- 7% [P < 0.05] and 7 +/- 3 vs. 34 +/- 8% [P < 0.01] in A2, respectively). AG treatment of diabetic animals did not prevent the development of this disturbance. Vasoconstrictor responses were not influenced by the diabetic state. In the intermediate arterioles of AG-treated control rats, a hyperresponse was observed after ANG II infusion (-10 +/- 2 vs. -2 +/- 2%; P < 0.05) and a hyporesponse was observed after ACh and LC infusion (2 +/- 3 and 15 +/- 6%, respectively; P < 0.05 vs. untreated control rats). These data indicate that 6 weeks of experimental diabetes is associated with a decreased endothelium-dependent and -independent vasodilatation. AG treatment had no beneficial effect on this disturbance.


A Nomogram for Predicting Severe Exacerbations in Stable COPD Patients.
To develop a practicable nomogram aimed at predicting the risk of severe exacerbations in COPD patients at three and five years. COPD patients with prospective follow-up data were extracted from Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) obtained from National Heart, Lung and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center. We comprehensively considered the demographic characteristics, clinical data and inflammation marker of disease severity. Cox proportional hazard regression was performed to identify the best combination of predictors on the basis of the smallest Akaike Information Criterion. A nomogram was developed and evaluated on discrimination, calibration, and clinical efficacy by the concordance index (C-index), calibration plot and decision curve analysis, respectively. Internal validation of the nomogram was assessed by the calibration plot with 1000 bootstrapped resamples. Among 1711 COPD patients, 523 (30.6%) suffered from at least one severe exacerbation during follow-up. After stepwise regression analysis, six variables were determined including BMI, severe exacerbations in the prior year, comorbidity index, post-bronchodilator FEV1% predicted, and white blood cells. Nomogram to estimate patients' likelihood of severe exacerbations at three and five years was established. The C-index of the nomogram was 0.74 (95%CI: 0.71-0.76), outperforming ADO, BODE and DOSE risk score. Besides, the calibration plot of three and five years showed great agreement between nomogram predicted possibility and actual risk. Decision curve analysis indicated that implementation of the nomogram in clinical practice would be beneficial and better than aforementioned risk scores. Our new nomogram was a useful tool to assess the probability of severe exacerbations at three and five years for COPD patients and could facilitate clinicians in stratifying patients and providing optimal therapies.


Reflex bradycardia during surgery.
Reflex bradycardia and sinus arrest may occur in a variety of surgical procedures, from neurosurgery to general abdominal, laparoscopic, ophthalmic and facial surgery and even procedures such as liver biopsies and electroconvulsive therapy. In most cases a vagally-mediated reflex has been implicated, although experimental support for this is often lacking. Drugs such as vecuronium, atracurium, halothane, fentanyl and succinylcholine may predispose to this reflex. Premedication with an anticholinergic is usually effective in preventing its occurrence.


CYNTENATOR: progressive gene order alignment of 17 vertebrate genomes.
Whole genome gene order evolution in higher eukaryotes was initially considered as a random process. Gene order conservation or conserved synteny was seen as a feature of common descent and did not imply the existence of functional constraints. This view had to be revised in the light of results from sequencing dozens of vertebrate genomes.It became apparent that other factors exist that constrain gene order in some genomic regions over long evolutionary time periods. Outside of these regions, genomes diverge more rapidly in terms of gene content and order.We have developed CYNTENATOR, a progressive gene order alignment software, to identify genomic regions of conserved synteny over a large set of diverging species. CYNTENATOR does not depend on nucleotide-level alignments and a priori homology assignment. Our software implements an improved scoring function that utilizes the underlying phylogeny.In this manuscript, we report on our progressive gene order alignment approach, a and give a comparison to previous software and an analysis of 17 vertebrate genomes for conservation in gene order.CYNTENATOR has a runtime complexity of and a space complexity of with being the gene number in a genome. CYNTENATOR performs as good as state-of-the-art software on simulated pairwise gene order comparisons, but is the only algorithm that works in practice for aligning dozens of vertebrate-sized gene orders.Lineage-specific characterization of gene order across 17 vertebrate genomes revealed mechanisms for maintaining conserved synteny such as enhancers and coregulation by bidirectional promoters. Genes outside conserved synteny blocks show enrichments for genes involved in responses to external stimuli, stimuli such as immunity and olfactory response in primate genome comparisons. We even see significant gene ontology term enrichments for breakpoint regions of ancestral nodes close to the root of the phylogeny. Additionally, our analysis of transposable elements has revealed a significant accumulation of LINE-1 elements in mammalian breakpoint regions. In summary, CYNTENATOR is a flexible and scalable tool for the identification of conserved gene orders across multiple species over long evolutionary distances.


Long-term survival after ablation of the atrioventricular node and implantation of a permanent pacemaker in patients with atrial fibrillation.
In patients with atrial fibrillation that is refractory to drug therapy, radio-frequency ablation of the atrioventricular node and implantation of a permanent pacemaker are an alternative therapeutic approach. The effect of this procedure on long-term survival is unknown. We studied all patients who underwent ablation of the atrioventricular node and implantation of a permanent pacemaker at the Mayo Clinic between 1990 and 1998. Observed survival was compared with the survival rates in two control populations: age- and sex-matched members of the Minnesota population between 1970 and 1990 and consecutive patients with atrial fibrillation who received drug therapy in 1993. A total of 350 patients (mean [+/-SD] age, 68+/-11 years) were studied. During a mean of 36+/-26 months of follow-up, 78 patients died. The observed survival rate was significantly lower than the expected survival rate based on the general Minnesota population (P<0.001). Previous myocardial infarction (P<0.001), a history of congestive heart failure (P=0.02), and treatment with cardiac drugs after ablation (P=0.03) were independent predictors of death. Observed survival among patients without these three risk factors was similar to expected survival (P=0.43). None of the 26 patients with lone atrial fibrillation died during follow-up (37+/-27 months). The observed survival rate among patients who underwent ablation was similar to that among 229 controls with atrial fibrillation (mean age, 67+/-12 years) who received drug therapy (P=0.44). In the absence of underlying heart disease, survival among patients with atrial fibrillation after ablation of the atrioventricular node is similar to expected survival in the general population. Long-term survival is similar for patients with atrial fibrillation, whether they receive ablation or drug therapy. Control of the ventricular rate by ablation of the atrioventricular node and permanent pacing does not adversely affect long-term survival.


Comparison of cartilage thickness with radiologic grade of knee osteoarthritis.
To compare joint space width (JSW) measurements obtained from magnetic resonance imaging (MRI) with a semi-automated computer algorithm to the Kellgren and Lawrence grading of osteoarthritis (OA). Three hundred and six patients (234 female, 72 male) with a mean age of 56.7 years (range 31-81 years) underwent MRI of their knees with a fast oblique spiral spoiled gradient (SPGR) sequence. A board-certified musculoskeletal radiologist graded the OA of all the patients in accordance with the Kellgren and Lawrence OA scale. A previously validated computer algorithm was used to determine the minimum JSW for both the tibiofemoral joint and the patellofemoral joint. An analysis of variance (ANOVA) with the Student-Newman-Kuels post-hoc test was used to determine if there were differences in JSW as a function of OA grade. The radiologic grade of OA was inversely associated with the JSW. In the medial compartment the JSW did not change significantly between grade 1 and grade 2, but there was a significant decrease in JSW between grade 0 (normal) and grade 1 and for each OA grade above grade 2. In the lateral compartment no statistical differences were found till grade 2, while grade 3 was found to be statistically different from the previous one. The number of patients with a grade 4 patellofemoral OA was too low for the statistical significance to be assessed. In the patellofemoral joint the JSW did not change significantly until grade 2, while a statistically significant reduction was found for both grade 3 and grade 4. This study showed that an inverse non-linear relationship exists between radiologic grade and JSW. The relationship differs for the tibiofemoral and the patellofemoral joint.


Cost-Effectiveness Analysis of the DiagnOSAS Screening Tool Compared With Polysomnography Diagnosis in Dutch Primary Care.
The growing recognition of obstructive sleep apnea (OSA) as a serious health condition, increasing waiting lists for sleep tests, and a high proportion of unnecessary referrals from general practice highlight the need for alternative diagnostic strategies for OSA. This study's objective was to investigate the cost-effectiveness of DiagnOSAS, a screening tool that strives to facilitate fast and well-informed referral to hospitals and sleep clinics for diagnosis, in The Netherlands. A Markov model was constructed to assess cost-effectiveness in men aged 50 years. The diagnostic process of OSA was simulated with and without DiagnOSAS, taking into account the occurrence of hazardous OSA effects: car accidents, myocardial infarction, and stroke. The cost-effectiveness of "DiagnOSAS Strategy" and a "Rapid Diagnosis Scenario," in which time to diagnosis was halved, was assessed. Base case results show that, within a 10-year time period, DiagnOSAS saves €226 per patient at a negligible decrease (< 0.01) in quality-adjusted life-years (QALYs), resulting in an incremental cost-effectiveness ratio of €56,997/QALY. The "Rapid Diagnosis Scenario" dominates usual care (ie, is both cheaper and more effective). For a willingness-to-pay threshold of €20,000/QALY the probability that the "DiagnOSAS Strategy" and "Rapid Diagnosis Scenario" are cost-effective equals 91.7% and 99.3%, respectively. DiagnOSAS appears to be a cost-saving alternative for the usual OSA diagnostic strategy in The Netherlands. When DiagnOSAS succeeds in decreasing time to diagnosis, it could substantially improve health outcomes as well.


SF-36: evaluation of quality of life in severe and mild insomniacs compared with good sleepers.
Despite many studies, the impact of chronic insomnia on daytime functioning is not well understood. The aim of our study was to detect this impact by evaluating quality of life (QoL) using a validated instrument, the 36-item Short Form Health Survey of the Medical Outcomes Study (SF-36), in three matched groups of severe insomniacs, mild insomniacs, and good sleepers selected from the general population. Three matched groups of 240 severe insomniacs, 422 mild insomniacs, and 391 good sleepers were recruited from the general French population after eliminating those with DSM-IV criteria for anxiety or depression. All subjects were asked to complete the SF-36. Scores for each QoL dimension were calculated and compared statistically among the three groups. Severe insomniacs had lower QoL scores in eight dimensions of the SF-36 than mild insomniacs and good sleepers. Mild insomniacs had lower scores in the same eight dimensions when compared with good sleepers. No dimension was significantly more altered than the other. The mental health status and role of emotional QoL dimensions were worse in severe and mild insomniacs than in good sleepers. This result held even though we screened for psychiatric diseases, which shows a clear interrelation between insomnia and emotional state. General health status was also worse in severe and mild insomniacs than in good sleepers. However, we could conclude only that insomnia was related to a worse health status and not whether it was a cause or consequence of this worse health status. Finally, the degradation of QoL scores was correlated with the severity of insomnia.


Mouse meningiocytes express Sox2 and yield high efficiency of chimeras after nuclear reprogramming with exogenous factors.
Induced pluripotent stem cell technology, also termed iPS, is an emerging approach to reprogram cells into an embryonic stem cell-like state by viral transduction with defined combinations of factors. iPS cells share most characteristics of embryonic stem cells, counting pluripotency and self-renewal, and have so far been obtained from mouse and humans, including patients with genetic diseases. Remarkably, autologous transplantation of cell lineages derived from iPS cells will eliminate the possibility of immunological rejection, as well as current ethical issues surrounding human embryonic stem cell research. However, before iPS can be used for clinical purposes, technical problems must be overcome. Among other considerations, full and homogeneous iPS reprogramming is an important prerequisite. However, despite the fact that cells from several mouse tissues can be successfully induced to iPS, the overall efficiency of chimera formation of these clones remains low even if selection for Oct4 or Nanog expression is applied. In this report, we demonstrate that cells from the mouse meningeal membranes express elevated levels of the embryonic master regulator Sox2 and are highly amenable to iPS. Meningeal iPS clones, generated without selection, are fully and homogeneously reprogrammed based on DNA methylation analysis and 100% chimera competent. Our results define a population of somatic cells that are ready to undergo iPS, thus highlighting a very attractive cell type for iPS research and application.


spib is required for primitive myeloid development in Xenopus.
Vertebrate blood formation occurs in 2 spatially and temporally distinct waves, so-called primitive and definitive hematopoiesis. Although definitive hematopoiesis has been extensively studied, the development of primitive myeloid blood has received far less attention. In Xenopus, primitive myeloid cells originate in the anterior ventral blood islands, the equivalent of the mammalian yolk sac, and migrate out to colonize the embryo. Using fluorescence time-lapse video microscopy, we recorded the migratory behavior of primitive myeloid cells from their birth. We show that these cells are the first blood cells to differentiate in the embryo and that they are efficiently recruited to embryonic wounds, well before the establishment of a functional vasculature. Furthermore, we isolated spib, an ETS transcription factor, specifically expressed in primitive myeloid precursors. Using spib antisense morpholino knockdown experiments, we show that spib is required for myeloid specification, and, in its absence, primitive myeloid cells retain hemangioblast-like characteristics and fail to migrate. Thus, we conclude that spib sits at the top of the known genetic hierarchy that leads to the specification of primitive myeloid cells in amphibians.


[A rare case of nasal hemorrhage from the internal carotid artery aneurism].
The objective of this paper is to report a rare clinical case of persistently recurring nasal hemorrhage. Reccurent nasal hemorrhage in the examined patient was associated with the presence of the false internal carotid artery aneurism. This condition was diagnosed and managed with the use of the angiographic technique in conjunction with subsequent selective endovascular embolization of the affected vessels that made it possible to purposefully block the source of hemorrhage. Angiography and selective endovascular embolization provide the sole reliable method for diagnostics and arrest of nasal hemorrhage as is confirmed by the present clinical observation.


Non-random chromosome arrangement in triploid endosperm nuclei.
The endosperm is at the center of successful seed formation in flowering plants. Being itself a product of fertilization, it is devoted to nourish the developing embryo and typically possesses a triploid genome consisting of two maternal and one paternal genome complement. Interestingly, endosperm development is controlled by epigenetic mechanisms conferring parent-of-origin-dependent effects that influence seed development. In the model plant Arabidopsis thaliana, we have previously described an endosperm-specific heterochromatin fraction, which increases with higher maternal, but not paternal, genome dosage. Here, we report a detailed analysis of chromosomal arrangement and association frequency in endosperm nuclei. We found that centromeric FISH signals in isolated nuclei show a planar alignment that may results from a semi-rigid, connective structure between chromosomes. Importantly, we found frequent pairwise association of centromeres, chromosomal segments, and entire arms of chromosomes in 3C endosperm nuclei. These associations deviate from random expectations predicted by numerical simulations. Therefore, we suggest a non-random chromosomal organization in the triploid nuclei of Arabidopsis endosperm. This contrasts with the prevailing random arrangement of chromosome territories in somatic nuclei. Based on observations on a series of nuclei with varying parental genome ratios, we propose a model where chromosomes associate pairwise involving one maternal and one paternal complement. The functional implications of this predicted chromosomal arrangement are discussed.