Genetic Characterization of Resistance to Wheat Stem Rust Race TTKSK in Landrace and Wild Barley Accessions Identifies the rpg4/Rpg5 Locus.
Race TTKSK of the wheat stem rust pathogen (Puccinia graminis f. sp. tritici) threatens the production of wheat and barley worldwide because of its broad-spectrum virulence on many widely grown cultivars. Sources of resistance against race TTKSK were recently identified in several barley landraces (Hordeum vulgare subsp. vulgare) and wild barley accessions (H. vulgare subsp. spontaneum). The objectives of this study were to characterize the inheritance of resistance to wheat stem rust race TTKSK in four barley landraces (Hv501, Hv545, Hv602, and Hv612) and two wild barley (WBDC213 and WBDC345) accessions, map the resistance genes, and determine the allelic relationships among the genes in these accessions and the previously described rpg4/Rpg5 locus. Resistant accessions were crossed with the susceptible cv. Steptoe and resulting F3 populations were evaluated for resistance to race TTKSK at the seedling stage. Segregation of F3 families in populations involving the resistance sources of Hv501, Hv545, Hv612, WBDC213, and WBDC345 fit a 1:2:1 ratio for homozygous resistant (HR)/segregating (SEG)/homozygous susceptible (HS) progenies (with χ2=2.27 to 5.87 and P=0.053 to 0.321), indicating that a single gene confers resistance to race TTKSK. Segregation of F3 families in cross Steptoe/Hv602 did not fit a 1:2:1 ratio (HR/SEG/HS of 20:47:43 with χ2=11.95 and P=0.003), indicating that more than one gene is involved in imparting resistance to race TTKSK. Bulked segregant analysis using >1,500 single-nucleotide polymorphism markers positioned a resistance locus in all six populations on chromosome 5HL in very close proximity to the known location of the rpg4/Rpg5 complex locus. Allelism tests were conducted by making crosses among resistant accessions Hv501, Hv545, and Hv612 and also Q21861 with the rpg4/Rpg5 complex. No segregation was observed in F2 families inoculated with race TTKSK, demonstrating that all Hv lines carry the same allele for resistance and that it resides at or very near the rpg4/Rpg5 locus. Phenotype evaluations of the six barley accessions with wheat stem rust race QCCJ revealed resistant infection types (ITs) at a low incubation temperature and susceptible ITs at a high incubation temperature, similar to Q21861, which carries the temperature-sensitive gene rpg4. The accessions also exhibited low ITs against the rye stem rust isolate 92-MN-90, suggesting that they also carry Rpg5. This result was confirmed through molecular analysis, which revealed that all six barley accessions contain the serine threonine protein kinase domain that confers Rpg5 resistance. These results indicate that cultivated barley is extremely vulnerable to African stem rust races such as TTKSK because even these diverse selections of landrace and wild barley accessions carry only one locus for resistance.


Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine.
Vesicular monoamine transporters are known to transport monoamines from the cytoplasm into secretory vesicles. We have used homologous recombination to generate mutant mice lacking the vesicular monoamine transporter 2 (VMAT2), the predominant form expressed in the brain. Newborn homozygotes die within a few days after birth, manifesting severely impaired monoamine storage and vesicular release. In heterozygous adult mice, extracellular striatal dopamine levels, as well as K+- and amphetamine-evoked dopamine release, are diminished. The observed changes in presynaptic homeostasis are accompanied by a pronounced supersensitivity of the mice to the locomotor effects of the dopamine agonist apomorphine, the psychostimulants cocaine and amphetamine, and ethanol. Importantly, VMAT2 heterozygous mice do not develop further sensitization to repeated cocaine administration. These observations stress the importance of VMAT2 in the maintenance of presynaptic function and suggest that these mice may provide an animal model for delineating the mechanisms of vesicular release, monoamine function, and postsynaptic sensitization associated with drug abuse.


Role of imatinib in the management of early, operable, and advanced GI stromal tumors (GISTs).
Gastrointestinal stromal tumors (GISTs), the most common sarcoma of the GI tract, have unique kinase mutations that serve as targets for medical therapy. This article reviews the data supporting the use of the tyrosine kinase inhibitor (TKI) imatinib in GIST patients, and how this treatment should be combined with surgical resection (when possible) to optimize patient outcomes. Although surgical resection remains the mainstay of treatment for these tumors, patients with resected GISTs have high relapse rates that can be reduced by 1 year of adjuvant imatinib. Data also support the use of imatinib for patients with recurrent or unresectable GIST. In these patients the drug should be continued until progression, intolerance, or the patients are rendered resectable. Patients with advanced GIST who are successfully resected after imatinib treatment should be placed back on imatinib postoperatively. Patients who develop generalized progression (progression at 2 or more sites) on imatinib should move to other treatments, such as newer TKIs or other targeted approaches currently under study. Genotyping of the tumor should be considered in all pediatric GISTs and high risk adult GISTs, especially if there is progression on imatinib. Quality of life and the cost/benefit of new therapies are important issues for further study in patients with GIST.


Discontinuation of nucleos(t)ide analogues is not associated with a higher risk of HBsAg seroreversion after antiviral-induced HBsAg seroclearance: a nationwide multicentre study.
Direct comparison of the clinical outcomes between nucleos(t)ide analogue (NA) discontinuation versus NA continuation has not been performed in patients with chronic hepatitis B who achieved HBsAg-seroclearance. Whether NA discontinuation was as safe as NA continuation after NA-induced surface antigen of HBV (HBsAg) seroclearance was investigated in the present study. This multicentre study included 276 patients from 16 hospitals in Korea who achieved NA-induced HBsAg seroclearance: 131 (47.5%) discontinued NA treatment within 6 months after HBsAg seroclearance (NA discontinuation group) and 145 (52.5%) continued NA treatment (NA continuation group). Primary endpoint was HBsAg reversion and secondary endpoints included serum HBV DNA redetection and development of hepatocellular carcinoma (HCC). During follow-up (median=26.9 months, IQR=12.2-49.2 months), 10 patients (3.6%) experienced HBsAg reversion, 6 (2.2%) showed HBV DNA redetection and 8 (2.9%) developed HCC. Compared with NA continuation, NA discontinuation was not associated with HBsAg reversion in both univariable (HR=0.45, 95% CI=0.12 to 1.76, log-rank p=0.24) and multivariable analyses (adjusted HR=0.65, 95% CI=0.16 to 2.59, p=0.54). The cumulative probabilities of HBsAg reversion at 1, 3 and 5 years were 0.8%, 2.3% and 5.0% in the NA discontinuation group, and 1.5%, 6.3% and 8.4% in the NA continuation group, respectively. NA discontinuation was not associated with higher risk of either HBV redetection (HR=0.83, 95% CI=0.16 to 4.16, log-rank p=0.82) or HCC development (HR=0.53, 95% CI=0.12 to 2.23, log-rank p=0.38). The discontinuation of NA was not associated with a higher risk of either HBsAg reversion, serum HBV DNA redetection or HCC development compared with NA continuation among patients who achieved HBsAg seroclearance with NA.


Predictive value of serum progesterone level on β-hCG check day in women with previous repeated miscarriages after in vitro fertilization.
To evaluate the predictive value of the progesterone level at the beta-human chorionic gonadotropin (β-hCG) check day for ongoing pregnancy maintenance in in vitro fertilization (IVF) cycles in women with previous unexplained repeated miscarriages. One hundred and forty-eight women, with visible gestational sac after IVF, were recruited in this observational study. All subjects had unexplained recurrent miscarriages in more than two previous IVF cycles. The progesterone level at the β-hCG check day (i.e. 14 days after oocyte retrieval) was assessed. The area under the curve (AUC) of the progesterone level was evaluated to predict the ongoing pregnancy or miscarriage outcomes. The overall ongoing pregnancy rate was 60.8% (90/148). The cut-off value with β-hCG levels higher than 126.5 mIU/mL and with progesterone levels higher than 25.2 ng/mL could be the predictive factors for ongoing pregnancy maintenance (AUC = 0.788 and 0.826; sensitivity = 0.788 and 0.723; specificity = 0.689 and 0.833; P < 0.0001 and P < 0.0001, respectively). The miscarriage rates were 19.5% (15/77) in the women with β-hCG > 126.5 mIU/mL and 13.0% (10/77) in those with > 25.2 ng/mL. In the comparison of the ROC curves between both values, a similar significance was found. The subjects with β-hCG > 126.5 mIU/mL and progesterone > 25.2 ng/mL showed higher ongoing pregnancy rates [98.0% (49/50) vs. 41.8% (41/98)] than those with β-hCG ≤ 126.5 mIU/mL or progesterone ≤ 25.2 ng/mL. The progesterone level at 14 days after oocyte retrieval can be a good predictive marker for ongoing pregnancy maintenance in women with repeated IVF failure with miscarriage, together with the β-hCG level. The combined cut-off value of progesterone > 25.2 ng/mL and β-hCG > 126.5 mIU/mL may suggest a good prognosis.


Colon and pancreas tumors enhance coagulation: role of hemeoxygenase-1.
Colon and pancreatic cancer are associated with significant thrombophilia. Colon and pancreas tumor cells have an increase in hemeoxygenase-1 (HO-1) activity, the endogenous enzyme responsible for carbon monoxide production. Given that carbon monoxide enhances plasmatic coagulation, we determined if patients undergoing resection of colon and pancreatic tumors had an increase in endogenous carbon monoxide and plasmatic hypercoagulability. Patients with colon (n = 17) and pancreatic (n = 10) tumors were studied. Carbon monoxide was determined by the measurement of carboxyhemoglobin (COHb). A thrombelastographic method to assess plasma coagulation kinetics and formation of carboxyhemefibrinogen (COHF) was utilized. Nonsmoking patients with colon and pancreatic tumors had abnormally increased COHb concentrations of 1.4 ± 0.9 and 1.9 ± 0.7%, respectively, indicative of HO-1 upregulation. Coagulation analyses comparing both tumor groups demonstrated no significant differences in any parameter; thus the data were combined for the tumor groups for comparison with 95% confidence interval values obtained from normal individuals (n = 30) plasma. Seventy percent of tumor patients had a velocity of clot formation greater than the 95% confidence interval value of normal individuals, with 53% of this hypercoagulable group also having COHF formation. Further, 67% of tumor patients had clot strength that exceeded the normal 95% confidence interval value, and 56% of this subgroup had COHF formation. Finally, 63% of all tumor patients had COHF formation. Future investigation of HO-1-derived carbon monoxide in the pathogenesis of colon and pancreatic tumor-related thrombophilia is warranted.


Attention following traumatic brain injury: Neuropsychological and driving simulator data, and association with sleep, sleepiness, and fatigue.
The objectives of this study were to compare individuals with traumatic brain injury (TBI) and healthy controls on neuropsychological tests of attention and driving simulation performance, and explore their relationships with participants' characteristics, sleep, sleepiness, and fatigue. Participants were 22 adults with moderate or severe TBI (time since injury ≥ one year) and 22 matched controls. They completed three neuropsychological tests of attention, a driving simulator task, night-time polysomnographic recordings, and subjective ratings of sleepiness and fatigue. Results showed that participants with TBI exhibited poorer performance compared to controls on measures tapping speed of information processing and sustained attention, but not on selective attention measures. On the driving simulator task, a greater variability of the vehicle lateral position was observed in the TBI group. Poorer performance on specific subsets of neuropsychological variables was associated with poorer sleep continuity in the TBI group, and with a greater increase in subjective sleepiness in both groups. No significant relationship was found between cognitive performance and fatigue. These findings add to the existing evidence that speed of information processing is still impaired several years after moderate to severe TBI. Sustained attention could also be compromised. Attention seems to be associated with sleep continuity and daytime sleepiness; this interaction needs to be explored further.


Treatment of postmenopausal osteoporosis in women: a systematic review.
Osteoporosis, a typical disease of the elderly, has become a frequent and relevant public health problem. Several drugs are available for treatment of osteoporosis, some of which are currently dispensed by the Brazilian Unified National Health System. The objective of this study was to present a systematic review of drugs for treatment of osteoporosis, focusing on the adequacy of clinical protocols based on existing evidence in the scientific literature. We conducted a search for randomized clinical trials in PubMed and LILACS that presented results for bone mineral density, incidence of vertebral fractures, and adverse effects. 32 articles met the review's inclusion criteria. Bisphosphonates were reported to have consistently reduced the risk of vertebral fractures. Hormone replacement therapy showed positive outcomes, but its use has been found to increase the risk of cardiovascular disease and breast cancer. Teriparatide and monofluorophosphate also showed efficacy against osteoporosis. Calcium and vitamin D were given to patients as food supplements.


Associating liver partition and portal vein ligation (ALPPS): Taking a view of trails.
Associating liver partition and portal vein ligation (ALPPS) is introduced as a modified two-staged hepatectomy for advanced liver malignancies, which requires extended hepatectomy with very small future remnant liver volume. It is characterized by rapid and large growth of future remnant liver and potential of widening the indication of curative resection with extended major hepatectomy for liver malignancies. It showed, however, much higher morbidity and mortality than extended hepatectomy after portal vein embolization. Here, we review the literatures and examine the role of ALPPS in Japan, where zero mortality after hepatectomy is highly expected.


Direct radical scavenging activity of benzbromarone provides beneficial antioxidant properties for hyperuricemia treatment.
Uric acid exerts an important antioxidant effect against external oxidative stress under physiological conditions. However, uric acid itself can increase oxidative stress via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation in adipocytes and vascular cells. Uric acid transporter 1 is involved in the generation of this oxidative stress. Furthermore, uric acid locally activates the renin-angiotensin system, thus producing angiotensin II and subsequently increasing intracellular oxidative stress. Benzbromarone has been reported to suppress uric acid reabsorption via uric acid transporter 1 inhibition in renal tubular cells. In this study we evaluated the in vitro antioxidant effect of benzbromarone from several perspectives. First, the direct radical-trapping capacity of benzbromarone was measured by chemiluminescence assay and electron paramagnetic resonance spectroscopy. Second, the intracellular antioxidant activity of benzbromarone in hyperuricemia was evaluated using endothelial cells. In light of these results, benzbromarone is hypothesized directly to scavenge the superoxide anion radical. In addition, benzbromarone inhibited reactive oxygen species production that was induced by angiotensin II or uric acid in endothelial cells. These findings suggest that benzbromarone possesses the ability directly to scavenge radicals and may act as an antioxidant against uric acid and angiotensin II-induced oxidative stresses in endothelial cells at therapeutically achievable levels in blood.


Wave-front sensing with time-of-flight phase diversity.
We present a new way to sense atmospheric wave-front phase distortion. Short collimated pulses of laser light at ~350nm are projected from a small auxilliary telescope. Rayleigh scattering from each pulse is recorded over a wide range of height through the main telescope aperture in a continuous sequence of fast video frames by a detector conjugate to mid-height. Phase diversity is thus naturally introduced as the pulses approach and pass through focus. We show that an iterative algorithm can extract the phase structure from the recorded images and do so with a much higher signal-to-noise ratio than is possible with existing techniques. If the requirements for real-time data recording and reduction can be met, the new method will address the need for tomographic wave-front sensing at planned 30-m-class telescopes.


Characterizing human mobility patterns in rural settings of sub-Saharan Africa.
Human mobility is a core component of human behavior and its quantification is critical for understanding its impact on infectious disease transmission, traffic forecasting, access to resources and care, intervention strategies, and migratory flows. When mobility data are limited, spatial interaction models have been widely used to estimate human travel, but have not been extensively validated in low- and middle-income settings. Geographic, sociodemographic, and infrastructure differences may impact the ability for models to capture these patterns, particularly in rural settings. Here, we analyzed mobility patterns inferred from mobile phone data in four Sub-Saharan African countries to investigate the ability for variants on gravity and radiation models to estimate travel. Adjusting the gravity model such that parameters were fit to different trip types, including travel between more or less populated areas and/or different regions, improved model fit in all four countries. This suggests that alternative models may be more useful in these settings and better able to capture the range of mobility patterns observed.


Guidelines on the irritable bowel syndrome: mechanisms and practical management.
IBS affects 5-11% of the population of most countries. Prevalence peaks in the third and fourth decades, with a female predominance. To provide a guide for the assessment and management of adult patients with irritable bowel syndrome. Members of the Clinical Services Committee of The British Society of Gastroenterology were allocated particular areas to produce review documents. Literature searching included systematic searches using electronic databases such as Pubmed, EMBASE, MEDLINE, Web of Science, and Cochrane databases and extensive personal reference databases. Patients can usefully be classified by predominant bowel habit. Few investigations are needed except when diarrhoea is a prominent feature. Alarm features may warrant further investigation. Adverse psychological features and somatisation are often present. Ascertaining the patients' concerns and explaining symptoms in simple terms improves outcome. IBS is a heterogeneous condition with a range of treatments, each of which benefits a small proportion of patients. Treatment of associated anxiety and depression often improves bowel and other symptoms. Randomised placebo controlled trials show benefit as follows: cognitive behavioural therapy and psychodynamic interpersonal therapy improve coping; hypnotherapy benefits global symptoms in otherwise refractory patients; antispasmodics and tricyclic antidepressants improve pain; ispaghula improves pain and bowel habit; 5-HT(3) antagonists improve global symptoms, diarrhoea, and pain but may rarely cause unexplained colitis; 5-HT(4) agonists improve global symptoms, constipation, and bloating; selective serotonin reuptake inhibitors improve global symptoms. Better ways of identifying which patients will respond to specific treatments are urgently needed.


Curcumin-induced suppression of adipogenic differentiation is accompanied by activation of Wnt/beta-catenin signaling.
Curcumin, a polyphenol found in the rhizomes of Curcuma longa, improves obesity-associated inflammation and diabetes in obese mice. Curcumin also suppresses adipocyte differentiation, although the underlying mechanism remains unclear. Here, we used 3T3-L1 cells to investigate the details of the mechanism underlying the anti-adipogenic effects of curcumin. Curcumin inhibited mitogen-activated protein kinase (MAPK) (ERK, JNK, and p38) phosphorylation that was associated with differentiation of 3T3-L1 cells into adipocytes. During differentiation, curcumin also restored nuclear translocation of the integral Wnt signaling component beta-catenin in a dose-dependent manner. In parallel, curcumin reduced differentiation-stimulated expression of CK1alpha, GSK-3beta, and Axin, components of the destruction complex targeting beta-catenin. Accordingly, quantitative PCR analysis revealed that curcumin inhibited the mRNA expression of AP2 (mature adipocyte marker) and increased the mRNA expression of Wnt10b, Fz2 (Wnt direct receptor), and LRP5 (Wnt coreceptor). Curcumin also increased mRNA levels of c-Myc and cyclin D1, well-known Wnt targets. These results suggest that the Wnt signaling pathway participates in curcumin-induced suppression of adipogenesis in 3T3-L1 cells.


SyntenyTracker: a tool for defining homologous synteny blocks using radiation hybrid maps and whole-genome sequence.
The recent availability of genomic sequences and BAC libraries for a large number of mammals provides an excellent opportunity for identifying comparatively-anchored markers that are useful for creating high-resolution radiation-hybrid (RH) and BAC-based comparative maps. To use these maps for multispecies genome comparison and evolutionary inference, robust bioinformatic tools are required for the identification of chromosomal regions shared between genomes and to localize the positions of evolutionary breakpoints that are the signatures of chromosomal rearrangements. Here we report an automated tool for the identification of homologous synteny blocks (HSBs) between genomes that tolerates errors common in RH comparative maps and can be used for automated whole-genome analysis of chromosome rearrangements that occur during evolution. We developed an algorithm and software tool (SyntenyTracker) that can be used for automated definition of HSBs using pair-wise RH or gene-based comparative maps as input. To verify correct implementation of the underlying algorithm, SyntenyTracker was used to identify HSBs in the cattle and human genomes. Results demonstrated 96% agreement with HSBs defined manually using the same set of rules. A comparison of SyntenyTracker with the AutoGRAPH synteny tool was performed using identical datasets containing 14,380 genes with 1:1 orthology in human and mouse. Discrepancies between the results using the two tools and advantages of SyntenyTracker are reported. SyntenyTracker was shown to be an efficient and accurate automated tool for defining HSBs using datasets that may contain minor errors resulting from limitations in map construction methodologies. The utility of SyntenyTracker will become more important for comparative genomics as the number of mapped and sequenced genomes increases.


Survival and differentiation of adenovirus-generated induced pluripotent stem cells transplanted into the rat striatum.
Induced pluripotent stem cells (iPSCs) offer certain advantages over embryonic stem cells in cell replacement therapy for a variety of neurological disorders. However, reliable procedures, whereby transplanted iPSCs can survive and differentiate into functional neurons, without forming tumors, have yet to be devised. Currently, retroviral or lentiviral reprogramming methods are often used to reprogram somatic cells. Although the use of these viruses has proven to be effective, formation of tumors often results following in vivo transplantation, possibly due to the integration of the reprogramming genes. The goal of the current study was to develop a new approach, using an adenovirus for reprogramming cells, characterize the iPSCs in vitro, and test their safety, survivability, and ability to differentiate into region-appropriate neurons following transplantation into the rat brain. To this end, iPSCs were derived from bone marrow-derived mesenchymal stem cells and tail-tip fibroblasts using a single cassette lentivirus or a combination of adenoviruses. The reprogramming efficiency and levels of pluripotency were compared using immunocytochemistry, flow cytometry, and real-time polymerase chain reaction. Our data indicate that adenovirus-generated iPSCs from tail-tip fibroblasts are as efficient as the method we used for lentiviral reprogramming. All generated iPSCs were also capable of differentiating into neuronal-like cells in vitro. To test the in vivo survivability and the ability to differentiate into region-specific neurons in the absence of tumor formation, 400,000 of the iPSCs derived from tail-tip fibroblasts that were transfected with the adenovirus pair were transplanted into the striatum of adult, immune-competent rats. We observed that these iPSCs produced region-specific neuronal phenotypes, in the absence of tumor formation, at 90 days posttransplantation. These results suggest that adenovirus-generated iPSCs may provide a safe and viable means for neuronal replacement therapies.


Melioidosis in northern Australia, 2001-02.
Melioidosis, caused by the gram negative bacterium Burkholderia pseudomallei, is endemic in northern Australia. Using data collated from centres in Western Australia, the Northern Territory and Queensland, this report describes the epidemiology of this disease between 1 November, 2001 and 31 October, 2002. There were 47 cases seen during this period with an average annual incidence of 5.8 cases per 100,000 population. In Indigenous Australians, an incidence of 25.5 cases per 100,000 population was seen. The timing and location of cases was generally correlated with rainfall across northern Australia. A case-cluster in a Queensland community was associated with post-cyclonic flooding. Risk factors included diabetes, alcohol-related problems and renal disease. Pneumonia (51%) was the most common clinical diagnosis. The mortality rate attributable to melioidosis was 21 per cent, although a number of other patients died of underlying disease. Despite improvements in recognition and treatment, melioidosis is still associated with a high morbidity and mortality, particularly in Indigenous Australians.


Biological, socio-demographic, work and lifestyle determinants of sitting in young adult women: a prospective cohort study.
Sitting is associated with health risks. Factors that influence sitting are however not well understood. The aim was to examine the biological, socio-demographic, work-related and lifestyle determinants of sitting time (including during transport, work and leisure) in young adult Australian women. Self-reported data from 11,676 participants (aged 22-27 years in 2000) in the Australian Longitudinal Study on Women's Health were collected over 9 years in 2000, 2003, 2006 and 2009. Generalised Estimating Equations were used to examine univariable and multivariable associations of body mass index (BMI), country of birth, area of residence, education, marital status, number of children, occupational status, working hours, physical activity, smoking, alcohol intake and stress with week- and weekend-day sitting time. Compared with women in the respective referent categories, (1) women with higher BMI, those born in Asia, those with less than University level education, doing white collar work, working 41-48 hours a week, current smokers, non, rare or risky/high risk drinkers and those being somewhat stressed had significantly higher sitting time; and (2) women living in rural and remote areas, partnered women, those with children, those without a paid job and blue collar workers, those working less than 34 hours a week, and active women had significantly lower sitting time. Among young adult Australian women, those with higher BMI, those born in Asia, those with higher level occupations and long working hours, were most at risk of higher sitting time. These results can be used to identify at-risk groups and inform intervention development.


Scalp reconstruction: an algorithmic approach and systematic review.
Reconstruction of the scalp after acquired defects remains a common challenge for the reconstructive surgeon, especially in a patient with a history of radiation to the area. To review the current literature and describe a novel algorithm to help guide the reconstructive surgeon in determining the optimal reconstruction from a cosmetic and functional standpoint. Pertinent surgical anatomy, considerations for patient and technique selection, reconstructive goals, as well as the reconstructive ladder, are also discussed. A PubMed and Medline search was performed of the entire English literature with respect to scalp reconstruction. Priority of review was given to those studies with higher-quality levels of evidence. Size, location, radiation history, and potential for hairline distortion are important factors in determining the ideal reconstruction. The tighter and looser areas of the scalp play a major role in the potential for primary or local flap closure. Patients with medium to large defects and a history of radiation will likely benefit from free tissue transfer. Ideal reconstruction of scalp defects relies on a comprehensive understanding of scalp anatomy, a full consideration of the armamentarium of surgical techniques, and a detailed appraisal of patient factors and expectations. The simplest reconstruction should be used whenever possible to provide the most functional and aesthetic scalp reconstruction, with the least amount of complexity. NA.


Exploring the role of testosterone in the cerebellum link to neuroticism: From adolescence to early adulthood.
Previous research has found an association between a smaller cerebellar volume and higher levels of neuroticism. The steroid hormone testosterone reduces stress responses and the susceptibility to negative mood. Together with in vitro studies showing a positive effect of testosterone on cerebellar gray matter volumes, we set out to explore the role of testosterone in the relation between cerebellar gray matter and neuroticism. Structural magnetic resonance imaging scans were acquired, and indices of neurotic personality traits were assessed by administering the depression and anxiety scale of the revised NEO personality inventory and Gray's behavioural avoidance in one hundred and forty-nine healthy volunteers between 12 and 27 years of age. Results demonstrated an inverse relation between total brain corrected cerebellar volumes and neurotic personality traits in adolescents and young adults. In males, higher endogenous testosterone levels were associated with lower scores on neurotic personality traits and larger cerebellar gray matter volumes. No such relations were observed in the female participants. Analyses showed that testosterone significantly mediated the relation between male cerebellar gray matter and measures of neuroticism. Our findings on the interrelations between endogenous testosterone, neuroticism and cerebellar morphology provide a cerebellum-oriented framework for the susceptibility to experience negative emotions and mood in adolescence and early adulthood.


Direct continuous measurement of draining vein pressure during Onyx embolization in a swine arteriovenous malformation model.
Periprocedural intracranial hemorrhage secondary to intranidal flow redirection may develop after arteriovenous malformation (AVM) embolization. We hypothesized that continuous draining vein pressure monitoring may identify clinically relevant hemodynamic changes during devascularization. Our goal was to characterize the draining vein pressures in a swine rete mirabile AVM model during embolization with Onyx. An acute swine AVM model was constructed in six animals. Baseline, transoperative and final AVM area measurements were used to determine the degree of AVM embolization. Continuous video recordings were captured at 10 s intervals of active embolization. Draining vein pressure, arterial feeder pressure and heart rate were continuously monitored. The baseline and post-embolization mean draining vein pressures were 49.8±17.2 and 33.0±11.7 mm Hg (p=0.01), mean arterial pressures were 79.8±19.4 and 79.6±25.2 mm Hg (p=0.94), mean transnidal pressures were 35.8±19.7 and 45.4±33.7 mm Hg (p=0.37) and mean heart rates were 81.1±11.9 and 83.1±12.8 bpm (p=0.38), respectively. The draining vein pressure was averaged according to the degree of AVM embolization and represented as a relative change compared with the baseline draining vein pressure, and the slopes were found to decrease in all cases (p=0.02). In half of the animals the draining vein pressure decreased progressively as the AVM was embolized. In the remaining animals the venous pressure only started to decline after the AVM had been devascularized by > 50%. The draining vein pressure response during Onyx embolization in the swine AVM model is heterogeneous. Continuous draining vein pressure monitoring is feasible and may potentially identify clinically relevant hemodynamic changes during AVM embolization.


Regulation of somatic myosin activity by protein phosphatase 1β controls Drosophila oocyte polarization.
The Drosophila body axes are established in the oocyte during oogenesis. Oocyte polarization is initiated by Gurken, which signals from the germline through the epidermal growth factor receptor (Egfr) to the posterior follicle cells (PFCs). In response the PFCs generate an unidentified polarizing signal that regulates oocyte polarity. We have identified a loss-of-function mutation of flapwing, which encodes the catalytic subunit of protein phosphatase 1β (PP1β) that disrupts oocyte polarization. We show that PP1β, by regulating myosin activity, controls the generation of the polarizing signal. Excessive myosin activity in the PFCs causes oocyte mispolarization and defective Notch signaling and endocytosis in the PFCs. The integrated activation of JAK/STAT and Egfr signaling results in the sensitivity of PFCs to defective Notch. Interestingly, our results also demonstrate a role of PP1β in generating the polarizing signal independently of Notch, indicating a direct involvement of somatic myosin activity in axis formation.


Randomised controlled comparative study of methyldopa and oxprenolol in treatment of hypertension in pregnancy.
One hundred pregnant women with hypertension (defined as diastolic blood pressure at or above 95 mm Hg) were allocated at random to treatment with methyldopa or oxprenolol and were compared with nonhypertensive controls matched according to parity and gestation at delivery. The patients were also stratified into those entering the study early (before 32 weeks' gestation) and those entering late (after 32 weeks' gestation). Although there were no differences in diastolic blood pressure between the hypertensive groups before or during treatment, in the early entry group the systolic blood pressure at entry of those allocated to oxprenolol was significantly higher than that of those receiving methyldopa; this difference remained throughout the treatment period. Also in the early entry group further increments of drug treatment were required to control blood pressure of patients receiving oxprenolol than in those receiving methyldopa. The eventual fetal outcome for all patients treated with methyldopa was the same as that for those treated with oxprenolol; birth weight, placental weight, head circumference, and Apgar score were not significantly different and there were no stillbirths in either group.


Pregnant women's secondhand smoke exposure and receipt of screening and brief advice by prenatal care providers in Argentina and Uruguay.
Secondhand smoke (SHS) exposure has negative effects on maternal and infant health. SHS exposure among pregnant women in Argentina and Uruguay has not been previously described, nor has the proportion of those who have received screening and advice to avoid SHS during prenatal care. Women who attended one of 21 clusters of publicly-funded prenatal care clinics were interviewed regarding SHS exposure during pregnancy at their delivery hospitalization during 2011-2012. Analyses were conducted using SURVEYFREQ procedure in SAS version 9.3 to account for prenatal clinic clusters. Of 3,427 pregnant women, 43.4 % had a partner who smoked, 52.3 % lived with household members who smoked cigarettes, and 34.4 % had no or partial smoke-free home rule. Of 528 pregnant women who worked outside of the home, 21.6 % reported past month SHS exposure at work and 38.1 % reported no or partial smoke-free work policy. Overall, 35.9 % of women were exposed to SHS at home or work. In at least one prenatal care visit, 67.2 % of women were screened for SHS exposure, and 56.6 % received advice to avoid SHS. Also, 52.6 % of women always avoided SHS for their unborn baby's health. In summary, a third of pregnant women attending publicly-funded prenatal clinics were exposed to SHS, and only half of pregnant women always avoided SHS for their unborn baby's health. Provider screening and advice rates can be improved in these prenatal care settings, as all pregnant women should be screened and advised of the harms of SHS and how to avoid it.


Assistive HCI-Serious Games Co-design Insights: The Case Study of i-PROGNOSIS Personalized Game Suite for Parkinson's Disease.
Human-Computer Interaction (HCI) and games set a new domain in understanding people's motivations in gaming, behavioral implications of game play, game adaptation to player preferences and needs for increased engaging experiences in the context of HCI serious games (HCI-SGs). When the latter relate with people's health status, they can become a part of their daily life as assistive health status monitoring/enhancement systems. Co-designing HCI-SGs can be seen as a combination of art and science that involves a meticulous collaborative process. The design elements in assistive HCI-SGs for Parkinson's Disease (PD) patients, in particular, are explored in the present work. Within this context, the Game-Based Learning (GBL) design framework is adopted here and its main game-design parameters are explored for the Exergames, Dietarygames, Emotional games, Handwriting games, and Voice games design, drawn from the PD-related i-PROGNOSIS Personalized Game Suite (PGS) (www.i-prognosis.eu) holistic approach. Two main data sources were involved in the study. In particular, the first one includes qualitative data from semi-structured interviews, involving 10 PD patients and four clinicians in the co-creation process of the game design, whereas the second one relates with data from an online questionnaire addressed by 104 participants spanning the whole related spectrum, i.e., PD patients, physicians, software/game developers. Linear regression analysis was employed to identify an adapted GBL framework with the most significant game-design parameters, which efficiently predict the transferability of the PGS beneficial effect to real-life, addressing functional PD symptoms. The findings of this work can assist HCI-SG designers for designing PD-related HCI-SGs, as the most significant game-design factors were identified, in terms of adding value to the role of HCI-SGs in increasing PD patients' quality of life, optimizing the interaction with personalized HCI-SGs and, hence, fostering a collaborative human-computer symbiosis.


Secretory cells of the supraoptic nucleus have central as well as neurohypophysial projections.
Conventional neuroanatomical methods may fail to demonstrate the presence of axons that are finer than 1 microm in diameter because such processes are near or below the limit of resolution of the light microscope. The presence of such axons can, however, be readily demonstrated by recording. The most easily interpreted type of recording for this purpose is the demonstration of antidromic activation of the cell body following stimulation of the region through which the axon passes. We have exploited this technique in the hypothalamus and have demonstrated the presence of double axonal projections or axons branching very near the cell bodies of the secretory cells of the neurohypophysial system in the rat supraoptic nucleus. We found that a small proportion of supraoptic magnocellular cells could be antidromically activated both from the neural stalk and from elsewhere in the hypothalamus, including the suprachiasmatic nucleus (8 cells of a total of 182) and the antero-ventral third ventricular region (AV3V; 4 of 182 cells) near the organum vasculosum of the lamina terminalis (OVLT). Collision of antidromic and orthodromic spikes showed that the cells were clearly antidromically (rather than synaptically, or orthodromically) activated from both sites. A stimulus applied to one of the axons prevented propagation of a spike evoked by a pulse delivered to the other axon until sufficient time had elapsed after the first stimulus for the resultant spike to have propagated from the first stimulus site along one cell process (towards the cell body or branch point), and from this point along the other axonal branch to the second stimulus site (there was also a short additional delay period during which the axon at the site of the second stimulus recovered from its absolute refractory period). If the interval between the stimuli was progressively reduced, there came a point where the second spike failed. Such a clear demonstration of dual projections in a system where the cells were previously thought to have only a single axon raises the possibility that many nerve cells in the CNS have previously unsuspected projections.


Endovascular repair of descending thoracic aneurysms: results with "on-label" application in the post Food and Drug Administration approval era.
Most studies of thoracic endovascular aortic repair (TEVAR) published since the technology gained US Food and Drug Administration (FDA) approval in March 2005 have included multiple applications including dissection, trauma, and "hybrid" approaches, all of which are currently "off-label." However, little post-approval data exist for the only FDA-approved application, namely descending thoracic aneurysm (DTA). The purpose of this study was to examine our experience with TEVAR for aneurysms limited to the descending thoracic aorta. Between March 23, 2005 (date of initial FDA approval) and April 6, 2009, 210 TEVAR procedures were performed at our institution. Of these, 79 (38%) were for saccular (n = 31) or fusiform (n = 48) DTA and form the basis of this report. Patients requiring "hybrid" approaches other than carotid-subclavian bypass were excluded. Devices utilized were Gore TAG (W. L. Gore Associates, Flagstaff, AZ) (n = 67; 85%), Zenith TX2 (Cook Medical Incorporated, Bloomington, IN) (n = 10; 13%), and Medtronic Talent (Medtronic, Inc, Santa Rosa, CA) (n = 5; 6%); 3 (4%) patients received more than one type of device. Median patient age was 73 +/- 4 years; 35 (44%) were female. Mean aortic diameter was 5.8 +/- 1.8 cm. Twenty-four (30%) procedures were urgent-emergent. Thirty-day in-hospital rates of death, stroke, and permanent paraplegia-paresis were 5.1% (n = 4; 1.9% elective mortality), 2.5% (n = 2), and 1.3% (n = 1), respectively. The median postoperative length of stay was 3.0 days (25th and 75th percentiles = 2 and 6, respectively). At a mean follow-up of 23 +/- 17 months (range, 6 to 55), there were 2 (2.5%) late aortic deaths from graft infection (n = 1) and aneurysm rupture (n = 1). Overall actuarial midterm survival is 73% at 55 months, with an aorta-specific actuarial survival of 86% during this same time interval. Five patients (6.3%) required late (>30 days) secondary endovascular re-intervention for type I (n = 4) or type II (n = 1) endoleak; re-intervention was successful in 4 of 5. Despite the advanced age, comorbid conditions, and significant incidence of urgent-emergent status of patients presenting with DTA, on-label application of TEVAR yields excellent 30-day and midterm outcomes, especially when compared with historic rates of morbidity and mortality with open repair. However, "on-label" applications represent a minority of current TEVAR use, likely due to the relative scarcity of DTA. These data appear to support the increasing utilization of TEVAR as a treatment strategy for this pathology.


Conditional Cash Transfers and HIV/AIDS Prevention: Unconditionally Promising?
Conditional cash transfers (CCT) have recently received considerable attention as a potentially innovative and effective approach to the prevention of HIV/AIDS. We evaluate a conditional cash transfer program in rural Malawi which offered financial incentives to men and women to maintain their HIV status for approximately one year. The amounts of the reward ranged from zero to approximately 3-4 months wage. We find no effect of the offered incentives on HIV status or on reported sexual behavior. However, shortly after receiving the reward, men who received the cash transfer were 9 percentage points more likely and women were 6.7 percentage points less likely to engage in risky sex. Our analyses therefore question the "unconditional effectiveness" of CCT program for HIV prevention: CCT Programs that aim to motivate safe sexual behavior in Africa should take into account that money given in the present may have much stronger effects than rewards offered in the future, and any effect of these programs may be fairly sensitive to the specific design of the program, the local and/or cultural context, and the degree of agency an individual has with respect to sexual behaviors.


Induction of palate epithelial mesenchymal transition by transforming growth factor β3 signaling.
Transforming growth factor (TGFβ)3 is essential for palate development, particularly during the late phase of palatogenesis when the disintegration of the palatal medial edge seam (MES) occurs resulting in mesenchymal confluence. The MES is composed of medial-edge epithelium (MEE) of opposite palatal shelves; its complete disintegration is essential for mediating correct craniofacial morphogenesis. This phenomenon is initiated by TGFβ3 upon adherence of opposing palatal shelves, and subsequently epithelial-mesenchymal transition (EMT) instigates the loss of E-Cadherin, causing the MES to break into small epithelial islands forming confluent palatal mesenchyme; however, apoptosis and cell migration or in combination of all are other established mechanisms of seam disintegration. To investigate the molecular mechanisms that cause this E-Cadherin loss, we isolated and cultured murine embryonic primary MES cells from adhered palates and employed several biological approaches to explore the mechanism by which TGFβ3 facilitates palatal seam disintegration. Here, we demonstrate that TGFβ3 signals by activating both Smad-dependent and Smad-independent pathways. However, activation of the two most common EMT related transcription factors, Snail and SIP, was facilitated by Smad-independent pathways, contrary to the commonly accepted Smad-dependent pathway. Finally, we provide the first evidence that TGFβ3-activated Snail and SIP1, combined with Smad4, bind to the E-Cadherin promoter to repress its transcription in response to TGFβ3 signaling. These results suggest that TGFβ3 uses multiple pathways to activate Snail and SIP1 and these transcription factors repress the cell-cell adhesion protein, E-Cadherin, to induce palatal epithelial seam EMT. Manipulation and intervention of the pathways stimulated by TGFβ3 during palate development may have a significant therapeutic potential.


Development and evaluation of oligonucleotide chip based on the 16S-23S rRNA gene spacer region for detection of pathogenic microorganisms associated with sepsis.
Oligonucleotide chips targeting the bacterial internal transcribed spacer region (ITS) of the 16S-23S rRNA gene, which contains genus- and species-specific regions, were developed and evaluated. Forty-three sequences were designed consisting of 1 universal, 3 Gram stain-specific, 9 genus-specific, and 30 species-specific probes. The specificity of the probes was confirmed using bacterial type strains including 54 of 52 species belonging to 18 genera. The performance of the probes was evaluated using 825 consecutive samples that were positive by blood culture in broth medium. Among the 825 clinical specimens, 708 (85.8%) were identified correctly by the oligonucleotide chip. Most (536 isolates, or 75.7%) were identified as staphylococci, Escherichia coli, or Klebsiella pneumoniae. Thirty-seven isolates (4.5%) did not bind to the corresponding specific probes. Most of these also were staphylococci, E. coli, or K. pneumoniae and accounted for 6.3% of total number of the species. Sixty-two specimens (7.5%) did not bind the genus- or species-specific probes because of lack of corresponding specific probes. Among them, Acinetobacter baumannii was the single most frequent isolate (26/62). The oligonucleotide chip was highly specific and sensitive in detecting the causative agents of bacteremia directly from positive blood cultures.


Amplification of Chromosome 1q Genes Encoding the Phosphoinositide Signalling Enzymes PI4KB, AKT3, PIP5K1A and PI3KC2B in Breast Cancer.
Little is known about the possible oncogenic roles of genes encoding for the phosphatidylinositol 4-kinases, a family of enzymes that regulate an early step in phosphoinositide signalling. To address this issue, the mutational status of all four human phosphatidylinositol 4-kinases genes was analyzed across 852 breast cancer samples using the COSMIC data resource. Point mutations in the phosphatidylinositol 4-kinase genes were uncommon and appeared in less than 1% of the patient samples however, 62% of the tumours had increases in gene copy number for PI4KB which encodes the phosphatidylinositol 4-kinase IIIbeta isozyme. Extending this analysis to subsequent enzymes in the phosphoinositide signalling cascades revealed that the only PIP5K1A, PI3KC2B and AKT3 genes exhibited similar patterns of gene copy number variation. By comparison, gene copy number increases for established oncogenes such as EGFR and HER2/Neu were only evident in 20% of the samples. The PI4KB, PIP5K1A, PI3KC2B and AKT3 genes are related in that they all localize to chromosome 1q which is often structurally and numerically abnormal in breast cancer. These results demonstrate that a gene quartet encoding a potential phosphoinositide signalling pathway is amplified in a subset of breast cancers.


Multiple origins of XY female mice (genus Akodon): phylogenetic and chromosomal evidence.
Despite the diversity in sex determination across organisms, theory predicts that the evolution of XY females is rare in mammals due to fitness consequences associated with infertility or the loss of YY zygotes. We investigated this hypothesis from a phylogenetic perspective by examining the inter- and intraspecific distribution of Y chromosomes in males and females (XY females) in South American field mice (Akodon). We found that XY females occurred at appreciable frequencies (10-66%) in at least eight Akodon species, raising the possibility that this system of sex determination has arisen multiple times independently. To determine the number of origins of XY females in Akodon, we constructed a molecular phylogeny of 16 species of Akodon based on mitochondrial DNA control region sequences. Both parsimony and maximum-likelihood reconstruction of ancestral states suggest that multiple steps (gains or losses of XY females) best explain the evolution of XY females, but do not clearly differentiate between single and multiple origins. We then directly compared functional and non-functional Y chromosomes in six species by Southern blot analysis. We found that male and female Y chromosome restriction fragment length polymorphism patterns were identical within species, but always differed between species, providing evidence that XY females arose at least six times within the Akodon lineage. To our knowledge, this pattern in Akodon is the first documentation of a novel sex-determining system arising multiple times within a tight clade of mammals. In addition, this system provides a clear test of the accuracy of phylogenetic methods to reconstruct ancestral states.


Reciprocal Prospective Relationships Between Loneliness and Weight Status in Late Childhood and Early Adolescence.
Adolescents who do not conform to weight ideals are vulnerable to disapproval and victimization from peers in school. But, missing from the literature is a prospective examination of weight status and feelings of loneliness that might come from those experiences. Using data from the Québec Longitudinal Study of Child Development, we filled that gap by examining the prospective associations between loneliness and weight status when the sample was aged 10-13 years. At ages 10, 12, and 13 years, 1042 youth (572 females; 92% from French speaking homes) reported on their loneliness and were weighed and measured. Family income sufficiency was included in our analyses given its relationship with weight status, but also its possible link with loneliness during early adolescence. The findings showed that (1) weight status and loneliness were not associated concurrently; (2) weight status predicted increases in loneliness from ages 12 to 13 years; and (3) loneliness predicted increases in weight from ages 12 to 13 years among female adolescents, but weight loss among male adolescents. The fact that loneliness was involved in weight gain for females suggests that interventions focused on reducing loneliness and increasing connection with peers during early adolescence could help in reducing obesity.


Why do zeolites induce an unprecedented electronic state on exchanged metal ions?
Understanding the exact position and the detailed role of the Al array in zeolites is essential for elucidating the origin of unique properties that can be derived from the metal-ion exchanged in zeolite samples and for designing zeolite materials with high efficiency in catalytic and adsorption processes. In this work, we investigate, for the first time, the important role of the Al array in the reactivity observed on the metal-ion exchanged in zeolites on the basis of the calculation method by utilizing the spontaneous heterolytic cleavage of H2 observed experimentally on the Zn2+-ion exchanged in MFI-type zeolites (Zn2+-MFI) as the model reaction. In the case of calculation, two main types of models for considering the Al positions in MFI-type zeolites were adopted: in the first type, the Al atoms with appropriate distances are aligned in the circumferential direction of the straight channel (abbreviated as a circumferentially arrayed Al-Al site); in the second type, the nearest neighbouring Al atoms with appropriate distances are directed toward the straight channel axis (abbreviated as a channel directionally arrayed Al-Al site). Results indicated that the Al-array direction governs the reactivity of Zn2+-MFI. The former type of array well explains the experimental fact that spontaneous and irreversible heterolysis of H2 takes place on Zn2+-MFI, even at room temperature, whereas the latter type of array is less reactive; high activation energy is required for the heterolytic cleavage of H2 (ca. >70 kJ mol-1). A detailed analysis of the geometric and electronic structures of a series of Zn2+-MFI models with various Al-array directions clarified the following facts: the circumferentially arrayed Al-Al site induces an inevitable environment around the Zn2+ site, with the simultaneous existence of both a Lewis acid point (coordinatively unsaturated and distorted Zn2+) and a Lewis base point (the lattice oxygen atom juxtaposed with exchanged Zn2+, which participates in the activation of H2: OjL). It is the circumferentially arrayed Al-Al atoms that confer acidic and basic nature on the metal ion and the lattice oxygen atom (OjL), and ultimately trigger the heterolytic dissociation of H2, even at 300 K.


The role of IgA determination by ELISA in the early serodiagnosis of Mycoplasma pneumoniae infection, in relation to IgG and mu-capture IgM methods.
Enzyme-linked immunosorbent assay (ELISA) for IgA, IgG and IgM was evaluated with sera from 50 adult patients with pneumonia, selected on the basis of a positive complement fixation (CF) test for diagnosis of Mycoplasma pneumoniae infection and with sera from 105 healthy blood donors. The ELISA antigen for IgG and IgA was a sonicated suspension of M. pneumoniae solubilised by deoxycholate. For the IgM assay, the same antigen was directly conjugated to alkaline phosphatase and used in a mu-capture format. ELISA gave positive results with high or rising titres for one or several antibody classes in 47 (94%) patients. In two of the three ELISA-negative cases, the diagnosis of M. pneumoniae infection indicated by the CF test seemed unlikely on clinical grounds. Specific IgA antibodies was developed more regularly and more rapidly than IgM. IgA titres also started to decrease earlier than IgM or the late-peaking IgG response. Thus, the determination of IgA antibodies was found to be valuable for the early diagnosis of M. pneumoniae infection. The study also demonstrated that the determination of all three antibody classes is necessary to obtain an optimal level of serodiagnosis.


Distortion of size perception in visuospatial neglect.
A number of studies have shown that most patients with symptoms of unilateral (left-sided) visuospatial neglect make consistently rightward errors when attempting to bisect a horizontal line at its midpoint. One possible interpretation of this impairment is that such patients misperceive the left half of the line: that is, that they underestimate its extent relative to the right half. We have carried out direct tests for such a perceptual distortion in three neglect patients by asking them to make matching judgements on pairs of horizontal rectangles, vertical rectangles or nonsense shapes, of varying relative size, presented on a computer screen. We report here that all of the patients tested showed a significant and substantial relative underestimation of the horizontal extent or area of stimuli presented on the left side of their egocentric space. There was no such misperception of vertical extent. It is suggested that size perception may be partially determined by a representational system that is anatomically centred in the parieto-temporal region of the brain. The results are interpreted in terms of damage to this system in neglect patients.


Measuring orthostatic hypotension with the Finometer device: is a blood pressure drop of one heartbeat clinically relevant?
The role of orthostatic hypotension in falls in older people is generally accepted. Because of the high degree of intra- and interobserver variability in conventional measurements of orthostatic hypotension, application of continuous measurement systems has been proposed. The clinical relevance of a blood pressure drop lasting one heartbeat, however, is unknown. We therefore investigated which time average of continuous-finger-blood-pressure measurement (Finometer) showed the best association between orthostatic hypotension and falls. This was also compared with conventional sphygmomanometer measurements. In 217 geriatric outpatients supine and standing (finger) blood pressure to diagnose orthostatic hypotension was monitored with Finometry (beat-to-beat and 1, 5, 10, 15, 20 and 30 s averages) and sphygmomanometry. History of fall incidents (previous year) was registered. The best association (C=0.22, P=0.003) with falls history was found for the 5-s average of Finometry, whereas falls and orthostatic hypotension assessed by sphygmomanometry did not correlate. The odds ratio of a fall according to orthostatic hypotension using the 5-s average was 2.54 (95% CI: 1.37 to 4.71). Orthostatic hypotension and falls are correlated when using Finometry, with the best association found when using 5-s averages. As the etiology of falls is often multifactorial, orthostatic hypotension and falls are poorly correlated, irrespective of the method or time average that is applied.


The hidden season: growing season is 50% longer below than above ground along an arctic elevation gradient.
There is compelling evidence from experiments and observations that climate warming prolongs the growing season in arctic regions. Until now, the start, peak, and end of the growing season, which are used to model influences of vegetation on biogeochemical cycles, were commonly quantified using above-ground phenological data. Yet, over 80% of the plant biomass in arctic regions can be below ground, and the timing of root growth affects biogeochemical processes by influencing plant water and nutrient uptake, soil carbon input and microbial activity. We measured timing of above- and below-ground production in three plant communities along an arctic elevation gradient over two growing seasons. Below-ground production peaked later in the season and was more temporally uniform than above-ground production. Most importantly, the growing season continued c. 50% longer below than above ground. Our results strongly suggest that traditional above-ground estimates of phenology in arctic regions, including remotely sensed information, are not as complete a representation of whole-plant production intensity or duration, as studies that include root phenology. We therefore argue for explicit consideration of root phenology in studies of carbon and nutrient cycling, in terrestrial biosphere models, and scenarios of how arctic ecosystems will respond to climate warming.


Plasmacytoma of the mesentery.
Extramedullary plasmacytoma represents 3%-5% of all plasma cell neoplasms. Plasmacytomas of the mesentery are extremely rare. We report the case of a 56-year-old man who presented with an abdominal mass and was diagnosed to have plasmacytoma of the mesentery. A literature review was also conducted on publications pertaining to solitary mesenteric plasmacytomas. These patients present late by which time the abdominal mass has reached a significant size. Radiation as a modality for local control has a limited role in treating mesenteric plasmacytomas. Surgery is the preferred modality for local control. Patients must be kept on a regular follow-up as there is a risk of transformation to multiple myeloma.


Transgenic expression of microRNA-181d augments the stress-sensitivity of CD4(+)CD8(+) thymocytes.
Physiological stress resulting from infections, trauma, surgery, alcoholism, malnutrition, and/or pregnancy results in a substantial depletion of immature CD4(+)CD8(+) thymocytes. We previously identified 18 distinct stress-responsive microRNAs (miRs) in the thymus upon systemic stress induced by lipopolysaccharide (LPS) or the synthetic glucocorticoid, dexamethasone (Dex). MiRs are short, non-coding RNAs that play critical roles in the immune system by targeting diverse mRNAs, suggesting that their modulation in the thymus in response to stress could impact thymopoiesis. MiR-181d is one such stress-responsive miR, exhibiting a 15-fold down-regulation in expression. We utilized both transgenic and gene-targeting approaches to study the impact of miR-181d on thymopoiesis under normal and stress conditions. The over-expression of miR-181d in developing thymocytes reduced the total number of immature CD4(+)CD8(+) thymocytes. LPS or Dex injections caused a 4-fold greater loss of these cells when compared with the wild type controls. A knockout mouse was developed to selectively eliminate miR-181d, leaving the closely spaced and contiguous family member miR-181c intact. The targeted elimination of just miR-181d resulted in a thymus stress-responsiveness similar to wild-type mice. These experiments suggest that one or more of three other miR-181 family members have overlapping or compensatory functions. Gene expression comparisons of thymocytes from the wild type versus transgenic mice indicated that miR-181d targets a number of stress, metabolic, and signaling pathways. These findings demonstrate that selected miRs enhance stress-mediated thymic involution in vivo.


Brain tissue pulsatility mediates cognitive and electrophysiological changes in normal aging: Evidence from ultrasound tissue pulsatility imaging (TPI).
Aging is characterized by a cognitive decline of fluid abilities and is also associated with electrophysiological changes. The vascular hypothesis proposes that brain is sensitive to vascular dysfunction which may accelerate age-related brain modifications and thus explain age-related neurocognitive decline. To test this hypothesis, cognitive performance was measured in 39 healthy participants from 20 to 80 years, using tests assessing inhibition, fluid intelligence, attention and crystallized abilities. Brain functioning associated with attentional abilities was assessed by measuring the P3b ERP component elicited through an auditory oddball paradigm. To assess vascular health, we used an innovative measure of the pulsatility of deep brain tissue, due to variations in cerebral blood flow over the cardiac cycle. Results showed (1) a classical effect of age on fluid neurocognitive measures (inhibition, fluid intelligence, magnitude and latency of the P3b) but not on crystallized measures, (2) that brain pulsatility decreases with advancing age, (3) that brain pulsatility is positively correlated with fluid neurocognitive measures and (4) that brain pulsatility strongly mediated the age-related variance in cognitive performance and the magnitude of the P3b component. The mediating role of the brain pulsatility in age-related effect on neurocognitive measures supports the vascular hypothesis of cognitive aging.


Network physiology reveals relations between network topology and physiological function.
The human organism is an integrated network where complex physiological systems, each with its own regulatory mechanisms, continuously interact, and where failure of one system can trigger a breakdown of the entire network. Identifying and quantifying dynamical networks of diverse systems with different types of interactions is a challenge. Here we develop a framework to probe interactions among diverse systems, and we identify a physiological network. We find that each physiological state is characterized by a specific network structure, demonstrating a robust interplay between network topology and function. Across physiological states, the network undergoes topological transitions associated with fast reorganization of physiological interactions on time scales of a few minutes, indicating high network flexibility in response to perturbations. The proposed system-wide integrative approach may facilitate the development of a new field, Network Physiology.


Psychologic distress and low back pain. Evidence from a prospective study in the general population.
The present is a prospective population-based cohort study. To determine whether psychologic distress in patients free of low back pain predicts future new episodes of such pain. An associating between symptoms of depression and anxiety and low back pain has been described in cross-sectional studies. It is unclear whether this represents cause or effect or whether it is found only in chronic pain sufferers attending specialist clinics. There is a need to investigate this prospectively in the general population. The study population was 4501 adults aged 18-75 years who responded to a questionnaire survey mailed to all those registered with two family practices in the United Kingdom. The survey inquired about low back pain during the previous month and included the 12-item General Health Questionnaire, a validated schedule for measuring psychologic distress in the general population. New episodes of low back pain during the 12 months after the survey were identified by two methods--continuous monitoring of all primary care consulters and a second postal survey at the end of the 12-month period to determine occurrences for which consultation had not been sought. Among 1638 subjects free of current low back pain in the baseline survey, the likelihood of developing a new episode of nonconsulting low back pain was higher among those with General Health Questionnaire scores in the upper third of the range compared with the lower third (adjusted odds ratio, 1.8 [1.4, 2.4]). This could not be explained either by age and gender differences or by general physical health. The increased risk persisted when analysis was restricted to those who at baseline could not recall ever having had low back pain in the past and to those with full-time employment. Symptoms of psychologic distress in individuals without back pain predict the subsequent onset of new episodes of low back pain. We calculate from these data that the proportion of new episodes of low back pain that might be attributable to such psychologic factors in the general population is 16%.


Microsurgical endodontic treatment of the upper molar teeth and their relationship with the maxillary sinus: a retrospective multicentric clinical study.
To assess the clinical and radiographic success rate of microsurgical endodontic treatment of upper molar teeth in relationship with the maxillary sinus, with 12 months follow-up. Patients treated with microsurgical endodontic treatment of upper molar teeth in the period between 2017 and 2019 were recruited from two dental clinics according to specific selection criteria. The outcomes were determined based on clinical and radiographic results taken three, six and 12 months post-operatively, compared with those taken immediately before and after surgery. Clinical and radiographic outcomes were recorded. The distance between the most apical part of the root and of the lesion to the maxillary sinus was measured on CBCT images before the surgery. Patient-related outcomes were recorded. Out of 35 patients evaluated, 21 were selected according with the selection criteria for a total of 27 roots and 29 canals treated. After 12 months, 18 patients showed a complete healing whereas three demonstrated incomplete healing. Consequently, the success rate in this study was 85.7% after one year. In 28.5% (6 patients) there was a perforation of the Schneiderian membrane that didn't seem to affect the outcome. All patients kept the molar one year later. The pain level decreased significantly over the time during the first week after surgery. Microsurgical Endodontic treatment of the upper molar teeth should be considered a valid and predictable treatment option even in case of Schneiderian membrane perforation. Future clinical studies with a larger sample size are needed to compare the results obtained.


Suppression in murine experimental autoimmune thyroiditis: in vivo inhibition of CD4+ T cell-mediated resistance by a nondepleting rat CD4 monoclonal antibody.
Genetically susceptible mice become resistant to experimental autoimmune thyroiditis (EAT) induction with mouse thyroglobulin (MTg) and lipopolysaccharide after pretreatment with deaggregated MTg (dMTg). Recent work showed this suppression to be mediated by CD4+ suppressor T cells (Ts). To study Ts action in vivo, we used a rat IgG2a monoclonal antibody (mAb), YTS 177.9, which modulates CD4 antigen in vivo without depleting CD4+ cells. Initial studies showed that after two 1-mg doses of mAb 7 days apart, extensive CD4 antigen modulation of peripheral blood leukocytes occurred within 4 days. Mice given CD4 mAb 24 hr before dMTg (2 doses, 7 days apart) were resistant to EAT induction when immunized with MTg and LPS 20 days later. Also, anti-rat IgG2a titers were reduced following challenge with heat-aggregated rat IgG2a compared to controls. Subsequent analysis of serum in CD4 mAb-treated animals revealed that mAb was present in the circulation for 14 days. Moreover, mice given CD4 mAb and dMTg, then challenged after only 10 days, when CD4 mAb was still circulating, developed a significantly higher incidence of thyroid damage than controls. These findings suggest that modulation of CD4 antigen does not interfere with Ts activation, but the presence of CD4 mAb, at the time of autoantigenic challenge, can interfere with tolerance to EAT induction. Thus, the direct relationship between the presence of CD4 mAb and inhibition of EAT suppression implicates a role for CD4 molecules in the mediation of suppression.


A DYNAMIC MODEL OF SELF-EMPLOYMENT AND SOCIOECONOMIC MOBILITY AMONG RETURN MIGRANTS: THE CASE OF URBAN MEXICO.
Return migrants engage in high rates of self-employment, which scholars commonly attribute to the accumulation of financial and human capital while working abroad. Central to this scholarship is the assumption that self-employment is positive and leads to upward economic mobility among return migrants. This scholarship is limited, however, because it relies on large surveys and cross-sectional census data that treat self-employment as a single uni-dimensional status measured at one point in time. To improve conceptualization and measurement of self- employment, we engage three bodies of research that have thus far had little cross-fertilization: the literature on work and self-employment in Latin America, the scholarship on return migration and self-employment, and developments in economic theories of international migration. Drawing on results from the first longitudinal analysis of the labor market trajectories of Mexican return migrants in a large urban area in central Mexico, we identify three types of self-employment - survivalist, temporary, and prosperous. To explain these divergent self-employment pathways, we draw on biographical narratives and identify two sets of mechanisms - human capital formation and life-course stage. Overall, our investigation of self-employment types suggests a complex relationship between international migration experiences and the labor market mobility of return migrants which cannot be understood without taking into consideration migrants' social and economic circumstances before, during, and after migration. Consequently, our study yields insights into economic theories of international migration and provides direction for future research on return migration and labor market reintegration.


Generation of a concise gene panel for outcome prediction in urinary bladder cancer.
This study sought to determine if alterations in molecular pathways could supplement TNM staging to more accurately predict clinical outcome in patients with urothelial carcinoma (UC). Expressions of 69 genes involved in known cancer pathways were quantified on bladder specimens from 58 patients with UC (stages Ta-T4) and five normal urothelium controls. All tumor transcript values beyond two standard deviations from the normal mean expression were designated as over- or underexpressed. Univariate and multivariable analyses were conducted to obtain a predictive expression signature. A published external data set was used to confirm the potential of the prognostic gene panels. In univariate analysis, six genes were significantly associated with time to recurrence, and 10 with overall survival. Recursive partitioning identified three genes as significant determinants for recurrence, and three for overall survival. Of all genes identified by either univariate or partitioning analysis, four were found to significantly predict both recurrence and survival (JUN, MAP2K6, STAT3, and ICAM1); overexpression was associated with worse outcome. Comparing the favorable (low or normal) expression of > or = three of four versus < or = two of four of these oncogenes showed 5-year recurrence probability of 41% versus 88%, respectively (P < .001), and 5-year overall survival probability of 61% versus 5%, respectively (P < .001). The prognostic potential of this four-gene panel was confirmed in a large independent external cohort (disease-specific survival, P = .039). We have documented the generation of a concise, biologically relevant four-gene panel that significantly predicts recurrence and survival and may also identify potential therapeutic targets for UC.


Language of Health of Young Australian Adults: A Qualitative Exploration of Perceptions of Health, Wellbeing and Health Promotion via Online Conversations.
Young adults (YA) are in a critical stage of life for the encouragement of healthy behaviours such as healthy eating and exercising. This research explored Australian YA values and perceptions related to health, healthy behaviours and health promotion efforts. This qualitative analysis involved n = 166, Australian 18-24 year-olds recruited through a market research field house. Participants (63% currently studying at tertiary level) engaged in a facilitated in-depth online conversation around health and healthy eating over four weeks. LeximancerTM and manual inductive thematic coding were utilised for analysis via the lens of emerging adulthood and health communication theories. Health was seen as multi-faceted, with particular importance placed on mental health and exercise. Some participants focussed on physical appearance, often fuelled by comparison to others. Many believed that at their age and health status, adopting health-enhancing behaviours without short-term tangible benefits was not a priority. Participants did not prioritise health-enhancing behaviours due to barriers such as a perceived lack of money, knowledge and time often due to studying or working and perceived effort. Strategies they proposed to encourage healthy eating included: incentivising healthy food; quick and affordable healthy recipes; and communicating the short-term tangible benefits of healthy behaviours. There is a need for focussed health messaging that address the needs and desires of YA and directly address the barriers they face.


Morphometric distances among five ethnic groups and evaluation of the secular trend in historical Libya.
This study analysed the variations, both in space and time, of 10 body dimensions and 2 anthropometric indexes of 745 adult males belonging to 5 ethnic groups of historical Lybia (el-Haràbi, el-Baraghìts, Marabtìn, Oases inhabitants and Tuareg). The data were collected in the years 1928 and 1932 by Puccioni and Cipriani, two Italian anthropologists. The aim was to reconstruct the biological history of Libya at the time, and thus contribute to the ongoing debate on the evolution of the biological standard of living in developing Countries. The subjects were analysed by ethnicity and by 10-year age groups, after adjusting for age. The results of ANCOVA and Tukey's post-hoc test show that among and between groups there are statistical significant differences overall for armspan, height, head breadth, bizygomatic breadth, biiliac breadth/height and head breadth/head length indexes. By means of the cluster analysis, the el-Haràbi, el-Baraghìts and Marabtìn groups cluster together, whereas the Tuareg and Oases inhabitants cluster separately one from the other and both from the other three ethnic groups. Within-group variations are not very marked in all ethnicities. In general, there is the tendency, not statistically significant, to the reduction and/or stasis of body dimensions from the older to the younger, and the differences are greater among the older than the younger age classes. In conclusion, it can be argued that these groups, all different culturally and geographically, were following the same tendency of stasis of the secular trend of the body dimensions considered in this study, and such stasis persisted since, at least, the last twenty years of the 19th century, when the older were born.


Searching for perceptual similarity within, and between, the (chemical) senses.
In this narrative historical review, I want to take a closer look at the concept of perceptual similarity both as it applies within, and between, the chemical senses (specifically taste and smell). The discussion is linked to issues of affective similarity and connotative meaning. The relation between intramodal and crossmodal judgments of perceptual similarity, and the putatively special status of those odorants that happen to take on taste qualities will also be discussed. An important distinction is drawn between the interrelated, though sometimes distinct, notions of perceptual similarity and crossmodal congruency, specifically as they relate to the comparison of chemosensory stimuli. Such phenomena are often referred to as crossmodal correspondences, or by others (incorrectly in my view), as a kind of ubiquitous synesthesia.


Cystatin D (CST5): An ultra-early inflammatory biomarker of traumatic brain injury.
Traumatic brain injury (TBI) is set to become the leading cause of neurological disability across all age groups. Currently, no reliable biomarkers exist to help diagnose the severity of TBI to identify patients who are at risk of developing secondary injuries. Thus, the discovery of reliable biomarkers for the management of TBI would improve clinical interventions. Inflammatory markers are particularly suited for biomarker discovery as TBI leads to very early alterations in inflammatory proteins. Using the Proseek Multiplex Inflammation assay, we measured in patients that had suffered mild TBI (n = 10) or severe TBI (n = 10) with extra-cranial injury or extracranial injury only (EC) (n = 10), 92 inflammation-associated proteins in serum obtained: <1 hr (within 1-hour), 4-12 hr and 48-72 hr post injury. Changes were compared to healthy volunteers (HV). Our results identified CST5, AXIN1 and TRAIL as novel early biomarkers of TBI. CST5 identified patients with severe TBI from all other cohorts and importantly was able to do so within the first hour of injury. AXIN1 and TRAIL were able to discriminate between TBI and HV at <1 hr. We conclude that CST5, AXIN1 and TRAIL are worthy of further study in the context of a pre-hospital or pitch-side test to detect brain injury.


What really matters in end-of-life discussions? Perspectives of patients in hospital with serious illness and their families.
The guideline-recommended elements to include in discussions about goals of care with patients with serious illness are mostly based on expert opinion. We sought to identify which elements are most important to patients and their families. We used a cross-sectional study design involving patients from 9 Canadian hospitals. We asked older adult patients with serious illness and their family members about the occurrence and importance of 11 guideline-recommended elements of goals-of-care discussions. In addition, we assessed concordance between prescribed goals of care and patient preferences, and we measured patient satisfaction with goals-of-care discussions using the Canadian Health Care Evaluation Project (CANHELP) questionnaire. Our study participants included 233 patients (mean age 81.2 yr) and 205 family members (mean age 60.2 yr). Participants reported that clinical teams had addressed individual elements of goals-of-care discussions infrequently (range 1.4%-31.7%). Patients and family members identified the same 5 elements as being the most important to address: preferences for care in the event of life-threatening illness, values, prognosis, fears or concerns, and questions about goals of care. Addressing more elements was associated with both greater concordance between patients' preferences and prescribed goals of care, and greater patient satisfaction. We identified elements of goals-of-care discussions that are most important to older adult patients in hospital with serious illness and their family members. We found that guideline-recommended elements of goals-of-care discussions are not often addressed by health care providers. Our results can inform interventions to improve the determination of goals of care in the hospital setting.


Fetal Alcohol Syndrome Disorder: diminished responsibility and mitigation of sentence.
The objective of this study was to consider the implications of a recent Western Australia Court of Appeal decision in which an indigenous youth who had been sentenced for the manslaughter of his neonate child was later diagnosed with Fetal Alcohol Syndrome Disorder. The increased use of the 2016 Australian guide to the diagnosis of fetal alcohol spectrum disorder should be encouraged to enable clinicians to not only diagnose and manage Fetal Alcohol Syndrome Disorder, but also counsel families to prevent it.


The impact of thyroid cancer and post-surgical radioactive iodine treatment on the lives of thyroid cancer survivors: a qualitative study.
Adjuvant treatment with radioactive iodine (RAI) is often considered in the treatment of well-differentiated thyroid carcinoma (WDTC). We explored the recollections of thyroid cancer survivors on the diagnosis of WDTC, adjuvant radioactive iodine (RAI) treatment, and decision-making related to RAI treatment. Participants provided recommendations for healthcare providers on counseling future patients on adjuvant RAI treatment. We conducted three focus group sessions, including WDTC survivors recruited from two Canadian academic hospitals. Participants had a prior history of WDTC that was completely resected at primary surgery and had been offered adjuvant RAI treatment. Open-ended questions were used to generate discussion in the groups. Saturation of major themes was achieved among the groups. There were 16 participants in the study, twelve of whom were women (75%). All but one participant had received RAI treatment (94%). Participants reported that a thyroid cancer diagnosis was life-changing, resulting in feelings of fear and uncertainty. Some participants felt dismissed as not having a serious disease. Some participants reported receiving conflicting messages from healthcare providers on the appropriateness of adjuvant RAI treatment or insufficient information. If RAI-related side effects occurred, their presence was not legitimized by some healthcare providers. The diagnosis and treatment of thyroid cancer significantly impacts the lives of survivors. Fear and uncertainty related to a cancer diagnosis, feelings of the diagnosis being dismissed as not serious, conflicting messages about adjuvant RAI treatment, and treatment-related side effects, have been raised as important concerns by thyroid cancer survivors.


Variation in lipid profiles within semen compartments--the bovine model of aging.
Semen lipid composition was examined in young and mature bulls. Given the specific roles of various semen compartments (i.e., seminal fluid, sperm head, and sperm tail) during fertilization, we hypothesized that altered fatty acid and cholesterol composition of a specific compartment might impair semen quality and sperm function. Semen samples were collected from five mature and five young Holstein Friesian bulls during the winter (December-January). Semen was evaluated by computerized sperm-quality analyzer for bulls and was centrifuged to separate the sperm from the seminal fluid. The sperm fraction was sonicated to separate its head and tail compartments. Cold extraction of lipids was performed, and fatty acids and cholesterol were identified and quantified by gas chromatography. Semen physiological features (concentration, motility, and progressive motility) did not differ between mature and young bulls. However, lipid composition within fractions varied between groups, with prominent impairments in the head compartment. In particular, the proportions of polyunsaturated fatty acids, omega-3 fatty acids, and docosahexaenoic acid in the intact sperm; seminal fluid; and sperm head were lower in semen collected from mature bulls than in that from young bulls. The finding suggests an age-differential absorption and/or metabolism through spermatogenesis. Reduced proportions of major fatty acids in mature bulls might reduce membrane fluidity, which in turn might affect the ability to undergo cryopreservation and/or oocyte-sperm fusion through fertilization.


Quantum efficiency of plasmonic-coupled quantum dot infrared photodetectors for single- color detection: the upper limit of plasmonic enhancement.
We report a measurement of the quantum efficiency for a surface plasma wave (SPW)-coupled InAs/In0.15Ga0.85As/GaAs dots-in-a-well (Dwell) quantum dot infrared photodetector (QDIP) having a single-color response at ∼10 µm. A gold film perforated with a square array of complex, non-circular apertures is employed to manipulate the near-fields of the fundamental SPW. The quantum efficiency is quantitatively divided into absorption efficiency strongly enhanced by the SPW, and collection efficiency mostly independent of it. In the absorption efficiency, the evanescent near-fields of the fundamental SPW critically enhances QDIP performance but undergoes the attenuation by the absorption in the Dwell that ultimately limits the quantum efficiency. For the highest quantum efficiency available with plasmonic coupling, an optimal overlap between Dwell and SPW near-fields is required. Based on experiment and simulation, the upper limit of the plasmonic enhancement in quantum efficiency for the present device is addressed.


Association between traumatic occlusal forces and periodontitis: A systematic review.
Occlusal adjustment is commonly recommended for patients with periodontitis and traumatic occlusion. The objective of this systematic review was to analyze available evidence for the association between traumatic occlusal forces and periodontitis. Two focused questions were proposed: What is the effect of traumatic occlusal forces on periodontal parameters in patients with and without periodontitis? And what is the effect of occlusal interventions on periodontal parameters in patients with periodontitis? A systematic review of clinical and observational studies was performed and presented in narrative form. After title and abstract review a total of 30 articles were retrieved and of these 14 full-text articles were retrieved for analysis. Two RCTs, 1 cohort, 4 retrospective and 7 cross-sectional studies were included. Cross-sectional studies reported a significant association between occlusal discrepancies and probing depth and clinical attachment level. However, the magnitude of the effect is negligible when groups with and without occlusal discrepancies are compared. Intervention studies reported a minimal effect on probing depth and clinical attachment level after occlusal adjustment in patients with periodontitis as compared to teeth without occlusal adjustment. Available human studies showed that there is limited evidence that traumatic occlusion is associated with periodontitis and to support the implementation of occlusal adjustment to significantly improve the periodontal condition in patients with periodontitis.


Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity.
A worldwide increase in the incidence of obesity indicates the unsuccessful battle against this disorder. Obesity and the associated health problems urgently require effective strategies of treatment. The new discovery that a substantial amount of functional brown adipose tissue (BAT) is retained in adult humans provides a potential target for treatment of human obesity. BAT is active metabolically and disposes of extra energy via generation of heat through uncoupling oxidative phosphorylation in mitochondria. The physiology of BAT is readily regulated by melatonin, which not only increases recruitment of brown adipocytes but also elevates their metabolic activity in mammals. It is speculated that the hypertrophic effect and functional activation of BAT induced by melatonin may likely apply to the human. Thus, melatonin, a naturally occurring substance with no reported toxicity, may serve as a novel approach for treatment of obesity. Conversely, because of the availability of artificial light sources, excessive light exposure after darkness onset in modern societies should be considered a potential contributory factor to human obesity as light at night dramatically reduces endogenous melatonin production. In the current article, the potential associations of melatonin, BAT, obesity and the medical implications are discussed.


Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia.
Activating mutations in the cytosolic 5'-nucleotidase II gene NT5C2 drive resistance to 6-mercaptopurine in acute lymphoblastic leukemia. Here we demonstrate that constitutively active NT5C2 mutations K359Q and L375F reconfigure the catalytic center for substrate access and catalysis in the absence of allosteric activator. In contrast, most relapse-associated mutations, which involve the arm segment and residues along the surface of the inter-monomeric cavity, disrupt a built-in switch-off mechanism responsible for turning off NT5C2. In addition, we show that the C-terminal acidic tail lost in the Q523X mutation functions to restrain NT5C2 activation. These results uncover dynamic mechanisms of enzyme regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies.


Spatial learning and memory in HIV-1 transgenic rats.
HIV-1 infection of the central nervous system impairs neural, cognitive, and behavioral functioning in patients despite antiretroviral therapy. However, studying mechanisms underlying HIV-1-related neurological and cognitive dysfunction has been limited without an adequate animal model. A novel, noninfectious HIV-1 transgenic (HIV-1Tg) rat model was recently created that expresses an HIV-1 provirus with a deletion of functional gag and pol genes. This HIV-1Tg rat reportedly develops clinical manifestations of human HIV disease and thus appears to mimic the persistent infection that results from the presence of HIV viral proteins in the host. We evaluated the HIV-1Tg rat model using the Morris water maze, a popular paradigm for testing learning and memory deficits in rodents. Because of congenital cataracts in HIV-1Tg rats, however, the traditional use of visual navigational cues in this paradigm were precluded. We first designed a modified Morris water maze and demonstrated that neurologically intact rats can effectively learn the water maze in the absence of visual cues and in the presence of non-visual navigation cues. We then tested HIV-1Tg rats in this modified Morris water maze. These HIV-1Tg rats showed a deficit in learning how to swim to the location of the hidden platform but did not show a deficit in their memory of the general location of the hidden platform. These results suggest that the noninfectious HIV-1Tg rat can be a valid model for the behavioral studies of HIV-related neurological dysfunction.


Cyclic AMP stimulates luteinizing-hormone (lutropin) exocytosis in permeabilized sheep anterior-pituitary cells. Synergism with protein kinase C and calcium.
Sheep anterior-pituitary cells permeabilized with Staphylococcus aureus alpha-toxin were used to investigate the role of cyclic AMP (cAMP) in exocytosis of luteinizing hormone (lutropin, LH) under conditions where the intracellular free Ca2+ concentration ([Ca2+]free) is clamped by Ca2+ buffers. At resting [Ca2+]free (pCa 7), cAMP rapidly stimulated LH exocytosis (within 5 min) and continued to stimulate exocytosis for at least 30 min. When cAMP breakdown was inhibited by 3-isobutyl-1-methylxanthine (IBMX), the concentration giving half-maximal response (EC50) for cAMP-stimulated exocytosis was 10 microM. cAMP-stimulated exocytosis required millimolar concentrations of MgATP, as has been found with Ca2(+)- and phorbol-ester-stimulated LH exocytosis. cAMP caused a modest enhancement of Ca2(+)-stimulated LH exocytosis by decreasing in the EC50 for Ca2+ from pCa 5.6 to pCa 5.9, but had little effect on the maximal LH response to Ca2+. Activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate (PMA) dramatically enhanced cAMP-stimulated LH exocytosis by both increasing the maximal effect 5-7-fold and decreasing the EC50 for cAMP to 3 microM. This synergism between cAMP and PMA was further augmented by increasing the [Ca2+]free. Gonadotropin-releasing hormone (gonadoliberin, GnRH) stimulated cAMP production in intact pituitary cells. Since GnRH stimulation is reported to activate PKC and increase the intracellular [Ca2+]free, our results suggest that a synergistic interaction of the cAMP, PKC and Ca2+ second-messenger systems is of importance in the mechanism of GnRH-stimulated LH exocytosis.


Enterococcal meningitis caused by Enterococcus casseliflavus. First case report.
Enterococcal meningitis is an uncommon disease usually caused by Enterococcus faecalis and Enterococcus faecium and is associated with a high mortality rate. Enterococcus casseliflavus has been implicated in a wide variety of infections in humans, but never in meningitis. A 77-year-old Italian female presented for evaluation of fever, stupor, diarrhea and vomiting of 3 days duration. There was no history of head injury nor of previous surgical procedures. She had been suffering from rheumatoid arthritis for 30 years, for which she was being treated with steroids and methotrexate. On admission, she was febrile, alert but not oriented to time and place. Her neck was stiff, and she had a positive Kernig's sign. The patient's cerebrospinal fluid was opalescent with a glucose concentration of 14 mg/dl, a protein level of 472 mg/dl, and a white cell count of 200/muL with 95% polymorphonuclear leukocytes and 5% lymphocytes. Gram staining of CSF revealed no organisms, culture yielded E. casseliflavus. The patient was successfully treated with meropenem and ampicillin-sulbactam. E. casseliflavus can be inserted among the etiologic agents of meningitis. Awareness of infection of central nervous system with Enterococcus species that possess an intrinsic vancomycin resistance should be increased.