Calcium requirements for bone growth in Canadian boys and girls during adolescence.
Adequate dietary intake during the growth period is critical for bone mineral accretion. In 1997, an adequate intake (AI) of 1300 mg/d Ca was set for North American adolescents aged 9-18 years based on best available data. We determined bone Ca accrual values from age 9 to 18 years taking into account sex and maturity. Furthermore, we used the accrual data to estimate adolescents' Ca requirements. Total body bone mineral content (TBBMC) of eighty-five boys and sixty-seven girls participating in the Saskatchewan Paediatric Bone Mineral Accrual Study were used to determine annual TBBMC accumulation over the pubertal growth period. Using a similar factorial approach as the AI, we estimated Ca requirements of adolescent boys and girls for two age groups: 9-13 and 14-18 years. Between 9 and 18 years, boys accrued 198.8 (SD 74.5) g bone mineral content (BMC) per year, equivalent to 175.4 (SD 65.7) mg Ca per d with the maximum BMC accrual of 335.9 g from age 13 to 14 years. Girls had 138.1 (SD 64.2) g BMC per year, equalling121.8 (SD 56.6) mg Ca per d with the maximum annual BMC accrual of 266.0 g from age 12 to 13 years. Differences were observed between both sex and age groups with respect to Ca needs: boys and girls aged 9-13 years would require 1000-1100 mg/d Ca, and from age 14 to 18 years, the mean Ca requirements would be relatively stable at 1000 mg/d for girls but would rise to 1200 mg/d for boys.


Development of 1.6 microm continuous-wave modulation hard-target differential absorption lidar system for CO2 sensing.
We have demonstrated the 1.6 mum cw modulation hard-target differential absorption lidar system for CO(2) sensing. In this system, ON and OFF wavelength laser lights are intensity modulated with cw signals. Received lights of the two wavelengths from the hard target are discriminated by modulation frequencies in the electrical signal domain. The optical circuit is fiber based, and this makes the system compact and reliable. It is shown that a stable CO(2) concentration measurement corresponding to a fluctuation of 4 ppm (rms) (ppm is parts per million) has been achieved in 32 s measurement intervals and the 1 km path.


Female genital mutilation: the role of medical professional organizations.
Female genital mutilation (FGM) refers to alteration of the external genitalia of girls without medical benefit. It is estimated by United Nations agencies that 200 million living girls and women have been subjected to different forms of FGM worldwide. Despite the criminalization of the procedure in the vast majority of countries where it is practiced, the decline in the incidence of this ritual is far from satisfactory. Immediate and long-term ill effects are well documented. Most publications of relevance originate from countries outside the map of FGM. In addition, there are major gaps in research related to this issue, considering the magnitude of the problem. International medical organizations and societies should assume their responsibility by providing a platform to professionals engaged in the prevention and treatment of the consequences of FGM, especially those living in the communities where the practice is endemic.


PARP1 Inhibitor Combined With Oxaliplatin Efficiently Suppresses Oxaliplatin Resistance in Gastric Cancer-Derived Organoids via Homologous Recombination and the Base Excision Repair Pathway.
Oxaliplatin (OXA) resistance in the treatment of different types of cancer is an important and complex problem. The culture of tumor organoids derived from gastric cancer can help us to provide a deeper understanding of the underlying mechanisms that lead to OXA resistance. In this study, our purpose was to understand the mechanisms that lead to OXA resistance, and to provide survival benefits to patients with OXA through targeted combination therapies. Using sequence analysis of OXA-resistant and non-OXA-resistant organoids, we found that PARP1 is an important gene that mediates OXA resistance. Through the patients' follow-up data, it was observed that the expression level of PARP1 was significantly correlated with OXA resistance. This was confirmed by genetic manipulation of PARP1 expression in OXA-resistant organoids used in subcutaneous tumor formation. Results further showed that PARP1 mediated OXA resistance by inhibiting the base excision repair pathway. OXA also inhibited homologous recombination by CDK1 activity and importantly made cancers with normal BRCA1 function sensitive to PARP inhibition. As a result, combination of OXA and Olaparib (PARP-1/2/3 inhibitor), inhibited in vivo and in vitro OXA resistant organoid growth and viability.


Histoplasmosis in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS): multicenter study of outcomes and factors associated with relapse.
Although discontinuation of suppressive antifungal therapy for acquired immunodeficiency syndrome (AIDS)-associated histoplasmosis is accepted for patients with immunologic recovery, there have been no published studies of this approach in clinical practice, and minimal characterization of individuals who relapse with this disease. We performed a multicenter retrospective cohort study to determine the outcome in AIDS patients following discontinuation of suppressive antifungal therapy for histoplasmosis. Ninety-seven patients were divided into a physician-discontinued suppressive therapy group (PD) (38 patients) and a physician-continued suppressive therapy group (PC) (59 patients). The 2 groups were not statistically different at baseline, but at discontinuation of therapy and at the most recent follow-up there were significant differences in adherence to therapy, human immunodeficiency virus (HIV) RNA, and urinary Histoplasma antigen concentration. There was no relapse or death attributed to histoplasmosis in the PD group compared with 36% relapse (p < 0.0001) and 5% death (p = 0.28) in the PC group. Relapse occurred in 53% of the nonadherent patients but not in the adherent patients (p < 0.0001). Sixty-seven percent of patients with initial central nervous system (CNS) histoplasmosis relapsed compared to 15% of patients without CNS involvement (p = 0.0004), which may be accounted for by nonadherence. In addition, patients with antigenuria above 2.0 ng/mL at 1-year follow-up were 12.82 times (95% confidence interval, 2.91-55.56) more likely to relapse compared to those with antigenuria below 2.0 ng/mL. Discontinuation of antifungal therapy was safe in adherent patients who completed at least 1 year of antifungal treatment, and had CD4 counts >150 cells/mL, HIV RNA <400 c/mL, Histoplasma antigenuria <2 ng/mL (equivalent to <4.0 units in second-generation method), and no CNS histoplasmosis.


Does engagement with life enhance survival of elderly people in Sweden? The role of social and leisure activities.
This research examined whether engagement with life, defined as involvement in social, leisure, and productive activities, produced a survival advantage among oldest old persons in Sweden. Survival was investigated with respect to activities that involved (a) social integration, (b) physical mobility, and (c) neither social nor physical aspects. The authors also investigated the degree to which any observed survival benefits were related to prior health differences that select older adults into active roles. Baseline data derived from the Swedish Panel Study of Living Conditions of the Oldest Old, a nationally representative sample of persons aged 77 years and older living in Sweden in 1992. The authors used factor analysis to apply a simplifying measurement structure to frequency of participation in 10 leisure activities. They used Cox proportional hazard regression to estimate the relative effects of activity factors and other independent variables on the logged hazard rate of mortality up to 1996. Analyses revealed 4 domains of activities that lie along 2 basic dimensions: solitary-social and sedentary-active. Among men, only participation in activities that were both solitary and active was significantly associated with reduced mortality risk when health variables were controlled. Among women, none of the activity domains was significant when health variables were controlled. For the entire sample, greater participation in solitary-active activities significantly reduced risk of mortality when all other activity domains and health factors were controlled. Although most of the observed associations between activity involvement and survival are a byproduct of the confound between poor initial health and low activity levels, solitary activities have a positive influence on the survival of very old individuals, especially men, suggesting that nonsocial aspects of activities may promote health and longevity in late old age.


Forest floor depth mediates understory vigor in xeric Pinus palustris ecosystems.
Longleaf pine (Pinus palustris) woodlands and savannas are among the most frequently burned ecosystems in the world with fire return intervals of 1-10 years. This fire regime has maintained high levels of biodiversity in terms of both species richness and endemism. Land use changes have reduced the area of this ecosystem by >95%, and inadequate fire frequencies threaten many of the remnants today. In the absence of frequent fire, rapid colonization of hardwoods and shrubs occurs, and a broad-leaved midstory develops. This midstory encroachment has been the focus of much research and management concern, largely based on the assumption that the midstory reduces understory plant diversity through direction competition via light interception. The general application of this mechanism of degradation is questionable, however, because midstory density, leaf area, and hardwood species composition vary substantially along a soil moisture gradient from mesic to extremely xeric sites. Reanalysis of recently reported data from xeric longleaf pine communities suggests that the development of the forest floor, a less conspicuous change in forest structure, might cause a decline in plant biodiversity when forests remain unburned. We report here a test of the interactions among fire, litter accumulation, forest floor development, and midstory canopy density on understory plant diversity. Structural equation modeling showed that within xeric sites, forest floor development was the primary factor explaining decreased biodiversity. The only effects of midstory development on biodiversity were those mediated through forest floor development. Boundary line analysis of functional guilds of understory plants showed sensitivity to even minor development of the forest floor in the absence of fire. These results challenge the prevailing management paradigm and suggest that within xeric longleaf pine communities, the primary focus of managed fire regime should be directed toward the restoration of forest floor characteristics rather than the introduction of high-intensity fires used to regulate midstory structure.


Attention and feature integration in the feature inheritance effect.
Features of neighboring elements are not processed independently. Often, it is assumed that nearby features are integrated by a (pre-attentive) pooling mechanism. Here, we show that in the feature inheritance effect some features are integrated across space whereas others are not. This result may be partly explained by a very focused spatial attention. Our findings challenge models based on a simple pooling mechanism.


Cell ingression and apical shape oscillations during dorsal closure in Drosophila.
Programmed patterns of gene expression, cell-cell signaling, and cellular forces cause morphogenic movements during dorsal closure. We investigated the apical cell-shape changes that characterize amnioserosa cells during dorsal closure in Drosophila embryos with in vivo imaging of green-fluorescent-protein-labeled DE-cadherin. Time-lapsed, confocal images were assessed with a novel segmentation algorithm, Fourier analysis, and kinematic and dynamical modeling. We found two generic processes, reversible oscillations in apical cross-sectional area and cell ingression characterized by persistent loss of apical area. We quantified a time-dependent, spatially-averaged sum of intracellular and intercellular forces acting on each cell's apical belt of DE-cadherin. We observed that a substantial fraction of amnioserosa cells ingress near the leading edges of lateral epidermis, consistent with the view that ingression can be regulated by leading-edge cells. This is in addition to previously observed ingression processes associated with zipping and apoptosis. Although there is cell-to-cell variability in the maximum rate for decreasing apical area (0.3-9.5 μm(2)/min), the rate for completing ingression is remarkably constant (0.83 cells/min, r(2) > 0.99). We propose that this constant ingression rate contributes to the spatiotemporal regularity of mechanical stress exerted by the amnioserosa on each leading edge during closure.


Evaluation of the Volumizing Performance of a New Volumizer Filler in Volunteers with Age-Related Midfacial Volume Defects.
The primary aim of this study was to evaluate the performance of the study product, in terms of volumizing activity as well as the duration of the effect, in women with age-related midfacial volume defects. In addition, the study allowed the evaluation of the tolerability of the product by both volunteers and investigators. Twenty-two female volunteers, aged 42-60 years, participated in this study, which was performed under dermatological control in a single center. After an initial visit at baseline to verify adherence to the protocol criteria, volunteers received an injection of Aliaxin® SV (IBSA Farmaceutici Italia Srl), followed 3-4 weeks later by a second touch-up treatment to treat eventual asymmetries. Four subsequent visits, the last performed 9 months from the first injection, were performed to evaluate clinically and instrumentally the efficacy of the treatment. Clinical and statistically significant improvement in cheek volume was recorded after the first postinjection visit, and the effect was maintained until the end of the study period. A clinically measurable amelioration of wrinkle severity was also observed. By 3D picture recording and subsequent quantitative analysis, it was possible to determine the efficacy in terms of increased facial volume, which was already appreciable at the first visit, was further increased at the second and third visits and was maintained at the fourth and last visits. The injections were very well tolerated by the volunteers, as determined by their self-evaluation questionnaires. The results of the study confirm the esthetic performance of the study product on age-related midfacial volume defects. The very strong high-volumizing activity of the study product was not only properly determined by the investigators but also confirmed by self-evaluation by the volunteers. These effects were obtained with no appreciable undesired effects.


Structural basis of the zinc inhibition of human tissue kallikrein 5.
Human kallikrein 5 (hK5) is a member of the tissue kallikrein family of serine peptidases. It has trypsin-like substrate specificity, is inhibited by metal ions, and is abundantly expressed in human skin, where it is believed to play a central role in desquamation. To further understand the interaction of hK5 with substrates and metal ions, active recombinant hK5 was crystallized in complex with the tripeptidyl aldehyde inhibitor leupeptin, and structures at 2.3 A resolution were obtained with and without Zn2+. While the overall structure and the specificity of S1 pocket for basic side-chains were similar to that of hK4, a closely related family member, both differed in their interaction with Zn2+. Unlike hK4, the 75-loop of hK5 is not structured to bind a Zn2+. Instead, Zn2+ binds adjacent to the active site, becoming coordinated by the imidazole rings of His99 and His96 not present in hK4. This zinc binding is accompanied by a large shift in the backbone conformation of the 99-loop and by large movements of both His side-chains. Modeling studies show that in the absence of bound leupeptin, Zn2+ is likely further coordinated by the imidazolyl side-chain of the catalytic His57 which can, similar to equivalent His57 imidazole groups in the related rat kallikrein proteinase tonin and in an engineered metal-binding rat trypsin, rotate out of its triad position to provide the third co-ordination site of the bound Zn2+, rendering Zn2+-bound hK5 inactive. In solution, this mode of binding likely occurs in the presence of free and substrate saturated hK5, as kinetic analyses of Zn2+ inhibition indicate a non-competitive mechanism. Supporting the His57 re-orientation, Zn2+ does not fully inhibit hK5 hydrolysis of tripeptidyl substrates containing a P2-His residue. The P2 and His57 imidazole groups would lie next to each other in the enzyme-substrate complex, indicating that incomplete inhibition is due to competition between both imidazole groups for Zn2+. The His96-99-57 triad is thus suggested to be responsible for the Zn2+-mediated inhibition of hK5 catalysis.


Brain insulin action regulates hypothalamic glucose sensing and the counterregulatory response to hypoglycemia.
An impaired ability to sense and appropriately respond to insulin-induced hypoglycemia is a common and serious complication faced by insulin-treated diabetic patients. This study tests the hypothesis that insulin acts directly in the brain to regulate critical glucose-sensing neurons in the hypothalamus to mediate the counterregulatory response to hypoglycemia. To delineate insulin actions in the brain, neuron-specific insulin receptor knockout (NIRKO) mice and littermate controls were subjected to graded hypoglycemic (100, 70, 50, and 30 mg/dl) hyperinsulinemic (20 mU/kg/min) clamps and nonhypoglycemic stressors (e.g., restraint, heat). Subsequently, counterregulatory responses, hypothalamic neuronal activation (with transcriptional marker c-fos), and regional brain glucose uptake (via (14)C-2deoxyglucose autoradiography) were measured. Additionally, electrophysiological activity of individual glucose-inhibited neurons and hypothalamic glucose sensing protein expression (GLUTs, glucokinase) were measured. NIRKO mice revealed a glycemia-dependent impairment in the sympathoadrenal response to hypoglycemia and demonstrated markedly reduced (3-fold) hypothalamic c-fos activation in response to hypoglycemia but not other stressors. Glucose-inhibited neurons in the ventromedial hypothalamus of NIRKO mice displayed significantly blunted glucose responsiveness (membrane potential and input resistance responses were blunted 66 and 80%, respectively). Further, hypothalamic expression of the insulin-responsive GLUT 4, but not glucokinase, was reduced by 30% in NIRKO mice while regional brain glucose uptake remained unaltered. Chronically, insulin acts in the brain to regulate the counterregulatory response to hypoglycemia by directly altering glucose sensing in hypothalamic neurons and shifting the glycemic levels necessary to elicit a normal sympathoadrenal response.


Awake functional MRI detects neural circuit dysfunction in a mouse model of autism.
MRI has potential as a translational approach from rodents to humans. However, given that mouse functional MRI (fMRI) uses anesthetics for suppression of motion, it has been difficult to directly compare the result of fMRI in "unconsciousness" disease model mice with that in "consciousness" patients. We develop awake fMRI to investigate brain function in 15q dup mice, a copy number variation model of autism. Compared to wild-type mice, we find that 15q dup is associated with whole-brain functional hypoconnectivity and diminished fMRI responses to odors of stranger mice. Ex vivo diffusion MRI reveals widespread anomalies in white matter ultrastructure in 15q dup mice, suggesting a putative anatomical substrate for these functional hypoconnectivity. We show that d-cycloserine (DCS) treatment partially normalizes these anormalies in the frontal cortex of 15q dup mice and rescues some social behaviors. Our results demonstrate the utility of awake rodent fMRI and provide a rationale for further investigation of DCS therapy.


Soluble P-selectin promotes acute myocardial infarction onset but not severity.
P‑selectin, an integral membrane glycoprotein of platelets and endothelial cells, and the soluble form of P‑selectin are hypothesized to play a role in the initiation of atherosclerosis and acute myocardial infarction (AMI). However, limited data are available with which to evaluate the main role of soluble P‑selectin (sP‑selectin) in the onset or the severity of AMI. In the present study, we investigated 15 patients who suffered from angina, 10 patients who underwent percutaneous coronary intervention (PCI) therapy and 10 patients who underwent thrombolysis therapy, compared with 15 volunteers with no cardiovascular disease. We confirmed that the plasma sP‑selectin levels were increased in patients with obesity (particularly pericardial obesity) and hyperlipidemia, positively correlated with plasma tumor necrosis factor (TNF)‑α and strongly negatively correlated with adiponectin in all patients regardless of AMI status. Furthermore, sP‑selectin levels were significantly higher in PCI and thrombolysis patients compared with angina patients and the control cohort. However, we observed that sP‑selectin levels did not change following PCI and thrombolysis therapy. In addition, there was no correlation between sP‑selectin levels and the severity of AMI in the cohort which received PCI or thrombolysis therapy. Therefore, we deduced that sP‑selectin only induced the onset of AMI but did not promote its severity. To confirm this hypothesis, a P‑selectin inhibitor was administered to an atherosclerosis formation model, plaque rapture model and neointimal hyperplasia model. We revealed that atherosclerotic plaque formation and rupture, neointimal formation and neointimal bleeding were suppressed by the sP‑selectin inhibitor. We concluded that sP‑selectin, induced by systemic inflammation in conditions including obesity and hyperlipidemia, promoted atherosclerotic plaque and neointimal formation, plaque rapture and neointimal bleeding, further leading to AMI. We also demonstrated that sP‑selectin had no effect on the severity of AMI.


Chemical characterization of oligosaccharides in chimpanzee, bonobo, gorilla, orangutan, and siamang milk or colostrum.
Neutral and acidic oligosaccharides were isolated from the milk or colostrum of four great ape species (chimpanzee (Pan troglodytes), bonobo (Pan paniscus), gorilla (Gorilla gorilla), and orangutan (Pongo pygmaeus)) and one lesser ape species (siamang (Symphalangus syndactylus)), and their chemical structures were characterized by (1)H-NMR spectroscopy. Oligosaccharides containing the type II unit (Gal(beta1-4)GlcNAc) were found exclusively (gorilla and siamang) or predominately (chimpanzee, bonobo, and orangutan) over those containing the type I unit (Gal(beta1-3)GlcNAc). In comparison, type I oligosaccharides predominate over type II oligosaccharides in human milk, whereas nonprimate milk almost always contains only type II oligosaccharides. The milk or colostrum of the great apes contained oligosaccharides bearing both N-glycolylneuraminic acid and N-acetylneuraminic acid, whereas human milk contains only the latter. Great ape milk, like that of humans, contained fucosylated oligosaccharides whereas siamang milk did not. Since these analyses are based on a limited number of individuals, further research on additional samples of great and lesser ape milk is needed to confirm phylogenetic patterns.


Test-retest reliability of neurophysiological tests of hand-arm vibration syndrome in vibration exposed workers and unexposed referents.
Exposure to hand-held vibrating tools may cause the hand-arm vibration syndrome (HAVS). The aim was to study the test-retest reliability of hand and muscle strength tests, and tests for the determination of thermal and vibration perception thresholds, which are used when investigating signs of neuropathy in vibration exposed workers. In this study, 47 vibration exposed workers who had been investigated at the department of Occupational and Environmental Medicine in Gothenburg were compared with a randomized sample of 18 unexposed subjects from the general population of the city of Gothenburg. All participants passed a structured interview, answered several questionnaires and had a physical examination including hand and finger muscle strength tests, determination of vibrotactile (VPT) and thermal perception thresholds (TPT). Two weeks later, 23 workers and referents, selected in a randomized manner, were called back for the same test-procedures for the evaluation of test-retest reliability. The test-retest reliability after a two week interval expressed as limits of agreement (LOA; Bland-Altman), intra-class correlation coefficients (ICC) and Pearson correlation coefficients was excellent for tests with the Baseline hand grip, Pinch-grip and 3-Chuck grip among the exposed workers and referents (N = 23: percentage of differences within LOA 91 - 100%; ICC-values ≥0.93; Pearson r ≥0.93). The test-retest reliability was also excellent (percentage of differences within LOA 96-100 %) for the determination of vibration perception thresholds in digits 2 and 5 bilaterally as well as for temperature perception thresholds in digits 2 and 5, bilaterally (percentage of differences within LOA 91 - 96%). For ICC and Pearson r the results for vibration perception thresholds were good for digit 2, left hand and for digit 5, bilaterally (ICC ≥ 0.84; r ≥0.85), and lower (ICC = 0.59; r = 0.59) for digit 2, right hand. For the latter two indices the test-retest reliability for the determination of temperature thresholds was lower and showed more varying results. The strong test-retest reliability for hand and muscle strength tests as well as for the determination of VPTs makes these procedures useful for diagnostic purposes and follow-up studies in vibration exposed workers.


Optimisation of an oviposition protocol employing human chorionic and pregnant mare serum gonadotropins in the barred frog Mixophyes fasciolatus (Myobatrachidae).
Protocols for the hormonal induction of ovulation and oviposition are essential tools for managing threatened amphibians with assisted reproduction, but responses vary greatly between species and even broad taxon groups. Consequently, it is necessary to assess effectiveness of such protocols in representative species when new taxa become targets for induction. The threatened genus Mixophyes (family Myobatrachidae) has amongst the highest proportion of endangered species of all the Australian amphibians. This study developed and optimised the induction of oviposition in a non-threatened member of this taxon, the great barred frog (Mixophyes fasciolatus). Gravid female M. fasciolatus were induced to oviposit on one or more occasions by administration of human chorionic gonadotropin (hCG) with or without priming with pregnant mare serum gonadotropin (PMSG). Treatments involved variations in hormone doses and combinations (administered via injection into the dorsal lymph sacs), and timing of administration. Pituitary homogenates from an unrelated bufonid species (Rhinella marina) were also examined with hCG. When injected alone, hCG (900 to 1400 IU) induced oviposition. However, priming with two time dependent doses of PMSG (50 IU, 25 IU) increased responses, with lower doses of hCG (200 IU). Priming increased response rates in females from around 30% (hCG alone) to more than 50% (p = 0.035), and up to 67%. Increasing the interval between the first PMSG dose and first hCG dose from 3 to 6 days also produced significant improvement (p<0.001). Heterologous pituitary extracts administered with hCG were no more effective than hCG alone (p = 0.628). This study found that M. fasciolatus is amongst the few amphibian species (including Xenopus (Silurana) and some bufonids) that respond well to the induction of ovulation utilising mammalian gonadotropins (hCG). The optimal protocol for M. fasciolatus involved two priming doses of PMSG (50 IU and 25 IU) administered at 6 and 4 days respectively, prior to two doses of hCG (100 IU), 24 hours apart. This study is also the first to demonstrate in an amphibian species that responds to mammalian gonadotropins that an increase in the ovulation rate occurs after priming with a gonadotropin (PMSG) with FSH activity.


Interleukin 10 suppresses experimental chronic, granulomatous inflammation induced by bacterial cell wall polymers.
Interleukin 10 (IL10) inhibits monocyte/macrophage and T lymphocyte effector functions. This study examined the effect of systemically administered IL10 on acute and chronic granulomatous enterocolitis, hepatitis, and arthritis in a rat model. Lewis rats were injected intramurally with streptococcal peptidoglycan-polysaccharide (PG-APS) polymers. Beginning 12 hours before PG-APS injection, rats were treated daily with subcutaneous murine recombinant IL10 or vehicle for three or 17 days. IL10 attenuated acute enterocolitis in a dose dependent fashion (p < 0.01). Protective effects were more profound in the chronic granulomatous phase with decreased enterocolitis and markedly inhibited leucocytosis, hepatic granulomas, and chronic erosive arthritis (p < 0.001). IL10 downregulated tissue IL1, IL6, tumour necrosis factor alpha, and interferon gamma gene expression, consistent with the in vitro effects of IL10 on PG-APS-stimulated splenocytes. Caecal IL1 protein concentrations and IL2 and interferon gamma secretion by in vitro stimulated mesenteric lymph nodes were downregulated in IL10 treated animals. These results indicate that exogenous IL10 can inhibit experimental granulomatous inflammatory responses and suggest that IL10 treatment could be an effective new therapeutic approach in human disorders such as Crohn's disease, rheumatoid arthritis, and sarcoidosis.


NF-kappaB mediates FGF signal regulation of msx-1 expression.
The nuclear factor-kappaB (NF-kappaB) family of transcription factors is involved in proliferation, differentiation, and apoptosis in a stage- and cell-dependent manner. Recent evidence has shown that NF-kappaB activity is necessary for both chicken and mouse limb development. We report here that the NF-kappaB family member c-rel and the homeodomain gene msx-1 have partially overlapping expression patterns in the developing chick limb. In addition, inhibition of NF-kappaB activity resulted in a decrease in msx-1 mRNA expression. Sequence analysis of the msx-1 promoter revealed three potential kappaB-binding sites similar to the interferon-gamma (IFN-gamma) kappaB-binding site. These sites bound to c-Rel, as shown by electrophoretic mobility shift assay (EMSA). Furthermore, inhibition of NF-kappaB activity significantly reduced transactivation of the msx-1 promoter in response to FGF-2/-4, known stimulators of msx-1 expression. These results suggest that NF-kappaB mediates the FGF-2/-4 signal regulation of msx-1 gene expression.


Correlation of the biologic responses of C3H/HEJ mice to endotoxin with the chemical and structural properties of the lipopolysaccharides from Pseudomonas aeruginosa and Escherichia coli.
The basis of the biologic responses of C3H/HeJ mice to endotoxin administration in relation to the structural linkages in the lipid A portion of the lipopolysaccharide (LPS) of Pseudomonas aeruginosa and Escherichia coli were investigated. P. aeruginosa LPS was found to be immunogenic, mitogenic, and toxic, but not lethal, in C3H/HeJ mice. The observed mitogenicity in spleen cells was directed toward immunoglobulin- (Ig) bearing cells, was present in response to isolated and solubilized lipid A, and was inhibitable by polymixin B. The P. aeruginosa LPS was chemically analyzed in order to define its composition and exclude the presence of contaminating proteins being responsible for the biologic responses of C3H/HeJ mice that were observed. Structural analysis of the linkages of the fatty acids to the glucosamine backbone in the lipid A of P. aeruginosa and E. coli revealed similarities in terms of the ratio of hydroxy fatty acids to straight chain fatty acids and the way in which these 2 types of fatty acids were linked to the backbone. Differences were seen in the carbon chain length of the fatty acid substituents, and the substituent on the hydroxy fatty acid that is directly ester linked to the glucosamine backbone. These data indicate that the refractivity of C3H/HeJ mice to the biologic effects after the administration of Gram-negative endotoxins may be limited to enterobacterial LPS. Those differences we found in the chain length and/or linkages of the fatty acid substituents in the lipid A portion of the LPS between P. aeruginosa and E. coli may be sufficient to render C3H/HeJ mice responsive to the biologic effects of nonenterobacterial endotoxins.


Influence of long-chain polyunsaturated fatty acids on oxidation of low density lipoprotein.
Enrichment of low density lipoprotein (LDL) with long-chain fatty acids, such as eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3) found in fish oil, is thought to increase its oxidative susceptibility although such an increase has not been clearly demonstrated. The purpose of this study was to determine the composition and fatty acid concentration of LDL obtained from postmenopausal women given a supplement of fish oil and relate these values to its oxidative susceptibility. Fish oil supplementation significantly increased LDL concentration of EPA (P = 0.0001) and DHA (P = 0.0001) and decreased that of linoleic acid P = 0.006). The concentration of free cholesterol, cholesterol ester, phospholipids and protein was unchanged while triglyceride concentration increased 8% (P = 0.02). Cu2+-mediated oxidation resulted in a shorter lag time, slower oxidation rate and similar concentrations of conjugated dienes of EPA/DHA-enriched LDL than EPA/DHA-unenriched LDL. Stepwise multiple regression indicated that the primary predictor of oxidative susceptibility of LDL was linoleic acid, even after enrichment with EPA and DHA. The oxidation rate of EPA/DHA-unenriched LDL correlated with the cholesteryl ester concentration (P = 0.003) while that of EPA/DHA-enriched correlated with the concentration of phospholipids (P = 0.03). These data suggest that EPA/DHA-enriched LDL have decreased oxidative susceptibility and that surface lipids may mediate its rate of oxidation.


Proteomic research and diagnosis in bladder cancer: state of the art review.
Proteomic biomarkers have been emerging as alternative methods to the gold standard procedures of cystoscopy and urine cytology in the diagnosis and surveillance of bladder cancer (BC). This review aims to update the state of the art of proteomics research and diagnosis in BC. We reviewed the current literature related to BC research on urinary, tissue, blood and cell line proteomics, using the Pubmed database. Two urinary protein biomarkers are FDA-approved (NMP22® and BTA® tests), only if performed along with cystoscopy for surveillance after initial diagnosis, but not in the primary diagnostic setting due to high false-positive rates in case of infections, stones and hematuria. There are a great number of non-FDA approved proteins being studied, with good preliminary results; panels of proteins seem valuable tools to be refined in ongoing trials. Blood proteins are a bigger challenge, because of the complexity of the serum protein profile and the scarcity of blood proteomic studies in BC. Previous studies with the BC tissue proteome do not correlate well with the urinary proteome, likely due to the tumor heterogeneity. Cell line proteomic research helps in the understanding of basic mechanisms that drive BC development and progression; the main difficulty is culturing low-grade tumors in vitro, which represents the majority of BC tumors in clinical practice. Protein biomarkers have promising value in the diagnosis, surveillance and prognostic of BC. Urine is the most appropriate body fluid for biomarker research in BC due to its easiness of sampling, stability and enrichment of shed and secreted tumor-specific proteins. Panels of biomarkers may exhibit higher sensitivity than single proteins in the diagnosis of BC at larger populations due to clinical and tumor heterogeneity. Prospective clinical trials are warranted to validate the relevance of proteomic data in the clinical management of BC.


Helicobacter pylori in Iran: A systematic review on the antibiotic resistance.
Helicobacter pylori (H. pylori) is a pathogenic bacterium that colonizes the stomachs of approximately 50% of the world's population. Resistance of H. pylori to antibiotics is considered as the main reason for the failure to eradicate this bacterium. The aim of this study was to determine the rate of resistant H. pylori strains to various antimicrobial agents in different areas of Iran. A systematic review of literatures on H. pylori antibiotic resistance in Iran was performed within the time span of 1997 to 2013. Data obtained from various studies were tabulated as following, 1) year of research and number strains tested, 2) number of H. pylori positive patients, 3) study place, 4) resistance of H. pylori to various antibiotics as percentage, and 5) methods used for evaluation of antibiotic resistance. Over the period, a total of 21 studies on H. pylori antibiotic resistance have been conducted in different parts of Iran. In these studies, H. pylori resistance to various antibiotics, including metronidazole, clarithromycin, amoxicillin, tetracycline, ciprofloxacin, levofloxacin and furazolidone were 61.6%, 22.4%, 16.0%, 12.2%, 21.0%, 5.3% and 21.6%, respectively. We found no study on H. pylori resistance to rifabutin in Iran. Compared to the global average, we noted that the prevalence of H. pylori resistance to metronidazole, clarithromycin, amoxicillin, and tetracycline has been rapidly growing in Iran. This study showed that in order to determine an appropriate drug regimen against H. pylori, information on antibiotic susceptibility of the bacterium within different geographical areas of Iran is required.


The compliance of the porcine pulmonary artery depends on pressure and heart rate.
1. The influence of mean pulmonary arterial pressure (mean Ppa) on dynamic (Cd) and pseudo-static compliance (Cps) of the pulmonary artery was studied at a constant and a changing heart rate. Cd is the change in cross-sectional area (CSA) relative to the change in Ppa throughout a heart cycle. Cps is the change in mean CSA relative to the change in mean Ppa. If Cd is known, pulmonary blood flow can be computed from the Ppa using a windkessel model. We investigated whether Cps can be interchanged with Cd. 2. In nine anaesthetized pigs, we determined the mean CSA and Cd of the pulmonary artery at various Ppa levels, ranging from approximately 30 to 10 mmHg, established by bleeding. Two series of measurements were carried out, one series at a spontaneously changing heart rate (n = 9) and one series at a constant heart rate (n = 6). To determine CSA a conductance method was used. 3. Cps depended on pressure. The mean CSA versus mean Ppa curves were sigmoid and steepest in the series with the increasing heart rate (established by bleeding). The CSA versus Ppa loop during a heart cycle, giving Cd, was approximately linear and almost closed. The Cd versus mean Ppa relationship was bell shaped. Its width was smaller if the heart rate increased during the series of measurements. The pressure, where Cd was maximum, was higher at higher heart rates. Furthermore, the maximum Cd was not affected by the heart rate. 4. Because the pulmonary artery constricts with increasing heart rate, Cps will be overestimated during procedures where heart rate increases. Cd should be determined on a beat-to-beat basis to calculate flow because it changes with mean pulmonary arterial pressure and heart rate.


Mean proportion and population proportion: two answers to the same question?
Two different, but equally correct, answers can be given to a question such as "What proportion of the cholesterol that is consumed comes from eggs?" This is because the question can have two different meanings, depending on whether one is referring to the mean proportion of cholesterol from eggs or the population proportion. The mean proportion of cholesterol from eggs for a group of persons is determined by first calculating the proportion of cholesterol from eggs for each person and then taking an arithmetic mean of all the proportions. The population proportion is calculated by summing the amount of cholesterol from eggs for all persons and then dividing that by the sum of the cholesterol from all foods for all persons. These two different formulas often yield similar results. Sometimes, however, the results can be quite different because of variation in the ratio, variation in the denominator, and/or the correlation between the ratio and the denominator. Each of these formulas is designed to answer a specific question: the mean proportion addresses the question about the average per person and the population proportion addresses the question of population intakes. But because either may be used to answer the same general question, confusion may result. This article discusses the factors influencing differences between the two formulas and the implications of those differences for reporting and interpreting dietary intake data.


Iron intake and the risk of colorectal cancer.
Prospectively gathered data from the National Health and Nutrition Examination Survey I and the National Health Evaluation Follow-Up Study were analyzed to evaluate the risk of colorectal cancer due to consumption of iron. Morbidity and mortality data due to colorectal cancer were available on 14,407 persons first interviewed in 1971 and followed through 1986. A total of 194 possible colorectal cancers occurred in this group over the 15-year period. Subsite analysis showed that the risk of colon cancer due to iron intake was elevated throughout the colon for both men and women, with the highest adjusted risks for the interquartile range seen in the proximal colon for females (relative risk, 1.51; 95% confidence interval, 1.41-1.60). The risk of rectal cancer was not significantly elevated for men or women. Elevated serum iron was also associated with increased risk; however, this effect was strongest in the distal (rather than proximal) colon and was significant only among females (adjusted relative risk, 1.73; 95% confidence interval, 1.03-2.92). The mean transferrin saturation was higher among cases than controls (30.7 versus 28.7%), but total iron-binding capacity did not seem to predict the occurrence of colorectal cancer. Proportional hazards models confirmed that the effects of iron and serum iron were not confounded by age, gender, energy consumption, fat intake, or other known risk factors for colorectal cancer. These data suggest that iron may confer an increased risk for colorectal cancer, and that the localization of risk may be attributable to the mode of epithelial exposure. It seems that luminal exposure to iron increases risk proximally, whereas humoral exposure increases risk distally. These differences may be due to such factors as oxidation state, binding proteins and the presence of other cofactors such as bile acids, products of bacterial metabolism.


The incidence of prescribing errors in hospital inpatients: an overview of the research methods.
Many different methods have been used to study the incidence of prescribing errors in hospital inpatients. The objectives of this review were to outline the methods used, highlight their strengths and limitations, and summarise the incidence of prescribing errors reported. Methods used may be retrospective or prospective and based on process or on outcome. Reported prescribing error rates vary widely, ranging from 0.3% to 39.1% of medication orders written and from 1% to 100% of hospital admissions. Unfortunately, there is no standard denominator for use when expressing prescribing error rates. It could be argued that the most meaningful is the number of medication orders written; however, it is also helpful to consider the number of medication orders written per patient stay in order to understand the risk that a given prescribing error rate poses to an individual patient. Because of wide variation in the definitions and methods used, it is difficult to make comparisons between different studies. Each method for identifying prescribing errors has advantages and disadvantages. Process-based studies potentially allow all errors to be identified, giving more scope for the identification of trends and learning opportunities, and it may be easier to collect sufficient data to show statistically significant changes in prescribing error rates following interventions to reduce them. However, studies based on process may be criticised for focusing on many minor errors that are very unlikely to have resulted in patient harm. Focusing instead on harm, as in outcome-based studies, allows efforts to reduce errors to be targeted on those areas that are likely to result in the highest impact. Therefore, the most appropriate method depends on the study's aims. However, using a combination of methods is likely to be the most useful approach if comprehensive data are required.


The coupling of bone and cartilage turnover in osteoarthritis: opportunities for bone antiresorptives and anabolics as potential treatments?
Osteoarthritis (OA) is the most common form of arthritic disease, and a major cause of disability and impaired quality of life in the elderly. OA is a complex disease of the entire joint, affecting bone, cartilage and synovium that thereby presents multiple targets for treatment. This manuscript will summarise emerging observations from cell biology, preclinical and preliminary clinical trials that elucidate interactions between the bone and cartilage components in particular. Bone and cartilage health are tightly associated. Ample evidence has been found for bone changes during progression of OA including, but not limited to, increased turnover in the subchondral bone, undermineralisation of the trabecular structure, osteophyte formation, bone marrow lesions and sclerosis of the subchondral plate. Meanwhile, a range of investigations has shown positive effects on cartilage health when bone resorption is suppressed, or deterioration of the cartilage when resorption is increased. Known bone therapies, namely oestrogens, selective oestrogen receptor modifiers (SERMs), bisphosphonates, strontium ranelate, calcitonin and parathyroid hormone, might prove useful for treating two critical tissue components of the OA joint, the bone and the cartilage. An optimal treatment for OA likely targets at least these two tissue components. The patient subgroups for whom these therapies are most appropriate have yet to be fully defined but would likely include, at a minimum, those with high bone turnover.


Partitioning of food resources amongst 18 abundant benthic carnivorous fish species in marine waters on the lower west coast of Australia.
The volumetric contributions made by prey and plant material to the diets of 4 elasmobranch and 14 teleost species, collected seasonally by trawling from waters along ca. 200 km of the lower west coast of Australia, have been compared. These benthic carnivores, which were all abundant and collectively contributed 83% to the total number of fish caught, represented nine families (Urolophidae, Scorpaenidae, Triglidae, Platycephalidae, Sillaginidae, Carangidae, Gerreidae, Mullidae and Pempherididae). Some species were numerous in both shallow (5-15 m) and deeper (20-35 m) waters and in both northern and southern regions, whereas others were largely confined to one of these water depths or regions. Comparisons between the diets of the different species, which utilised data collected from individuals throughout the study area, demonstrated that the dietary composition of any given species was almost invariably significantly different from that of every other species. This partly reflected the fact that, while errant polychaetes, gammarid amphipods and tanaids were ingested by all species, their contributions to the diets of the different species varied. Furthermore, echinoderms contributed to the diets of just nine species, and this was substantial only in the case of two sillaginid species, while teleosts were never consumed by six species and only made a marked contribution to the diets of the single species of platycephalid. The diet of each species underwent size-related changes, reflecting a shift from the consumption by smaller fish of prey such as amphipods, mysids and copepods, to the ingestion by larger fish of prey such as polychaetes, carid decapods, isopods and small teleosts. The interspecific and intraspecific differences in dietary compositions would spread the food resources amongst and within species, thereby reducing the potential for competition for those resources within the fish community. Non-metric multi-dimensional scaling (MDS) ordination plots emphasised that the dietary compositions of species within each family possessed some obvious similarities, reflecting similarities in body and mouth morphology and feeding behaviour. However, the extent to which the dietary compositions of the different families were similar or different was often not related to the phylogenetic relationships amongst those families. Furthermore, while differences in mouth size and morphology could sometimes be used to account for differences amongst the diets of the full suite of species, this was not always the case. Thus, the ways in which species feed and use their ancillary feeding structures were also employed to help elucidate the basis for variations in diets.


Possible involvement of IFNT in lymphangiogenesis in the corpus luteum during the maternal recognition period in the cow.
The corpus luteum (CL), which secretes large amounts of progesterone and is thus essential for establishing pregnancy, contains various types of immune cells that may play essential roles in CL function by generating immune responses. The lymphatic system is the second circulation system and is necessary for immune function, but the lymphatic system of the bovine CL has not been characterized in detail. We collected bovine CLs on days 12 and 16 of the estrous cycle (C12 and C16) and days 16 and 40 of early pregnancy (P16 and P40). Lymphatic endothelial hyaluronan receptor 1 (LYVE1) protein was detected in the CL by immunohistochemistry and western blotting and increased at P40 compared with C16. The mRNA expression levels of lymphangiogenic factors, such as vascular endothelial growth factor-C (VEGFC), VEGFD, and their common receptor VEGFR3, as well as the lymphatic endothelial cell (LyEC) marker podoplanin, increased in P16 and P40 CLs. Thus, it is suggested that the lymphatic system of the bovine CL reconstitutes during early pregnancy. Interferon tau (IFNT) from the conceptus in the uterus is a candidate for activating luteal lymphangiogenesis during the maternal recognition period (MRP). We found that treatment of LyECs isolated from internal iliac lymphatic vessels with IFNT stimulated LyEC proliferation and significantly increased mRNA expression of VEGFC and IFN-stimulated gene 15. Moreover, both IFNT and VEGFC induced LyECs to form capillary-like tubes in vitro. In conclusion, it is suggested that new lymphangiogenesis in the bovine CL begins during the MRP and that IFNT may mediate this novel phenomenon.


Intra-arterial Thrombolysis in Second Trimester of Pregnancy. A Case Report.
Here we present a successful intra-arterial thrombolysis performed in the second trimester of pregnancy (21 weeks). The intervention resulted in complete recanalization of the occluded right middle cerebral artery and favourable clinical and gestational outcome. Together with cases described in respective medical literature our report affirms that in pregnancy acute ischemic stroke could be treated effectively applying intra-arterial thrombolysis (using rt-PA). This therapy could provide opportunity to help in such desperate situations.


T-cell responses induced by ChAdOx1 nCoV-19 (AZD1222) vaccine to wild-type severe acute respiratory syndrome coronavirus 2 among people with and without HIV in South Africa.
This study aimed to investigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cell responses 14 days after single-dose ChAdOx1 nCoV-19 (AZD1222) vaccination in black Africans with and without HIV in South Africa, as well as determine the effect of AZD1222 vaccination on cell-mediated immune responses in people with HIV (PWH) with prior SARS-CoV-2 infection. A total of 70 HIV-uninfected people and 104 PWH were prospectively enrolled in the multicentre, randomized, double-blinded, placebo-controlled, phase Ib/IIa trial (COV005). Peripheral blood mononuclear cells (PBMCs) were collected from trial participants 14 days after receipt of first dose of study treatment (placebo or AZD1222 vaccine). T-cell responses against the full-length spike (FLS) glycoprotein of wild-type SARS-CoV-2 and mutated S-protein regions found in the Alpha, Beta and Delta variants were assessed using an ex-vivo ELISpot assay. Among AZD1222 recipients without preceding SARS-CoV-2 infection, T-cell responses to FLS of wild-type SARS-CoV-2 were similarly common in PWH and HIV-uninfected people (30/33, 90.9% vs. 16/21, 76.2%; P = 0.138); and magnitude of response was similar among responders (78 vs. 56 SFCs/106 PBMCs; P = 0.255). Among PWH, AZD1222 vaccinees with prior SARS-CoV-2 infection, displayed a heightened T-cell response magnitude compared with those without prior infection (186 vs. 78 SFCs/106 PBMCs; P = 0.001); and similar response rate (14/14, 100% vs. 30/33, 90.9%; P = 0.244). Our results indicate comparable T-cell responses following AZD1222 vaccination in HIV-uninfected people and PWH on stable antiretroviral therapy. Our results additionally show that hybrid immunity acquired through SARS-CoV-2 infection and AZD1222 vaccination, induce a heightened T-cell response.


Computation provides chemical insight into the diverse hydride NMR chemical shifts of [Ru(NHC)4(L)H]0/+ species (NHC = N-heterocyclic carbene; L = vacant, H2, N2, CO, MeCN, O2, P4, SO2, H-, F- and Cl-) and their [Ru(R2PCH2CH2PR2)2(L)H]+ congeners.
Relativistic density functional theory calculations, both with and without the effects of spin-orbit coupling, have been employed to model hydride NMR chemical shifts for a series of [Ru(NHC)4(L)H]0/+ species (NHC = N-heterocyclic carbene; L = vacant, H2, N2, CO, MeCN, O2, P4, SO2, H-, F- and Cl-), as well as selected phosphine analogues [Ru(R2PCH2CH2PR2)2(L)H]+ (R = iPr, Cy; L = vacant, O2). Inclusion of spin-orbit coupling provides good agreement with the experimental data. For the NHC systems large variations in hydride chemical shift are shown to arise from the paramagnetic term, with high net shielding (L = vacant, Cl-, F-) being reinforced by the contribution from spin-orbit coupling. Natural chemical shift analysis highlights the major orbital contributions to the paramagnetic term and rationalizes trends via changes in the energies of the occupied Ru dπ orbitals and the unoccupied σ*Ru-H orbital. In [Ru(NHC)4(η2-O2)H]+ a δ-interaction with the O2 ligand results in a low-lying LUMO of dπ character. As a result this orbital can no longer contribute to the paramagnetic shielding, but instead provides additional deshielding via overlap with the remaining (occupied) dπ orbital under the Lz angular momentum operator. These two effects account for the unusual hydride chemical shift of +4.8 ppm observed experimentally for this species. Calculations reproduce hydride chemical shift data observed for [Ru(iPr2PCH2CH2PiPr2)2(η2-O2)H]+ (δ = -6.2 ppm) and [Ru(R2PCH2CH2PR2)2H]+ (ca. -32 ppm, R = iPr, Cy). For the latter, the presence of a weak agostic interaction trans to the hydride ligand is significant, as in its absence (R = Me) calculations predict a chemical shift of -41 ppm, similar to the [Ru(NHC)4H]+ analogues. Depending on the strength of the agostic interaction a variation of up to 18 ppm in hydride chemical shift is possible and this factor (that is not necessarily readily detected experimentally) can aid in the interpretation of hydride chemical shift data for nominally unsaturated hydride-containing species. The synthesis and crystallographic characterization of the BArF4- salts of [Ru(IMe4)4(L)H]+ (IMe4 = 1,3,4,5-tetramethylimidazol-2-ylidene; L = P4, SO2; ArF = 3,5-(CF3)2C6H3) and [Ru(IMe4)4(Cl)H] are also reported.


Bleeding risk during treatment of acute thrombotic events with subcutaneous LMWH compared to intravenous unfractionated heparin; a systematic review.
Low Molecular Weight Heparins (LMWH) are at least as effective antithrombotic drugs as Unfractionated Heparin (UFH). However, it is still unclear whether the safety profiles of LMWH and UFH differ. We performed a systematic review to compare the bleeding risk of fixed dose subcutaneous LMWH and adjusted dose UFH for treatment of venous thromboembolism (VTE) or acute coronary syndromes (ACS). Major bleeding was the primary end point. Electronic databases (MEDLINE, EMBASE, and the Cochrane Library) were searched up to May 2010 with no language restrictions. Randomized controlled trials in which subcutaneous LMWH were compared to intravenous UFH for the treatment of acute thrombotic events were selected. Two reviewers independently screened studies and extracted data on study design, study quality, incidence of major bleeding, patients' characteristics, type, dose and number of daily administrations of LMWH, co-treatments, study end points and efficacy outcome. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using the random effects model. Twenty-seven studies were included. A total of 14,002 patients received UFH and 14,635 patients LMWH. Overall, no difference in major bleeding was observed between LMWH patients and UFH (OR = 0.79, 95% CI 0.60-1.04). In patients with VTE LMWH appeared safer than UFH, (OR = 0.68, 95% CI 0.47-1.00). The results of our systematic review suggest that the use of LMWH in the treatment of VTE might be associated with a reduction in major bleeding compared with UFH. The choice of which heparin to use to minimize bleeding risk must be based on the single patient, taking into account the bleeding profile of different heparins in different settings.


Changes in gametogenesis and fecundity of acroporid corals that were exposed to elevated nitrogen and phosphorus during the ENCORE experiment.
Colonies of two scleractinian reef coral species, Acropora longicyathus and Acropora aspera were transplanted into patch reefs at One Tree Reef, Great Barrier Reef, Australia as part of the ENCORE experiment. These corals and colonies of A. aspera which were naturally present in the patch reefs were exposed to four treatments over two years: controls with normal seawater, elevated levels of nitrogen only, phosphorus only, or nitrogen plus phosphorus. These corals were sampled and used to determine whether gametogenic cycles and fecundity were affected by nutrient enrichment. Acropora longicyathus had a single annual gametogenic cycle. Corals exposed to elevated nitrogen produced significantly smaller and fewer eggs and contained less testes material than those which were not exposed to nitrogen. Exposure to elevated phosphorus only resulted in corals producing more but smaller eggs, and more testes material. Egg numbers of colonies from other treatments decreased as the gametogenic cycles continued, but those of the phosphorus colonies showed almost no reduction in egg numbers between the early and late stages of the gametogenic cycles. These results have important management implications for coral reefs as they demonstrate that small increases in concentrations of nitrogen and phosphorus can have severe effects on reproductive activity in these species of scleractinian corals.


A novel WD-40 repeat protein WDR26 suppresses H2O2-induced cell death in neural cells.
WD-40 repeat proteins play important roles in a variety of cellular functions, such as cell growth, proliferation, apoptosis and intracellular signal transduction. We previously identified a novel member of this family, WDR26. To examine the biological function of WDR26, we used hWDR26 plasmids and antisense phosphorothioate oligodeoxynucleotides (asODNs) against WDR26 to examine its role in response to oxidative stress in human SH-SY5Y neuroblastoma cells. Our results showed that H2O2 at 0.5mM substantially induced cell death and significantly up-regulated the WDR26 expression, and WDR26 over-expression in turn strongly suppressed H2O2-induced cell death. Moreover, asODNs markedly inhibited the de novo biosynthesis of WDR26, which contributed to enhanced cell death induced by H2O2. Finally, we found that WDR26 over-expression also down-regulated the transcriptional activity of AP-1 during H2O2-induced SH-SY5Y cell death. Taken together, these results indicated that WDR26 was up-regulated by oxidative stress and played a key role in H2O2-induced SH-SY5Y cell death, which may be mediated by the down-regulation of AP-1 transcriptional activity.


Isolating response inhibition in the brain: Parietal versus frontal contribution.
Response inhibition is a main function of cognitive control and its neural substrates have been studied extensively. However, it is still a question whether previous brain imaging investigations were successful in isolating specific response inhibition activation. In the current study we attempted to pinpoint response inhibition in the brain using a Go/No-go task and fMRI, by contrasting rare-No-go trials with prevalent-No-go trials. Although inhibition is required in all No-go trials, task variants with rare-No-go cases (25%) create a prepotent response which elicits a strong demand for inhibition, while task variants with prevalent-No-go cases (75%) require very little inhibition effort. Since the neural activation in this design is extracted solely from No-go trials, differing only in the extent of inhibitory demand, the analysis avoids contamination of the data with motor effects or visual factors. Using this experimental design we highlight the contribution of the parietal cortex (bilaterally) to inhibitory processes, while casting doubts about the specificity of frontal activation in such processes. Future studies are required to verify that bilateral intraparietal sulcus and left temporo-parietal junction activations could be markers of inhibitory control.


Development of SmokeFree Baby: a smoking cessation smartphone app for pregnant smokers.
Pregnant smokers may benefit from digital smoking cessation interventions, but few have been designed for this population. The aim was to transparently report the development of a smartphone app designed to aid smoking cessation during pregnancy. The development of a smartphone app ('SmokeFree Baby') to help pregnant women stop smoking was guided by frameworks for developing complex interventions, including the Medical Research Council (MRC), Multiphase Optimization Strategy (MOST) and Behaviour Change Wheel (BCW). Two integrative behaviour change theories provided the theoretical base. Evidence from the scientific literature and behaviour change techniques (BCTs) from the BCT Taxonomy v1 informed the intervention content. The app was developed around five core modules, each with a distinct intervention target (identity change, stress management, health information, promoting use of face-to-face support and behavioural substitution) and available in a 'control' or 'full' version. SmokeFree Baby has been developed as part of a multiphase intervention optimization to identify the optimum combination of intervention components to include in smartphone apps to help pregnant smokers stop smoking.


Nondisclosure of smoking status to health care providers among current and former smokers in the United States.
An unintended consequence of tobacco control's success in marginalizing smoking is that smokers may conceal their smoking from those who are best positioned to help them quit: health care providers (HCPs). The purpose of this study was to identify the prevalence of, and factors related to, nondisclosure of smoking to HCPs. Data were obtained from a cross-sectional survey of adults from a nationally representative Knowledge Networks online panel in March to April 2011. Current and former smokers (n = 2,803) were asked questions about nondisclosure, tobacco use, cessation behavior, and perceived social unacceptability of smoking. All variables significantly related (p < .05) to nondisclosure in bivariate logistic regression were included in the multivariate logistic regression model, which also adjusted for gender, age, race, marital status, and education. Approximately 1 in 10 smokers (12.9%) and 5.8% of former smokers has withheld their smoking status from HCPs. Ever smokers who were 18 to 34 years, those who had used a prescription medication or behavioral therapy in their last quit attempt, and those who were uncomfortable discussing smoking with their HCP were more likely to report nondisclosure than those in their respective comparison groups. Respondents who perceived either medium or high smoker-related stigma (odds ratio [OR] = 1.70, 95% confidence interval [CI] = 1.05, 2.77 and OR = 2.60, 95% CI = 1.51, 4.48, respectively) and those who reported concealing smoking to gain benefits from health insurance were also significantly more likely to have kept smoking a secret from an HCP (OR = 5.66, 95% CI = 1.88, 17.02). Smokers should be encouraged to be forthright about their smoking in order for practitioners to offer treatment and services that increase their chances of quitting.


Development of a Comorbidity Index to Identify Patients With Small Bowel Bleeding at Risk for Rebleeding and Small Bowel Vascular Diseases.
We aimed to establish a comorbidity index for small bowel vascular diseases (SBVD) associated with small bowel bleeding (SBB) and recurrent bleeding. We performed a retrospective analysis of 404 patients diagnosed with SBB via double-balloon enteroscopy, at 2 hospitals in Japan from June 2003 through July 2016. We collected data on comorbidities, computed Charlson Comorbidity Index and anticoagulation and risk factors in atrial fibrillation (ATRIA) scores, and analyzed associations with SBVD, rebleeding, and overall survival associated with bleeding and/or comorbidities. We used these data to develop a comorbidity index to identify patients at risk for SBVD, rebleeding, and reduced survival time. We validated our findings in a separate, prospective cohort of 88 patients with SBB. We developed a weighted index (the Ohmiya index) that identified patients who developed SBVD with an area under the receiver operating characteristic (AUROC) curve of 0.7758; this value was higher than that of the Charlson index score (0.6828; P < .0001) or ATRIA score (0.6728; P < .0001) alone. Among the 51 patients taking oral anticoagulants, there was no significant difference in AUROCs for the Ohmiya score (0.5254) vs the outcomes registry for better informed treatment score (0.5857; P = .4300). In the retrospective cohort, the Ohmiya index identified patients with SBVD with 68% sensitivity (93/137), 84% specificity (223/267), and 78% accuracy (316/404); in the validation cohort, these values were 63% (22/35), 85% (45/53), and 76% (67/88), respectively. Onset age <50 years and index score <2 identified patients with Meckel's diverticulum and Crohn's disease with 53% accuracy. Onset age ≥50 years and index score <2 identified patients with inflammatory diseases, drug-induced injuries, or tumors with 72% accuracy. An index score ≥2 identified patients with SBVD with 68% accuracy, regardless of age. Among patients with Ohmiya index scores ≥2, 33% had rebleeding; among patients with scores <2, 15% had rebleeding (hazard ratio for score ≥2, 1.729; 95% CI, 1.038-2.882; P = .0355). We developed an index, based on comorbidities and age of onset of SBB, that identified patients at risk for rebleeding and vascular disease (for example, enteroscopic hemostasis for SBVD, medication for inflammatory diseases, surgery with enteroscopic tattooing for tumors and diverticula). UMIN: 000025693.


Clinical utility of a commercial LAM-ELISA assay for TB diagnosis in HIV-infected patients using urine and sputum samples.
The accurate diagnosis of TB in HIV-infected patients, particularly with advanced immunosuppression, is difficult. Recent studies indicate that a lipoarabinomannan (LAM) assay (Clearview-TB(R)-ELISA) may have some utility for the diagnosis of TB in HIV-infected patients; however, the precise subgroup that may benefit from this technology requires clarification. The utility of LAM in sputum samples has, hitherto, not been evaluated. LAM was measured in sputum and urine samples obtained from 500 consecutively recruited ambulant patients, with suspected TB, from 2 primary care clinics in South Africa. Culture positivity for M. tuberculosis was used as the reference standard for TB diagnosis. Of 440 evaluable patients 120/387 (31%) were HIV-infected. Urine-LAM positivity was associated with HIV positivity (p = 0.007) and test sensitivity, although low, was significantly higher in HIV-infected compared to uninfected patients (21% versus 6%; p<0.001), and also in HIV-infected participants with a CD4 <200 versus >200 cells/mm(3) (37% versus 0%; p = 0.003). Urine-LAM remained highly specific in all 3 subgroups (95%-100%). 25% of smear-negative but culture-positive HIV-infected patients with a CD4 <200 cells/mm(3) were positive for urine-LAM. Sputum-LAM had good sensitivity (86%) but poor specificity (15%) likely due to test cross-reactivity with several mouth-residing organisms including actinomycetes and nocardia species. These preliminary data indicate that in a high burden primary care setting the diagnostic usefulness of urine-LAM is limited, as a rule-in test, to a specific patient subgroup i.e. smear-negative HIV-infected TB patients with a CD4 count <200 cells/mm(3), who would otherwise have required further investigation. However, even in this group sensitivity was modest. Future and adequately powered studies in a primary care setting should now specifically target patients with suspected TB who have advanced HIV infection.


Chemoprevention of colorectal neoplasia by estrogen: potential role of vitamin D activity.
Postmenopausal hormone replacement therapy lowers colon cancer incidence. In humans, the mechanism is unknown, but animal models suggest that it may involve activation of the vitamin D receptor (VDR) pathway. The aims of our study were to determine whether estrogen intervention affects global gene expression in rectal mucosal biopsies and whether vitamin D-related genes are affected. Estradiol was given to raise serum estradiol to premenopausal levels in 10 postmenopausal women under close nutritional control. Primary end points were expression of VDR, CYP24A1, CYP27B1, and E-cadherin in rectal mucosa by reverse transcription-PCR and examining response to estradiol by genome-wide arrays. Responses in gene expression in rectal biopsies to estrogen were determined in each subject individually and compared with a human estrogen response gene array database and a custom array in vitro-generated database. Cluster analysis showed that subjects maintained their overall gene expression profile and that interindividual differences were greater than intraindividual differences after intervention. Eight of 10 subjects showed significant enrichment in estrogen-responsive genes. Gene array group analysis showed activation of the VDR pathway and down-regulation of inflammatory and immune signaling pathways. Reverse transcription-PCR analysis showed significant up-regulation of VDR and E-cadherin, a downstream target of vitamin D action. These data suggest that the chemopreventive action of hormone replacement therapy on colon neoplasia results, at least in part, from changes in vitamin D activity. Evaluation of gene arrays is useful in chemopreventive intervention studies in small groups of subjects.


Island Sign: An Imaging Predictor for Early Hematoma Expansion and Poor Outcome in Patients With Intracerebral Hemorrhage.
The aim of the study was to investigate the usefulness of the computed tomography (CT) island sign for predicting early hematoma growth and poor functional outcome. We included patients with spontaneous intracerebral hemorrhage (ICH) who had undergone baseline CT within 6 hours after ICH symptom onset in our hospital between July 2011 and September 2016. Two readers independently assessed the presence of the island sign on the admission noncontrast CT scan. Multivariable logistic regression analysis was used to analyze the association between the presence of the island sign on noncontrast admission CT and early hematoma growth and functional outcome. A total of 252 patients who met the inclusion criteria were analyzed. Among them, 41 (16.3%) patients had the island sign on baseline noncontrast CT scans. In addition, the island sign was observed in 38 of 85 patients (44.7%) with hematoma growth. Multivariate logistic regression analysis demonstrated that the time to baseline CT scan, initial hematoma volume, and the presence of the island sign on baseline CT scan independently predicted early hematoma growth. The sensitivity of the island sign for predicting hematoma expansion was 44.7%, specificity 98.2%, positive predictive value 92.7%, and negative predictive value 77.7%. After adjusting for the patients' age, baseline Glasgow Coma Scale score, presence of intraventricular hemorrhage, presence of subarachnoid hemorrhage, admission systolic blood pressure, baseline ICH volume, and infratentorial location, the presence of the island sign (odds ratio, 3.51; 95% confidence interval, 1.26-9.81; P=0.017) remained an independent predictor of poor outcome in patients with ICH. The island sign is a reliable CT imaging marker that independently predicts hematoma expansion and poor outcome in patients with ICH. The noncontrast CT island sign may serve as a potential marker for therapeutic intervention.


In Situ Synthesis of Metal Nanoparticle Embedded Hybrid Soft Nanomaterials.
The allure of integrating the tunable properties of soft nanomaterials with the unique optical and electronic properties of metal nanoparticles has led to the development of organic-inorganic hybrid nanomaterials. A promising method for the synthesis of such organic-inorganic hybrid nanomaterials is afforded by the in situ generation of metal nanoparticles within a host organic template. Due to their tunable surface morphology and porosity, soft organic materials such as gels, liquid crystals, and polymers that are derived from various synthetic or natural compounds can act as templates for the synthesis of metal nanoparticles of different shapes and sizes. This method provides stabilization to the metal nanoparticles by the organic soft material and advantageously precludes the use of external reducing or capping agents in many instances. In this Account, we exemplify the green chemistry approach for synthesizing these materials, both in the choice of gelators as soft material frameworks and in the reduction mechanisms that generate the metal nanoparticles. Established herein is the core design principle centered on conceiving multifaceted amphiphilic soft materials that possess the ability to self-assemble and reduce metal ions into nanoparticles. Furthermore, these soft materials stabilize the in situ generated metal nanoparticles and retain their self-assembly ability to generate metal nanoparticle embedded homogeneous organic-inorganic hybrid materials. We discuss a remarkable example of vegetable-based drying oils as host templates for metal ions, resulting in the synthesis of novel hybrid nanomaterials. The synthesis of metal nanoparticles via polymers and self-assembled materials fabricated via cardanol (a bioorganic monomer derived from cashew nut shell liquid) are also explored in this Account. The organic-inorganic hybrid structures were characterized by several techniques such as UV-visible spectroscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Utilization of silver nanoparticle-based hybrid nanomaterials as an antimicrobial material is another illustration of the advantage of hybrid nanomaterials. We envision that the results summarized in this Account will help the scientific community to design and develop diverse organic-inorganic hybrid materials using environmentally benign methods and that these materials will yield advanced properties that have multifaceted applications in various research fields.


Clinicopathological and molecular characterisation of USP6-rearranged soft tissue neoplasms: the evidence of genetic relatedness indicates an expanding family with variable bone-forming capacity.
USP6 rearrangement underpins self-limiting fibroblastic/myofibroblastic neoplasms, including nodular fasciitis (NF), myositis ossificans (MO), aneurysmal bone cyst (ABC), and related variants. The aim of this study was to characterise UPS6 and fusion partners in order to delineate the clinicopathological, genetic and bone-forming features in such lesions of soft tissue (ST). Break-apart fluorescence in-situ hybridisation (FISH) validated USP6 rearrangement in 31 of 35 NF [comprising three of three fasciitis ossificans (FO) cases, seven of eight cellular variant of fibroma of tendon sheath (C-FTS), four of six MO, three of three ST-ABC, and two of two fibro-osseous pseudotumours of digits (FOPD)]. As determined with FISH and reverse transcription polymerase chain reaction, MYH9-USP6 was the commonest fusion in four C-FTS and 20 NF, including one intravascular case and two infantile (one retroperitoneal) cases. The presence of MYH9-USP6 confirmed the diagnosis of two NFs> 50 mm with prominent ischaemic necrosis. COL1A1-USP6 was predominant in ossifying lesions, including all FO, MO, ST-ABC and FOPD with identified partner genes, and was also present in non-ossifying head and neck NF (HN-NF) and C-FTS in two cases each. A cervical NF of a 14-month-old girl harboured the novel COL1A2-USP6. Ossifying lesions showed considerable genetic and morphological overlaps. Sharing COL1A1-USP6, FO and FOPD showed similar central or haphazard bone matrix deposition. Besides zonation of outward bone maturation, four COL1A1-USP6-positive MO had incipient to sieve-like pseudocysts reminiscent of ST-ABC. MYH9-USP6 is present in some C-FTS and most NF, including rare variants, but is unrelated to bone formation. All bone-forming USP6-rearranged lesions adopt COL1A1 as the 5' partner, indicating close genetic kinships. However, COL1A1/COL1A2 also contributes to the pathogenesis of minor subsets of non-ossifying USP6-rearranged HN-NF and C-FTS.


What to see when you are looking at confusion: a review of the neuroimaging of acute encephalopathy.
Acute encephalopathy is a clinical conundrum in neurocritical care facing physicians with diagnostic and therapeutic challenges. Encephalopathy arises from several concurrent causes, and delayed diagnosis adds to its grim prognosis. Diagnosis is reached by melding clinical, neurophysiological and biochemical features with various neuroimaging studies. We aimed to compile the pathophysiology of acute encephalopathies in adults, and the contribution of cerebral CT, MRI, MR spectroscopy (MRS), positron emission tomography (PET) and single-photon emission CT (SPECT) to early diagnosis, treatment and prognostication. Reports from 1990 to 2013 were identified. Therefore, reference lists were searched to identify additional publications. Encephalopathy syndromes best studied by neuroimaging emerge from hypoxic-ischaemic injury, sepsis, metabolic derangements, autoimmune diseases, infections and rapidly evolving dementias. Typical and pathognomonic neuroimaging patterns are presented. Cerebral imaging constitutes an important component of diagnosis, management and prognosis of acute encephalopathy. Its respective contribution is dominated by rapid exclusion of acute cerebral lesions and further varies greatly depending on the underlying aetiology and the range of possible differential diagnoses. CT has been well studied, but is largely insensitive, while MRI appears to be the most helpful in the evaluation of encephalopathies. MRS may provide supplementary biochemical information and determines spectral changes in the affected brain tissue. The less frequently used PET and SPECT may delineate areas of high or low metabolic activity or cerebral blood flow. However, publications of MRS, PET and SPECT are limited only providing anecdotal evidence of their usefulness and sensitivity.


Sucking patterns in fullterm infants between birth and 10 weeks of age.
Coordinating sucking, swallowing and breathing to achieve effective sucking is a complex process and even though sucking is essential for nutrition, little is known about sucking patterns after birth. Our objective was to study sucking patterns in healthy fullterm infants and to describe the age-specific variations. We studied the sucking patterns of 30 healthy, fullterm infants longitudinally from 2 or 3 days after birth to 10 weeks of age. During this time we recorded five to seven feeding episodes that we assessed off-line with the Neonatal Oral-Motor Assessment Scale (NOMAS). We found a normal sucking pattern on the second or third day after birth in 27 out of 30 infants. During the following weeks we found abnormal sucking patterns in 23 out of 171 feeding episodes (14%) and normal patterns in 148 episodes (86%). Altogether, between 38 and 50 weeks' postmenstrual age (10 weeks after birth), 10 infants displayed a deviating, arrhythmical sucking pattern. Dysfunctional sucking patterns and problems of coordinating sucking, swallowing and breathing did not occur. Birth weight, gestational age, type of labour and gender did not influence sucking patterns. Arrhythmical sucking was seen more often in bottle-fed infants. Our study demonstrated that practically all healthy fullterm infants started off with a normal sucking pattern soon after birth. One-third of the infants displayed one or more deviating episodes up to the age of 10 weeks. Apart from bottle-feeding, no other factors were found that influenced sucking patterns.


ABCB1 2677G>T/A variant enhances chemosensitivity to anti-cancer agents acting on microtubule dynamics through LAMP1 inhibition.
Overexpression of ABCB1 associated with single nucleotide variants in cancers was reported to encode a protein responsible for drug resistance. We studied chemosensitivity-related genes associated with ABCB1 2677G>T/A variant. The associated genes were identified based on the results of the significance analysis of microarray, and then prediction accuracy was evaluated using the prediction analysis of microarray. Functional assay of the selected gene was performed by using siRNA and drug accumulation study. A higher frequency of chemoresistance to microtubule-modulating agents was found in cell lines with wild-type ABCB1 compared to cell lines with 2677G>T/A ABCB1 variant. Based on the pharmacogenetic association study with 2677 variant, we identified seven genes that could predict chemosensitivity to microtubule dynamics modulators. The classification accuracy with these seven genes was 90.0%, and the predicted probability was 0.73. LAMP1 was the only gene that was commonly related to chemosensitivity. LAMP1 expression levels were relatively higher in chemoresistant ABCB1 wild-type compared to chemosensitive polymorphic cells. But, there was no difference in ABCB1 expression levels between the two groups. Following LAMP1 siRNA, chemosensitivity was restored due to increased intracellular drug accumulation in wild type cell line. In conclusion, ABCB1 2677G>T/A variant enhances chemosensitivity on microtubule dynamics through LAMP1 inhibition.


Assessment of canine BEST1 variations identifies new mutations and establishes an independent bestrophinopathy model (cmr3).
Mutations in bestrophin 1 (BEST1) are associated with a group of retinal disorders known as bestrophinopathies in man and canine multifocal retinopathies (cmr) in the dog. To date, the dog is the only large animal model suitable for the complex characterization and in-depth studies of Best-related disorders. In the first report of cmr, the disease was described in a group of mastiff-related breeds (cmr1) and the Coton de Tulear (cmr2). Additional breeds, e.g., the Lapponian herder (LH) and others, subsequently were recognized with similar phenotypes, but linked loci are unknown. Analysis of the BEST1 gene aimed to identify mutations in these additional populations and extend our understanding of genotype-phenotype associations. Animals were subjected to routine eye exams, phenotypically characterized, and samples were collected for molecular studies. Known BEST1 mutations were assessed, and the canine BEST1 coding exons were amplified and sequenced in selected individuals that exhibited a cmr compatible phenotype but that did not carry known mutations. Resulting sequence changes were genotyped in several different breeds and evaluated in the context of the phenotype. Seven novel coding variants were identified in exon 10 of cBEST1. Two linked mutations were associated with cmr exclusive to the LH breed (cmr3). Two individuals of Jämthund and Norfolk terrier breeds were heterozygous for two conservative changes, but these were unlikely to have disease-causing potential. Another three substitutions were found in the Bernese mountain dog that were predicted to have a deleterious effect on protein function. Previously reported mutations were excluded from segregation in these populations, but cmr1 was confirmed in another mastiff-related breed, the Italian cane corso. A third independent canine model for human bestrophinopathies has been established in the LH breed. While exhibiting a phenotype comparable to cmr1 and cmr2, the novel cmr3 mutation is predicted to be based on a distinctly different molecular mechanism. So far cmr2 and cmr3 are exclusive to a single dog breed each. In contrast, cmr1 is found in multiple related breeds. Additional sequence alterations identified in exon 10 of cBEST1 in other breeds exhibit potential disease-causing features. The inherent genetic and phenotypic variation observed with retinal disorders in canines is complicated further by cmr3 being one of four distinct genetic retinal traits found to segregate in LH. Thus, a combination of phenotypic, molecular, and population analysis is required to establish a strong phenotype-genotype association. These results indicate that cmr has a larger impact on the general dog population than was initially suspected. The complexity of these models further confirms the similarity to human bestrophinopathies. Moreover, analyses of multiple canine models will provide additional insight into the molecular basis underlying diseases caused by mutations in BEST1.


Sex-contingent face after-effects suggest distinct neural populations code male and female faces.
Exposure to faces biases perceptions of subsequently viewed faces. Faces similar to those seen previously are judged more normal and attractive than they were prior to exposure. Here we show sex-contingent after-effects following adaptation to eye-spacing (experiment 1), facial identity (experiment 2) and masculinity (experiment 3). Viewing faces of one sex with increased eye-spacing and faces of the other sex with decreased eye-spacing simultaneously induced opposite after-effects for male and female faces (assessed by normality judgments). Viewing faces transformed in identity or masculinity increased preferences for novel faces with characteristics similar to those viewed only when the sex of the faces presented in the adaptation phase and in post-adaptation preference tests were congruent. Because after-effects reflect changes in responses of neural populations that code faces, our findings indicate that distinct neural populations code male and female faces.


Predictors of opioid misuse in patients with chronic pain: a prospective cohort study.
Opioid misuse can complicate chronic pain management, and the non-medical use of opioids is a growing public health problem. The incidence and risk factors for opioid misuse in patients with chronic pain, however, have not been well characterized. We conducted a prospective cohort study to determine the one-year incidence and predictors of opioid misuse among patients enrolled in a chronic pain disease management program within an academic internal medicine practice. One-hundred and ninety-six opioid-treated patients with chronic, non-cancer pain of at least three months duration were monitored for opioid misuse at pre-defined intervals. Opioid misuse was defined as: 1. Negative urine toxicological screen (UTS) for prescribed opioids; 2. UTS positive for opioids or controlled substances not prescribed by our practice; 3. Evidence of procurement of opioids from multiple providers; 4. Diversion of opioids; 5. Prescription forgery; or 6. Stimulants (cocaine or amphetamines) on UTS. The mean patient age was 52 years, 55% were male, and 75% were white. Sixty-two of 196 (32%) patients committed opioid misuse. Detection of cocaine or amphetamines on UTS was the most common form of misuse (40.3% of misusers). In bivariate analysis, misusers were more likely than non-misusers to be younger (48 years vs 54 years, p < 0.001), male (59.6% vs. 38%; p = 0.023), have past alcohol abuse (44% vs 23%; p = 0.004), past cocaine abuse (68% vs 21%; p < 0.001), or have a previous drug or DUI conviction (40% vs 11%; p < 0.001%). In multivariate analyses, age, past cocaine abuse (OR, 4.3), drug or DUI conviction (OR, 2.6), and a past alcohol abuse (OR, 2.6) persisted as predictors of misuse. Race, income, education, depression score, disability score, pain score, and literacy were not associated with misuse. No relationship between pain scores and misuse emerged. Opioid misuse occurred frequently in chronic pain patients in a pain management program within an academic primary care practice. Patients with a history of alcohol or cocaine abuse and alcohol or drug related convictions should be carefully evaluated and followed for signs of misuse if opioids are prescribed. Structured monitoring for opioid misuse can potentially ensure the appropriate use of opioids in chronic pain management and mitigate adverse public health effects of diversion.


Roles of conceptus secretory proteins in establishment and maintenance of pregnancy in ruminants.
Reproduction in ruminant species is a highly complex biological process requiring a dialogue between the developing conceptus (embryo-fetus and associated placental membranes) and maternal uterus which must be established during the peri-implantation period for pregnancy recognition signaling and regulation of gene expression by uterine epithelial and stromal cells. The uterus provide a microenvironment in which molecules secreted by uterine epithelia and transported into the uterine lumen represent histotroph, also known as the secretome, that are required for growth and development of the conceptus and receptivity of the uterus to implantation by the elongating conceptus. Pregnancy recognition signaling as related to sustaining the functional lifespan of the corpora lutea, is required to sustain the functional life-span of corpora lutea for production of progesterone which is essential for uterine functions supportive of implantation and placentation required for successful outcomes of pregnancy. It is within the peri-implantation period that most embryonic deaths occur in ruminants due to deficiencies attributed to uterine functions or failure of the conceptus to develop appropriately, signal pregnancy recognition and/or undergo implantation and placentation. The endocrine status of the pregnant ruminant and her nutritional status are critical for successful establishment and maintenance of pregnancy. The challenge is to understand the complexity of key mechanisms that are characteristic of successful reproduction in humans and animals and to use that knowledge to enhance fertility and reproductive health of ruminant species in livestock enterprises.


Bone morphogenetic protein-5 (BMP-5) promotes dendritic growth in cultured sympathetic neurons.
BMP-5 is expressed in the nervous system throughout development and into adulthood. However its effects on neural tissues are not well defined. BMP-5 is a member of the 60A subgroup of BMPs, other members of which have been shown to stimulate dendritic growth in central and peripheral neurons. We therefore examined the possibility that BMP-5 similarly enhances dendritic growth in cultured sympathetic neurons. Sympathetic neurons cultured in the absence of serum or glial cells do not form dendrites; however, addition of BMP-5 causes these neurons to extend multiple dendritic processes, which is preceded by an increase in phosphorylation of the Smad-1 transcription factor. The dendrite-promoting activity of BMP-5 is significantly inhibited by the BMP antagonists noggin and follistatin and by a BMPR-IA-Fc chimeric protein. RT-PCR and immunocytochemical analyses indicate that BMP-5 mRNA and protein are expressed in the superior cervical ganglia (SCG) during times of initial growth and rapid expansion of the dendritic arbor. These data suggest a role for BMP-5 in regulating dendritic growth in sympathetic neurons. The signaling pathway that mediates the dendrite-promoting activity of BMP-5 may involve binding to BMPR-IA and activation of Smad-1, and relative levels of BMP antagonists such as noggin and follistatin may modulate BMP-5 signaling. Since BMP-5 is expressed at relatively high levels not only in the developing but also the adult nervous system, these findings suggest the possibility that BMP-5 regulates dendritic morphology not only in the developing, but also the adult nervous system.


Mercury as an environmental stimulus in the development of autoimmunity - A systematic review.
Autoimmune diseases result from an interplay of genetic predisposition and factors which stimulate the onset of disease. Mercury (Hg), a well-established toxicant, is an environmental factor reported to be linked with autoimmunity. Hg exists in several chemical forms and is encountered by humans in dental amalgams, certain vaccines, occupational exposure, atmospheric pollution and seafood. Several studies have investigated the effect of the various forms of Hg, including elemental (Hg0), inorganic (iHg) and organic mercury (oHg) and their association with autoimmunity. In vitro studies using peripheral blood mononuclear cells (PBMC) from healthy participants have shown that methylmercury (MeHg) causes cell death at lower concentrations than iHg albeit exposure to iHg results in a more enhanced pro-inflammatory profile in comparison to MeHg. In vivo research utilising murine models susceptible to the development of metal-induced autoimmunity report that exposure to iHg results in a lupus-like syndrome, whilst mice exposed to MeHg develop autoimmunity without the formation of immune complexes. Furthermore, lower concentrations of IgE are detected in MeHg-treated animals in comparison with those treated with iHg. It appears that, oHg has a negative impact on animal models with existing autoimmunity. The research conducted on humans in this area is diverse in study design and the results are conflicting. There is currently no evidence to implicate a role for Hg0 exposure from dental amalgams in the development or perpetuation of autoimmune disease, apart from some suggestion of individual sensitivity. Several studies have consistently shown a positive correlation between iHg exposure and serum autoantibody concentrations in gold miners, although the clinical impact of iHg remains unknown. Furthermore, a limited number of studies have reported individuals with autoimmune disease have higher concentrations of blood Hg compared to healthy controls. In summary, it appears that iHg perpetuates markers of autoimmunity to a greater extent than oHg, albeit the impact on clinical outcomes in humans is yet to be elucidated.


Prevalence of psychiatric and physical morbidity in an urban geriatric population.
With a rapidly increasing population of older aged people, epidemiological data regarding the prevalence of mental and physical illnesses are urgently required for proper health planning. However, there is a scarcity of such data from India. To study the frequency and pattern of psychiatric morbidity present and the association of physical illness with psychiatric morbidity in an elderly urban population. Cross-sectional, epidemiological study. All the consenting elderly persons in a municipal ward division (n=202) were enrolled after surveying a total adult population of 7239 people. A door to door survey was undertaken where the participants were interviewed and physically examined. General Health Questionnaire-12, Mini Mental State Examination, CAGE Questionnaire and Geriatric Depression Scale were used in the interview apart from consulting the available documents. Other family members were also interviewed to verify the information. Chi-square test with Yates correction. Psychiatric illnesses were detected in 26.7% while physical illnesses were present in 69.8% of the population surveyed. Predominant psychiatric diagnoses were depressive disorders, dementia, generalized anxiety disorder, alcohol dependence and bipolar disorder. The most common physical illness was visual impairment, followed by cardiovascular disease, rheumatic illnesses, pulmonary illnesses, hearing impairment, genitourinary diseases and neurological disorders. Presence of dementia was associated with increased age, single/widowed/separated status, nuclear family, economic dependence, low education, cardiovascular disorders, rheumatic disorders and neurological disorders. Depression was associated with female sex, single/widowed/separated status, staying in nuclear families, economic dependence on others and co-morbid physical illnesses, specifically cardiovascular disorders and visual impairment. This study presented a higher rate of dementia and old age depression. The interesting association with several sociodemographic factors as well as physical illnesses may have important implications for health planning.