Multiple cholinergic nicotinic receptor genes affect nicotine dependence risk in African and European Americans.
Several independent studies show that the chromosome 15q25.1 region, which contains the CHRNA5-CHRNA3-CHRNB4 gene cluster, harbors variants strongly associated with nicotine dependence, other smoking behaviors, lung cancer and chronic obstructive pulmonary disease. We investigated whether variants in other cholinergic nicotinic receptor subunit (CHRN) genes affect the risk of nicotine dependence in a new sample of African Americans (AAs) (N = 710). We also analyzed this AA sample together with a European American (EA) sample (N = 2062, 1608 of which have been previously studied), allowing for differing effects in the two populations. Cases are current nicotine-dependent smokers and controls are non-dependent smokers. Variants in or near CHRND-CHRNG, CHRNA7 and CHRNA10 show modest association with nicotine dependence risk in the AA sample. In addition, CHRNA4, CHRNB3-CHRNA6 and CHRNB1 show association in at least one population. CHRNG and CHRNA4 harbor single nucleotide polymorphisms (SNPs) that have opposite directions of effect in the two populations. In each of the population samples, these loci substantially increase the trait variation explained, although no loci meet Bonferroni-corrected significance in the AA sample alone. The trait variation explained by three key associated SNPs in CHRNA5-CHRNA3-CHRNB4 is 1.9% in EAs and also 1.9% in AAs; this increases to 4.5% in EAs and 7.3% in AAs when we add six variants representing associations at other CHRN genes. Multiple nicotinic receptor subunit genes outside chromosome 15q25 are likely to be important in the biological processes and development of nicotine dependence, and some of these risks may be shared across diverse populations.


Plasma membrane restricted RhoGEF activity is sufficient for RhoA-mediated actin polymerization.
The small GTPase RhoA is involved in cell morphology and migration. RhoA activity is tightly regulated in time and space and depends on guanine exchange factors (GEFs). However, the kinetics and subcellular localization of GEF activity towards RhoA are poorly defined. To study the mechanism underlying the spatiotemporal control of RhoA activity by GEFs, we performed single cell imaging with an improved FRET sensor reporting on the nucleotide loading state of RhoA. By employing the FRET sensor we show that a plasma membrane located RhoGEF, p63RhoGEF, can rapidly activate RhoA through endogenous GPCRs and that localized RhoA activity at the cell periphery correlates with actin polymerization. Moreover, synthetic recruitment of the catalytic domain derived from p63RhoGEF to the plasma membrane, but not to the Golgi apparatus, is sufficient to activate RhoA. The synthetic system enables local activation of endogenous RhoA and effectively induces actin polymerization and changes in cellular morphology. Together, our data demonstrate that GEF activity at the plasma membrane is sufficient for actin polymerization via local RhoA signaling.


Early predictive factors on mortality in head injured patients: a retrospective analysis of 112 traumatic brain injured patients.
Early hyperglycemia is a feature of traumatic brain injured (TBI) patients. The aim of our study was to analyze the impact of early hyperglycemia on in-ICU mortality in isolated TBI and its correlations with other factors responsible for secondary injury. We studied admission values (AV) and worse values in the first 48 hours (WV 48 h) of 112 ICU TBI patients (mortality 29.6%) of blood glucose (BG), base excess (BE), mean arterial pressure (MAP), PaO2/FiO2 ratio and serum hemoglobin (Hb). Predictive strength as the area under the receiver operating curves (AUROC) and correlation between all variables were calculated. Data are expressed as median, 1st-3rd quartile. Both BG AV (147.5, 126-182 mg/dL; AUROC 0.716, P=0.0002) and WV 48 h (156.5, 132-192 mg/dL; AUROC 0.721, P=0.0001) are predictive of mortality. AV and WV 48 h are respectively: PaO2/FiO2 (366.8, 237.2-477.6 vs. 320, 214.4-426; P=0.05), MAP (90, 80-100.5 vs. 75, 66-83 mmHg; P<0.0001) and Hb (11.4, 9.7-13.1 vs. 10.6, 9-12.2 g/dL; P<0.02). BG AV and WV 48 h correlates with: age (r=0.419, P<0.0001 and r=0.489, P<0.0001), PaO2/FiO2 AV (r -0.223, P<0.03 and r -0.236, P<0.02), PaO2/FiO2 WV 48 h (r -0.215, P<0.03 and r -0.279, P<0.005) and MAP WV 48 h (r -0.216, P<0.03 and r -0.261, P<0.007). Early hyperglycemia is a major predictor of mortality and correlates with other factors responsible for secondary injury. Early hyperglycemia seems to be a marker of inflammatory reaction responsible for early cardiovascular and respiratory impairment.


Inhibition of Triple-Negative Breast Cancer Tumor Growth by Electroacupuncture with Encircled Needling and Its Mechanisms in a Mice Xenograft Model.
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer without effective targeted drugs. While breast cancer patients often use acupuncture for the relief of cancer-induced pain or the side effects of chemo- or radiation therapy, little information is known regarding the direct effects of electroacupuncture on TNBC tumor and its potential mechanisms. Here, we created a mice model of TNBC and electroacupuncture with encircled needling around the tumors was given to the animals daily for 3 weeks at 15-20 Hz (3 min, each time). For sham electroacupuncture control, the skin was punctured to a depth of 5 mm and then the needle was quickly withdrawn without electrical stimulation or manual needle manipulation. We found that electroacupuncture significantly inhibited TNBC tumor growth and the inhibitory rate increased gradually overtime. Mechanistic analysis showed that electroacupuncture inhibited tumor angiogenesis by reducing the expression of vascular endothelial growth factor A (VEGF-A), its receptor VEGF-R and neuropilin 1 (NRP-1). Electroacupuncture also led to a significant decrease of matrix metalloproteinase-2 (MMP-2) expression and an increase of tissue inhibitor of MMP (TIMP-2) expression. Additionally, the expression of semaphorin 3A (Sema3A) and nerve growth factor receptor (NGFR) p75 in TNBC tissue was significantly upregulated in response to electroacupuncture. Furthermore, tumor necrosis factor (TNF)-alpha level in the serum was dramatically reduced after electroacupuncture. These results showed that electroacupuncture could directly inhibit TNBC tumor growth through the inhibition of proteins related to tumor angiogenesis and extracellular matrix, the suppression of TNBC-induced inflammation and the upregulation of nerve growth factor receptors.


Electroacupuncture for reproductive hormone levels in patients with diminished ovarian reserve: a prospective observational study.
Effective methods for the treatment of reproductive dysfunction are limited. Previous studies have reported that acupuncture can modulate female hormone levels, improve menstrual disorders, alleviate depression and improve pregnancy rates. However, studies of acupuncture for diminished ovarian reserve (DOR) are lacking. To carry out a prospective observational study aimed at assessing the effect of EA on the reproductive hormone levels of patients with DOR seeking fertility support and consider its safety. Eligible patients with DOR received EA for 12 weeks: five times a week for 4 weeks followed by three times a week for 8 weeks. The primary outcome was the change in mean follicle-stimulating hormone (FSH) level at week 12. Mean luteinising hormone (LH) and serum oestradiol (E2) levels, FSH/LH ratios and symptom scale scores were simultaneously observed. Twenty-one patients with DOR were included in the final analysis. Mean FSH levels fell from 19.33±9.47 mIU/mL at baseline to 10.58±6.34 mIU/mL at week 12 and 11.25±6.68 mIU/mL at week 24. Change in mean FSH from baseline was -8.75±11.13 mIU/mL at week 12 (p=0.002) and -8.08±9.56 mIU/mL at week 24 (p=0.001). Mean E2 and LH levels, FSH/LH ratios and irritability scores were improved at weeks 12 and/or 24. Approximately 30% patients reported subjective increases in menstrual volume after treatment. EA may modulate reproductive hormone levels and the effects seem to persist for at least 12 weeks after treatment with no significant side effects. EA may improve the ovarian reserve of patients with DOR, though further research is needed. NCT02229604; Results.


The roles of outlet density and norms in alcohol use disorder.
Alcohol outlet density and norms shape alcohol consumption. However, due to analytic challenges we do not know: (a) if alcohol outlet density and norms also shape alcohol use disorder, and (b) whether they act in combination to shape disorder. We applied a new targeted minimum loss-based estimator for rare outcomes (rTMLE) to a general population sample from New York City (N = 4000) to examine the separate and combined relations of neighborhood alcohol outlet density and norms around drunkenness with alcohol use disorder. Alcohol use disorder was assessed using the World Mental Health Comprehensive International Diagnostic Interview (WMH-CIDI) alcohol module. Confounders included demographic and socioeconomic characteristics, as well as history of drinking prior to residence in the current neighborhood. Alcohol use disorder prevalence was 1.78%. We found a marginal risk difference for alcohol outlet density of 0.88% (95% CI 0.00-1.77%), and for norms of 2.05% (95% CI 0.89-3.21%), adjusted for confounders. While each exposure had a substantial relation with alcohol use disorder, there was no evidence of additive interaction between the exposures. Results indicate that the neighborhood environment shapes alcohol use disorder. Despite the lack of additive interaction, each exposure had a substantial relation with alcohol use disorder and our findings suggest that alteration of outlet density and norms together would likely be more effective than either one alone. Important next steps include development and testing of multi-component intervention approaches aiming to modify alcohol outlet density and norms toward reducing alcohol use disorder.


Neurofunctional correlates of vulnerability to psychosis: a systematic review and meta-analysis.
An understanding of the neurobiological correlates of vulnerability to psychosis is fundamental to research on schizophrenia. We systematically reviewed data from studies published from 1992 to 2006 on the neurocognitive correlates (as measured by fMRI) of increased vulnerability to psychosis. We also conducted a meta-analysis of abnormalities of activation in the prefrontal cortex (PFC) in high-risk and first episode subjects, and reviewed neuroimaging studies of high-risk subjects that used PET, SPECT and MRS. Twenty-four original fMRI papers were identified, most of which involved tasks that engaged the PFC. In fMRI studies, vulnerability to psychosis was associated with medium to large effect sizes when prefrontal activation was contrasted with that in controls. Relatives of patients affected with psychosis, the co-twins of patients and subjects with an At Risk Mental State (ARMS) appear to share similar neurocognitive abnormalities. Furthermore, these are qualitatively similar but less severe than those observed in the first episode of illness. These abnormalities have mainly been described in the prefrontal and anterior cingulated cortex, the basal ganglia, hippocampus and cerebellum.


The effect of combined treatment with niacin and chromium (III) chloride on the different tissues of hyperlipemic rats.
We investigated the effects of a combined treatment with chromium (Cr) and niacin on the spleen, tongue, and lens tissues in terms of lipid peroxidation (LPO), glutathione (GSH), serum catalase (CAT), lactate dehydrogenase (LDH), serum cholesterol, and total lipid levels in normal and hyperlipemic rats. In this study, female 1-year-old Swiss albino rats were used. The rats were randomly divided into four groups. Group I rats (control) were fed with standard pellet chow. Group II rats were fed a lipogenic diet in which 2% cholesterol, 0.5% cholic acid, and 20% sunflower oil were added and were given 3% alcoholic water for 60 days. Group III rats were fed with the same lipogenic diet and were treated with a dose of 250 microg/kg body weight CrCI3 x 6H2O and 100 mg/kg body weight niacin, for 45 days, by gavage. The rats in group IV were fed with pellet chow and treated with 250 microg/kg body weight CrCI3 x 6H2O and 100 mg/kg body weight niacin, by gavage, for 45 days. After 2 weeks, the animals showed symptoms of hyperlipemia. On the 60th day, tissue and blood samples were taken. We have observed decreased CAT activity and GSH levels, increased LDH activity, cholesterol, total lipid, and LPO levels in hyperlipemic rats. Niacin and Cr administration to hyperlipemic rats increased tissue GSH levels and CAT activity and decreased tissue LPO levels and LDH activity, cholesterol, and total lipid levels compared with hyperlipemic rats. We conclude that the administration of a combination of niacin and chromium has a protective effect against oxidative damage to tongue, lens, and spleen tissues as a result of hyperlipemia.


Plastic waste sacks alter the rate of decomposition of dismembered bodies within.
As a result of criminal activity, human bodies are sometimes dismembered and concealed within sealed, plastic waste sacks. Consequently, due to the inhibited ingress of insects and dismemberment, the rate of decomposition of the body parts within may be different to that of whole, exposed bodies. Correspondingly, once found, an estimation of the postmortem interval may be affected and lead to erroneous inferences. This study set out to determine whether insects were excluded and how rate of decomposition was affected inside such plastic sacks. The limbs, torsos and heads of 24 dismembered pigs were sealed using nylon cable ties within plastic garbage sacks, half of which were of a type claimed to repel insects. Using a body scoring scale to quantify decomposition, the body parts in the sacks were compared to those of ten exposed, whole pig carcasses. Insects were found to have entered both types of plastic sack. There was no difference in rate of decomposition in the two types of sack (F 1,65 = 1.78, p = 0.19), but this was considerably slower than those of whole carcasses (F 1,408 = 1453, p < 0.001), with heads showing the largest differences. As well as a slower decomposition, sacks resulted in formation of some adipocere tissue as a result of high humidity within. Based upon existing methods, postmortem intervals for body parts within sealed sacks would be significantly underestimated.


Health workers' perceptions of access to care for children and pregnant women with precarious immigration status: health as a right or a privilege?
The Canadian government's recent cuts to healthcare coverage for refugee claimants has rekindled the debate in Canada about what medical services should be provided to individuals with precarious immigration status, and who should pay for these services. This article further explores this debate, focussing on the perceptions of healthcare workers in Montreal, a large multiethnic Canadian city. In April-June 2010, an online survey was conducted to assess how clinicians, administrators, and support staff in Montreal contend with the ethical and professional dilemmas raised by the issue of access to healthcare services for pregnant women and children who are partially or completely uninsured. Drawing on qualitative analysis of answers (n = 237) to three open-ended survey questions, we identify the discursive frameworks that our respondents mobilized when arguing for, or against, universal access to healthcare for uninsured patients. In doing so, we highlight how their positions relate to their self-evaluations of Canada's socioeconomic situation, as well as their ideological representations of, and sense of social connection to, precarious status immigrants. Interestingly, while abstract values lead some healthcare workers to perceive uninsured immigrants as "deserving" of universal access to healthcare, negative perceptions of these migrants, coupled with pragmatic considerations, pushed most workers to view the uninsured as "underserving" of free care. For a majority of our respondents, the right to healthcare of precarious status immigrants has become a "privilege", that as taxpayers, they are increasingly less willing to contribute to. We conclude by arguing for a reconsideration of access to healthcare as a right, and offer recommendations to move in this direction.


Immunoelectron microscopy of Giardia lamblia cytoskeleton using antibody to acetylated alpha-tubulin.
Giardia lamblia trophozoites contain acetylated alpha-tubulin but lack detectable levels of tyrosinolated alpha-tubulin, as demonstrated in immunoblots with monoclonal antibodies specific for these tubulin forms. By immunofluorescence microscopy, acetylated alpha-tubulin is localized in axonemes, median bodies and in the adhesive disk. Post-embeddment immunogold labeling of thin sections of cells was used to evaluate acetylation at the level of individual microtubules by electron microscopy. Cells were fixed with glutaraldehyde and embedded in the acrylic resin LR Gold. Results indicate all microtubules in adhesive disk, axonemes, basal bodies, funis and the median bodies contain acetylated alpha-tubulin. Unlike immunofluorescence labeling, all microtubules of the adhesive disk and the funis could be gold labeled. No nonspecific labeling of the cytoplasm or of structures other than microtubules was observed. Acetylated microtubules in G. lamblia do not appear to be a subset of microtubules and acetylation appears uniform along the entire length of individual microtubules. Acetylation and the tyrosinolation state of microtubules in Giardia are discussed in the context of microtubule stability and crosslinked features of the cytoskeleton.


Family cluster of atrial septal defect.
Atrial septal defect is one of the most common congenital cardiac defects, occurring in 9% to 15% of live births. This defect has been reported to have a genetic etiology in some cases, although the full extent of genetic involvement in atrial septal defect is not known. Because symptoms are often lacking in childhood and manifest primarily in adulthood and because physical findings may be lacking, it is important to take a family history in patients in whom the defect is suspected. When evaluating children, a family history of atrial septal defect should raise suspicion of increased risk so that early diagnosis and treatment can be made. The author reports a cluster of 11 diagnosed atrial septal defects within one 32-member family group, 6 of whom required surgery to repair the defects. It is significant that most of the individuals were lacking in objective findings on physical examination, notably a murmur, as well as in subjective complaints. Diagnoses were made by use of two-dimensional echocardiography with color-enhanced Doppler ultrasonography in all but two cases--one diagnosed with transesophageal echocardiography and one, serendipitously, during cardiac catheterization. Echocardiography also revealed mitral valve prolapse, thin atrial septal wall, with aneurysm in some cases, and regurgitation of mitral or tricuspid valves in several individuals. Cardiac enlargement, usually of the right atrium, was seen in most of the individuals.


Serum amyloid A mediates the inhibitory effect of Ganoderma lucidum polysaccharides on tumor cell adhesion to endothelial cells.
Ganoderma ludicum polysaccharides (GlPS) are the major bioactive composition of Ganoderma lucidum, a well-recognized oriental medical fungus. The published data have shown a complementary effect of GlPS in cancer therapy. The present study was designed to determine the anti-tumor efficacy of GlPS and the possible mechanism covering this effect. Murine Sarcoma 180 (S180) model was established, and GlPS administered orally for 10 days. On the 10th day, tumors were weighed to assess the inhibitory effect of GlPS and sera were collected for proteomic analysis and in vitro study. The in vivo results demonstrated that 25, 50 and 100 mg/kg GlPS inhibited S180 growth by 32.67, 44.80 and 45.24%, respectively (P<0.01). Proteomic study revealed marked protein changes after the process of treatment. Three significantly changed proteins were identified by ESI-Q-TOF-MS and database search indicated that they were haptoblobin, apolipoprotein A-II and serum amyloid A (SAA), respectively. Additionally, the expression change of SAA was confirmed by both Western blot and RT-PCR. The adhesion assay showed that GlPS-treated sera dramatically inhibited the adhesion ability of human prostate carcinoma (PC-3M) cells to human umbilical cord vascular endothelial cells (HUVECs), and this effect partially recovered after immunodepletion by the antibody against SAA. Collectively, these results suggest that GlPS inhibited the tumor growth and tumor cell adhesion to HUVECs via up-regulation of SAA protein expression.


RNA degradation in antiviral immunity and autoimmunity.
Post-transcriptional control determines the fate of cellular RNA molecules. Nonsense-mediated decay (NMD) provides quality control of mRNA, targeting faulty cellular transcripts for degradation by multiple nucleases including the RNA exosome. Recent findings have revealed a role for NMD in targeting viral RNA molecules, thereby restricting virus infection. Interestingly, NMD is also linked to immune responses at another level: mutations affecting the NMD or RNA exosome machineries cause chronic activation of defence programmes, resulting in autoimmune phenotypes. Here we place these observations in the context of other links between innate antiviral immunity and type I interferon mediated disease and examine two models: one in which expression or function of pathogen sensors is perturbed and one wherein host-derived RNA molecules with a propensity to activate such sensors accumulate.


A case of progressive pseudorheumatoid arthropathy of 'childhood' with the diagnosis delayed to the fifth decade.
Progressive pseudorheumatoid arthropathy of childhood (PPAC) is a rare single gene disorder which is frequently misdiagnosed as juvenile rheumatoid arthritis. It is characterised with arthralgia, joint contractures, bony swelling of metacarpophalangeal and interphalangeal joints and platyspondyly. Clinical and laboratory signs of joint inflammation such as synovitis, a high erythrocyte sedimentation rate and an elevated C-reactive protein level are usually absent. Although the disease begins early in life (usually between 3 and 8 years of age), the diagnosis may be delayed. In the present case report, we describe a male patient diagnosed with PPAC at the age of 46 years, although he had been exhibiting the typical radiological and clinical features of the disease since the age of 7 years.


[Treatment of massive bleeding: summary of the updated European guidelines].
Despite improved strategies in the treatment of polytraumatized patients the mortality rate of severely injured patients remains high. Thus, worldwide 5 million patients die due to trauma or trauma-related complications each year. As the majority of early trauma-related deaths are attributed to or caused by exsanguination the prevention and treatment of coagulopathy is of paramount significance. With the aim of developing guidelines and improve strategies to treat polytraumatized patients the multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2005. Under consideration of new clinical studies, an updated version of the original publication from 2007 has recently been published. Based on a systematic review of published literature the recommendations were formed according to "Grading of Recommendations Assessment, Development and Evaluation" (GRADE). This publication summarizes the main recommendations with a special emphasis on revisions and new aspects.


Mouse connexin37: cloning and functional expression of a gap junction gene highly expressed in lung.
The coding sequence (333 amino acids) of a new connexin protein, designated mouse connexin37 (Cx37 or Cx37.6) due to the deduced theoretical molecular mass of 37.600 kD, has been determined from cDNA and genomic clones. As seen in other connexins, its gene has no introns within the coding region and the deduced amino acid sequence is predicted to have similar topology to other connexins that form intercellular channels. The amino acid sequence of mouse Cx37 is most similar to rat connexin43 (59% identity) and Xenopus connexin38 (66% identity) when compared from the NH2 terminus to the end of the fourth putative transmembrane region. When expressed in Xenopus oocytes Cx37 forms functional intercellular channels that exhibit more sensitive and rapid gating in response to voltage than any previously characterized vertebrate gap junction. Under stringent conditions the Cx37 cDNA hybridizes to an mRNA of 1.7 kb that is found highly abundant in lung and to progressively lesser extents in brain, kidney, skin, spleen, liver, intestine, and heart. Embryonic brain, kidney, and skin express two to fivefold higher levels of the Cx37 transcript than the corresponding adult tissues. Cx37 transcripts were also found to increase two to threefold in response to retinoic acid treatment of cultured embryonic carcinoma F9 cells.


Position of the American Dietetic Association: child and adolescent nutrition assistance programs.
t is the position of the American Dietetic Association that children and adolescents should have access to an adequate supply of healthful and safe foods that promote optimal physical, cognitive, and social growth and development. Nutrition assistance programs, such as food assistance and meal service programs and nutrition education initiatives, play a vital role in meeting this critical need. Nutrition assistance programs create a safety net that ensures that children and adolescents at risk for poor nutritional intakes have access to a safe, adequate, and nutritious food supply. Federally funded nutrition assistance programs help ensure that children and adolescents receive meals that provide adequate energy and nutrients to meet their growth and development needs; children and adolescents have access to adequate food supplies; and women, infants, and children who have nutritional or medical risk factors, such as iron-deficiency anemia or overweight, receive supplemental nutritious foods as well as nutrition education. In addition, federally funded nutrition assistance programs serve as a means to combat hunger and food insecurity and as a vehicle for nutrition education and promotion of physical activity designed to prevent or reduce obesity and chronic disease. It is important that continued funding be provided for these programs that have been consistently shown to have a positive influence on child and adolescent well-being. Registered dietitians and dietetic technicians, registered, are uniquely qualified to design, implement, and evaluate nutrition assistance programs for children and adolescents. Registered dietitians and dietetic technicians, registered, are the only food and nutrition practitioners with adequate training in food science, nutrition, and food systems to implement research and surveillance programs to monitor, evaluate, and improve the nutritional status of children and adolescents.


Diallyl sulfide treatment protects against acetaminophen-/carbon tetrachloride-induced acute liver injury by inhibiting oxidative stress, inflammation and apoptosis in mice.
The purpose of the present study was to investigate the effects and underlying mechanisms of diallyl sulfide (DAS), an organosulfur compound extracted from garlic, on drug-induced or chemical-induced liver injury caused by acetaminophen (APAP) or carbon tetrachloride (CCl4) in mice. DAS (100, 200, or 400 μmol kg-1) was orally administered 1 hour before APAP or CCl4 intraperitoneal injection, and the serum and liver tissue were collected 24 hours after APAP or CCl4 exposure. The serum aminotransferase activities and liver histopathological examination showed that DAS exhibited obvious hepatoprotective effects against acute liver injury induced by APAP or CCl4. In addition, exposure to APAP or CCl4 resulted in an increased content of malonaldehyde as well as a decreased ratio of reduced to oxidized glutathione, and a decreased level of superoxide dismutase and catalase activity in the liver (p < 0.05); however, pretreatment with DAS restored the perturbations of the antioxidant system in the liver. Beyond that, DAS pretreatment reduced the APAP-/CCl4-induced increase in phosphorylation of inhibitor of kappa B alpha (IκBα) and p65 subunit of nuclear factor kappa B (NF-κB) expression in the cytoplasm and nucleus in the liver. DAS pretreatment also decreased the excessive level of TNF-α caused by APAP or CCl4 in serum (p < 0.05). Moreover, DAS pretreatment regulated the expression of cleaved caspase 3, Bax and Bcl-2 in the liver and suppressed APAP-/CCl4-induced hepatocyte apoptosis. In conclusion, DAS exhibits hepatoprotective effects against drug-induced and chemical-induced liver injuries induced by APAP or CCl4 in mice, probably due to its ability to reduce hepatic oxidative stress and inhibit inflammatory injury and hepatocyte apoptosis.


The TREX2 3'-->5' exonuclease physically interacts with DNA polymerase delta and increases its accuracy.
Proofreading function by the 3'-->5' exonuclease of DNA polymerase delta (pol delta) is consistent with the observation that delta efficiency of the associated exonuclease can lead to a strong mutation phenotype, high error rates during DNA replication, and ultimately cancer. We have isolated pol delta from isotonic (pol delta(i)) and detergent (pol delta(d)) calf thymus extracts. Pol delta had a 20-fold higher ratio of exonuclease to DNA polymerase than pol deltai. This was due to the physical association of the TREX2 3'-->5' exonuclease to pol delta(d), which was missing from pol delta(i). Pol delta(d) was fivefold more accurate than pol i under error-prone conditions (1 mM dGTP and 20 dATP, dCTP, and dTTP) in a M13mp2 DNA forward mutation assay, and fourfold more accurate than pol delta(i) under error-prone conditions (1 mM dGTP and 20 microM dATP, dCTP, and dTTP) in a M13mp2 DNA forward mutation assay, and fourfold more accurate in an M13mp2T90 reversion assay. Under error-free conditions (20 microM each of the four dNTPs), however, both polymerases showed equal fidelity. Our data suggested that autonomous 3' --> 5' exonucleases, such as TREX2, through its association with pol delta can guarantee high fidelity under difficult conditions in the cell (e.g., imbalance of dNTPs) and can add to the accuracy of the DNA replication machinery, thus preventing mutagenesis.


[Loneliness and social relations among mothers with infants].
To provide support for child-rearing mothers under circumstances in which they are likely to experience loneliness by studying the status of their social network (contact frequency) and social support as well as the relationship of these variables with loneliness. An anonymous questionnaire was distributed to 978 mothers who visited 4 health care centers in Ward A in Tokyo for medical check-ups of their infants aged 3-4 months between August and November 2008. Examined parameters were the revised UCLA Loneliness Scale; basic attributes of mothers and infants; child-rearing environment; presence/absence of a husband (partner), biological parents, friends who were also mothers (''mother friends''), and other friends; presence/absence of an active social network (contact frequency); and social support. Contact frequency was counted and classified according to face-to-face contacts and other contacts. The first multiple regression analysis was performed with loneliness score as the dependent variable and presence/absence of a husband (partner), biological parents, mother friends, and friends as independent variables. The second multiple regression analysis used the loneliness score as a dependent variable to examine relationships among loneliness, social support, and contact frequency with a husband (partner), biological parents, mother friends, and friends. Those with no contact person or supporter or with a missing value were excluded. Therefore, a sub-analysis among mothers with no mother friends was performed. In total, 432 questionnaires were completed and 417 had effective responses (effective response rate, 43.3%). The mean Loneliness Scale score was 34.4±9.0 points. Multiple regression analysis showed that the Loneliness Scale score was higher in those with no mother friend or friends. Mothers with all types of contact persons and supporters had higher loneliness scores if they had longer conversations with husband (partner), less frequent face-to-face contact with mother friends and friends, and less social support from biological parents, mother friends, and friends. However, having supporters and contact persons without mother friends had no apparent relationship with contact frequency, social support, or the loneliness score, but correlated with interpersonal attitudes and mother's awareness. To prevent and mitigate the loneliness of mothers engaged in child care, it is important to assess the presence/absence of mother friends and friends; relationships with biological parents, mother friends, and friends; and interpersonal attitudes and awareness of mothers, and then take actions to enhance positive images of maternal roles, provide opportunities for face-to-face contact with mother friends and friends, and obtain social support from biological parents, mother friends, and friends.


Do you see what I see? A randomised pilot study to evaluate the effectiveness and efficiency of simulation-based training with videolaryngoscopy for neonatal intubation.
Direct laryngoscopy (DL) and airway intubation are critical for neonatal resuscitation. A challenge in teaching DL is that the instructor cannot assess the learners' airway view. Videolaryngoscopy (VL), which allows display of a patient's airway on a monitor, enables the instructor to view the airway during the procedure. This pilot study compared deliberate practice using either VL with instruction (I-VL) or traditional DL. We hypothesised that I-VL would improve the efficiency and effectiveness of neonatal intubation (NI) training. Participants (students, paediatric interns and neonatal fellows) were randomised to I-VL or DL. Baseline technical skills were assessed using a skills checklist and global skills assessment. Following educational sessions, deliberate practice was performed on mannequins using the Storz C-MAC. With I-VL, the instructor could guide training using a real-time airway monitor view. With DL, feedback was based solely on technique or direct visual confirmation, but the instructor and learner views were not concurrent. During summative assessment, procedural skills checklists were used to evaluate intubation ability on a neonatal airway trainer. The duration of attempts was recorded, and recorded airway views were blindly reviewed for airway grade. 'Effectiveness' reflected achievement of the minimum passing score (MPS). 'Efficiency' was the duration of training for learners achieving the MPS. 58 learners were randomised. Baseline demographics were similar. All participants had a significant improvement in knowledge, skills and comfort/confidence following training. There were no significant differences between randomised groups in efficiency or effectiveness, but trends towards improvement in each were noted. Fellows were more likely to achieve 'competency' postinstruction compared to non-fellows (p<0.001). This educational intervention to teach NI increased the learner's knowledge, technical skills and confidence in procedural performance in both groups. I-VL did not improve training effectiveness. The small sample size and participant diversity may have limited findings, and future work is indicated.


Parapharyngeal liposarcoma: a case report.
Parapharyngeal liposarcoma is a very rare malignant tumor that often causes nonspecific clinical symptoms, such as progressive dysphagia, globus sensation and/or respiratory disturbances. The combination of radiological imaging techniques and histopathological analysis provides information for diagnosis; however, the pathogenesis is still uncertain. A 30-year-old male patient presented with a pharyngeal cavity mass, which had been present for 2 years. The clinical syndrome included obstructive sleep apnea symptoms (i.e., respiratory disturbances, excessive daytime somnolence, and headache) and difficulty swallowing. The radiological examination (CT) demonstrated that there was a low-density irregular solid lesion on the posterior wall of the oropharynx and laryngopharynx, which descended to the superior mediastinum and extended to the left parapharyngeal space and sternocleidomastoid muscle. The boundaries of the lesion were clear, and the lesion's density was nonuniform. Several septations inside the lesion were observed. The CT values of the lesion at the epiglottis and the vocal folds were 11 HU and minus 30 HU, respectively. After enhanced scanning, there was no apparent enhancement of the lesion: the surrounding tissue and blood vessels were squeezed and shifted, but the neighboring sclerotin of the cervical vertebrae was not invaded. The mass was removed via a transcervical approach, resulting in a complete amelioration of the patient's symptoms. Interestingly, immunohistochemistry showed that the tumor cells expressed members of the B7 superfamily, including B7-H1, B7-DC and B7-H3. In addition, the expression of TIM-containing molecules, including TIM-3 and TIM-4, was observed. CT and MRI demonstrated that the mass was a parapharyngeal liposarcoma. Furthermore, carcinoma-associated B7 and TIM-containing molecules were observed in the tissue, indicating that these molecules are most likely active in the pathogenesis of this disease. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1907794973876202.


A paper-based potentiometric cell for decentralized monitoring of Li levels in whole blood.
A novel approach to monitor Li levels in blood in decentralized (out of the lab) settings is presented. The approach uses a potentiometric cell fully made with filter paper as a support. Electrodes were built using carbon nanotubes ink to create a conductive path and a suitable polymeric membrane. Solid-state ion-selective electrodes for Li and a reference electrode were built and optimized. The results obtained on real samples of serum and whole blood are comparable with those obtained by conventional standard approaches. This platform shows an outstanding performance for the direct, fast and low-cost monitoring of Li levels in blood.


Spatially resolved amplitude and phase characterization of femtosecond optical pulses.
Ultrabroadband pulses exhibit a frequency-dependent mode size owing to the wavelength dependence of free-space diffraction. Additionally, rather complex lateral dependence of the temporal pulse shape has been reported for Kerr-lens mode-locked lasers and broadband amplifier chains and in frequency-domain pulse shapers, for example. We demonstrate an ultrashort-pulse characterization technique that reveals lateral pulse-shape variations by spatially resolved amplitude and phase measurements by use of spectral phase interferometry for direct electric-field reconstruction (SPIDER). Unlike with autocorrelation techniques, with SPIDER we can obtain spatially resolved pulse characterization even after the nonlinear process. Thus, with this method the spectral phase of the pulse can be resolved very rapidly along one lateral beam axis in a single measurement.


Genome sequencing and population genomic analyses provide insights into the adaptive landscape of silver birch.
Silver birch (Betula pendula) is a pioneer boreal tree that can be induced to flower within 1 year. Its rapid life cycle, small (440-Mb) genome, and advanced germplasm resources make birch an attractive model for forest biotechnology. We assembled and chromosomally anchored the nuclear genome of an inbred B. pendula individual. Gene duplicates from the paleohexaploid event were enriched for transcriptional regulation, whereas tandem duplicates were overrepresented by environmental responses. Population resequencing of 80 individuals showed effective population size crashes at major points of climatic upheaval. Selective sweeps were enriched among polyploid duplicates encoding key developmental and physiological triggering functions, suggesting that local adaptation has tuned the timing of and cross-talk between fundamental plant processes. Variation around the tightly-linked light response genes PHYC and FRS10 correlated with latitude and longitude and temperature, and with precipitation for PHYC. Similar associations characterized the growth-promoting cytokinin response regulator ARR1, and the wood development genes KAK and MED5A.


The structural basis of the inhibition of human alpha-mannosidases by azafuranose analogues of mannose.
Eight pyrrolidine, five pyrrolizidine and one indolizidine analogue(s) of the known alpha-mannosidase inhibitor, the azafuranose, 1,4-dideoxy-1,4-imino-D-mannitol (DIM), have been tested for inhibition of the multiple forms of alpha-mannosidase in human liver in vitro. Substitution of the ring nitrogen markedly decreased or abolished inhibition, but loss of the C-6 hydroxy group, as in 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM, enhanced inhibition, particularly of the lysosomal alpha-mannosidase. Addition of the anomeric substituent-CH2OH decreased inhibition. To be a potent inhibitor of the lysosomal, Golgi II and neutral alpha-mannosidases, a polyhydroxylated pyrrolidine must have the same substituents and chirality as mannofuranose at C-2, C-3, C-4 and C-5. These four chiral centres can also be part of a polyhydroxylated indolizidine, e.g. swainsonine, but not of a pyrrolizidine, e.g. cyclized DIM, ring-contracted swainsonine or 1,7-diepi-australine. DIM did not inhibit lysosomal alpha-mannosidase intracellularly, but both 6-deoxy-DIM and 6-deoxy-6-fluoro-DIM caused accumulation of partially catabolized glycans in normal human fibroblasts. Analysis of these induced storage products by h.p.l.c. showed that both compounds also inhibited Golgi alpha-mannosidase II and that 6-deoxy-6-fluoro-DIM was also a good inhibitor of the endoplasmic reticulum alpha-mannosidase and specific lysosomal alpha (1-6)-mannosidase. None of the mannofuranose analogues appeared to inhibit Golgi alpha-mannosidase I.


Association Between WIC Enrollment and Exclusive Breastfeeding at 3 Months Postpartum Among Low-Income Mothers.
Existing literature suggests participation in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in the prenatal and postnatal periods is associated with lower rates of breastfeeding among WIC-eligible mothers. However, minimal research has been published on the association between WIC enrollment and exclusive breastfeeding. To examine the association between WIC exposure and exclusive breastfeeding at 3 months postpartum. We conducted a secondary data analysis using information on 784 low-income women who participated in the longitudinal population-based Infant Feeding Practices Study II between May 2005 and June 2007. The main outcome of interest was exclusive breastfeeding at 3 months postpartum. Logistic regression analysis was used to estimate OR and 95% CI for exclusive breastfeeding relative to WIC enrollment status, controlling for the confounding effects of other maternal characteristics. We further conducted a subgroup analysis among those participating in WIC prenatally to examine the association between receipt of information about infant feeding from WIC and exclusive breastfeeding at 3 months postpartum. The crude prevalence of exclusive breastfeeding at 3 months postpartum was 18.1% of women enrolled in WIC and 41.1% of WIC-eligible nonparticipants (P<.0001). After adjusting for sociodemographic, behavioral, and anthropometric factors, the odds of exclusive breastfeeding at 3 months were lower for women enrolled in WIC (OR, 0.57; 95% CI, 0.37-0.88) when compared with women not enrolled in WIC. In the subgroup analysis, receipt of information from WIC about feeding infants during the prenatal period was not significantly associated with exclusive breastfeeding at 3 months (OR, 0.86; 95% CI, 0.39-1.89). Women who were enrolled in WIC and who received information about feeding infants were less likely to exclusively breastfeed than women not in WIC. Continued improvement and adjustment to the existing WIC breastfeeding program could potentially improve these rates. Additional studies that examine the quality of WIC services provided, especially those pertaining to breastfeeding programs, are warranted.


Long-distance movement factor: a transport function of the potyvirus helper component proteinase.
Transport of viruses from cell to cell in plants typically involves one or more viral proteins that supply dedicated movement functions. Transport from leaf to leaf through phloem, or long-distance transport, is a poorly understood process with requirements differing from those of cell-to-cell movement. Through genetic analysis of tobacco etch virus (TEV; potyvirus group), a novel long-distance movement factor was identified that facilitates vascular-associated movement in tobacco. A mutation in the central region of the helper component proteinase (HC-Pro), a TEV-encoded protein with previously described activities in aphid-mediated transmission and polyprotein processing, inactivated long-distance movement. This mutant virus exhibited only minor defects in genome amplification and cell-to-cell movement functions. In situ histochemical analysis revealed that the mutant was capable of infecting mesophyll, bundle sheath, and phloem cells within inoculated leaves, suggesting that the long-distance movement block was associated with entry into or exit from sieve elements. The long-distance movement defect was specifically complemented by HC-Pro supplied in trans by a transgenic host. The data indicate that HC-Pro functions in one or more steps unique to long-distance transport.


Detection of long non-coding RNA in archival tissue: correlation with polycomb protein expression in primary and metastatic breast carcinoma.
A major function of long non-coding RNAs (lncRNAs) is regulating gene expression through changes in chromatin state. Experimental evidence suggests that in cancer, they can influence Polycomb Repressive Complexes (PRC) to retarget to an occupancy pattern resembling that of the embryonic state. We have previously demonstrated that the expression level of lncRNA in the HOX locus, including HOTAIR, is a predictor of breast cancer metastasis. In this current project, RNA in situ hybridization of probes to three different lncRNAs (HOTAIR, ncHoxA1, and ncHoxD4), as well a immunohistochemical staining of EZH2, is undertaken in formalin-fixed paraffin-embedded breast cancer tissues in a high throughput tissue microarray format to correlate expression with clinicopathologic features. Though overall EZH2 and HOTAIR expression levels were highly correlated, the subset of cases with strong HOTAIR expression correlated with ER and PR positivity, while the subset of cases with strong EZH2 expression correlated with an increased proliferation rate, ER and PR negativity, HER2 underexpression, and triple negativity. Co-expression of HOTAIR and EZH2 trended with a worse outcome. In matched primary and metastatic cancers, both HOTAIR and EZH2 had increased expression in the metastatic carcinomas. This is the first study to show that RNA in situ hybridization of formalin fixed paraffin-embedded clinical material can be used to measure levels of long non-coding RNAs. This approach offers a method to make observations on lncRNAs that may influence the cancer epigenome in a tissue-based technique.


Protein-engineering of an amine transaminase for the stereoselective synthesis of a pharmaceutically relevant bicyclic amine.
Application of amine transaminases (ATAs) for stereoselective amination of prochiral ketones represents an environmentally benign and economically attractive alternative to transition metal catalyzed asymmetric synthesis. However, the restrictive substrate scope has limited the conversion typically to non-sterically demanding scaffolds. Recently, we reported on the identification and design of fold class I ATAs that effect a highly selective asymmetric synthesis of a set of chiral aromatic bulky amines from the corresponding ketone precursors in high yield. However, for the specific amine synthetic approach extension targeted here, the selective formation of an exo- vs. endo-isomer, these biocatalysts required additional refinement. The chosen substrate (exo-3-amino-8-aza-bicyclo[3.2.1]oct-8-yl-phenyl-methanone), apart from its pharmacological relevance, is a demanding target for ATAs as the bridged bicyclic ring provides substantial steric challenges. Protein engineering combining rational design and directed evolution enabled the identification of an ATA variant which catalyzes the specific synthesis of the target exo-amine with >99.5% selectivity.


Peer support for family carers of people with dementia, alone or in combination with group reminiscence in a factorial design: study protocol for a randomised controlled trial.
Peer support interventions can improve carer wellbeing and interventions that engage both the carer and person with dementia can have significant mutual benefits. Existing research has been criticised for inadequate rigour of design or reporting. This paper describes the protocol for a complex trial that evaluates one-to-one peer support and a group reminiscence programme, both separately and together, in a factorial design. A 2 × 2 factorial multi-site randomised controlled trial of individual peer support and group reminiscence interventions for family carers and people with dementia in community settings in England, addressing both effectiveness and cost-effectiveness. The methods described in this protocol have implications for research into psychosocial interventions, particularly complex interventions seeking to test both individual and group approaches.


When the present visits the past: updating traumatic memories in social phobia.
Research suggests that distorted images of the self are common in social phobia and play a role in maintaining the disorder. The images are often linked in thematic and sensory detail to distressing memories that are clustered around the onset or worsening of the disorder. This has led to speculation about the likely benefit of working directly with these memories to improve symptoms of social phobia. In this exploratory study, we describe a process of cognitive restructuring followed by imagery rescripting to update the meanings of distressing memories and images in social phobia. We first present illustrative clinical examples and then data of 14 patients with social phobia, on whom we developed this approach. Patients attended an imagery rescripting session in which a semi-structured interview was used to identify their recurrent images, the associated memories and their meanings. Next the identified memory was evoked and elaborated. We updated the meaning of the memory by first using cognitive restructuring to arrive at new perspectives and then linking these perspectives with the memory using imagery techniques. The procedure resulted in significant within session change in beliefs, and in image and memory distress and vividness. One week later significant change was seen in social phobia cognitions and a self-report measure of social anxiety. Rescripting distressing memories in social phobia appears to be an effective way of modifying maladaptive beliefs linked to recurrent negative imagery. This paper presents our exploratory investigation of how to work with the memories and encourages more rigorous investigation in this area.


Transcription factor YY1 expression in human gastrointestinal cancer cells.
Over-expression of the multifunctional zinc-finger transcription factor Yin Yang 1 (YY1) has been associated with cellular proliferation and resistance to apoptotic stimuli. In this study, we report that YY1 was uniformly highly over-expressed in a wide range of human cancer cell lines and in human colon cancer tissue samples. The examination of YY1-specific mRNA expression demonstrated at least six mRNA isoforms ubiquitously expressed in normal human adult and fetal tissues. Substantial over-expression of two specific mRNA isoforms of 7.5 and 2.9 kb size, respectively, was detected in gastrointestinal and other cancer cells in vitro, whereby mRNA stability differed significantly between various cell lines. YY1 protein expression levels were similar in different colon cancer cell lines. Using FISH analysis of several colorectal cancer cell lines, the human YY1 locus was expectedly identified on chromosome 14q32 and no evidence of gene amplification and chromosomal translocation was observed. However, varying degree of aneuploidy was noted in vitro. YY1 immunoreactivity in human colon tumor samples was found more intense in poorly differentiated tumors than in moderately and well differentiated colon cancers and lower expression levels tended to be associated with shorter survival. In conclusion, YY1 was over-expressed in colon cancer in the absence of gene amplification and chromosomal translocation. YY1 mRNA and protein stability are important regulatory mechanisms of YY1 expression in colon cancer.


TRPC6 mutations in children with steroid-resistant nephrotic syndrome and atypical phenotype.
Mutations in the TRPC6 gene have been recently identified as the cause of late-onset autosomal-dominant focal segmental glomerulosclerosis (FSGS). To extend the screening, we analyzed TRPC6 in 33 Italian children with sporadic early-onset SRNS and three Italian families with adult-onset FSGS. TRPC6 mutation analysis was performed through PCR and sequencing. The effects of the detected amino acid substitutions were analyzed by bioinformatics tools and functional in vitro studies. The expression levels of TRPC6 and nephrin proteins were evaluated by confocal microscopy. Three heterozygous missense mutations (c.374A>G_p.N125S, c.653A>T_p.H218L, c.2684G>T_p.R895L) were identified. The first new mutation, p.H218L, was found in a 18-year-old boy who presented a severe form of FSGS at the age of 8 years. The second, p.R895L, a new de novo mutation, was identified in a girl with collapsing glomerulosclerosis at the age of 2 years. The former mutation, p.N125S, was found in two siblings with early-onset steroid-resistant nephrotic syndrome (SRNS) at the ages of 4 and 14 years. Renal immunofluorescence revealed upregulated expression of TRPC6 and loss of nephrin in glomeruli. The intracellular calcium concentrations were significantly higher in the cells expressing all mutant TRPC6 channels compared with cells expressing wild-type TRPC6. Our findings suggest that TRPC6 variants can also be detected in children with early-onset and sporadic SRNS (4 of 33 patients). Moreover, in one patient a new de novo TRPC6 mutation was associated with a rare severe form of childhood collapsing glomerulosclerosis with rapid progression to uremia.


The IMPACT clinic: innovative model of interprofessional primary care for elderly patients with complex health care needs.
The growing number of elderly patients with multiple chronic conditions presents an urgent challenge in primary care. Current practice models are not well suited to addressing the complex health care needs of this patient population. The primary objective of the IMPACT (Interprofessional Model of Practice for Aging and Complex Treatments) clinic was to design and evaluate a new interprofessional model of care for community-dwelling seniors with complex health care needs. A secondary objective was to explore the potential of this new model as an interprofessional training opportunity. The IMPACT clinic is an innovative new model of interprofessional primary care for elderly patients with complex health care needs. The comprehensive team comprises family physicians, a community nurse, a pharmacist, a physiotherapist, an occupational therapist, a dietitian, and a community social worker. The model is designed to accommodate trainees from each discipline. Patient appointments are 1.5 to 2 hours in length, during which time a diverse range of medical, functional, and psychosocial issues are investigated by the full interprofessional team. The IMPACT model is congruent with ongoing policy initiatives in primary care reform and enhanced community-based care for seniors. The clinic has been pilot-tested in 1 family practice unit and modeled at 3 other sites with positive feedback from patients and families, clinicians, and trainees. Evaluation data indicate that interprofessional primary care models hold great promise for the growing challenge of managing complex chronic disease.


Excess dNTPs Trigger Oscillatory Surface Flow in the Early Drosophila Embryo.
During the first 2 hours of Drosophila development, precisely orchestrated nuclear cleavages, cytoskeletal rearrangements, and directed membrane growth lead to the formation of an epithelial sheet around the yolk. The newly formed epithelium remains relatively quiescent during the next hour as it is patterned by maternal inductive signals and zygotic gene products. We discovered that this mechanically quiet period is disrupted in embryos with high levels of dNTPs, which have been recently shown to cause abnormally fast nuclear cleavages and interfere with zygotic transcription. High levels of dNTPs are associated with robust onset of oscillatory two-dimensional flows during the third hour of development. Tissue cartography, particle image velocimetry, and dimensionality reduction techniques reveal that these oscillatory flows are low dimensional and are characterized by the presence of spiral vortices. We speculate that these aberrant flows emerge through an instability triggered by deregulated mechanical coupling between the nascent epithelium and three-dimensional yolk. These results highlight an unexplored connection between a core metabolic process and large-scale mechanics in a rapidly developing embryo.


Acidic and basic fibroblast growth factors in the nervous system: distribution and differential alteration of levels after injury of central versus peripheral nerve.
Acidic and basic fibroblast growth factors (aFGF and bFGF) are known to stimulate mitogenesis in a variety of non-neuronal cell types. Recent work has also established that FGFs can act as neurotrophic factors that promote the survival and regeneration in vitro of a variety of neurons. The present study investigates the distribution of aFGF and bFGF in vivo by using a mitogenic bioassay on AKR-2B cells coupled with Western-blot analysis to estimate the levels of aFGF and bFGF in different areas of the rat nervous system. Acidic FGF and bFGF from extracts of nervous tissue were found to differ considerably in their relative dependencies upon heparin to potentiate their mitogenic activities: the effect of aFGF was strongly dependent upon heparin, whereas the effect of bFGF was only slightly potentiated by heparin. Heparin was also found to stimulate differentially the mitogenic activity of extracts prepared from different areas of the nervous system, indicating that spinal cord, cortex, pituitary, and optic nerve contained different ratios of aFGF to bFGF, whereas sciatic nerve contained extremely high levels of only aFGF. These results were confirmed in Western-blot experiments, using antibodies specific for either aFGF or bFGF. Transection of nerves had opposing effects in sciatic and optic nerves: aFGF rapidly declined in the sciatic nerve distal to the cut, whereas bFGF increased slightly in the distal portion of the cut optic nerve. This differential effect of injury on FGF levels in central versus peripheral nerves may reflect the differential regenerative potential of these two types of nerves.


Tailored Helicobacter pylori eradication based on prior intake of macrolide antibiotics allows the use of triple therapy with optimal results in an area with high clarithromycin resistance.
the previous intake of macrolide antibiotics is associated with a failure to eradicate Helicobacter pylori (H. pylori) with clarithromycin-containing regimens. However, the standard triple therapy achieves eradication rates of over 90% in patients without a previous use of macrolides in our health area. The aim of this study was to evaluate the efficacy of an H. pylori eradication strategy based on the intake of macrolides by the patient during the previous years. one hundred and sixty-nine patients with H. pylori infection were prospectively included in the study. The electronic medical record of each patient was reviewed at the time of inclusion. Depending on their previous intake of macrolides, patients were assigned to one of two eradication regimens: group A) patients without a previous intake of macrolides received an optimized triple therapy for 14 days; and group B) patients with a previous intake of macrolides received bismuth quadruple therapy for ten days. ninety-one patients (53.84%) without a previous intake of macrolides received an optimized triple therapy (group A) and 78 patients (46.15%) with a previous intake of macrolides received bismuth quadruple therapy (group B). In group A, the H. pylori eradication rates were 90.11% in the intention-to-treat and 95.35% in the per-protocol analysis. In group B, the H. pylori eradication rates were 85.89% in the intention-to-treat and 98.5% in the per-protocol analysis. The overall eradication rates obtained using this strategy were 88.16% (95% CI: 82.32-92.02%) in the intention-to-treat and 96.75% (95% CI: 92.59-98.94%) in the per-protocol analysis. an H. pylori eradication strategy based on the intake of macrolides during the previous years achieves overall eradication rates close to 90% and allows the use of standard triple therapy in more than half of the patients from a health area with a high level of clarithromycin resistance.


Clinical and molecular rationale to retain the cancer descriptor for Gleason score 6 disease.
Treatment choices for men with indolent prostate cancer include active surveillance or definitive local therapy. Overtreatment of these patients is an important current problem. Treatment decisions are often made jointly by the clinician and the patient, partly based on the tumour's Gleason score. To reduce the burden of overtreatment, the clinical significance of Gleason score 3 + 3 = 6 prostate cancer has been questioned and some have advocated that Gleason pattern 3 should be stripped of its cancer status. However, removing the cancer descriptor would have far-reaching clinical consequences that might result in poor patient outcomes, as the evidence of a lack of malignancy is inconclusive in several areas. For example, molecular data suggest that the genomic instability underlying tumour progression precedes histologically visible changes and the absolute risk of metastasis or mortality from Gleason score 6 prostate cancer is not zero. Extreme caution is required when weighing a decision to reclassify Gleason pattern 3 disease as a non-cancer.


Economic Evaluation of Five Tobacco Control Policies Across Seven European Countries.
Economic evaluations of tobacco control policies targeting adolescents are scarce. Few take into account real-world, large-scale implementation costs; few compare cost-effectiveness of different policies across different countries. We assessed the cost-effectiveness of five tobacco control policies (nonschool bans, including bans on sales to minors, bans on smoking in public places, bans on advertising at points-of-sale, school smoke-free bans, and school education programs), implemented in 2016 in Finland, Ireland, the Netherlands, Belgium, Germany, Italy, and Portugal. Cost-effectiveness estimates were calculated per country and per policy, from the State perspective. Costs were collected by combining quantitative questionnaires with semi-structured interviews on how policies were implemented in each setting, in real practice. Short-term effectiveness was based on the literature, and long-term effectiveness was modeled using the DYNAMO-HIA tool. Discount rates of 3.5% were used for costs and effectiveness. Sensitivity analyses considered 1%-50% short-term effectiveness estimates, highest cost estimates, and undiscounted effectiveness. Nonschool bans cost up to €253.23 per healthy life year, school smoking bans up to €91.87 per healthy life year, and school education programs up to €481.35 per healthy life year. Cost-effectiveness depended on the costs of implementation, short-term effectiveness, initial smoking rates, dimension of the target population, and weight of smoking in overall mortality and morbidity. All five policies were highly cost-effective in all countries according to the World Health Organization thresholds for public health interventions. Cost-effectiveness was preserved even when using the highest costs and most conservative effectiveness estimates. Economic evaluations using real-world data on tobacco control policies implemented at a large scale are scarce, especially considering nonschool bans targeting adolescents. We assessed the cost-effectiveness of five tobacco control policies implemented in 2016 in Finland, Ireland, the Netherlands, Belgium, Germany, Italy, and Portugal. This study shows that all five policies were highly cost-effective considering the World Health Organization threshold, even when considering the highest costs and most conservative effectiveness estimates.


Management of tricuspid regurgitation in congenital heart disease: is survival better with valve repair?
Tricuspid valve (TV) regurgitation in congenital heart disease includes a heterogeneous group of lesions, and few series have documented the outcomes. We reviewed the records of 553 patients with congenital heart disease who had undergone TV surgery for tricuspid regurgitation from January 1993 to December 2010. Patients with Ebstein malformation were excluded. Their mean age was 32 ± 21 years, and 300 were female (54%). The most common diagnoses were conotruncal anomaly in 216 patients (39%), previous ventricular septal defect closure in 83 (15%), atrioventricular septal defect in 77 (14%), and pulmonary atresia with an intact ventricular septum in 11 (2%). Preoperative right-sided heart failure was present in 124 patients (22%), and 55 patients (10%) had pulmonary hypertension. TV repair was performed in 442 (80%) and TV replacement in 111 (20%) patients. Repeat sternotomy was performed in 415 patients (75%). Previous TV repair was present in 44 patients (8%); of these, 17 (38.6%) underwent repeat TV repair. The overall early mortality was 3.1% (17 patients) and was 2.5% for TV repair and 5.4% for TV replacement (P = .001). The mean follow-up period was 4.5 ± 4.1 years (maximum, 18). The overall survival at 1, 5, and 10 years was 97%, 93%, and 85%, respectively. Survival was better for patients with repair than with replacement. TV repair was an independent predictor of better survival (P = .001). Important tricuspid regurgitation can occur with a variety of congenital diagnoses. Early mortality is low and late survival is superior with tricuspid repair than with valve replacement. Surgical treatment of tricuspid regurgitation in congenital heart disease should be performed before the onset of heart failure.


Promoter ChIP-chip analysis in mouse testis reveals Y chromosome occupancy by HSF2.
The mammalian Y chromosome is essential for spermatogenesis, which is characterized by sperm cell differentiation and chromatin condensation for acquisition of correct shape of the sperm. Deletions of the male-specific region of the mouse Y chromosome long arm (MSYq), harboring multiple copies of a few genes, lead to sperm head defects and impaired fertility. Using chromatin immunoprecipitation on promoter microarray (ChIP-chip) on mouse testis, we found a striking in vivo MSYq occupancy by heat shock factor 2 (HSF2), a transcription factor involved in spermatogenesis. HSF2 was also found to regulate the transcription of MSYq resident genes, whose transcriptional regulation has been unknown. Importantly, disruption of Hsf2 caused a similar phenotype as the 2/3 deletion of MSYq, i.e., altered expression of the multicopy genes and increased mild sperm head abnormalities. Consequently, aberrant levels of chromatin packing proteins and more frequent DNA fragmentation were detected, implying that HSF2 is required for correct chromatin organization in the sperm. Our findings define a physiological role for HSF2 in the regulation of MSYq resident genes and the quality of sperm.


The role of C-kinase in the physiological activation of the neutrophil oxidase. Evidence from using pharmacological manipulation of C-kinase activity in intact cells.
The role of C-kinase in the triggering of the neutrophil oxidase by two stimuli (latex beads and the chemotactic peptide fMet-Leu-Phe), representative of endocytotic and exocytotic routes of activation, were investigated by using experimental agents that activate, or inhibit C-kinase, in intact cells. The activation by the phagocytotic stimulus latex beads was mimicked by C-kinase activators giving the same characteristic lag (20-30s), followed by a constant oxygen consumption rate with the same maximum rate and affinity for oxygen (Km approx. 13 microM), competed with activation by PMA (4 beta-phorbol 12-myristate 13-acetate) in a simple common-target manner, and was inhibited by retinal, an inhibitor shown to inhibit activation by PMA. In contrast, activation by chemotactic peptide was not mimicked by C-kinase activation alone, chemotactic peptide inducing biphasic oxygen consumption with a Km for oxygen of the second prolonged phase of 3.9 microM, did not compete with activation by PMA, and was not inhibited by retinal. However, PMA and retinal produced slight enhancements of activation by chemotactic peptide and production of monophasic oxygen consumption. It was concluded that C-kinase activation plays a simple central transducing role in activation of the oxidase by latex beads, but that its role in activation by chemotactic peptide is a part of a more complex set of interactions that involve other Ca2+-activated and non-Ca2+-activated processes.


Psychometric evaluation of the Danish and Swedish Satisfaction with Life Scale in first episode psychosis patients.
To psychometrically evaluate the Satisfaction with Life Scale in two cohorts of first-episode psychosis patients in the Danish National Schizophrenia Project and in the Swedish Parachute Project. Four properties of the Satisfaction with Life Scale were examined in the Danish cohort (explorative investigation) and then confirmed in the Swedish cohort: (1) the factor structure; (2) correlations between subscales; (3) internal consistencies of subscales; and (4) main tendencies (arithmetic means) and variations (standard deviations) of subscales. The relations between the Satisfaction with Life Scale and various life conditions were investigated in the Swedish cohort. For both samples, the analysis indicated that the obtained four-dimensional 11-item scale had satisfactory properties. Moderately high scores were obtained in the four subscales: "living," "social relationships," "self and present life" and "work." They correlated positively with each other, the internal consistencies of the subscales were acceptable and the means for the subscales indicated no apparent floor or ceiling effects. The four dimensions obtained seem relevant and presented good face validity. The dimensions were confirmed in the Swedish sample. The Satisfaction with Life Scale shows satisfactory psychometric properties and seems valid and useful among first-episode psychosis patients.


Modulation of growth and immunity by dietary supplementation with resveratrol in young chickens receiving conventional vaccinations.
To determine the effects of resveratrol (RES) on growth and immune status in chickens receiving conventional vaccinations. Two hundred forty 1-day-old layer chickens. Chickens received conventional vaccinations throughout the study and were randomly assigned to 1 of 4 treatments in 6 replicate pens/treatment. Treatments included 1 control group (basal diet) and 3 experimental groups fed the basal diet plus 200, 400, and 800 mg of RES/kg of diet. At 40 days of age, 1 bird/pen was randomly selected to have blood and tissues collected to determine serum immunity indices; mRNA relative expression of proinflammatory cytokines in splenocytes; mRNA relative expression of nuclear transcription factor-κB, growth hormone receptor, and insulin-like growth factor-1 in hepatocytes; cell proliferation; and apoptosis. Average daily gain, antibody titers against Newcastle disease virus and avian influenza viruses H5 and H9, and insulin-like growth factor-1 expression were quadratically increased with increasing RES concentration. In hepatocytes, growth hormone receptor gene mRNA relative expression was quadratically increased and nuclear transcription factor-κB gene mRNA relative expression was linearly decreased with increasing RES concentration. In splenocytes, nterleukin-1β and tumor necrosis factor-α mRNA relative expression was linearly decreased with increasing RES concentration. Resveratrol supplementation delayed cell proliferation and reduced apoptosis in immunocytes. With increasing RES concentration, proliferation index and relative weight of the thymus, ratio of CD4+ to CD8+ cells, and CD4+ cell count were quadratically increased, and IgM concentration was linearly increased. Dietary resveratrol supplementation improved growth, protected immunocytes against antigen-induced apoptosis, and upregulated immune response in chickens that received conventional vaccinations.


Identification of candidate substrates for ectodomain shedding by the metalloprotease-disintegrin ADAM8.
ADAM proteases are type I transmembrane proteins with extracellular metalloprotease domains. As for most ADAM family members, ADAM8 (CD156a, MS2) is involved in ectodomain shedding of membrane proteins and is linked to inflammation and neurodegeneration. To identify potential substrates released under these pathologic conditions, we screened 10-mer peptides representing amino acid sequences from extracellular domains of various membrane proteins using the ProteaseSpot system. A soluble ADAM8 protease containing a pro- and metalloprotease domain was expressed in E. coli and purified as active protease owing to autocatalytic prodomain removal. From 34 peptides tested in the peptide cleavage assay, significant cleavage by soluble ADAM8 was observed for 14 peptides representing membrane proteins with functions in inflammation and neurodegeneration, among them the beta-amyloid precursor protein (APP). The in vivo relevance of the ProteaseSpot method was confirmed by cleavage of full-length APP with ADAM8 in human embryonic kidney 293 cells expressing tagged APP. ADAM8 cleaved APP with similar efficiency as ADAM10, whereas the inactive ADAM8 mutant did not. Exchanging amino acids at defined positions in the cleavage sequence of myelin basic protein (MBP) revealed sequence criteria for ADAM8 cleavage. Taken together, the results allowed us to identify novel candidate substrates that could be cleaved by ADAM8 in vivo under pathologic conditions.


[Fingerprint of X-ray diffraction of Tibetan medicine dairy Nanhanshuishi and its application in processing by microwave].
The characteristic fingerprint of conventional dairy Nanhanshuishi was established by X-ray diffraction (XRD), based on similarity of caculation on public peaks by MATLAB software, and the feasibility of new dairy technology of microwave method was explored between XRD and the dissolution rate in artificial simulation gastric juices. The result showed that similarity of shared peak in XRD of conventional dairy Nanhanshuishi was > 95%, This XRD characteristic fingerprint of conventional dairy Nanhanshuishi had strong specificity, could be used to provide a reference for identification and quality evaluation. This study also showed that the similarity of microware dairy products and conventional dairy products was good, and the sample of microwave 15 min was the best, and new dairy method by the microwave could replace the traditional method.


Occupational safety: effects of workplace radiofrequencies on hearing function.
The effects of radio frequency (RF) and microwave radiation on humans have been the subject of continuous investigation. Clinical investigations related to occupational RF/microwave exposure have been reported by investigators (1). Since one of the major groups occupationally exposed to RF and microwave radiation includes those working in radio broadcasting and TV transmitter stations, this study investigates whether RF affects auditory systems of people exposed to RF. The study is carried out with people working in radio broadcasting stations and living in employee residential houses close to the broadcasting stations. All subjects in the control group were similar in age, work regime, socioeconomic status, and lack of experience in working with RF sources. Brainstem Evoked Response Audiometer (BERA) and Pure Tone Audiometry (PTA) were used to measure the effects of RF under investigation on hearing functions of the subjects. In BERA measurements, I-III, III-V and I-V interpeak latencies were evaluated. In pure tone audiometric measurements, 250 Hz, 500 Hz, 1000 Hz, 2000 Hz, 4000 Hz and 8000 Hz frequencies of hearing threshold were measured in subjects of experimental and control groups. Interpeak latencies and bone conduction hearing thresholds of subjects in the experimental group were compared with those of the control group. BERA results showed that I-III, I-V and III-V interpeak latencies of people occupationally exposed to RF were not higher than subjects in control groups (p>0.05). Results of BERA indicated no statistically significant differences between exposure and control subjects. In audiometric evaluation, hearing threshold of people occupationally exposed to RF were found higher than the control group subjects for frequencies of 4000 Hz and 8000 Hz in terms of bone and air conduction of right and left ear (p < 0.01). The results of traditional audiometer indicated that RF promotes sensorineural hearing loss and affects cochlea parts related to 4000 Hz and 8000 Hz. These findings may have immediate implications and considerations for workplace safety in order to provide an occupationally safe environment to employees working in such settings.


Enhanced Amygdala-Striatal Functional Connectivity during the Processing of Cocaine Cues in Male Cocaine Users with a History of Childhood Trauma.
Childhood trauma is associated with increased levels of anxiety later in life, an increased risk for the development of substance use disorders, and neurodevelopmental abnormalities in the amygdala and frontostriatal circuitry. The aim of this study was to investigate the (neurobiological) link among childhood trauma, state anxiety, and amygdala-frontostriatal activity in response to cocaine cues in regular cocaine users. In this study, we included 59 non-treatment seeking regular cocaine users and 58 non-drug using controls. Blood oxygenation level-dependent responses were measured using functional magnetic resonance imaging while subjects performed a cue reactivity paradigm with cocaine and neutral cues. Psychophysiological interaction analyses were applied to assess functional connectivity between the amygdala and other regions in the brain. Self-report questionnaires were used to measure childhood trauma, state anxiety, drug use, drug use severity, and craving. Neural activation was increased during the presentation of cocaine cues, in a widespread network including the frontostriatal circuit and amygdala in cocaine users but not in controls. Functional coupling between the amygdala and medial prefrontal cortex was reduced in response to cocaine cues, in both cocaine users and controls, which was further diminished with increasing state anxiety. Importantly, amygdala-striatal connectivity was positively associated with childhood trauma in regular cocaine users, while there was a negative association in controls. At the behavioral level, state anxiety was positively associated with cocaine use severity and craving related to negative reinforcement. Childhood trauma is associated with enhanced amygdala-striatal connectivity during cocaine cue reactivity in regular cocaine users, which may contribute to increased habit behavior and poorer cognitive control. While we cannot draw conclusions on causality, this study provides novel information on how childhood trauma may contribute to the development and persistence of cocaine use disorder.


Impact on Employee Productivity From Presenteeism and Absenteeism: Evidence From a Multinational Firm in Sri Lanka.
This study examines the effects of 13 psychological and physical health conditions on work productivity. One hundred fifty-two staff at the headquarters of a Sri Lankan multinational firm completed a questionnaire asking whether they experienced 13 health conditions common in workplaces, and about their related absenteeism and presenteeism. Most respondents (85.5%) reported absenteeism, presenteeism, or both. Among those reporting a health condition, 57.6% reported losing days due to absenteeism, and 69.5% reported losing additional days to presenteeism. Among those caring for a sick adult or child, 57.3% reported losing days due to absenteeism, and 36.5% reported losing additional days due to presenteeism. Overall productivity loss was 10.43 days each year, 3.95% of employee capacity, equating to about Sri Lanka Rupees 8 million (US$54,421) for all headquarters employees. The health conditions' effects on productivity significantly increased employee costs.


RNA helicase A interacts with divergent lymphotropic retroviruses and promotes translation of human T-cell leukemia virus type 1.
The 5' untranslated region (UTR) of retroviruses contain structured replication motifs that impose barriers to efficient ribosome scanning. Two RNA structural motifs that facilitate efficient translation initiation despite a complex 5' UTR are internal ribosome entry site (IRES) and 5' proximal post-transcriptional control element (PCE). Here, stringent RNA and protein analyses determined the 5' UTR of spleen necrosis virus (SNV), reticuloendotheliosis virus A (REV-A) and human T-cell leukemia virus type 1 (HTLV-1) exhibit PCE activity, but not IRES activity. Assessment of SNV translation initiation in the natural context of the provirus determined that SNV is reliant on a cap-dependent initiation mechanism. Experiments with siRNAs identified that REV-A and HTLV-1 PCE modulate post-transcriptional gene expression through interaction with host RNA helicase A (RHA). Analysis of hybrid SNV/HTLV-1 proviruses determined SNV PCE facilitates Rex/Rex responsive element-independent Gag production and interaction with RHA is necessary. Ribosomal profile analyses determined that RHA is necessary for polysome association of HTLV-1 gag and provide direct evidence that RHA is necessary for efficient HTLV-1 replication. We conclude that PCE/RHA is an important translation regulatory axis of multiple lymphotropic retroviruses. We speculate divergent retroviruses have evolved a convergent RNA-protein interaction to modulate translation of their highly structured mRNA.


Molecular basis for the distinct cellular functions of the Lsm1-7 and Lsm2-8 complexes.
Eukaryotes possess eight highly conserved Lsm (like Sm) proteins that assemble into circular, heteroheptameric complexes, bind RNA, and direct a diverse range of biological processes. Among the many essential functions of Lsm proteins, the cytoplasmic Lsm1-7 complex initiates mRNA decay, while the nuclear Lsm2-8 complex acts as a chaperone for U6 spliceosomal RNA. It has been unclear how these complexes perform their distinct functions while differing by only one out of seven subunits. Here, we elucidate the molecular basis for Lsm-RNA recognition and present four high-resolution structures of Lsm complexes bound to RNAs. The structures of Lsm2-8 bound to RNA identify the unique 2',3' cyclic phosphate end of U6 as a prime determinant of specificity. In contrast, the Lsm1-7 complex strongly discriminates against cyclic phosphates and tightly binds to oligouridylate tracts with terminal purines. Lsm5 uniquely recognizes purine bases, explaining its divergent sequence relative to other Lsm subunits. Lsm1-7 loads onto RNA from the 3' end and removal of the Lsm1 carboxy-terminal region allows Lsm1-7 to scan along RNA, suggesting a gated mechanism for accessing internal binding sites. These data reveal the molecular basis for RNA binding by Lsm proteins, a fundamental step in the formation of molecular assemblies that are central to eukaryotic mRNA metabolism.


The undernourished neonatal mouse metabolome reveals evidence of liver and biliary dysfunction, inflammation, and oxidative stress.
Undernutrition contributes to half of all childhood deaths under the age of 5 y, and confers upon survivors a life-long predisposition to obesity, type 2 diabetes, and cardiovascular disease. Mechanisms underlying the link between early nutrient deprivation and noncommunicable diseases are unknown. Using outbred CD1 neonatal mice, we measured metabolic profile differences between conventionally reared mice given unrestricted access to nursing, the control group, and undernourished mice subjected to protein-calorie deprivation through timed separation from lactating mothers. After 11 d of undernutrition, urine, plasma, liver, ileal fluid, cecal fluid, and stool were harvested from 8 pools of 4 neonatal mice per group. The metabolome was identified using a multiplatform mass spectrometry-based approach, and random forest metrics were used to identify the most important metabolites that distinguished the undernourished from the control group. Our data reveal striking metabolic changes in undernourished mice consistent with the known mammalian response to starvation, including evidence of muscle and fat catabolism and increased reliance on the tricarboxylic acid cycle for energy. However, we also revealed evidence of liver and biliary injury, anomalies in bile acid metabolism, oxidative stress and inflammation, accelerated heme breakdown, and altered regulation of DNA methylation. Among the metabolites that most strongly distinguished the 2 groups were 2-hydroxyisobutyrate, increased 3-fold in plasma of undernourished mice (P = 2.19 × 10(-11)); urobilinogen, increased 11-fold in urine of undernourished mice (P = 4.22 × 10(-7)); deoxycholate, decreased 94% in stool of undernourished mice (P = 3.0 × 10(-4)); and 12 different products of the enzyme γ-glutamyltransferase, increased in all 6 compartments of undernourished mice. This model of the undernourished neonatal metabolome illustrates the wide range of pathways disrupted by undernutrition in early development, and suggests mechanistic links between early starvation and persistent metabolic diseases.


Discharge against Medical Advice among Children in Oman: A university hospital experience.
Discharge against medical advice (DAMA) is a major problem in healthcare delivery as it can complicate the health problems from which patients are suffering. The aim of this study was to understand DAMA among children in a tertiary teaching hospital in Oman and to evaluate the documentation of the events in the medical records. A retrospective survey of the medical records of patients discharged against medical advice over a two-year interval was performed (2004-2006). Of the 11,802 admissions, there were 38 cases of DAMA, giving a prevalence rate of 0.32%. In 39.5% of the cases, the discharge happened within 24 hours of hospital admission. The majority of the cases were infants (n = 24; 63.25%). The diagnosis at discharge in some cases included life-threatening conditions. However, in 57.9% of the cases, the reasons for DAMA were neither reported nor documented in the patients' medical records. Although the results of this study yielded a low prevalence rate compared to the rates reported in other studies, the occurrence of DAMA for children in a tertiary hospital is a distressing phenomenon. It was evident that the documentation of the DAMA process was poor. More studies should be conducted to understand the details of the problem. Policies should be established and implemented in order to attempt to reduce DAMA among child patients and to protect them from the consequences of such discharges.


Mesh expansion release of the lateral patellar retinaculum during total knee arthroplasty.
Release of the lateral patellar retinaculum can be used to treat patellofemoral instability and to balance the extensor mechanism during knee replacement operations. However, conventional lateral release disrupts the integrity of the lateral knee capsule, may damage the blood supply to the patella, and is associated with several other potential complications. Mesh expansion release of the lateral patellar retinaculum was developed to achieve the goal of lateral release and to reduce the potential for postoperative morbidity. Thirteen consecutive knees in eleven patients were treated with mesh expansion lateral release during a total knee arthroplasty and were evaluated after a minimum duration of follow-up of two years. The mesh release technique consisted of multiple, longitudinal, parallel 5 to 10-mm stab incisions to mesh and expand the lateral patellar retinaculum and thereby medialize the patella in the trochlear groove of the femoral implant. Mesh expansion lateral release balanced the extensor mechanism in each knee, maintained the mechanical integrity of the lateral capsule, and avoided disruption of the lateral genicular blood supply to the patella. After a minimum duration of follow-up of two years, no complications had been noted in association with mesh expansion lateral release. Mesh expansion release of the lateral patellar retinaculum effectively balanced the patellofemoral joint during total knee arthroplasty, maintained the integrity of the lateral capsule, and preserved the lateral genicular blood supply.


Systemic therapy in bladder cancer.
Systemic chemotherapy is essential for the management of muscle-invasive bladder cancer (MIBC) and metastatic bladder cancer (BCa). Neoadjuvant chemotherapy is key to the management of MIBC with many cisplatin-based regimens. Adjuvant chemotherapy may be considered for selected patients who did not receive neoadjuvant therapy. Systemic chemotherapy with radiotherapy is a critical component of a trimodal bladder-preserving approach and is superior to radiotherapy alone. Cisplatin-based chemotherapy has been the mainstay for metastatic BCa. Immunotherapy in the form of checkpoint inhibitors is a promising new drug for the treatment of BCa. Molecular characterization of each individual BCa is likely to lead to a target-directed therapeutic revolution.


Surveillance for Violent Deaths - National Violent Death Reporting System, 27 States, 2015.
In 2015, approximately 62,000 persons died in the United States as a result of violence-related injuries. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) regarding violent deaths from 27 U.S. states for 2015. Results are reported by sex, age group, race/ethnicity, location of injury, method of injury, circumstances of injury, and other selected characteristics. 2015. NVDRS collects data regarding violent deaths obtained from death certificates, coroner/medical examiner reports, law enforcement reports, and secondary sources (e.g., child fatality review team data, supplemental homicide reports, hospital data, and crime laboratory data). This report includes data from 27 states that collected statewide data for 2015 (Alaska, Arizona, Colorado, Connecticut, Georgia, Hawaii, Kansas, Kentucky, Maine, Maryland, Massachusetts, Michigan, Minnesota, New Hampshire, New Jersey, New Mexico, New York, North Carolina, Ohio, Oklahoma, Oregon, Rhode Island, South Carolina, Utah, Vermont, Virginia, and Wisconsin). NVDRS collates documents for each death and links deaths that are related (e.g., multiple homicides, a homicide followed by a suicide, or multiple suicides) into a single incident. For 2015, NVDRS captured 30,628 fatal incidents involving 31,415 deaths in the 27 states included in this report. The majority (65.1%) of deaths were suicides, followed by homicides (23.5%), deaths of undetermined intent (9.5%), legal intervention deaths (1.3%) (i.e., deaths caused by law enforcement and other persons with legal authority to use deadly force, excluding legal executions), and unintentional firearm deaths (<1.0%). (The term "legal intervention" is a classification incorporated into the International Classification of Diseases, Tenth Revision [ICD-10] and does not denote the lawfulness or legality of the circumstances surrounding a death caused by law enforcement.) Demographic patterns varied by manner of death. Suicide rates were highest among males, non-Hispanic American Indian/Alaska Natives, non-Hispanic whites, adults aged 45-54 years, and men aged ≥75 years. The most common method of injury was a firearm. Suicides often were preceded by a mental health, intimate partner, substance abuse, or physical health problem, or a crisis during the previous or upcoming 2 weeks. Homicide rates were higher among males and persons aged <1 year and 20-34 years. Among males, non-Hispanic blacks accounted for the majority of homicides and had the highest rate of any racial/ethnic group. Homicides primarily involved a firearm, were precipitated by arguments and interpersonal conflicts, were related to intimate partner violence (particularly for females), or occurred in conjunction with another crime. When the relationship between a homicide victim and a suspected perpetrator was known, an acquaintance/friend or an intimate partner frequently was involved. Legal intervention death rates were highest among males and persons aged 20-54 years; rates among non-Hispanic black males were approximately double the rates of those among non-Hispanic white males. Precipitating circumstances for legal intervention deaths most frequently were an alleged criminal activity in progress, the victim reportedly using a weapon in the incident, a mental health or substance abuse problem (other than alcohol abuse), an argument or conflict, or a recent crisis (during the previous or upcoming 2 weeks). Unintentional firearm deaths were more frequent among males, non-Hispanic whites, and persons aged 10-24 years; these deaths most often occurred while the shooter was playing with a firearm and most often were precipitated by a person unintentionally pulling the trigger or mistakenly thinking the firearm was unloaded. Deaths of undetermined intent were more frequent among males, particularly non-Hispanic black and American Indian/Alaska Native males, and persons aged 30-54 years. Substance abuse, mental health problems, physical health problems, and a recent crisis were the most common circumstances preceding deaths of undetermined intent. In 2015, approximately 3,000 current or former military personnel died by suicide. The majority of these decedents were male, non-Hispanic white, and aged 45-74 years. Most suicides among military personnel involved a firearm and were precipitated by mental health, physical health, and intimate partner problems, as well as a recent crisis. This report provides a detailed summary of data from NVDRS for 2015. The results indicate that deaths resulting from self-inflicted or interpersonal violence most frequently affect males and certain age groups and minority populations. Mental health problems, intimate partner problems, interpersonal conflicts, and general life stressors were primary precipitating events for multiple types of violent deaths, including suicides among current or former military personnel. NVDRS data are used to monitor the occurrence of violence-related fatal injuries and assist public health authorities in the development, implementation, and evaluation of programs and policies to reduce and prevent violent deaths. For example, Virginia VDRS data are used to help identify suicide risk factors among active duty service members, Oregon VDRS suicide data are used to coordinate information and activities across community agencies that support veterans and active duty service members, and Arizona VDRS data are used to develop recommendations for primary care providers who deliver care to veterans. The continued development and expansion of NVDRS to include all 50 states, U.S. territories, and the District of Columbia are essential to public health efforts to reduce deaths due to violence.