Endoscopic treatment of chronic pancreatitis in pediatric population: Long-term efficacy and safety.
Chronic pancreatitis (CP) in children is an inreasingly recognized disease. The purpose of study was to analyse the safety and long-term efficacy of endoscopic treatment in children with CP. Records of 38 patients aged <18 years, referred to the Digestive Endoscopy Unit at Catholic University, Fondazione Policlinico "A. Gemelli" IRCCS between 1991 and 2017, were reviewed. Abdominal pain, analgesia and number of episodes of acute pancreatitis in the pre- and post- endoscopic retrograde cholangiopancreatography (ERCP) period were evaluated. Need for surgery was assessed. Therapeutic intervention data and complications were interrogated. In total 158 ERCPs were performed. Median post-ERCP follow-up was 7 years. The majority of patients had CP type IV (47%) and type Ib (37%) (Cremer's classification). Major papilla pancreatic sphincterotomy was performed in 47%, major and minor in 24% and minor in 29% of patients. Stones/plugs were removed in at least one ERCPs in 66% individuals. Eleven out of 38 patients had stricture of the pancreatic duct; these were dilated and stented in 5/11 and stented in 6/11. Five complications were recorded (3%). Severity and frequency of abdominal pain improved significantly; p < 0.001. Use of analgesia and number of episodes of acute pancreatitis decreased significantly; p < 0.001. One child required subsequent surgery. Endoscopic management of symptomatic CP in children is safe and effective.


Dopaminergic regulation of the serotonergic raphe-striatal pathway: microdialysis studies in freely moving rats.
Morphological evidence demonstrates the existence of dopaminergic afferent pathways and dopamine (DA)-containing neurons in the dorsal raphe nucleus (DRN). In a recent report, a DA D2-like receptor-mediated regulation of serotonin (5-HT) extracellular concentration in DRN has been found. Given the existence of somatodendritic 5-HT1A autoreceptors in the DRN, changes of the extracellular concentration of 5-HT in the vicinity of cell bodies and dendrites may be relevant for the control of the activity of ascending serotonergic pathways. In the present brain microdialysis study we have used a chromatographic method (HPLC) enabling the simultaneous measurement of DA, 5-HT, and their main metabolites dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA). The presence of a neuronal pool of DA within the DRN was revealed by the local infusion of amphetamine (10 microM), which significantly increased the extracellular concentration of both amines. The local striatal infusion (10 microM) of the selective DA D1-like agonist SKF-38393, the selective DA D2-like agonist quinpirole (LY 171,555), or the nonselective DA agonist apomorphine markedly decreased DA and DOPAC extracellular concentrations and failed to modify 5-HT or 5-HIAA in the striatum, indicating the lack of terminal (striatal) control of 5-HT release by dopaminergic transmission. In contrast, the systemic administration of apomorphine (2.8 mumol/kg, s.c.) significantly increased the extracellular concentration of 5-HT in the DRN and decreased it in the striatum. The reduction of striatal 5-HT extracellular concentration was prevented by the previous administration of the selective 5-HT1A receptor antagonist WAY 100135 (17.6 mumol/kg, s.c.), which by itself did not change extracellular 5-HT in striatum.(ABSTRACT TRUNCATED AT 250 WORDS)


Eupafolin regulates non-small-cell lung cancer cell proliferation,migration, and invasion by suppressing MMP9 and RhoA via FAK/PI3K/AKT signaling pathway.
Non-small-cell lung cancer (NSCLC) predominates lung cancer with a striking percentage of 85%. Eupafolin is documented to possess anti-tumor efficacy, which prompts efforts to uncover its impacts on the pathology of diseases including cancers. Focal adhesion kinase (FAK)-mediated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) has been found to be associated with several carcinomas. Nevertheless, how eupafolin exerts its effects in NSCLC and whether FAK/PI3K/AKT is related to the corresponding mechanism remain unclear. Thus, the relevant experiments were carried out with NSCLC cells treated with eupafolin and/or LY294002 at first. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing, and transwell assays were used to assess cell viability, proliferation, migration, and invasion, respectively. Western blot assay was performed to measure the relative protein expressions of phosphorylated (p)-FAK/FAK, p-PI3K/ PI3K, p-AKT/AKT, matrix metalloproteinase 9 (MMP9), and ras homolog gene family member A (RhoA), and to determine transfection efficiency. From experimental results, it was found that eupafolin inhibited the viability, proliferation, migration, and invasion of NSCLC cells, and inactivated the FAK/PI3K/AKT pathway by downregulating the ratios of p-FAK/FAK, p-PI3K/PI3K, and p-AKT/AKTand the expressions of MMP9 and RhoA. On the contrary, overexpressed FAK upregulated the expressions of FAK, MMP9, and RhoA and the ratios of p-PI3K/ PI3K and p-AKT/AKT, and promoted cell proliferation, migration, and invasion. LY294002, conversely, could partly reverse the effects of FAK on the aforementioned aspects of NSCLC cells. Collectively, it was verified in our study that eupafolin regulates the proliferation, migration, and invasion of NSCLC cells by downregulating MMP9 and RhoA expressions via the FAK/PI3K/AKT axis, which may provide a promising avenue for cancer therapy.


Identification and characterization of cDNA clones encoding two homologous proteins that are part of the asialoglycoprotein receptor.
The asialoglycoprotein receptor (ASGP-R) from rat liver contains the following three distinct protein species when it is analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis: RHL1 (42 kilodaltons), RHL2 (49 kilodaltons), and RHL3 (54 kilodaltons). In this paper we describe the isolation of cDNA clones encoding RHL1 and RHL2 from a cDNA library constructed from rat liver mRNA. A comparison of the predicted coding sequence for RHL2 with that for RHL1 showed that these sequences are highly homologous. The library also contained numerous cDNA clones for both RHL1 and RHL2 that were derived from unspliced precursor mRNAs. Differential splicing at the 5' end of the RHL1 transcript was inferred from the finding that two different types of RHL1 cDNA were identified, each having a different 5' terminus.


Cytokine use and survival in the first-line treatment of ovarian cancer: a Gynecologic Oncology Group Study.
Granulocyte colony stimulating factor (G-CSF) and erythropoietin stimulating agents (ESA) may be used to support patients during chemotherapy. We assessed whether G-CSF or ESA were associated with progression or death in patients with ovarian cancer. Patients with ovarian cancer following surgery, were on a protocol to evaluate bevacizumab with chemotherapy. Guidelines for administering G-CSF and ESA were specified in the protocol. Overall survival (OS) was analyzed with landmark procedures and multivariate, time-dependent hazard models. Eighteen-hundred-seventy-three women were enrolled, with no differences in clinical and pathologic variables among treatment group. Performance status, hemoglobin, and white cell counts were associated with G-CSF and/or ESA usage during treatment. Nine patients received no protocol directed therapy, leaving 1864 patients for this review. One-thousand-one-hundred-twenty-five patients received neither ESA nor G-CSF; 311 received G-CSF but no ESA; 241 received ESA but no G-CSF; and 187 received both. Median survival following a five month landmark from the start of treatment was 34 versus 38 months for those who did versus did not receive ESA (multivariate hazard ratio: 0.989; 95% confidence interval: 0.849-1.15) and 40 versus 37 months for those who did versus did not receive G-CSF (multivariate hazard ratio: 0.932; 95% confidence interval: 0.800-1.08). Neither ESA nor G-CSF had a negative impact on survival after adjustment of prognostic factors among patients with ovarian cancer receiving chemotherapy. ESA may appear to be associated with shorter survival in univariate analyses because factors prognostic for ESA use are also prognostic for progression-free survival.


Impact of achieving a complete response to initial therapy of multiple myeloma and predictors of subsequent outcome.
Achievement of a complete response (CR) in multiple myeloma (MM) correlates with improvement in survival outcomes; however, its impact on prognostic variables at baseline outside of clinical trial settings is not well described. We sought to determine the impact of achieving a CR within 2 years from diagnosis, its effect on the prognostic value of fluorescence in situ hybridization (FISH) and International Staging System (ISS) risk, and examined additional predictors of outcome among those achieving a CR in a routine clinical setting. We evaluated 1869 newly diagnosed MM patients who had ≥ 2 monoclonal protein immunofixation studies in the serum and urine available within 24 months from diagnosis, categorizing those with ≥ 2 negative serum and urine immunofixations as achieving CR. With a landmark at 24 months, median progression-free survival (PFS) for CR versus non-CR patients was 29.8 versus 20.9 months (p ≤ .0002); median overall survival (OS) was 104 versus 70 months (p < .0001). The impact of achieving a CR was retained after adjusting for FISH, ISS, sex, transplant status, and involved heavy chain. Baseline FISH and ISS stage were not associated with PFS or OS among patients achieving a CR. The following variables were found as predictors of inferior OS within the CR cohort: age > 75 years, male gender, hypoalbuminemia, and non-immunoglobulin G involved heavy chain. Our study confirms that achievement of CR within 2 years from diagnosis is associated with improvement in survival outcomes and neutralization of the impact of FISH and ISS risk, thereby confirming observations from the clinical trial setting among a clinical practice cohort.


Glucose counterregulation during prolonged hypoglycemia in normal humans.
To study glucose counterregulation under conditions approximating those of clinical disorders in which hypoglycemia develops gradually and is reversed over a prolonged period, we injected regular insulin subcutaneously, in a dose (0.15 U/kg) selected to produce two- to threefold increases in plasma insulin, in 11 normal human volunteers and measured plasma glucose, insulin, C-peptide, and counterregulatory hormone concentrations as well as rates of glucose production, glucose utilization, and insulin secretion over 12 h. The data suggest that the mechanisms of gradual recovery from prolonged hypoglycemia may differ from those of rapid recovery from short-term hypoglycemia produced by intravenous injection of insulin in that 1) both stimulation of glucose production and limitation of glucose utilization contribute to recovery from prolonged hypoglycemia; 2) increases in glucagon, epinephrine, growth hormone, and cortisol secretion as well as a decrease in insulin secretion may all participate in glucose counterregulation during prolonged hypoglycemia; 3) epinephrine may play a more important role than glucagon during prolonged hypoglycemia. The latter two conclusions are based primarily on the temporal relationships between changes in the rates of glucose turnover and changes in plasma hormone concentrations and should not be considered proved. However, they provide the basis for testable hypotheses concerning the physiology of gradual recovery from prolonged hypoglycemia that can be expected to be relevant to the pathophysiology of clinical hypoglycemia.


Selecting Valid Correlation Areas for Automated Bullet Identification System Based on Striation Detection.
Some automated bullet identification systems calculate a correlation score between two land impressions to measure their similarity. When extracting a compressed profile from the land impression of a fired bullet, inclusion of areas that do not contain valid individual striation information may lead to sub-optimal extraction and therefore may deteriorate the correlation result. In this paper, an edge detection algorithm and selection process are used together to locate the edge points of all tool-mark features and filter out those not corresponding to striation marks. Edge points of the resulting striation marks are reserved and expanded to generate a mask image. By imposing the mask image on the topography image, the weakly striated area(s) are removed from the expressed profile extraction. Using this method, 48 bullets fired from 12 gun barrels of six manufacturers resulted in a higher matching rate than previous studies.


Upregulation of VEGF and FGF2 in normal rat brain after experimental intraoperative radiation therapy.
The expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)2 in the irradiated brain was examined to test how a single high dose radiation, similar to that used for intraoperative radiation therapy given to the normal cerebrum, can affect the vascular endothelium. After a burr hole trephination in the rat skull, the cerebral hemisphere was exposed to a single 10 Gy dose of gamma rays, and the radiation effect was assessed at 1, 2, 4, 6, and 8 weeks after irradiation. Histological changes, such as reactive gliosis, inflammation, vascular proliferation and necrosis, were correlated with the duration after irradiation. Significant VEGF and FGF2 expression in the 2- and 8-week were detected by enzyme-linked immunosorbent assay quantification in the radiation group. Immunohistochemical study for VEGF was done and the number of positive cells gradually increased over time, compared with the sham operation group. In conclusion, the radiation injuries consisted of radiation necrosis associated with the expression of VEGF and FGF2. These findings indicate that VEGF and FGF2 may play a role in the radiation injuries after intraoperative single high-dose irradiation.


Precambrian perspectives.
The Precambrian record is interpreted in terms of an evolutionary progression that moves in the direction of increasing continental stability. An early, highly mobile microplate tectonics phase progressed through a more stable, largely intracratonic, ensialic, mobile belt phase to the modern macroplate tectonics phase that involves large, rigid lithospheric plates. Various phases are characterized by distinctive crustal associations. Three controls-bulk earth heat production, crustal fractionation and cratonization, and atmospheric oxygen accumulation-are viewed as the cumulative cause of the trends and events that characterize the crust at different stages of development, from its inception approximately 4.6 billion years ago to the present.


Nicotine dependence and its association with health utility ratings among a sample of Indian dental patients.
To measure utility ratings and quality-adjusted life-years(QALYs) for nicotine dependence-related health states using the standard gamble approach among a sample of dental patients; investigate the possible associations of nicotine dependence, and study the influences on tobacco-related health state utilities estimates among patients. A sample of 200 adult outpatients who were current or former consumers of tobacco were included in the cross-sectional study. Demographic, oral health self-rating and tobacco-related data (Fagerstrom scale for nicotine dependence, type of tobacco consumed, frequency and duration of the habit) were collected. A standard gamble method of utility valuation was also carried out. Older age, lower educational attainment, higher frequency of consumption, increased duration of the habit, consumption of chewing tobacco, as opposed to smoking tobacco, and poor oral health were associated with higher nicotine dependence. Lower nicotine dependence, better oral health and quitting the habit were associated with better health utility estimates. QALYs lost due to the habit among the 'low to moderate' and 'significant' nicotine dependence groups were 2.7 (sd, 3.7) and 6.7 (sd, 8.0) years, respectively. Higher health utility ratings were seen among patients with 'low to moderate' nicotine dependence, better oral health status and quitters of the tobacco habit. Quality of life weights generated through this method could be used for cost-utility analyses of tobacco cessation/prevention interventions in different settings and cultures.


Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy.
Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 (V(1393)I, K(1584)E) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6(V(1393)I) and TRPM6(K(1584)E), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T(1391)) and TRPM6(S(1583)). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6(V(1393)I) and TRPM6(K(1584)E) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6(V(1393)I) and TRPM6(K(1584)E) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.


Immunopurification and characterization of rat adipocyte caveolae suggest their dissociation from insulin signaling.
Adipocytes play an important role in the insulin-dependent regulation of organismal fuel metabolism and express caveolae at levels as high or higher than any other cell type. Recently, a link between insulin signaling and caveolae has been suggested; nevertheless, adipocyte caveolae have been the subject of relatively few studies, and their contents have been minimally characterized. With the aid of a new monoclonal antibody, we developed a rapid procedure for the immunoisolation of caveolae derived from the plasma membrane of adipocytes, and we characterized their protein content. We find that immunopurified adipocyte caveolae have a relatively limited protein composition, and they lack the raft protein, flotillin, and insulin receptors. Immunogold labeling and electron microscopy of the adipocyte plasma membrane confirmed the lack of insulin receptors in caveolae. In addition to caveolins, the structural components of caveolae, their major protein constituents, are the semicarbazide-sensitive amine oxidase and the scavenger lipoprotein receptor CD36. The results are consistent with a role for caveolae in lipid flux in and of adipocytes.


Assortative pairing in Ixodes ricinus (Acari: Ixodidae), the European vector of Lyme borreliosis.
In sexual organisms, the way in which gametes associate can greatly influence the maintenance of genetic variation, the structure of this variation in space, and ultimately organismal evolution. Based on patterns of genetic structure previously found, we explicitly tested whether adults of the sheep tick Ixodes ricinus pair according to their genetic relatedness. We sampled tick pairs from the vegetation in four natural populations and genotyped individual ticks at seven microsatellite loci. Based on this data, we observed highly significant assortative mating in two of the four locations, a pattern that could not be accounted for by a spatial autocorrelation in the distribution of related ticks. One explanation for these observations may be the existence of local host associations that develop independently in different populations. Assortative mating in I. ricinus will have clear consequences for its population dynamics and, through processes of adaptation and transmission, may significantly alter the epidemiological patterns of the pathogens it carries, including the Lyme disease agent Borrelia burgdorferi s.l. Future tests will now be required to examine the mechanisms leading to this pattern and its epidemiological consequences.


IQGAP2, A candidate tumour suppressor of prostate tumorigenesis.
Loss of IQGAP2 contributes to the tumorigenesis of hepatocellular carcinoma and gastric cancer. However, whether IQGAP2 also suppresses prostate tumorigenesis remains unclear. We report here that IQGAP2 is a candidate tumour suppressor of prostate cancer (PC). Elevated IQGAP2 was detected in prostatic intraepithelial neoplasia (PIN), early stages of PCs (Gleason score ≤3), and androgen-dependent LNCaP PC cells. However, IQGAP2 was expressed at substantially reduced levels not only in prostate glands and non-tumorigenic BPH-1 prostate epithelial cells but also in advanced (Gleason score 4 or 5) and androgen-independent PCs. Furthermore, xenograft tumours that were derived from stem-like DU145 cells displayed advanced features and lower levels of IQGAP2 in comparison to xenograft tumours that were produced from non stem-like DU145 cells. Collectively, these results suggest that IQGAP2 functions in the surveillance of prostate tumorigenesis. Consistent with this concept, ectopic IQGAP2 reduced the proliferation of DU145, PC3, and 293T cells as well as the invasion ability of DU145 cells. While ectopic IQGAP2 up-regulated E-cadherin in DU145 and PC3 cells, knockdown of IQGAP2 reduced E-cadherin expression. In primary PC and DU145 cells-derived xenograft tumours, the majority of tumours with high levels of IQGAP2 were strongly-positive for E-cadherin. Therefore, IQGAP2 may suppress PC tumorigenesis, at least in part, by up-regulation of E-cadherin. Mechanistically, overexpression of IQGAP2 significantly reduced AKT activation in DU145 cells and inhibition of AKT activation upregulated E-cadherin, suggesting that IQGAP2 increases E-cadherin expression by inhibiting AKT activation. Taken together, we demonstrate here that IQGAP2 is a candidate tumour suppressor of PC.


Reduction of myoblast differentiation following multiple population doublings in mouse C2 C12 cells: a model to investigate ageing?
Ageing skeletal muscle displays declines in size, strength, and functional capacity. Given the acknowledged role that the systemic environment plays in reduced regeneration (Conboy et al. [2005] Nature 433: 760-764), the role of resident satellite cells (termed myoblasts upon activation) is relatively dismissed, where, multiple cellular divisions in-vivo throughout the lifespan could also impact on muscular deterioration. Using a model of multiple population doublings (MPD) in-vitro thus provided a system in which to investigate the direct impact of extensive cell duplications on muscle cell behavior. C(2) C(12) mouse skeletal myoblasts (CON) were used fresh or following 58 population doublings (MPD). As a result of multiple divisions, reduced morphological and biochemical (creatine kinase, CK) differentiation were observed. Furthermore, MPD cells had significantly increased cells in the S and decreased cells in the G1 phases of the cell cycle versus CON, following serum withdrawal. These results suggest continued cycling rather than G1 exit and thus reduced differentiation (myotube atrophy) occurs in MPD muscle cells. These changes were underpinned by significant reductions in transcript expression of: IGF-I and myogenic regulatory factors (myoD and myogenin) together with elevated IGFBP5. Signaling studies showed that decreased differentiation in MPD was associated with decreased phosphorylation of Akt, and with later increased phosphorylation of JNK1/2. Chemical inhibition of JNK1/2 (SP600125) in MPD cells increased IGF-I expression (non-significantly), however, did not enhance differentiation. This study provides a potential model and molecular mechanisms for deterioration in differentiation capacity in skeletal muscle cells as a consequence of multiple population doublings that would potentially contribute to the ageing process.


Molecular surveillance of rotavirus strains circulating in Yaoundé, Cameroon, September 2007-December 2012.
Rotavirus is the most common cause of severe diarrheal disease in children under 5 years of age worldwide. The World Health Organization (WHO) estimated that 453,000 rotavirus-attributable deaths occur annually. Through the WHO, the Rotavirus Sentinel Surveillance Program was established in Cameroon in September 2007 with the Mother and Child Center (MCC) in Yaoundé playing the role of sentinel site and national laboratory for this program. The objectives of this surveillance were to assess the rotavirus disease burden and collect baseline information on rotavirus strains circulating in Cameroon. Diarrheal stool samples were collected in a pediatric hospital from children under 5, using the WHO case definition for rotavirus diarrhea. Antigen detection of rotavirus was performed by using an enzyme immunoassay (EIA). The genotypic characterization was performed using multiplexed semi-nested reverse transcription-polymerase chain reaction (RT-PCR) assays. Between September 2007 and December 2012, 2444 stool samples were received at the MCC laboratory for rotavirus antigen detection, of which 999 (41%) were EIA positive. Among EIA positive samples 898 were genotyped. Genotype prevalence varied each year. Genotype G9P[8] was the dominant type during 2007 (32%) and 2008 (24%), genotype G3P[6] predominated in 2010 (36%) and 2011 (25%), and G1P[8] was predominant in 2012 (44%). The findings showed that the rotavirus disease burden is high and there is a broad range of rotavirus strains circulating in Yaoundé. These data will help measure the impact of vaccination in the future.


Genome oligopaint via local denaturation fluorescence in situ hybridization.
Cas9 in complex with a programmable guide RNA targets specific double-stranded DNA for cleavage. By harnessing Cas9 as a programmable loader of superhelicase to genomic DNA, we report a physiological-temperature DNA fluorescence in situ hybridization (FISH) method termed genome oligopaint via local denaturation (GOLD) FISH. Instead of global denaturation as in conventional DNA FISH, loading a superhelicase at a Cas9-generated nick allows for local DNA denaturation, reducing nonspecific binding of probes and avoiding harsh treatments such as heat denaturation. GOLD FISH relies on Cas9 cleaving target DNA sequences and avoids the high nuclear background associated with other genome labeling methods that rely on Cas9 binding. The excellent signal brightness and specificity enable us to image nonrepetitive genomic DNA loci and analyze the conformational differences between active and inactive X chromosomes. Finally, GOLD FISH could be used for rapid identification of HER2 gene amplification in patient tissue.


Accessing primary health care: a meta-ethnography of the experiences of British South Asian patients with diabetes, coronary heart disease or a mental health problem.
To develop an explanatory framework of the problems accessing primary care health services experienced by British South Asian patients with a long-term condition or mental health problem. This study used meta-ethnographic methods. Published qualitative studies were identified from a structured search of six databases and themes synthesized across studies to develop a new explanatory framework. Initial searches identified 951 potentially relevant records from which a total of 27 articles were identified that met inclusion and exclusion criteria. Twelve of these articles were chosen on the basis of their quality and relevance. These 12 articles described themes relating to the cultural, spatial and temporal dimensions of patient experiences of accessing and using health care. Our interpretive synthesis showed that access to primary care among British South Asians with diabetes, coronary heart disease and psychological health problems is co-constructed and negotiated over time and space along the key domains of the candidacy model of access: from help-seeking to interactions at the interface to following treatment advice. In the case of each condition, British South Asians' claims to candidacy were constrained where their individual as well as broader social and cultural characteristics lacked fit with professionals' ways of working and cultural typifications. Interventions that positively affect professionals' capacity to support patient claims to candidacy are likely to help support British South Asians overcome a broad range of barriers to care for physical and mental health problems.


Association of altered hemorheology with oxidative stress and inflammation in metabolic syndrome.
We have shown increased whole blood viscosity (WBV), decreased erythrocyte deformability, and increased erythrocyte aggregation in metabolic syndrome (MetS) in our previous study. The objective of the study was to find out if the altered hemorheology shown in MetS in our previous study is associated with chronic inflammation and oxidative stress in the same subjects. One hundred recruited participants were classified into three groups based on the number of the MetS components present following National Cholesterol Education Program, Adult Treatment Panel III definitions. WBV, erythrocyte aggregation, erythrocyte deformability, oxidative stress markers (erythrocyte reduced glutathione (GSH), superoxide dismutase (SOD), and urinary isoprostanes), inflammatory markers high-sensitivity C-reactive protein (hsCRP), and thrombotic marker D-dimer were measured. Data were analyzed by IBM SPSS 20 software. We found a significant association of altered hemorheology with chronic inflammation and oxidative stress in MetS. There was a linear increase in the level of hsCRP and a linear decrease in the level of SOD and GSH across the quartiles of erythrocyte aggregation. Similarly, the thrombotic marker D-dimer showed a linear increase and oxidative stress marker GSH showed a linear decrease trend across the quartiles of WBV. Alterations of hemorheology in MetS are probably due to the effect of chronic inflammation and oxidative stress. The negative effects of chronic inflammation and oxidative stress on the cardiovascular system could be due to the resulting altered hemorheology.


Effect of cardiopulmonary bypass and surgical intervention on the natriuretic hormone system in children.
We sought to determine the effect of cardiopulmonary bypass and surgical intervention on the natriuretic hormone system in children and to assess whether such changes are associated with morbidity. At 6 perioperative time points in 25 patients, plasma levels of atrial natriuretic peptide, brain natriuretic peptide, and guanosine 3', 5'-monophosphate were measured, and the biologic activity of the natriuretic hormone system was quantified. Relationships were sought between changes in brain natriuretic peptide levels, biologic activity, and a number of morbidity indicators. There was a significant change in atrial natriuretic peptide levels (P = .037), brain natriuretic peptide levels (P = .001), and biologic activity of the natriuretic hormone system (P = .009) over the first 4 time points in the study. Atrial natriuretic peptide levels transiently decreased from baseline to 12 hours after surgical intervention. Compared with baseline values, brain natriuretic peptide levels were increased at 12 hours after surgical intervention and on postoperative day 1. The increase in brain natriuretic peptide levels from baseline to 12 hours after surgical intervention was associated with cardiopulmonary bypass time (r(s) = 0.4, P = .047). The biologic activity transiently decreased from baseline to intensive care unit admission but was not associated with any morbidity indicators. Increased postoperative brain natriuretic peptide levels are associated with longer bypass times. The biologic activity of the natriuretic hormone system is transiently impaired. Larger studies should investigate brain natriuretic peptide as a predictor of postoperative morbidity and the potential for natriuretic hormone infusions to improve postoperative hemodynamics and urine output.


Childhood cognitive ability accounts for associations between cognitive ability and brain cortical thickness in old age.
Associations between brain cortical tissue volume and cognitive function in old age are frequently interpreted as suggesting that preservation of cortical tissue is the foundation of successful cognitive aging. However, this association could also, in part, reflect a lifelong association between cognitive ability and cortical tissue. We analyzed data on 588 subjects from the Lothian Birth Cohort 1936 who had intelligence quotient (IQ) scores from the same cognitive test available at both 11 and 70 years of age as well as high-resolution brain magnetic resonance imaging data obtained at approximately 73 years of age. Cortical thickness was estimated at 81 924 sampling points across the cortex for each subject using an automated pipeline. Multiple regression was used to assess associations between cortical thickness and the IQ measures at 11 and 70 years. Childhood IQ accounted for more than two-third of the association between IQ at 70 years and cortical thickness measured at age 73 years. This warns against ascribing a causal interpretation to the association between cognitive ability and cortical tissue in old age based on assumptions about, and exclusive reference to, the aging process and any associated disease. Without early-life measures of cognitive ability, it would have been tempting to conclude that preservation of cortical thickness in old age is a foundation for successful cognitive aging when, instead, it is a lifelong association. This being said, results should not be construed as meaning that all studies on aging require direct measures of childhood IQ, but as suggesting that proxy measures of prior cognitive function can be useful to take into consideration.


Microbiome Modulation-Toward a Better Understanding of Plant Microbiome Response to Microbial Inoculants.
Plant-associated microorganisms are involved in important functions related to growth, performance and health of their hosts. Understanding their modes of action is important for the design of promising microbial inoculants for sustainable agriculture. Plant-associated microorganisms are able to interact with their hosts and often exert specific functions toward potential pathogens; the underlying in vitro interactions are well studied. In contrast, in situ effects of inoculants, and especially their impact on the plant indigenous microbiome was mostly neglected so far. Recently, microbiome research has revolutionized our understanding of plants as coevolved holobionts but also of indigenous microbiome-inoculant interactions. Here we disentangle the effects of microbial inoculants on the indigenous plant microbiome and point out the following types of plant microbiome modulations: (i) transient microbiome shifts, (ii) stabilization or increase of microbial diversity, (iii) stabilization or increase of plant microbiome evenness, (iv) restoration of a dysbiosis/compensation or reduction of a pathogen-induced shift, (v) targeted shifts toward plant beneficial members of the indigenous microbiota, and (vi) suppression of potential pathogens. Therefore, we suggest microbiome modulations as novel and efficient mode of action for microbial inoculants that can also be mediated via the plant.


Macroscopic assessment of the quality of cold perfusion after deceased-donor kidney procurement: A United Kingdom population-based cohort study.
Concern regarding the quality of cold perfusion (QOP) during macroscopic assessment of procured kidneys is a common reason for discard. In the UK, QOP is routinely graded by both retrieving and implanting teams during back-bench surgery as: 1 (good), 2 (fair), 3 (poor) or 4 (patchy). We evaluated the association of this grading with organ utilization, graft outcomes, and agreement between teams. Data on all deceased-donor kidneys procured between January 2000 and December 2016 were analyzed for discard rates, while association with graft outcomes was studied in single adult transplants. Of 31,167 kidneys procured, 90.6%, 5.7%, 1.7%, and 2.1% were assigned grades 1, 2, 3, and 4, respectively, at retrieval. QOP was an independent risk factor of discard, with the highest rates observed in grade 3 kidneys (41.8%), compared to 6.5% in grade 1 (aOR 7.67, 95% CI 5.44-10.82, p < .001). Grading at retrieval was an independent predictor of delayed graft function (p = .019) and primary non-function (p = .001), but not long-term graft survival (p = .111). Implanting grade was an independent predictor of all three outcomes (p < .001, p < .001, and p = .002, respectively). Consistency of grading between teams was poor (Kappa = 0.179). QOP influences utilization and predicts outcomes, but a standardized and validated scoring system is required.


Lanosterol Disrupts the Aggregation of Amyloid-β Peptides.
Lanosterol, an amphipathic molecule, was discovered only very recently to effectively hinder the aggregation of lens proteins and dissolve the extremely stable fibrillar aggregates in cataracts. Here, we combined computational and experimental approaches to study how lanosterol disrupts the aggregation of another important peptide, amyloid-β (Aβ) peptide, associated with the Alzheimer's Disease (AD). Molecular dynamics simulations using the core amyloidogenic segment (KLVFFA) of Aβ peptide revealed that lanosterol exhibits at least two types of inhibition mechanism on the self-assembly of Aβ peptides. First, lanosterol entangles with peptides and forms a hydrophobic core with residues Phe-19 and Phe-20 in particular. Second, it interferes with the steric zipper interaction at the β-sheet-β-sheet interface. These simulation data suggest that lanosterol induces the unfolding of the Aβ peptide and the separation of the β-sheet layers. This predicted inhibition effect of lanosterol was then confirmed by an in vitro ThT fluorescence assay and AFM imaging. The cell toxicity assay also showed that the treatment of lanosterol indeed mitigates the cytotoxicity of the Aβ peptide in PC-12 cells. Moreover, lanosterol shows a stronger suppression effect on Aβ peptides' aggregation than cholesterol because of its higher hydrophobicity. This result establishes a foundation for the development of lanosterol-based potential therapies for AD and other protein conformational diseases.


Healthcare professionals' perceptions of the barriers to living donor kidney transplantation among African Americans.
The number of African Americans participating in living donations continues to remain low. Although researchers have identified multiple barriers to cadaveric donation, relatively little is known about barriers to living kidney donation among this population. We conducted three focus groups of healthcare professionals from a transplant center in South Carolina to determine their perceptions of barriers to living kidney donation among African Americans. An African-American and a Caucasian member of the project team facilitated the groups. Sessions were taped, transcribed and analyzed for key themes. Eighteen transplant professionals participated in the three focus groups, including physicians, transplant coordinators, pharmacists and a data coordinator. Analysis of the transcripts revealed the following perceived barriers to living kidney donation among African Americans: 1) pre-existing medical conditions, 2) financial concerns, 3) reluctance to ask family members and/or friends, 4) distrust of the medical community, 5) fear of surgery, and 6) lack of awareness about living donor kidney transplantation. In addition to previously described barriers to cadaveric donation, this study identified barriers unique to living donation, such as pre-existing medical conditions, financial concerns, reluctance to ask a living donor and fear of surgery.


Malignant lymphoma of the skin in children.
The clinical and histopathologic findings in eight cases of malignant lymphoma of the skin in children are presented. All patients had skin lesions as a primary manifestation of the disorder. Three patients had simultaneous regional lymph node involvement documented by the findings of subsequent biopsies. The majority (five patients) had solitary nodules involving the skin of the head and neck region. Three of the skin biopsy specimens were classified as lymphoblastic lymphoma, two large cell lymphoma, two mixed small and large cell lymphoma, and one small cleaved cell lymphoma. Disseminated disease subsequently developed in four patients in an interval that ranged from 4 to 30 months after diagnosis. The follow-up period ranged from 8 to 56 months, and median survival was 56 months. A literature review of 33 previously reported patients and our eight patients indicate that: skin of the head and the neck region is the most common site of involvement (56%); the majority of lymphomas are diffuse (93%); lymphoblastic lymphoma is the predominant type (53%), with a high proportion showing a non-T-cell phenotype; Burkitt's lymphoma and Hodgkin's disease of the skin are extremely rare; and most patients presented in an early clinical stage (Stage IE 56%, Stage IIE 21%), and prolonged disease-free survival was seen mostly in Stage I patients. The cumulative probability of survival for Stage I patients at 24 months was 0.71; while for Stages II to IV patients combined, it was 0.33 at 26 months.


Tribocorrosion in shoulder arthroplasty humeral component retrievals.
Tribocorrosion at the modular taper connections of total hip implants has been associated with trunnionosis and adverse local tissue reactions. Modularity is also widely used in shoulder arthroplasty implants, but little information exists about the potential for tribocorrosion. This study hypothesized that there would be mild or no tribocorrosion in a series of retrieved shoulder implants. A total of 28 implants with a mean implantation time of 6.2 ± 6.0 years were evaluated using a validated damage scoring method. Implant tapers on the head and stem were divided into upper (deepest) and lower zones and independently scored for fretting and corrosion damage from 1 (none) to 4 (severe). Corrosion was present on 32% of heads and 38% of stems, whereas fretting was present on 36% of heads and 46% of stems. There was significantly greater (P = .02) corrosion in the lower zone of the retrieved stems (1.4 ± 0.5) than there was in the upper zone (1.1 ± 0.3). Correlation between the head and stem corrosion for lower zone was moderate (r = 0.41; P = .04). Tribocorrosion was present on the heads and stems of some of the retrieved shoulder implants examined in this study. The incidence of tribocorrosion in shoulder implants was lower than in reported cases of retrieved hip implants. The greatest damage was in the lower zone of the taper, where the connection may be exposed to the surrounding joint fluid. It remains to be seen whether this leads to any clinical presentation of trunnionosis.


Pulse propagation effects in optical 2D Fourier-transform spectroscopy: experiment.
In optical two-dimensional Fourier-transform (2DFT) spectroscopy, understanding how the spectral line shape is affected by pulse propagation in the sample is crucial for an accurate interpretation of spectra. We report an experimental study of pulse propagation effects in 2DFT spectroscopy performed in a dense atomic vapor. The spectral line shape can be dramatically distorted due to high optical density as well as the physical thickness of a sample. The spectral distortion can be partially corrected by using a reference pulse copropagating with the signal combined with appropriate data processing.


A multi-body model for comparative study of cervical traction simulation - development, improvement and validation.
A computer simulation model was developed to study the dynamic behavior of the cervical spine during cervical traction therapy in inclined and sitting traction positions. The model improved upon an old model with additional components to represent the behavior of the intervertebral discs and the posterior ligaments. The simulation result of the new model was compared against the cervical traction data from a radiographic experiment in both positions. The simulation results of the old model and new model were compared to illustrate the improvement. Using the new model, we compared the timing response of cervical traction in the inclined and sitting positions.


Efficacy of different doses of sugammadex after continuous infusion of rocuronium.
To evaluate the effects of two different doses of sugammadex after maintenance anesthesia with sevofluorane and remifentanil and deep rocuronium-induced neuromuscular blockade (NMB). Patients between 20 and 65 years of age, with American Society of Anesthesiologists physical status classification I-II, undergoing gynecological surgery were included in a prospective, comparative and randomized study. NMB was induced with an injection of 0.6 mg/kg of rocuronium followed by continuous infusion of 0.3-0.6 mg/kg per hour to maintain a deep block. Anesthesia was maintained with sevofluorane and remifentanil. Finally, when surgery was finished, a bolus of 2 mg/kg (group A) or 4 mg/kg (group B) of sugammadex was applied when the NMB first response in the train-of-four was reached. The primary clinical endpoint was time to recovery to a train-of-four ratio of 0.9. Other variables recorded were the time until recovery of train-of-four ratio of 0.7, 0.8, hemodynamic variables (arterial blood pressure and heart rate at baseline, starting sugammadex, and minutes 2, 5 and 10) and adverse events were presented after one hour in the post-anesthesia care unit. Thirty-two patients were included in the study: 16 patients in group A and 16 patients in group B. Only 14 patients each group were recorded because arterial pressure values were lost in two patients from each group in minute 10. The two groups were comparable. Median recovery time from starting of sugammadex administration to a train-of-four ratio of 0.9 in group A and B was 129 and 110 s, respectively. The estimated difference in recovery time between groups was 24 s (95%CI: 0 to 45 s, Hodges-Lehmann estimator), entirely within the predefined equivalence interval. Times to recovery to train-of-four ratios of 0.8 (group A: 101 s; group B: 82.5 s) and 0.7 (group A: 90 s; group B: 65 s) from start of sugammadex administration were not equivalent between groups. There was not a significant variation in the arterial pressure and heart rate values between the two groups and none of the patients showed any clinical evidence of residual or recurrent NMB. A dose of 2 mg/kg of sugammadex after continuous rocuronium infusion is enough to reverse the NMB when first response in the Train-Of-Four is reached.


Semi-Automated Training of Rat Ultrasonic Vocalizations.
Rats produce ultrasonic vocalizations (USVs) for conspecific communication. These USVs are valuable biomarkers for studying behavioral and mechanistic changes in a variety of diseases and disorders. Previous work has demonstrated operant conditioning can progressively increase the number of USVs produced by rats over multiple weeks. This operant conditioning paradigm is a useful model for investigating the effects of increased laryngeal muscle use on USV acoustic characteristics and underlying central and peripheral laryngeal sensorimotor mechanisms. Previous USV operant conditioning studies relied on manual training to elicit USV productions, which is both time and labor intensive and can introduce human variability. This manuscript introduces a semi-automated method for training rats to increase their rate of USV production by pairing commercially available operant conditioning equipment with an ultrasonic detection system. USV training requires three basic components: elicitation cue, detection of the behavior, and a reward to reinforce the desired behavior. With the semi-automated training paradigm, indirect exposure to the opposite sex or an olfactory cue can be used to elicit USV production. The elicited USV is then automatically detected by the ultrasonic acoustic system, which consequently triggers the release of a sucrose pellet reward. Our results demonstrate this semi-automated procedure produces a similar increase in USV production as the manual training method. Through automation of USV detection and reward administration, staffing requirements, human error, and subject behavioral variability may be minimized while scalability and reproducibility are increased. This automation may also result in greater experimental flexibility, allowing USV training paradigms to become more customizable for a wider array of applications. This semi-automated USV behavioral training paradigm improves upon manual training techniques by increasing the ease, speed, and quality of data collection.


Breast cancer mortality in Appalachia: reversing patterns of disparity over time.
Breast cancer death rates in the U.S. have decreased in recent decades, however areas such as Appalachia with fewer cancer care resources may not have experienced comparable mortality declines. This study examines trends in breast cancer mortality rate disparities in Appalachian states and the continental U.S. using data from SEER mortality files 1969-2007 and the Area Resource File. Overall breast cancer mortality rates decreased significantly, with a smaller decline in Appalachian counties (17.5%) compared with non-Appalachian counties in Appalachian states (30.5%), and compared with non-Appalachia U.S. counties (28.3%). After accounting for poverty, rural/urban status, education, health care resources, and proportion White in the population, residence in Appalachian counties except for those in the Northern subregion was significantly associated with smaller reduction in breast cancer mortality rates. Lower levels of education, physician density, and percent White in the population were also associated with smaller reductions in breast cancer mortality.


Urological Outcome after Fetal Spina Bifida Repair: Data from the Zurich Cohort.
Neurogenic lower urinary tract dysfunction (NLUTD) represents a severe burden for patients with open spina bifida (OSB). The effect of fetal OSB repair on the urological outcome remains unclear, as controversial data exist. The aim of this study was to further increment existing outcome data and to demonstrate that our earlier published positive preliminary results are not erratic. Data from standardized urological follow-up appointments of patients with fetal OSB repair operated at our center were analyzed. Data were obtained from urodynamic studies (UDSs) and radiologic exams performed in the newborn (gestational age 37-39 weeks), at ages of 6, 12, 18, and 24 months, and then at yearly intervals. Of 82 patients (mean age 2.6 years, range 6 months to 7 years), 26 (32%) had a normal bladder function as demonstrated by UDSs. Of the 56 (68%) patients with NLUTD, 29 (51%) patients showed initially a normal UDS, but developed NLUTD in the follow-up, 19 (66%) of them spontaneously and another 10 (34%) in association with growth and development, or surgery of inclusion cysts. Radiologic abnormalities (upper tract dilatation and vesico-uretero-renal reflux) were seen in 15%, mainly patients with NLUTD. Our results add an important set of information to the existing body of evidence. The data reconfirm our earlier published favorable preliminary results and support other studies that show a possible benefit of prenatal OSB repair on the urological outcome, but they also demonstrate that the positive effect remains limited.


Comparison of performance of conventional and ThinPrep gynecologic preparations in the College of American Pathologists Gynecologic Cytology Program.
Results of clinical trials suggest that interpretation of liquid-based cytology preparations is more accurate and is associated with less screening error than interpretation of conventional preparations. In this study, the performance of participants in interpreting ThinPrep (TP) preparations was compared with participants' performance on conventional Papanicolaou tests in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology (PAP). The results of the PAP from the year 2002 were reviewed, and the discordancies to series and exact-match error rates for the 2 cytologic methods were compared. For this study, a total of 89 815 interpretations from conventional smears and 20 886 interpretations from TP samples were analyzed. Overall, interpretations of TP preparations had both significantly fewer false-positive (1.6%) and false-negative (1.3%) rates than those of conventional smears (P =.001 and P =.02, respectively) for validated or validated-equivalent slides, as assessed by concordance with the correct diagnostic series. In this assessment of concordance to series, interpretations of educational TP and conventional preparations were similar, except for high-grade squamous intraepithelial lesion, in which the performance was significantly worse for educational TP preparations (false-negative rate of 8.1% vs 4.1% for conventional smears, P <.001). When interpretations were matched to the exact diagnosis, validated-equivalent TP preparations were generally more accurate for diagnoses in the 100 series and 200 series than were conventional smears. Notably, for the reference diagnosis of squamous cell carcinoma, the exact-match error rate on validated equivalent TP slides was significantly greater than that of conventional slides (44.5% vs 23.1%, P <.001). Interpretations of educational TP preparations also had a significantly higher error rate in matching to the exact reference diagnosis for squamous cell carcinoma (33.7% vs 22.8%, P =.007). Overall, TP preparations in this program were associated with significantly lower error rates than conventional smears for both validated and educational cases. However, unlike the negative for intraepithelial lesion and malignancy, not otherwise specified, low-grade squamous intraepithelial lesion, and adenocarcinoma cytodiagnostic challenges, participants' responses indicated some difficulty in recognizing high-grade squamous intraepithelial lesion and squamous cell carcinoma.


Membrane-binding properties of filensin, a cytoskeletal protein of the lens fiber cells.
Filensin is a 100/110 kDa membrane-associated protein found in lens fiber cells. Previous studies have shown that this protein polymerizes in vitro and binds strongly to vimentin and to another 47 kDa lens membrane protein. Using cosedimentation assays, flotation assays and immunoelectron microscopy, we have examined the properties of purified filensin and measured its binding to lens membranes. Filensin behaves as a ureaextractable, hydrophilic protein which does not partition with Triton X-114 and is not affected by 1 M hydroxylamine at alkaline pH, an agent known to release fatty-acylated proteins from the membrane. Immunoblotting of urea-extracted lens membranes with two different affinity-purified antibodies reveals that, unlike intact filensin, a COOH-terminal filensin degradation product (51 kDa) remains tightly associated with the membranes. Purified filensin binds directly to urea-stripped lens membranes, but not to protein-free vesicles reconstituted from total lens lipids. The binding of filensin is not significantly influenced by the purified 47 kDa protein. Interestingly, the filensin-binding capacity of urea-extracted membranes is increased at least two-fold after trypsin treatment, which removes entirely the 51 kDa peptide from the membranes and presumably unmasks additional filensin-acceptor sites. Consistent with this, filensin binds to trypsinized and non-trypsinized membranes with similar affinities (2 x 10(-7) and 4 x 10(-7) M, respectively). Treatment of the membranes with thrombin, which also eliminates the 51 kDa peptide, does not increase their binding capacity, apparently because filensin-acceptor sites are also destroyed during proteolysis.(ABSTRACT TRUNCATED AT 250 WORDS)


A single-dose comparison of the bioavailability of aluminium from two formulations of sucralphate in normal volunteers.
The oral bioavailability of aluminium was compared after administration of 1 g sucralphate as either a tablet or a suspension (1 g/5 ml) in a crossover study in 16 healthy volunteers. Aluminium levels were detectable in all subjects pre-dose (21.4 +/- 8.8 micrograms l-1 before tablet; 21.4 +/- 7.4 micrograms l-1 before suspension) and there was a measurable increase in the plasma concentrations of aluminium in all subjects after administration of the suspension, and in 14 of the subjects after administration of the tablet formulation, with Cmax reached within the first 8 h in most subjects. Plasma levels were still elevated 72 h after dosing. The variability in plasma levels of aluminium was significantly higher after administration of the suspension (CV 39-53%) than after administration of the tablet (CV 29-44%), reflecting greater absorption of aluminium from the suspension formulation in three subjects. Similarly, the variance of the Cmax, AUC(0-72 h), and AUC(0-infinity) (for both the raw data and the baseline adjusted data) were all higher for the suspension than for the tablet. A point estimate of the difference of the pharmacokinetic parameters (determined from the median of the arithmetic Walsh averages) indicated little or no difference in Cmax, Tmax, or AUC(0-infinity) in the two formulations. In summary, the performance of the suspension formulation of sucralphate is more variable than the tablet formulation in vivo and some patients may therefore have higher circulating levels of aluminium on therapy with the suspension formulation.


Ca2+, annexins, and GTP modulate exocytosis from maize root cap protoplasts
Protoplasts isolated from root cap cells of maize were shown to secrete fucose-rich polysaccharides and were used in a patch-clamp study to monitor changes in whole-cell capacitance. Ca2+ was required for exocytosis, which was measured as an increase in cell capacitance during intracellular dialysis with Ca2+ buffers via the patch pipette. Exocytosis was stimulated significantly by small increases above normal resting [Ca2+]. In the absence of Ca2+, protoplasts decreased in size. In situ hybridization showed significant expression of the maize annexin p35 in root cap cells, differ-entiating vascular tissue, and elongating cells. Dialysis of protoplasts with maize annexins stimulated exocytosis at physiological [Ca2+], and this could be blocked by dialysis with antibodies specific to maize annexins. Dialysis with milli-molar concentrations of GTP strongly inhibited exocytosis, causing protoplasts to decrease in size. GTPgammaS and GDPbetaS both caused only a slight inhibition of exocytosis at physiological Ca2+. Protoplasts were shown to internalize plasma membrane actively. The results are discussed in relation to the regulation of exocytosis in what is usually considered to be a constitutively secreting system; they provide direct evidence for a role of annexins in exocytosis in plant cells.


Vehicle Detection in Urban Traffic Surveillance Images Based on Convolutional Neural Networks with Feature Concatenation.
Vehicle detection with category inference on video sequence data is an important but challenging task for urban traffic surveillance. The difficulty of this task lies in the fact that it requires accurate localization of relatively small vehicles in complex scenes and expects real-time detection. In this paper, we present a vehicle detection framework that improves the performance of the conventional Single Shot MultiBox Detector (SSD), which effectively detects different types of vehicles in real-time. Our approach, which proposes the use of different feature extractors for localization and classification tasks in a single network, and to enhance these two feature extractors through deconvolution (D) and pooling (P) between layers in the feature pyramid, is denoted as DP-SSD. In addition, we extend the scope of the default box by adjusting its scale so that smaller default boxes can be exploited to guide DP-SSD training. Experimental results on the UA-DETRAC and KITTI datasets demonstrate that DP-SSD can achieve efficient vehicle detection for real-world traffic surveillance data in real-time. For the UA-DETRAC test set trained with UA-DETRAC trainval set, DP-SSD with the input size of 300 × 300 achieves 75.43% mAP (mean average precision) at the speed of 50.47 FPS (frames per second), and the framework with a 512 × 512 sized input reaches 77.94% mAP at 25.12 FPS using an NVIDIA GeForce GTX 1080Ti GPU. The DP-SSD shows comparable accuracy, which is better than those of the compared state-of-the-art models, except for YOLOv3.


The Herbert bone screw and its applications in foot surgery.
The author presents multiple indications of the Herbert bone screw in foot surgery. Both cannulated and noncannulated systems are discussed along with operative steps for several of the more common procedures performed by the author with this type screw. The Herbert bone screw systems provide another alternative for internal fixation to the surgeon.


Orthopaedic Problems in 35 Patients With Organic Acid Disorders.
Organic acid disorders (OADs) are a subset of inborn errors of metabolism that result in a toxic accumulation of organic acids in the body, which can lead to metabolic derangements and encephalopathy. Patients with these disorders are managed by a team of biochemical geneticists and metabolic nutritionists. However, subspecialists such as neurologists and orthopaedic surgeons are often needed to help manage the sequelae of the metabolic derangements. The breadth of orthopaedic sequelae of these disease states is poorly understood. Herein, we describe orthopaedic problems associated with 5 types of OAD most commonly seen at our institution: maple syrup urine disease, methylmalonic aciduria, propionic aciduria, pyruvate dehydrogenase deficiency, and glutaric aciduria type 1. We retrospectively reviewed medical records of 35 patients with an OAD who were seen at our academic tertiary care center from May 1999 to May 2020. Patients were grouped into cohorts according to OAD type and analyzed for orthopaedic presentations of hip, knee, or foot disorders, presence and severity of scoliosis, history of fracture, movement disorders, and osteopenia/osteoporosis. Of the 35 patients, 13 had maple syrup urine disease, 12 had methylmalonic aciduria, 4 had propionic aciduria, 4 had pyruvate dehydrogenase deficiency, and 2 had glutaric aciduria type 1. Associated orthopaedic problems included spasticity causing neuromuscular scoliosis and/or hip subluxation or dislocation (10 patients), fractures (7 patients), and osteopenia/osteoporosis (7 patients). Overall, 22 of 35 patients had some orthopaedic condition. Most in this cohort of patients with OAD also had an orthopaedic abnormality. It is important for physicians treating these patients to understand their propensity for musculoskeletal problems. When treating patients with OAD, it is important to initiate and maintain communication with specialists in several disciplines and to develop collaborative treatments for this unique population. Level IV-prognostic study.


Laryngeal microsurgery without intubation.
Reviewed are 200 cases in which endolaryngeal suspension microsurgical procedures were done using intravenous anesthesia and Venturi insufflation oxygenation. Patients included 177 adults and 23 children, ranging in age from 20 months to 88 years. No significant complications were observed. The technic allowed the glottic space to remain free of cumbersome intraluminal apparatus. Arterial blood studies revealed that adequate oxygenation is achieved while normal pH and PaCO2 levels are maintained.


Alcohol use in multiracial American youth compared with monoracial youth: A meta-analysis.
Although multiracial people comprise the fastest growing population in the United States, multiracial youth are nearly invisible in alcohol research. This meta-analysis synthesized the youth alcohol literature to estimate the magnitude of difference in alcohol use as a function of multiracial status. Empirical studies reporting multiracial and monoracial comparisons in youth (aged 10-24 years) alcohol use were identified through a systematic literature search. A random-effects meta-analysis was conducted using 85 effect sizes extracted from 16 studies assessing life-time, past-year, past-month and binge alcohol use. A total of n=1 555 635 youth were assessed in the United States. Multiracial youth are suggested to be more likely to endorse life-time alcohol use than Asian youth [number of studies (k) = 3; odds ratio (OR) = 1.81, 95% confidence interval (CI) = 1.01, 3.24; p = 0.04], with significant between-study heterogeneity (Q = 8.42; p < 0.001; I2 = 76%) in effect size comparisons. Multiracial youth are suggested to be more likely to endorse past-month alcohol use than Black (k = 6; OR = 1.54, 95% CI = 1.38, 1.71; p < 0.001) and Asian (k = 4; OR = 2.09, 95% CI = 1.52, 2.88; p < 0.001) youth, but less likely than White (k = 6; OR = 0.87, 95% CI = 0.84, 0.91; p < 0.001) youth, with significant between-study heterogeneity for Black youth (Q = 11.94; p = 0.03; I2 = 58%) in effect size comparisons. Lastly, multiracial youth are suggested to be more likely to endorse binge alcohol use than Black (k = 4; OR = 1.98, 95% CI = 1.62, 2.44; p < 0.001) and Asian (k = 4; OR = 2.82, 95% CI = 2.28, 3.48; p < 0.001) youth, but less likely than White (k = 5; OR = 0.75, 95% CI = 0.70, 0.81; p < 0.001) and American Indian/Alaska Native (k = 3; OR = 0.78, 95% CI = 0.71, 0.85; p < 0.001) youth, with significant between-study heterogeneity among Black (Q = 23.99; p < 0.001; I2 = 87%) and Asian (Q = 17.76; p < 0.001; I2 = 83%) youth in effect size comparisons. In the United States, multiracial youth report distinct alcohol use patterns compared with monoracial youth and may be at elevated alcohol use risk compared with Black and Asian youth.


Some ethical and design challenges of screening programs and screening tests.
There are many examples of inadequate screening studies because of design faults and consent problems. Informed consent is the right of each person engaged in a clinical interaction, including service and research involvement in presymptomatic screening. Any screening approach must answer questions of efficacy, effectiveness, availability and efficiency. Accurate information, presented in clear language, must state a realistic assessment of the limitations, harms and benefits of the screening, including the consequences of false positive and false negative tests. There must be no coercive element in obtaining consent. Written and oral information should be presented. It is also important to recognize cultural differences between societies that emphasize individual autonomy and those in which autonomy derives from membership of a family, group or community, thus requiring different strategies to protect the vulnerable. Testing for genetic disorders presents additional challenges, partly due to the presence of relatively small numbers of affected individuals in the population, but also because of the complexity of counseling, confidentiality issues and the potential for social, insurance or employment discrimination. It is becoming increasingly difficult to present the data for many screening procedures in ways that can be understood by possible participants, and at the same time deal clearly with the costs to society and the efficacy and efficiency of the tests.


[Ethiopia-Netherlands AIDS research project].
The 'Ethiopia-Netherlands AIDS Research Project' (ENARP), started in 1994, is a long-term collaboration between AIDS researchers in Amsterdam and the Ethiopian Health and Nutrition Research Institute in Addis Ababa. The ENARP's primary objectives include conducting studies on HIV and AIDS in Ethiopia, especially by means of some large-scale prospective cohort studies, training Ethiopian scientists in PhD programmes in epidemiology, immunology and virology and establishing a reference laboratory for HIV and AIDS in Ethiopia and neighbouring countries. External funding for ENARP amounts to 32 million Dutch guilders for two periods of four years and is being provided by the Dutch Government. ENARP is the largest third world biomedical project supported by the Dutch Government. In 2000 two Ethiopian students obtained their doctorates from the University of Amsterdam. Five new PhD students commenced their training in 1999. ENARP hopes to set up HIV-1 vaccine phase I and phase II trials in the near future.


Potential interactions between uraemic toxins and drugs: an application in kidney transplant recipients treated with calcineurin inhibitors.
The uraemic toxins that accumulate as renal function deteriorates can potentially affect drug pharmacokinetics. This study's objective was to determine whether plasma concentrations of certain uraemic toxins are correlated with blood concentrations of two immunosuppressants. DRUGTOX was a cross-sectional study of 403 adult patients followed up after kidney transplantation and who had undergone therapeutic drug monitoring (TDM) of calcineurin inhibitors (tacrolimus or cyclosporin) between August 2019 and March 2020. For each patient, immunosuppressant trough concentrations (C0) were measured in whole blood samples and then normalized against the total daily dose (C0:D ratio). The sample was assayed for five uraemic toxins [urea, trimethylamine N-oxide (TMAO), indole acetic acid (IAA), p-cresylsulphate (PCS) and indoxylsulphate (IxS)] using liquid chromatography-tandem mass spectrometry. The median age was 56 years [interquartile range (IQR) 48-66] and the median estimated glomerular filtration rate was 41 mL/min/1.73 m2 (IQR 30-57). Age, sex, body mass index (BMI), urea, IxS and PCS were significantly associated with an increment in the tacrolimus C0:D ratio. A multivariate analysis revealed an independent association with IxS [odds ratio 1.36 (95% confidence interval 1.00-1.85)] after adjustment for sex, age and BMI, whereas adjustment for age weakened the association for PCS and urea. In a univariate logistic analysis, age, sex, BMI and the TMAO level (but not PCS, IxS, IAA or urea) were significantly associated with an increment in the cyclosporine C0:D ratio. Even though TDM and dose adaptation of immunosuppressants keep levels within the therapeutic window, increased exposure to tacrolimus (but not cyclosporine) is associated with an accumulation of PCS, IxS and urea.


Colloidal, Room-Temperature Growth of Metal Oxide Shells on InP Quantum Dots.
We demonstrate colloidal, layer-by-layer growth of metal oxide shells on InP quantum dots (QDs) at room temperature. We show with computational modeling that native InP QD surface oxides give rise to nonradiative pathways due to the presence of surface-localized dark states near the band edges. Replacing surface indium with zinc to form a ZnO shell results in reduced nonradiative decay and a density of states at the valence band edge that resembles defect-free, stoichiometric InP. We then developed a synthetic strategy using stoichiometric amounts of common atomic layer deposition precursors in alternating cycles to achieve layer-by-layer growth. Metal-oxide-shelled InP QDs show bulk and local structural perturbations as determined by X-ray diffraction and extended X-ray absorption fine structure spectroscopy. Upon growing ZnSe shells of varying thickness on the oxide-shelled QDs, we observe increased photoluminescence (PL) quantum yields and narrowing of the emission linewidths that we attribute to decreased ion diffusion to the shell, as supported by phosphorus X-ray emission spectroscopy. These results present a versatile strategy to control QD interfaces for novel heterostructure design by leveraging surface oxides. This work also contributes to our understanding of the connections between structural complexity and PL properties in technologically relevant colloidal optoelectronic materials.


Milestones in antihypertensive drug treatment.
Hypertension provoked since the beginning of the 19th century a medical debate between physicians. The early antihypertensive agents were poorly tolerated. Progress towards more effective drugs, appeared after the 2nd World War. Thiocyanates, dehydrogenated alkaloids of ergot, barbiturates, bismuth and bromides, were soon replaced by phenoxbenzamine, hexamethonium, pentolinium, and mecamylamine. Thiazide diuretics were the biggest breakthrough during the early 1960's. Then Beta(β)-blockers and angiotensin-converting enzyme inhibitors heralded a new era, until 1995, when losartan, the first non-peptide anti-hypertensive drug, was introduced. The plethora of the antihypertensive drugs changed the relationship between physicians and patients, pushed medicine towards prevention, and altered the medical marketing forever.


Smashing mantis shrimp strategically impact shells.
Many predators fracture strong mollusk shells, requiring specialized weaponry and behaviors. The current shell fracture paradigm is based on jaw- and claw-based predators that slowly apply forces (high impulse, low peak force). However, predators also strike shells with transient intense impacts (low impulse, high peak force). Toward the goal of incorporating impact fracture strategies into the prevailing paradigm, we measured how mantis shrimp (Neogonodactylus bredini) impact snail shells, tested whether they strike shells in different locations depending on prey shape (Nerita spp., Cenchritis muricatus, Cerithium spp.) and deployed a physical model (Ninjabot) to test the effectiveness of strike locations. We found that, contrary to their formidable reputation, mantis shrimp struck shells tens to hundreds of times while targeting distinct shell locations. They consistently struck the aperture of globular shells and changed from the aperture to the apex of high-spired shells. Ninjabot tests revealed that mantis shrimp avoid strike locations that cause little damage and that reaching the threshold for eating soft tissue is increasingly difficult as fracture progresses. Their ballistic strategy requires feed-forward control, relying on extensive pre-strike set-up, unlike jaw- and claw-based strategies that can use real-time neural feedback when crushing. However, alongside this pre-processing cost to impact fracture comes the ability to circumvent gape limits and thus process larger prey. In sum, mantis shrimp target specific shell regions, alter their strategy depending on shell shape, and present a model system for studying the physics and materials of impact fracture in the context of the rich evolutionary history of predator-prey interactions.


Semiquantitative assessment of skeletal response to enzyme replacement therapy for Gaucher's disease using the bone marrow burden score.
The purpose of this study was to evaluate the use of a recently described assessment tool to quantify bone marrow response to enzyme replacement therapy in a cohort of adult patients with type 1 Gaucher's disease. Serial MR images of the femurs, lumbar spine, or both of 57 subjects with a diagnosis of Gaucher's disease, 44 of whom were being treated with enzyme replacement therapy, were evaluated by two musculoskeletal radiologists using the bone marrow burden (BMB) scoring system. This system gives a score out of a possible 8 for the lumbar spine and a score out of a possible 8 for the femurs, so the total BMB score is out of 16. The mean total BMB scores at baseline and final measurement were 13 (95% CI, 12.0-13.8) and 6.5 (95% CI, 5.2-7.9), respectively. Total BMB scores improved by 2-12 points (mean, 6.3 points) for 15 subjects in whom total BMB scores obtained before enzyme replacement therapy and at least one time point after commencement of therapy were available. In 39 subjects for whom only baseline and final femoral BMB scores were available, 24 subjects (62%, 95% CI, 47-76%) improved by 2 or more points while on enzyme replacement therapy. In 24 subjects for whom only baseline and final lumbar BMB scores were available, the BMB score in 16 subjects (67%, 95% CI, 48-85%) improved by 2 or more points. The use of the BMB score enabled semiquantitative assessment of bone marrow response to enzyme replacement therapy in adult patients with type 1 Gaucher's disease in Australia. The ability to assess therapy response will facilitate the tailoring of dosage regimens in the future.


Exported 18-kDa isoform of fibroblast growth factor-2 is a critical determinant of bone mass in mice.
The role of the 18-kDa isoform of fibroblast growth factor-2 (FGF2) in the maintenance of bone mass was examined in Col3.6-18-kDa FGF2-IRES-GFPsaph transgenic (18-kDa TgFGF2) mice in which a 3.6-kb fragment of the type I collagen 5'-regulatory region (Col3.6) drives the expression of only the 18-kDa isoform of FGF2 with green fluorescent protein-sapphire (GFPsaph). Vector only transgenic mice (Col3.6-IRES-GFPsaph, VTg) were also developed as a control, and mice specifically deficient in 18-kDa FGF2 (FGF2(lmw)(-/-)) were also examined. Bone mineral density, femoral bone volume, trabecular thickness, and cortical bone area and thickness were significantly increased in 18-kDa TgFGF2 mice compared with VTg. Bone marrow cultures (BMSC) from 18-kDa TgFGF2 mice produced more mineralized nodules than VTg. Increased bone formation was associated with reduced expression of the Wnt antagonist secreted frizzled receptor 1 (sFRP-1). In contrast to 18-kDa TgFGF2 mice, FGF2(lmw)(-/-) mice have significantly reduced bone mineral density and fewer mineralized nodules, coincident with increased expression of sFRP-1 in bones and BMSC. Moreover, silencing of sFRP-1 in BMSC from FGF2(lmw)(-/-) mice reversed the decrease in beta-catenin and Runx2 mRNA. Assay of Wnt/beta-catenin-mediated transcription showed increased and decreased TCF-luciferase activity in BMSC from 18-kDa TgFGF2 and FGF2(lmw)(-/-) mice, respectively. Collectively, these results demonstrate that the 18-kDa FGF2 isoform is a critical determinant of bone mass in mice by modulation of the Wnt signaling pathway.


Early treatment of obstructive apnoea and stroke outcome: a randomised controlled trial.
The aim of the present study was to assess the impact of nasal continuous positive airway pressure (nCPAP) in ischaemic stroke patients followed for 2 yrs. Stroke patients with an apnoea-hypopnoea index ≥ 20 events·h⁻¹ were randomised to early nCPAP (n = 71; 3-6 days after stroke onset) or conventional treatment (n = 69). The Barthel Index, Canadian Scale, Rankin Scale and Short Form-36 were measured at baseline, and at 1, 3, 12 and 24 months. The percentage of patients with neurological improvement 1 month after stroke was significantly higher in the nCPAP group (Rankin scale 90.9 versus 56.3% (p < 0.01); Canadian scale 88.2 versus 72.7% (p < 0.05)). The mean time until the appearance of cardiovascular events was longer in the nCPAP group (14.9 versus 7.9 months; p = 0.044), although cardiovascular event-free survival after 24 months was similar in both groups. The cardiovascular mortality rate was 0% in the nCPAP group and 4.3% in the control group (p = 0.161). Early use of nCPAP seems to accelerate neurological recovery and to delay the appearance of cardiovascular events, although an improvement in patients' survival or quality of life was not shown.


Public awareness of and support for smoke-free legislation in Turkey: a national survey using the lot quality sampling technique.
Six months after new legislation in Turkey banning smoking in all public places, a national survey was carried out to assess its implementation. This paper summarizes the main findings on the public's awareness of and support for the new law. In a household interview survey of 32 972 adults representative of the Turkish adult population, a high proportion of both non-smokers and current smokers (91.4% and 67.2% respectively) strongly supported the new law. Knowledge about the health hazards of passive smoking and support for the law, however, were relatively lower among smokers than non-smokers. After controlling for smoking status, people with better knowledge about passive smoking were over 5 times more likely to support the new law. Tobacco control activities should be tailored to local needs, with afocus on increasing awareness about the health hazards of passive smoking. The study also demonstrated application of the lot quality sampling technique (LQT) for monitoring tobacco control activities in a national survey.


Elevated Unconjugated Bilirubin in Schizophrenia Compared to Bipolar Affective Disorder.
The evidence linking schizophrenia and total and unconjugated bilirubin is primarily from retrospective studies. To overcome this limitation, we conducted a prospective study of total and unconjugated bilirubin levels of patients diagnosed with schizophrenia or bipolar affective disorder. Serum total and unconjugated bilirubin levels were compared between patients diagnosed with schizophrenia (n = 50) and bipolar affective disorder (n = 43) (ICD-10 criteria) admitted to an inpatient psychiatric unit of a tertiary hospital in India. The study was conducted between October 2013 and July 2015. The median serum levels (mg/dL) of total and unconjugated bilirubin were significantly higher (P = .027 and P = .004, respectively) among patients with schizophrenia compared to those with bipolar affective disorder. Analysis of covariance revealed that unconjugated bilirubin was significantly higher (P = .029) in patients with schizophrenia compared to those with bipolar affective disorder, even after controlling for the effects of age, sex, and medications. In this prospective study, serum levels of unconjugated bilirubin were significantly higher in patients with schizophrenia compared to patients with bipolar affective disorder. The findings suggest that serum unconjugated bilirubin could be a potential marker for schizophrenia. However, the results need to be replicated in a larger sample including patients living in the community.


Indicators of Health-Related Quality of Life in Cats With Degenerative Joint Disease: Systematic Review and Proposal of a Conceptual Framework.
Objectives: The assessment of health-related quality of life (HRQoL) is becoming increasingly important in companion animals. This study describes a systematic review and development of a proposed conceptual framework to assess HRQoL in cats with osteoarthritis (OA). Methods: The conceptual framework was developed according to published guidelines. A comprehensive search of the CAB Direct, Scopus, PubMed, and Web of Science databases was carried out for publications in English from inception to November 12, 2019. Search words used were "cat", "feline", "chronic pain", "pain", and "quality of life". Publications were selected if they were full-text and peer-reviewed, based on primary data, and identified or measured behavioral symptoms of chronic musculoskeletal pain in cats. A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A data extraction form was developed from categories identified in the literature review and piloted on a small number of studies to ascertain the appropriateness for relevant data extraction. Categories were then finalized, and key domains were identified. The domains were then synthesized to develop a conceptual framework. Results: A total of 454 studies were identified, of which 14 met the eligibility criteria and were included in the meta-synthesis. All 14 were assessed to be of good quality. Seven domains related to HRQoL in cats with OA were thematically identified from the data: mobility, physical appearance, energy and vitality, mood, pain expression, sociability, and physical and mental wellbeing. The three main HRQoL domains were pain expression, mobility, and physical and mental wellbeing, which impacted all the others. Pain and mobility impacted all six other domains, with increased pain and decreased mobility negatively impacting physical appearance, energy and vitality, mood, sociability, and physical and mental wellbeing. Conclusions and Relevance: This is the first study to develop an evidence-based conceptual framework for the assessment of HRQoL in cats with OA. The proposed conceptual framework suggests that effective management of chronic pain in cats may improve their overall HRQoL.


Distributional Measures of Semantic Abstraction.
This article provides an in-depth study of distributional measures for distinguishing between degrees of semantic abstraction. Abstraction is considered a "central construct in cognitive science" (Barsalou, 2003) and a "process of information reduction that allows for efficient storage and retrieval of central knowledge" (Burgoon et al., 2013). Relying on the distributional hypothesis, computational studies have successfully exploited measures of contextual co-occurrence and neighbourhood density to distinguish between conceptual semantic categorisations. So far, these studies have modeled semantic abstraction across lexical-semantic tasks such as ambiguity; diachronic meaning changes; abstractness vs. concreteness; and hypernymy. Yet, the distributional approaches target different conceptual types of semantic relatedness, and as to our knowledge not much attention has been paid to apply, compare or analyse the computational abstraction measures across conceptual tasks. The current article suggests a novel perspective that exploits variants of distributional measures to investigate semantic abstraction in English in terms of the abstract-concrete dichotomy (e.g., glory-banana) and in terms of the generality-specificity distinction (e.g., animal-fish), in order to compare the strengths and weaknesses of the measures regarding categorisations of abstraction, and to determine and investigate conceptual differences. In a series of experiments we identify reliable distributional measures for both instantiations of lexical-semantic abstraction and reach a precision higher than 0.7, but the measures clearly differ for the abstract-concrete vs. abstract-specific distinctions and for nouns vs. verbs. Overall, we identify two groups of measures, (i) frequency and word entropy when distinguishing between more and less abstract words in terms of the generality-specificity distinction, and (ii) neighbourhood density variants (especially target-context diversity) when distinguishing between more and less abstract words in terms of the abstract-concrete dichotomy. We conclude that more general words are used more often and are less surprising than more specific words, and that abstract words establish themselves empirically in semantically more diverse contexts than concrete words. Finally, our experiments once more point out that distributional models of conceptual categorisations need to take word classes and ambiguity into account: results for nouns vs. verbs differ in many respects, and ambiguity hinders fine-tuning empirical observations.


Histone deacetylase 8 in neuroblastoma tumorigenesis.
The effects of pan-histone deacetylase (HDAC) inhibitors on cancer cells have shown that HDACs are involved in fundamental tumor biological processes such as cell cycle control, differentiation, and apoptosis. However, because of the unselective nature of these compounds, little is known about the contribution of individual HDAC family members to tumorigenesis and progression. The purpose of this study was to evaluate the role of individual HDACs in neuroblastoma tumorigenesis. We have investigated the mRNA expression of all HDAC1-11 family members in a large cohort of primary neuroblastoma samples covering the full spectrum of the disease. HDACs associated with disease stage and survival were subsequently functionally evaluated in cell culture models. Only HDAC8 expression was significantly correlated with advanced disease and metastasis and down-regulated in stage 4S neuroblastoma associated with spontaneous regression. High HDAC8 expression was associated with poor prognostic markers and poor overall and event-free survival. The knockdown of HDAC8 resulted in the inhibition of proliferation, reduced clonogenic growth, cell cycle arrest, and differentiation in cultured neuroblastoma cells. The treatment of neuroblastoma cell lines as well as short-term-culture neuroblastoma cells with an HDAC8-selective small-molecule inhibitor inhibited cell proliferation and clone formation, induced differentiation, and thus reproduced the HDAC8 knockdown phenotype. Global histone 4 acetylation was not affected by HDAC8 knockdown or by selective inhibitor treatment. Our data point toward an important role of HDAC8 in neuroblastoma pathogenesis and identify this HDAC family member as a specific drug target for the differentiation therapy of neuroblastoma.


Clinical use of methacholine bronchial challenge testing.
Whereas the research applications have been well established, the clinical utility of bronchial challenge testing is still being defined. In 19 of 22 patients referred for testing (86%), the results of a methacholine challenge test helped to confirm a clinical suspicion of asthma or to suggest that alternative diagnoses should be investigated. There was a discrepancy between the pretest suspicion of the referring physician and the results of the challenge test in six of these 19 patients (32%). Thus our experience suggests that bronchial challenge testing provides useful information to supplement clinical acumen in the diagnosis of asthma.


Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families.
Genes that, when mutated, cause Fanconi anemia or greatly increase breast cancer risk encode for proteins that converge on a homology-directed DNA damage repair process. Mutations in the SLX4 gene, which encodes for a scaffold protein involved in the repair of interstrand cross-links, have recently been identified in unclassified Fanconi anemia patients. A mutation analysis of SLX4 in German or Byelorussian familial cases of breast cancer without detected mutations in BRCA1 or BRCA2 has been completed, with globally negative results. The genomic region of SLX4, comprising all exons and exon-intron boundaries, was sequenced in 94 Spanish familial breast cancer cases that match a criterion indicating the potential presence of a highly-penetrant germline mutation, following exclusion of BRCA1 or BRCA2 mutations. This mutational analysis revealed extensive genetic variation of SLX4, with 21 novel single nucleotide variants; however, none could be linked to a clear alteration of the protein function. Nonetheless, genotyping 10 variants (nine novel, all missense amino acid changes) in a set of controls (138 women and 146 men) did not detect seven of them. Overall, while the results of this study do not identify clearly pathogenic mutations of SLX4 contributing to breast cancer risk, further genetic analysis, combined with functional assays of the identified rare variants, may be warranted to conclusively assess the potential link with the disease.


Induction of hypothyroidism and hypoprolactinemia by growth hormone producing rat pituitary tumors.
The GH3 rat pituitary tumor cell line which secretes both growth hormone (GH) and prolactin (PRL) stopped releasing PRL when transplanted to animals; furthermore, it suppressed PRL production by the hosts' pituitary glands. When the same tumor was transferred back to cell culture, PRL production resumed. The PRL to GH ratio in cell culture medium and cells ranged from 5 to 1 while in the tumor and serum of the host animals it averaged 0.09 and 0.001, respectively. To investigate further this phenomenon, female rats were transplanted with GH3 tumors (T) and compared to intact normal (N) and to thyroidectomized (Tx) rats. T animals were larger and had splanchnomegaly but smaller pituitaries and thyroids. Serum PRL concentrations in the basal state were decreased, as were levels of triiodothyronine (T3), thyroxine (T4), and free T4 index. Despite reduced serum thyroid hormone concentrations, and in contrast to Tx animals, the serum thyrotropin (TSH) level in T rats was not elevated and they did not show a supranormal TSH response to thyrotropin-releasing hormone (TRH) administration. The PRL response to TRH in T animals was completely abolished while all N and Tx animals responded by a significant increase in serum PRL. Serum corticosteroids and estrogens were normal in T rats. Pituitary content of PRL was decreased and that of TSH increased in T rats. Tx animals, however, had a reduced pituitary content of PRL, TSH, and GH. When GH3 cells were grown in cell culture media containing serum from T animals, there was a reduction of PRL content in cells and released in the medium. Addition of T3 to the T serum did not alter its suppressive effect on PRL nor did rat GH added to N serum alter PRL production and release in vitro. In a preliminary experiment, rats injected ip with 50 mug hGH in two divided doses for eighteen days, suppressed serum T4 and T3 concentrations; pituitary content of TSH was significantly increased and that of PRL slightly decreased. Injection with 250 mug oPRL or saline, on the same schedule and for the same length of time, had no significant effect on the levels of serum thyroid hormones. Thus, GH, but also possibly other substance(s) secreted by GH3 tumors in vivo a) suppress the production of tumor and pituitary PRL; b) suppress the release of TSH, causing mild hypothyroidism; c) inhibit the PRL and TSH responses to TRH; and d) decrease the production of PRL in tissue culture. Although no simple and unifying theory could explain these findings, an hypothesis implicating somatomedin is presented.


Medication reviews with computerised expert support: evaluation of a method to improve the quality of drug utilisation in the elderly.
This paper aims to examine whether a computerised system for medication reviews can support physicians' decisions and improve the quality of drug treatment in the elderly. This is a descriptive intervention study. The study included 275 patients living in community settings and nursing homes in Stockholm, Sweden. Patient data were analysed using computer software and scrutinised by a clinical pharmacologist. Pharmaco-therapeutic advice was sent to the physician responsible for each patient. The main outcome measures were initiation and discontinuation of drugs, changes of doses and rates of identified drug-related problems. Expert opinions were given by the clinical pharmacologist, for 275 patients, mean age 85 years; 70 per cent female. An average of 3.3 remarks was given concerning unsuitable drugs, unclear indication, dosing when the kidney function was decreased, drug-drug interactions and quality indicators. On average 1.5 drug-related problems (DRP) per patient were attended to by the responsible physician at each unit. The most common action taken was withdrawal of a drug (n = 208). On average the drug use decreased from 10.4 to 9.5 drugs per patient, and several quality indicators were met. The drug costs decreased, and resulted in a more cost-effective drug therapy. The paper develops and tests a method for intervention in the care of elderly patients. The method is based on a computerised expert support system for medication reviews at a distance and on education of the staff. A safer drug therapy with improved quality and cost-effectiveness is thus provided.


[Community integrative therapy: situations of emotional suffering and patients' coping strategies].
Community Integrative Therapy (CIT) has emerged as a strategy to support the mental health of users of the public Unified Health System (SUS). This study had the objective to identify the principal problems presented by patients of group therapy, and to identify strategies that they use to cope with situations that cause emotional suffering. Secondary research carried out at the Municipal Secretary of Health, with information sources being organization forms with data from CIT The results demonstrate that the most frequent problem fcause of suffering] is stress, the coping strategy most used is spirituality, and through the discourses of the participants it is possible to perceive the positive perception that they have of the meetings. CIT is a space where the relationships that are forged transmit emotional support, strengthen ties and diminish cases of social exclusion.


[Role of estrogens in the regulation of composition of bile acids of the enterohepatic system in rats and monkeys with extrahepatic cholestasis].
Analysis of the thin-layer chromatography and gas chromatography data on the free and conjugated bile acid contents in the blood leaving intestine, hepatocytes and bile of ovariectomized rabbits and monkeys with acalculous cholecystitis revealed a heterogeneity of bile acid distribution in these biological media and an uniformity of specific alterations manifested in increased glyco-conjugation, decreased free bile acids in hepatocytes and blood, decreased cholesterol level and reduced lithogenic index of the bile. Results obtained are indicative of involvement of the gonadal steroids and estradiol dipropionate in regulation of bile acid conjugation in liver and, therefore, in development of one of the early factors of the gallstone formation.