Pathological, biochemical and haematological investigations on the protective effect of alpha-lipoic acid in experimental aflatoxin toxicosis in chicks.
1. The purpose of this study was to investigate the protective effect of alpha-lipoic acid (LA) on aflatoxin (AF) toxicosis in chicks. 2. Groups of 10 Ross PM3 chicks were given, for 21 d, no AF (C), 60 mg/kg/bwt of alpha-lipoic acid (LA), 150 ppb of aflatoxin (AF1), 150 ppb of aflatoxin plus 60 mg/kg/bwt of alpha-lipoic acid (AF1 + LA), 300 ppb of aflatoxin (AF2), and 300 ppb of aflatoxin plus 60 mg/kg/bwt of alpha-lipoic acid (AF2 + LA). Before the animals were killed, blood samples were drawn for haematological analysis, and then tissue samples were collected for histopathological investigation. Immunohistochemical staining was performed against inducible nitric oxide synthase (iNOS) and nitrotyrosine on liver samples. Apoptotic cell death in liver was assessed by in situ TUNEL assay. The malondialdehyde (MDA) and reduced glutathione (GSH) concentrations in liver and kidney were also determined. 3. Hydropic degeneration and occasional necrosis, bile duct hyperplasia and periportal fibrosis were observed in the livers of AF-treated groups. The severity of these changes was reduced in LA-supplemented AF groups. Occasionally, thymic cortical atrophy, lymphoid depletion in spleen and bursa of Fabricius, and degeneration in the kidney tubule epitheliums were detected in AF groups. The severity of these degenerative changes was slightly reduced in LA supplemented groups. 4. There was moderate to strong iNOS and nitrotyrosine immunoreactivity in the livers of AF groups, while decreased immunoreactivity was observed against both antibodies in the LA supplemented groups. Apoptotic cells were numerous in the AF groups, while greatly reduced in LA supplemented groups. 5. In the liver and kidney of AF-treated groups given 300 ppb of aflatoxin, MDA concentrations were increased as GSH decreased, compared to the control group. LA supplementation of AF-treated birds improved the results compared to the AF only groups, however a statistical difference was observed only in liver tissues between AF2 + LA and AF2 groups. Haematological variables showed no differences among the groups. 6. In conclusion, supplementation of feed with the antioxidant LA, might ameliorate the degenerative effects caused by aflatoxin due to lipid peroxidation.


Allogeneic hematopoietic stem cell transplant following chemotherapy containing l-asparaginase as a promising treatment for patients with relapsed or refractory extranodal natural killer/T cell lymphoma, nasal type.
The prognosis of advanced extranodal NK/T cell lymphoma (ENKTL) is poor. Allogeneic hematopoietic stem cell transplant (allo-HSCT) has been suggested to be a promising treatment for this disease, but its utility has yet to be established. Here we retrospectively analyzed five cases of ENKTL treated with allo-HSCT in our institute. After induction chemotherapy, disease status at allo-HSCT was second CR in three patients and refractory in two patients. All patients received a myeloablative conditioning regimen, and GVHD prophylaxis consisted of tacrolimus or cyclosporine with short-term methotrexate. Only one patient who received conventional induction chemotherapy developed severe complications, which needed long-term treatment, while others who received chemotherapy containing l-asparaginase did not have severe complications. There were no cases of treatment-related mortality, and all patients survived without disease for a median follow-up period of 1911 days. These results suggested that allo-HSCT following l-asparaginase-containing induction chemotherapy might improve the outcome of advanced ENKTL.


The novel HDAC inhibitor OBP-801/YM753 enhances the effects of 5-fluorouracil with radiation on esophageal squamous carcinoma cells.
Histone deacetylase (HDAC) inhibitors have been shown to enhance the effects of 5-fluorouracil (5-FU) against various cancer cells; however, no report has shown that an HDAC inhibitor may enhance the effects of 5-FU with radiation. Therefore, we investigated whether the novel HDAC inhibitor OBP-801/YM753 could enhance the effects of 5-FU with radiation on esophageal squamous carcinoma KYSE170 cells. The inhibition of the cell growth was significantly stronger with the combination of OBP-801/YM753 with 5-FU than with the 5-FU treatment only. Furthermore, inhibition of the colony formation was the most effective with the combined treatment of OBP-801/YM753, 5-FU, and radiation. Western blot analysis showed that OBP-801/YM753 suppressed the expression of thymidylate synthase induced by 5-FU. Therefore, this three-combined therapy is promising for patients with esophageal squamous carcinoma.


Cardiovascular responses to external compression of human calf muscle vary during graded metaboreflex stimulation.
This study investigated the cardiovascular response to a standard external muscle compression during concomitant muscle metaboreflex stimulation of varying intensity in human calf muscle. Eleven healthy male subjects (mean (s.d.) age, 26 (5.6) years; height, 177 (5) cm; weight, 74.3 (6.8) kg) were seated in an isometric dynamometer with the angle of the knee at 90 deg, and the angle of the ankle at 85 deg. After a 150-s rest period, subjects were asked to either perform isometric plantar flexion at 20, 30, 40, 50, 60, 70 or 80% of previously determined maximum isometric contractile force (MVC) for 90 s, or to sit at rest for this period. A thigh cuff maintained circulatory occlusion throughout the exercise period and for 180 s post exercise. After 60 s of post-exercise circulatory occlusion (PECO), a calf cuff was inflated to 300 mmHg for 60 s followed by a further 60 s of PECO alone after which the thigh cuff was deflated. During PECO the mean arterial pressure (MAP) increase from rest was dependent upon the preceding exercise intensity (P < 0.001). Compression elicited a further significant change in MAP, and the magnitude of this change from the PECO baseline was also dependent upon the preceding exercise intensity (P < 0.01). These results are compatible with activation of a metabolically sensitised population of mechanoreceptive afferents in human muscle during external compression.


Effects of dextroamphetamine, lithium chloride, sodium valproate and carbamazepine on intraplatelet Ca2+ levels.
To explore the possible involvement of second-messenger pathways in the pathophysiology of bipolar disorder and the mechanism of action of mood stabilizers, we investigated the effects of dextroamphetamine (a model for mania) and the most widely used mood stabilizers, lithium chloride, sodium valproate and carbamazepine, on intraplatelet levels of calcium ion ([Ca2+). In the first part of the study, dextroamphetamine was administered in vivo in a double-blind, placebo-controlled, crossover design. In the second part of the study, platelets from untreated subjects were incubated in vitro with dextroamphetamine, lithium chloride, sodium valproate or carbamazepine. Fifteen healthy men between 18 and 45 years of age. Basal, thrombin-induced and serotonin- (5-HT) induced intraplatelet [Ca2+] determined by means of fura-2 fluorescent intensity. In vivo administration of dextroamphetamine had no effect on basal or agonist-induced intraplatelet [Ca2+]. However, in vitro basal platelet [Ca2+] was significantly higher in samples incubated with dextroamphetamine (86.8 nmol/L [standard error of the mean, SEM, 3.9], p < 0.001), lithium chloride (76.4 nmol/L [SEM 3.1], p < 0.002), sodium valproate (82.7 nmol/L [SEM 3.7], p < 0.001) and carbamazepine (84.8 nmol/L [SEM 3.3], p < 0.001) than in the controls (58.2 nmol/L [SEM 2.3]). Thrombin-induced and 5-HT-induced peak cytosolic [Ca2+] were significantly greater than control levels in samples incubated with carbamazepine (277.1 nmol/L [SEM 19.9] v. 195.8 nmol/L [SEM 12.2], p < 0.002; and 153.0 nmol/L [SEM 8.2] v. 115.4 nmol/L [SEM 5.7], p < 0.003, respectively). This study does not support the involvement of intraplatelet [Ca2+] in the dextroamphetamine model of mania; however, the modulation of intraplatelet [Ca2+] by the mood stabilizers lithium chloride, sodium valproate and carbamazepine implicates intracellular [Ca2+] in the therapeutic mechanisms of these drugs and the pathophysiological basis of mania.


Quantitative determination of hydroxy pentacyclic triterpene acids in vegetable oils.
A simple and precise analytical method for the determination of hydroxy pentacyclic triterpene acids (HPTAs) in vegetable oils was developed. The acidic fraction was isolated by solid-phase extraction using bonded aminopropyl cartridges, and the extract was silylated and analyzed by gas chromatography. Repeatability and recovery of the method were determined. In virgin olive oils, similar amounts of oleanolic (3beta-hydroxyolean-12-en-28-oic) and maslinic (2alpha,3beta-dihydroxyolean-12-ene-28oic) acids and traces of ursolic (3beta-hydroxyurs-12-en-28-oic) acid were found. The main factor affecting HPTA concentration was the oil quality since that increases as the quality decreases, while olive variety, olive ripeness, and oil extraction system had less influence. In crude olive pomace oils, the concentrations were very much higher than in virgin olive oils. During refining processes, total or significant losses of HPTAs were observed. Esterified derivatives of HPTAs were not found.


Molecular characterization of birnaviruses isolated from wild marine fishes at the Flemish Cap (Newfoundland).
Several isolates of aquatic birnaviruses were recovered from different species of wild fish caught in the Flemish Cap, a Newfoundland fishery close to the Atlantic coast of Canada. The nucleotide sequence of a region of the NS gene was identical among the isolates and was most similar to the Dry Mills and West Buxton reference strains of infectious pancreatic necrosis virus (IPNV). Phylogenetic analysis of the sequence of a region of the VP2 gene demonstrated that the isolates were most closely aligned with the American strains of IPNV serotype A1. Electron microscopy of virus structures clarified and concentrated from cultures of infected chinook salmon embryo (CHSE-214) cells revealed a majority of typical IPNV-like icosahedral particles, as well as a low proportion of type I tubules having a diameter of approximately 55 nm and a variable length of up to 2 microm. The tubules could be propagated in cell cultures, but always in the presence of low proportions of icosahedral particles. Cloning of selected isolates by serial dilution yielded preparations with a high proportion of the tubular structures with a density in CsCl gradients of approximately 1.30 g cm(-3). Polyacrylamide gel electrophoresis revealed the material in the band was composed of the IPNV pVP2 and VP2 proteins.


Influence of age on real-life effects of doxycycline for acute exacerbations among COPD outpatients: a population-based cohort study.
Although bacteria contribute significantly to acute exacerbations of chronic obstructive pulmonary disease (AECOPD), the added value of antibiotics remains controversial, especially in outpatient settings. Age may affect antibiotic effectiveness, but real-world evidence is lacking. We aimed to assess the influence of age on the effectiveness of doxycycline for AECOPD. A retrospective cohort study among outpatients with the first recorded AECOPD treated with oral corticosteroids was conducted using a large pharmacy dispensing database. The primary outcome was treatment failure within 15-31 days after treatment start. Secondary outcome was time to second exacerbation. All analyses were stratified by age groups. We identified 6300 outpatients with the first AECOPD. 2261 (36%) received doxycycline and 4039 (64%) did not receive any antibiotic (reference group). Overall, there was no difference in treatment failure (adjusted OR: 0.97, 95% CI: 0.84 to 1.12) between two groups. Similarly, no difference in treatment failure was observed in younger groups. However, in patients with advanced age (≥75 years), treatment failure was significantly reduced by doxycycline compared with reference (16% vs 20%, adjusted OR: 0.77, 95% CI: 0.62 to 0.97). Overall, median time to second exacerbation was 169 days (95% CI: 158 to 182 days) in doxycycline group compared with 180 days (95% CI: 169 to 191 days) in reference group (adjusted HR: 1.06, 95% CI: 0.99 to 1.12). Although in older patients there was a trend within 3 months towards longer time of next exacerbation by doxycycline, it did not achieve statistical significance. Our findings showed short-term treatment benefit of doxycycline added to oral corticosteroids for chronic obstructive pulmonary disease patients with advanced age. This value remains unclear for persons aged under 75 years in current primary care. Long-term preventive benefits of doxycycline for the next exacerbation were not observed, irrespective of age.


Highly potent, orally active novel small-molecule HPK1 inhibitor DS21150768 induces anti-tumor responses in multiple syngeneic tumor mouse models.
Augmenting T-cell activity is a promising approach to enhance the efficacy of cancer immunotherapy treatment. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in immune cells and negatively regulates T-cell receptor signaling. It is reported that inhibition of the kinase function of HPK1 results in tumor growth suppression by enhancing cancer immunity. Thus, developing HPK1 inhibitors has attracted considerable attention as a future cancer immunotherapy approach. However, despite recent progress in HPK1 biology and pharmacology, various challenges still remain, such as developing HPK1 inhibitors with favorable pharmacological profiles and identifying tumor characteristics that can be applied to define susceptibility to HPK1 inhibition. Here, we present the identification and pharmacological evaluation of DS21150768, a potent small-molecule HPK1 inhibitor with a novel chemical scaffold. DS21150768 shows remarkable inhibition of HPK1 kinase activity, and in vitro studies demonstrated its potent activity to enhance T-cell function. DS21150768 is orally bioavailable and shows sustained plasma exposure, which leads to enhanced cytokine responses in vivo. We conducted a comparison of the anti-tumor efficacy of DS21150768 alone or in combination with anti-PD-1 antibody in 12 different mouse cancer cell models, and observed that the treatments suppressed tumor growth in multiple models. Furthermore, Gene Set Enrichment Analysis demonstrated significant enrichment of immune-related gene signatures in the tumor models responsive to DS21150768 treatment. Our results provide a path forward for the future development of HPK1 inhibitors and fundamental insights into biomarkers of HPK1-targeted therapy.


Subchondral bone and cartilage repair with bioactive glasses, hydroxyapatite, and hydroxyapatite-glass composite.
The repair of an osteochondral defect in rabbit femur was studied with three kinds of bioactive glasses (BG), hydroxyapatite (HA), and hydroxyapatite-glass (HAG) composite. Seventy-two osteochondral defects were created in 18 rabbits. Sixty-four cylinders were implanted and eight defects were left empty as controls. Histomorphometry, scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDXA) were used for evaluation. Small osteochondral defects in rabbit femur found to heal themselves by regeneration. The three BGs, HA, and HAG led to direct lamellar bone repair of subchondral bone and restoration of articular surfaces mostly with hyalinelike cartilage in 12 weeks. However, the composition of the materials affects their behavior. Chondrogenesis took place earlier with the BGs than with HA. HAG degraded too much, glass 14 was too reactive and brittle, and the high alumina content in glass 11 disturbed its bone-bonding ability. Glass 7 and HA were the most balanced in the repair process. A special preparation method was used to retain soft tissues fairly unchanged and enable them to the observed together with hard tissues in SEM analysis.


A meta-analysis of motivational interviewing process: Technical, relational, and conditional process models of change.
In the present meta-analysis, we test the technical and relational hypotheses of Motivational Interviewing (MI) efficacy. We also propose an a priori conditional process model where heterogeneity of technical path effect sizes should be explained by interpersonal/relational (i.e., empathy, MI Spirit) and intrapersonal (i.e., client treatment seeking status) moderators. A systematic review identified k = 58 reports, describing 36 primary studies and 40 effect sizes (N = 3,025 participants). Statistical methods calculated the inverse variance-weighted pooled correlation coefficient for the therapist to client and the client to outcome paths across multiple target behaviors (i.e., alcohol use, other drug use, other behavior change). Therapist MI-consistent skills were correlated with more client change talk (r = .55, p < .001) as well as more sustain talk (r = .40, p < .001). MI-inconsistent skills were correlated with more sustain talk (r = .16, p < .001), but not change talk. When these indicators were combined into proportions, as recommended in the Motivational Interviewing Skill Code, the overall technical hypothesis was supported. Specifically, proportion MI consistency was related to higher proportion change talk (r = .11, p = .004) and higher proportion change talk was related to reductions in risk behavior at follow up (r = -.16, p < .001). When tested as two independent effects, client change talk was not significant, but sustain talk was positively associated with worse outcome (r = .19, p < .001). Finally, the relational hypothesis was not supported, but heterogeneity in technical hypothesis path effect sizes was partially explained by inter- and intrapersonal moderators. This meta-analysis provides additional support for the technical hypothesis of MI efficacy; future research on the relational hypothesis should occur in the field rather than in the context of clinical trials. (PsycINFO Database Record


Prevalence and Predictors of Distress, Anxiety, Depression, and Quality of Life in Bereaved Family Caregivers of Patients With Advanced Cancer.
To investigate prevalence and predictors of postloss distress, depressive and anxiety symptoms, and quality of life among bereaved family caregivers of patients with advanced cancer. Prospective multicenter study. Family caregivers (N = 160, mean age 56.8 years, 66% female) completed validated outcome measures (Distress Thermometer, Generalized Anxiety Disorder 7-item scale, Patient Health Questionnaire depression module 9-item scale, SF-8 Health Survey Questionnaire) 6 months after patient's discharge or death at specialist inpatient palliative care ward. Clinically relevant distress was observed in 82% with sadness (89%), exhaustion (74%), sleeping problems (68%), loneliness (53%), and sorrows (52%) being the most common distress-causing problems. Moderate/severe anxiety and depressive symptoms were observed in 27% and 35%, respectively. Compared to an adjusted norm sample, quality of life was significantly impaired with exception of "bodily pain" and physical component score. Preloss caregiving (odds ratio [OR] 2.195) and higher preloss distress (OR 1.345) predicted high postloss distress. Utilization of psychosocial support services (OR 2.936) and higher preloss anxiety symptoms (OR 1.292) predicted moderate/severe anxiety symptoms, lower preloss physical quality of life (OR 0.952), and higher preloss depressive symptoms (OR 1.115) predicted moderate/severe depressive symptoms. Preloss mental burden showed to be a consistent predictor for postloss burden and should be addressed during palliative care. Future research should examine specific caregiver-directed interventions during specialist palliative care.


Increased incidence of mitral valve prolapse in children with pectus chest wall deformity.
Pectus anomalies constitute 95% of chest anomalies. Pectus carinatum (PC) and excavatum (PE) are often asymptomatic in childhood. However, symptoms and signs such as chest pain, dyspnea, and mitral valve prolapse (MVP) can be seen in pectus anomalies. Demographic characteristics and accompanying cardiac signs in children with pectus deformity were investigated. In this study, the clinical findings for children with pectus deformity, and the incidence of MVP and other concomitant heart diseases detected in echocardiographic examinations were evaluated. Eighty-two children with PE, 27 with PC, and 107 healthy children were included in this study. In the echocardiographic examination of PE, PC patients, and healthy children, MVP was detected with frequencies of 25%, 33%, and 2% respectively. The study showed that pectus anomalies were associated with an increased incidence of MVP. All patients with pectus deformity should therefore undergo a screening echocardiogram in adolescence to assess for the presence of MVP.


Reinforcement of smoking and drinking: tobacco marketing strategies linked with alcohol in the United States.
We investigated tobacco companies' knowledge about concurrent use of tobacco and alcohol, their marketing strategies linking cigarettes with alcohol, and the benefits tobacco companies sought from these marketing activities. We performed systematic searches on previously secret tobacco industry documents, and we summarized the themes and contexts of relevant search results. Tobacco company research confirmed the association between tobacco use and alcohol use. Tobacco companies explored promotional strategies linking cigarettes and alcohol, such as jointly sponsoring special events with alcohol companies to lower the cost of sponsorships, increase consumer appeal, reinforce brand identity, and generate increased cigarette sales. They also pursued promotions that tied cigarette sales to alcohol purchases, and cigarette promotional events frequently featured alcohol discounts or encouraged alcohol use. Tobacco companies' numerous marketing strategies linking cigarettes with alcohol may have reinforced the use of both substances. Because using tobacco and alcohol together makes it harder to quit smoking, policies prohibiting tobacco sales and promotion in establishments where alcohol is served and sold might mitigate this effect. Smoking cessation programs should address the effect that alcohol consumption has on tobacco use.


[Health issues and preventive health strategies for adolescent girls].
As adolescent girls have specific healthcare needs, this paper was designed to provide a better understanding of their healthcare needs in both physical and psychosocial terms. After conducting a targeted review of the literature on children and adolescents, we identified factors of importance to physical health as body weight, physical activity, menstruation, sexual knowledge and attitude and to psychosocial health as anxiety, interpersonal relationships, depression, and suicide behavior. Reflecting these factors, this paper presents four preventive suggestions to clinical practice, education, and research to facilitate improvements in adolescent girl's health. These suggestions include: 1) strengthening health education and media responsibility with regard to adolescent girl health; 2) improving awareness of the needs of adolescent girls within healthcare and education organizations; 3) making health guidelines for promoting proper health behavior in adolescent girls; and 4) mobilizing nurses to assert the health of adolescent girls in clinical, education, and research fields. This is the first paper that focuses on the health needs of adolescent Taiwanese girls. The authors hope that more people become involved in the care of adolescent girl's health in Taiwan.


Fully Complex-Valued Gated Recurrent Neural Network for Ultrasound Imaging.
Ultrasound imaging is widely used in medical diagnosis. It has the advantages of being performed in real time, cost-efficient, noninvasive, and nonionizing. The traditional delay-and-sum (DAS) beamformer has low resolution and contrast. Several adaptive beamformers (ABFs) have been proposed to improve them. Although they improve image quality, they incur high computation cost because of the dependence on data at the expense of real-time performance. Deep-learning methods have been successful in many areas. They train an ultrasound imaging model that can be used to quickly handle ultrasound signals and construct images. Real-valued radio-frequency signals are typically used to train a model, whereas complex-valued ultrasound signals with complex weights enable the fine-tuning of time delay for enhancing image quality. This work, for the first time, proposes a fully complex-valued gated recurrent neural network to train an ultrasound imaging model for improving ultrasound image quality. The model considers the time attributes of ultrasound signals and uses complete complex-number calculation. The model parameter and architecture are analyzed to select the best setup. The effectiveness of complex batch normalization is evaluated in training the model. The effect of analytic signals and complex weights is analyzed, and the results verify that analytic signals with complex weights enhance the model performance to reconstruct high-quality ultrasound images. The proposed model is finally compared with seven state-of-the-art methods. Experimental results reveal its great performance.


In Vitro and In Vivo Synergistic Antitumor Activity of the Combination of BKM120 and Erlotinib in Head and Neck Cancer: Mechanism of Apoptosis and Resistance.
We previously reported that the EGFR-targeted inhibitor erlotinib induces G1 arrest of squamous cell carcinoma of the head and neck (SCCHN) cell lines without inducing significant apoptosis. Large-scale genomic studies suggest that >50% of SCCHN cases have activation of PI3K pathways. This study investigated whether cotargeting of EGFR and PI3K has synergistic antitumor effects and apoptosis induction. We examined growth suppression, apoptosis, and signaling pathway modulation resulting from single and combined targeting of EGFR and PI3K with erlotinib and BKM120, respectively, in a panel of SCCHN cell lines and a xenograft model of SCCHN. In a panel of 12 cell lines, single targeting of EGFR with erlotinib or PI3K with BKM120 suppressed cellular growth without inducing significant apoptosis. Cotargeting of EGFR and PI3K synergistically inhibited SCCHN cell line and xenograft tumor growth, but induced variable apoptosis; some lines were highly sensitive, others were resistant. Mechanistic studies revealed that the combination inhibited both axes of the mTORC1 (S6 and 4EBP1) pathway in apoptosis-sensitive cell lines along with translational inhibition of Bcl-2, Bcl-xL, and Mcl-1, but failed to inhibit p-4EBP1, Bcl-2, Bcl-xL, and Mcl-1 in an apoptosis-resistant cell line. siRNA-mediated knockdown of eIF4E inhibited Bcl-2 and Mcl-1 and sensitized this cell line to apoptosis. Our results strongly suggest that cotargeting of EGFR and PI3K is synergistic and induces apoptosis of SCCHN cell lines by inhibiting both axes of the AKT-mTOR pathway and translational regulation of antiapoptotic Bcl-2 proteins. These findings may guide the development of clinical trials using this combination of agents. Mol Cancer Ther; 16(4); 729-38. ©2017 AACR.


New approaches to treatment of chronic viral hepatitis.
Despite rapid progress in knowledge of the biology of hepatitis viruses, the ability to treat chronic infection is limited. In fact, interferon-alpha 2b is the only FDA-approved therapy for chronic HBV and chronic HCV. The authors report on the interferons and evolving therapies for chronic viral hepatitis and conclude with a discussion of liver transplantation.


Comparison of clinical, biochemical and histological features of alcoholic steatohepatitis and non-alcoholic steatohepatitis in Asian Indian patients.
Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) are significant forms of liver disease and may progress to end-stage liver disease, cirrhosis and potentially malignant complications. The most difficult aspect of establishing a diagnosis of NASH is distinguishing it from ASH. Laboratory markers such as AST, ALT and GGT lack sufficient sensitivity and specificity. To study the clinical, biochemical and histological differences between non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH). Sixty histologically confirmed cases of non-alcoholic steatohepatitis and 38 cases of alcoholic steatohepatitis were included in the study. A modified form of scoring system proposed by Yip and Burt was used to grade histological features of NASH and ASH. Mean age was 42.85 +/- 12.36 years in ASH group and 35.07 +/- 8.06 years for NASH group. Male: Female ratio was 37:1 in ASH and 4:1 in NASH. The mean ALT (P = 0.012), SAP (P = 0.003), serum bilirubin (P = 0.001), AST/ALT ratio (P = 0.03), steatosis (P < 0.001), ballooning degeneration of hepatocytes (P < 0.001), portal inflammation (P < 0.001), Mallory hyaline (P = 0.001), ductular proliferation and fibrosis (P < 0.001) showed a significant difference between ASH and NASH cases. Older age, male sex, larger derangement of serum biochemistry, high serum bilirubin, AST/ALT > 1, more ballooning degeneration, portal inflammation, Mallory's hyaline, hepatocytic and ductular cholestasis, ductular proliferation and higher stage of fibrosis favors a diagnosis of ASH. Younger age, high ALT, AST/ALT < 1, higher grade of steatosis and absence of extensive neutrophilic portal inflammation favors a diagnosis of NASH.


Male breast cancer in the United States: Treatment patterns and prognostic factors in the 21st century.
Male breast cancer (MBC) is a rare disease for which there is limited understanding of treatment patterns and prognostic factors. Men with TNM stage I to stage III breast cancer diagnosed between 2004 and 2014 in the National Cancer Data Base were included. Trends in treatment modalities were described using the average annual percentage change (AAPC) and estimated using Joinpoint software for the analysis of trends. Kaplan-Meier curves and the multivariate Cox proportional hazards regression model were used to compare survival between subgroups and to identify prognostic factors. A total of 10,873 MBC cases were included, with a median age at diagnosis of 64 years. Breast-conserving surgery was performed in 24% of patients, and 70% of patients undergoing breast conservation received radiotherapy. Approximately 44% of patients received chemotherapy, and 62% of patients with estrogen receptor-positive disease received endocrine therapy. Oncotype DX was ordered in 35% of patients with lymph node-negative, estrogen receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors. During the study period, there was a significant increase in the rates of total mastectomy, contralateral prophylactic mastectomy, radiotherapy after breast conservation, ordering of Oncotype DX, and the use of endocrine therapy (P < .05). On multivariate analysis, factors found to be associated with worse overall survival were older age, black race, higher Charlson Comorbidity Index, high tumor grade and stage of disease, and undergoing total mastectomy. Residing in a higher income area; having progesterone receptor-positive tumors; and receipt of chemotherapy, radiotherapy, and endocrine therapy were associated with better overall survival. Despite the lack of prospective randomized trials in patients with MBC, the results of the current study demonstrated that the treatment of this disease has evolved over the years. These findings further the understanding of the modern treatment and prognosis of MBC, and identify several areas for further research.


Second-harmonic generation in sound beams reflected from, and transmitted through, immersed elastic solids.
Second-harmonic generation in sound beams reflected from and transmitted through thick isotropic elastic solids is investigated experimentally. Measurements of diffraction patterns are compared with a theoretical model based on integral solutions for harmonic generation in sound beams. The solutions are connected by classical linear theory for reflection and transmission at fluid-solid interfaces. Nonspecular phenomena associated with rapid phase variations near critical angles are accurately described. The principal restriction is that the solid is sufficiently thick that internal reflections may be ignored.


Long non-coding RNA CASC2 suppresses the proliferation of gastric cancer cells by regulating the MAPK signaling pathway.
Long non-coding RNAs (lncRNAs) have been shown to play important roles in tumorigenesis. However, the biological functions and molecular mechanisms underlying aberrantly expressed lncRNAs in gastric cancer (GC) is still unclear. In this study, a novel lncRNA CASC2 was chosen to evaluate the effect on GC cell growth and the possible mechanism. Our results showed that CASC2 was significantly downregulated in human GC tissues and cell lines by quantitative RT-PCR. Overexpression of CASC2 in GC cells significantly inhibited the cell growth in vitro and in vivo. We further found that MAPK pathway especially the ERK1/2 and JNK component were involved in the CASC2 mediated GC cell proliferation. Moreover, combination treatment of CASC2 overexpression and suppression ERK1/2 or JNK produced synergistic inhibitory effects in vitro. Thus, these results indicated that CASC2 might serve as a tumor suppressor lncRNA that suppressed cell proliferation by inactivation of MAPK pathway. These findings suggested that CASC2 could be a potential therapeutic target for the treatment of GC patients.


Design and evaluation of a feedback based phased array system for ultrasound surgery.
A driving system has been designed for phased array ultrasound applicators. The system is designed to-operate in the bandwidth 1.2 to 1.8 MHz, with independent channel power control up to 60 W (8 bit resolution) for each array element. To reduce power variation between elements, the system utilizes switching regulators in a feedback loop to automatically adjust the DC supply of a class D/E power converter. This feedback reduces the RF electrical power variation from 20% to 1% into a 16 element array. DC-to-RF efficiencies close to 70% for all power levels eliminates the need for large heat sinks. In addition to power control, each channel may be phase shifted 360 degrees with a minimum of 8 bit resolution. To ensure proper operation while driving ultrasound arrays with varying element sizes, each RF driving channel implements phase feedback such that proper phase of the driving signal is produced either at the amplifier output before the matching circuitry or after the matching circuitry at the transducer face. This feedback has been experimentally shown to increase the focal intensities by 20 to 25% of two tested phased arrays without array calibration using a hydrophone.


The old-world Zygonini tr. nov. (Hemiptera, Cercopoidea, Clastopteridae), with new taxa from the related Machaerotinae.
Three new species of old-world Clastopteridae belonging to Machaerotinae are described, two in new monobasic genera: Allox transfigurata (Hindolini) from Borneo and Irridiculum deformatum (Machaerotini) from Sulawesi. One new species Machaeropsis dramatica (Hindolini) is described from Borneo. It is the first male known from the genus and shows that Machaeropsis Melichar is not synonymous with Metaenderleinia Lallemand. Five other new species are described, belonging to a new, related tribe Zygonini. Two of these new species (Ambonga lanceolata and Pseudomachaerota cucullata) belong to formerly monobasic genera from Madagascar incorrectly assigned to Cercopidae and Aphrophoridae respectively. These are related to 3 new genera: (1) from Madagascar, Pseudoclastoptera with new species P. irrubesco and P. invidia; from sub-Saharan Africa, (2) Zygon with 1 new species Z. desegregatum, and (3) Hemizygon, the latter with 2 new combinations from Pseudomachaerota: H. grande (Maa) and H. saturnus (Linnavuori). Zygon is possibly the most basal genus in Clastopteridae, according to its remarkable antennal characters with 5 different types of sensilla that show how basiconic and coeloconic sensilla are homodynamous. Genera related to Zygon are widely divergent from other spittlebugs as measured by mDNA "barcode" data from the COI gene.


[Social and hygienic aspects of mandible fractures in Republic of Sakha (Yakutia)].
Comprehensive social and hygienic survey of 209 patients with mandible fracture was conducted. Their social features were: young adults, predominantly male, ethnicity mainly yakuts, temporarily unemployed, with secondary and post-secondary education and health behavior problems. The majority of jaw injuries were caused by household (26.21 ± 0.92%) and street traumas (63.03 ± 0.46%). High prevalence of major oral diseases depends strongly on the low sanitary culture, which had a negative impact on the development of posttraumatic complications.


Evaluating metal phytorremediation and biondication potential of Spartina alterniflora in a South American estuary.
Soil metal pollution has been widely studied in salt marshes but mainly regarding non-essential metals. The aim of this study was to assess the levels of two essential metals (Fe and Mn) and one non-essential one (Cd) in Spartina alterniflora salt marshes in a South American estuary in order to evaluate the potential of this species as a phytoremediator and/or bioindicator of Fe, Mn and Cd and to analyze the distribution of these metals according to the edaphic conditions. The metals present in the soils varied among the three sites studied according to the content of organic matter and fine sediments. In comparison with other Spartina-dominated salt marshes worldwide, in this study Fe and Mn were approximately in the same range, whereas Cd levels were always lower, with a high number of samples below the method detection limit (MDL). All metals were highly correlated with each other suggesting an association of Cd with Mn and Fe oxides/hydroxides or sulfides and/or a common anthropogenic source. Metals in plant tissues also varied from site to site and between the aboveground and belowground tissues. Compared to the metal levels in Spartina tissues in other salt marshes, our levels of Fe and Mn were in the same range, whereas the Cd levels were lower, among most samples, especially those from aboveground tissues that were below the MDL. The bioconcentration factor (metal in belowground tissues/metal in soil) was always lower than one for Fe and Mn meaning that there is no accumulation of these metals in belowground tissues, but this factor for Cd was sometimes higher than one, even as high as 3.45, implying that S. alterniflora can accumulate this metal in its tissues, pointing to a potential role of this species in Cd phytoremediation. Translocation factors (metal in aboveground tissues/metal in belowground tissues) were always lower than one for Fe and could not be calculated for Cd but were usually higher than one for Mn, showing the role of this element in photosynthetic tissues and a possible function of this species for phytoextraction of Mn. In most samples the Fe levels in plant tissues were higher than the permissible levels reported in the literature, suggesting a potential role of S. alterniflora in Fe phytoremediation. No correlation was observed between metal concentrations in soils and aboveground tissues; therefore, S.alterniflora is not a good bioindicator for the metals studied. Although our results are not conclusive, they reinforce the importance of local edaphic conditions on the behavior of metals in salt marshes and shed light on the potential role of S. alterniflora in the phytoremediation of highly toxic metals such as Cd or poorly studied metals such as Fe and Mn.


"It should not have happened": metaphorical expressions, idioms, and narrative descriptions related to trauma in an indigenous community in India.
Purpose: Psychological trauma can be viewed as a metaphor which originates from somatic medicine and comes from the Greek word "wound". To gain a better understanding of trauma in a culturally sensitive way, the present project aimed to explore alternative metaphors used to describe extreme aversive or catastrophic events. Methods: This ethnopsychological study was carried out among the Adivasis indigenous people in tribal communities in Pune, India. We performed 28 interviews with lay persons and key informants, focusing on collectively shared metaphors. The data were examined using systematic metaphor analysis. Results: While the most prevalent metaphorical concepts found related to shock and wound, we also identified culture-specific idioms and common themes in the descriptions related to trauma. The most predominant expression, which was used by all of the participants, was "this should not have happened" (asa nahi vhayala pahije hota). These findings indicate that metaphorical concepts reflect implicit worldviews and beliefs in the community under study. Conclusion: The main implication of the results found is to increase awareness of different expressions in clinical settings, pointing to potential approaches to the cultural adaptation of clinical interventions in general.


Induction of cancer, actinic keratosis, and specific p53 mutations by UVB light in human skin maintained in severe combined immunodeficient mice.
To study the mechanism and risk of human skin cancer from solar light, we exposed human skin transplanted to severe combined immunodeficient mice to daily doses of UVB for periods of approximately 2 years. We have succeeded for the first time in inducing cancer and solar (actinic) keratosis in human skin by UVB. Of 18 normal skins exposed to doses of 7.3 x 10(5) to 1.8 x 10(6) J/m2, 14 actinic keratoses (77.8%) and 3 squamous cell carcinomas (16.7%) developed, whereas neither actinic keratosis nor cancer was observed in 15 human skins not exposed to UVB. Each human skin showed a different susceptibility, and skins sensitive for actinic keratosis were also sensitive for cancer induction. Among p53 mutations at various sites, mutation at codon 242 (C TGC --> C CGC; Cys --> Arg) was specifically observed in both skin cancers and actinic keratoses. Furthermore, double or triple mutations were induced in all UVB-induced skin cancers and in three of eight actinic keratoses. Most of the mutations (17 of 20) occurred at dipyrimidine sites.


Molecular mechanisms underlying levodopa-induced dyskinesia.
Although levodopa remains the most effective drug for the symptomatic treatment of Parkinson's disease, chronic therapy with this pharmacological compound initiates a complex cascade of cellular and molecular downstream effects resulting in the development of abnormal involuntary movements. The precise mechanisms underlying the development of levodopa induced dyskinesia, however, are far from being completely elucidated. In the present review, we will describe changes in long-term synaptic excitability following dopamine (DA) denervation and long-term levodopa treatment leading to abnormal involuntary movements. In particular, we will address the role of both DA D1 receptors and NMDA glutamate receptors in the induction and maintenance of dyskinesia and abnormal synaptic plasticity. We will also describe the possible interaction between these two receptors in the pathophysiology of dyskinesia taking the advantage of the existing knowledge concerning the mechanisms underlying drug abuse. This latter pathophysiological condition, in fact, seems to share several biochemical transduction pathways with those implicated in levodopa-induced dyskinesia. Finally, we will briefly discuss the possible implication of A2A adenosine receptors in long-term motor complications of levodopa therapy and focus on the interaction between A2A and D2 receptors. Future studies are required to understand how the interaction between these various biochemical steps converge to produce a long-term change in neuronal excitability within the basal ganglia leading to abnormal involuntary movements following levodopa treatment in the DA-denervated state.


Norovirus RNA synthesis is modulated by an interaction between the viral RNA-dependent RNA polymerase and the major capsid protein, VP1.
Using a cell-based assay for RNA synthesis by the RNA-dependent RNA polymerase (RdRp) of noroviruses, we previously observed that VP1, the major structural protein of the human GII.4 norovirus, enhanced the GII.4 RdRp activity but not that of the related murine norovirus (MNV) or other unrelated RNA viruses (C. V. Subba-Reddy, I. Goodfellow, and C. C. Kao, J. Virol. 85:13027-13037, 2011). Here, we examine the mechanism of VP1 enhancement of RdRp activity and the mechanism of mouse norovirus replication. We determined that the GII.4 and MNV VP1 proteins can enhance cognate RdRp activities in a concentration-dependent manner. The VP1 proteins coimmunoprecipitated with their cognate RdRps. Coexpression of individual domains of VP1 with the viral RdRps showed that the VP1 shell domain (SD) was sufficient to enhance polymerase activity. Using SD chimeras from GII.4 and MNV, three loops connecting the central β-barrel structure were found to be responsible for the species-specific enhancement of RdRp activity. A differential scanning fluorimetry assay showed that recombinant SDs can bind to the purified RdRps in vitro. An MNV replicon with a frameshift mutation in open reading frame 2 (ORF2) that disrupts VP1 expression was defective for RNA replication, as quantified by luciferase reporter assay and real-time quantitative reverse transcription-PCR (qRT-PCR). Trans-complementation of VP1 or its SD significantly recovered the VP1 knockout MNV replicon replication, and the presence or absence of VP1 affected the kinetics of viral RNA synthesis. The results document a regulatory role for VP1 in the norovirus replication cycle, further highlighting the paradigm of viral structural proteins playing additional functional roles in the virus life cycle.


Local modulation of steroid action: rapid control of enzymatic activity.
Estrogens can induce rapid, short-lived physiological and behavioral responses, in addition to their slow, but long-term, effects at the transcriptional level. To be functionally relevant, these effects should be associated with rapid modulations of estrogens concentrations. 17β-estradiol is synthesized by the enzyme aromatase, using testosterone as a substrate, but can also be degraded into catechol-estrogens via hydroxylation by the same enzyme, leading to an increase or decrease in estrogens concentration, respectively. The first evidence that aromatase activity (AA) can be rapidly modulated came from experiments performed in Japanese quail hypothalamus homogenates. This rapid modulation is triggered by calcium-dependent phosphorylations and was confirmed in other tissues and species. The mechanisms controlling the phosphorylation status, the targeted amino acid residues and the reversibility seem to vary depending of the tissues and is discussed in this review. We currently do not know whether the phosphorylation of the same amino acid affects both aromatase and/or hydroxylase activities or whether these residues are different. These processes provide a new general mechanism by which local estrogen concentration can be rapidly altered in the brain and other tissues.


OsSPL14 promotes panicle branching and higher grain productivity in rice.
Identification of alleles that improve crop production and lead to higher-yielding varieties are needed for food security. Here we show that the quantitative trait locus WFP (WEALTHY FARMER'S PANICLE) encodes OsSPL14 (SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 14, also known as IPA1). Higher expression of OsSPL14 in the reproductive stage promotes panicle branching and higher grain yield in rice. OsSPL14 controls shoot branching in the vegetative stage and is affected by microRNA excision. We also demonstrate the feasibility of using the OsSLP14(WFP) allele to increase rice crop yield. Introduction of the high-yielding OsSPL14(WFP) allele into the standard rice variety Nipponbare resulted in increased rice production.


Serum vitamin D levels in relation to schizophrenia: a systematic review and meta-analysis of observational studies.
Although several observational studies have investigated the association between vitamin D status and schizophrenia, we are aware of no comprehensive meta-analysis in this regard. We aimed to conduct a systematic review and a meta-analysis of observational studies to summarize the available data on the association between serum vitamin D levels and schizophrenia. A systematic research on all published articles until October 2013 was conducted in PubMed, ISI (Web of science), SCOPUS, and Google Scholar. All observational studies that had measured serum vitamin D levels in schizophrenic patients were included in the systematic review. After considering exclusion criteria, we had 19 studies for the systematic review that were included in three separate meta-analyses: 1) a meta-analysis on mean levels of 25-hydroxyvitamin D [25(OH)D] (n = 13); 2) a meta-analysis on the prevalence of vitamin D deficiency (n = 8); 3) a meta-analysis on odds ratios (n = 8). Findings from a meta-analysis on means revealed that the overall mean difference in serum 25(OH)D levels between schizophrenic patients and control participants was -5.91 ng/mL [95% confidence interval (CI) -10.68, -1.14]. Subgroup analyses based on study design, the patient's hospitalization status, study quality, and study location did not explain between-study heterogeneity; however, type of biomarker assessed [25-hydroxyvitamin D3 vs 25-hydroxyvitamin D (D2 & D3)] could account for some degree of heterogeneity. RESULTS from the meta-analysis on the prevalence of vitamin D deficiency indicated that the overall prevalence of vitamin D deficiency in schizophrenic patients was 65.3% (95% CI 46.4%-84.2%). Findings from the meta-analysis on odds ratios indicated that vitamin D-deficient persons were 2.16 times (95% CI 1.32, 3.56) more likely to have schizophrenia than those with vitamin D sufficiency. No evidence of heterogeneity was detected. We found a strong association between vitamin D deficiency and schizophrenia. However, randomized clinical trials are required to confirm our findings.


Disparate movement behavior and feeding ecology in sympatric ecotypes of Atlantic cod.
Coexistence of ecotypes, genetically divergent population units, is a widespread phenomenon, potentially affecting ecosystem functioning and local food web stability. In coastal Skagerrak, Atlantic cod (Gadus morhua) occur as two such coexisting ecotypes. We applied a combination of acoustic telemetry, genotyping, and stable isotope analysis to 72 individuals to investigate movement ecology and food niche of putative local "Fjord" and putative oceanic "North Sea" ecotypes-thus named based on previous molecular studies. Genotyping and individual origin assignment suggested 41 individuals were Fjord and 31 were North Sea ecotypes. Both ecotypes were found throughout the fjord. Seven percent of Fjord ecotype individuals left the study system during the study while 42% of North Sea individuals left, potentially homing to natal spawning grounds. Home range sizes were similar for the two ecotypes but highly variable among individuals. Fjord ecotype cod had significantly higher δ13C and δ15N stable isotope values than North Sea ecotype cod, suggesting they exploited different food niches. The results suggest coexisting ecotypes may possess innate differences in feeding and movement ecologies and may thus fill different functional roles in marine ecosystems. This highlights the importance of conserving interconnected populations to ensure stable ecosystem functioning and food web structures.


Discrimination of early/intermediate and advanced/complicated coronary plaque types by radiofrequency intravascular ultrasound analysis.
Radiofrequency intravascular ultrasound (IVUS-RF) analysis, as an extension of conventional IVUS imaging, may provide more accurate plaque discrimination. Thirty-two autopsy atherosclerotic coronary arteries were investigated. Corresponding sectors in different plaques were matched by histologic and RF analysis. Histologic analysis utilized the American Heart Association plaque classification. The backscattered ultrasound RF signal was analyzed by fast-Fourier transform, providing the underlying frequency components of its power spectrum. The normalized backscattered signal power (in decibels [dB]) for frequencies between 15.3 and 40.3 MHz was then measured for plaque discrimination. Advanced/complicated plaque types showed a higher signal power at all frequencies than early/intermediate lesion types (p <0.001 to p = 0.005). Discrimination of advanced/complicated lesion types was best at 15.3 MHz, with a cut-off point of 2.5 dB (sensitivity 93%, specificity 79%), and second best at 17.6 MHz (sensitivity 87%, specificity 71%, cut-off point 1.9 dB). With conventional IVUS, plaque discrimination was weaker; the best sensitivity for diagnosing early/intermediate lesion types was reached for "soft plaque" (sensitivity 63%, specificity 73%). Compared with conventional IVUS, IVUS-RF can discriminate between advanced/complicated and early/intermediate coronary atherosclerotic lesions with relatively high sensitivity and specificity in vitro.


No difference in mortality in undetected coeliac disease compared with the general population: a UK cohort study.
Studies of mortality in undetected coeliac disease compared with the general population give contradictory findings, suggesting it is either increased fourfold compared with the general population or not at all. To establish all-cause and cause-specific mortality in undiagnosed coeliac disease, identified by anti-endomysial antibody (EMA) positivity, in the Cambridge GP Health Survey cohort. This cohort was recruited in 1990 from the general population aged 45-76 years. All deaths were ascertained from the Office for National Statistics. Mortality rates were calculated per 1000 person years and adjusted for age, gender, smoking and socioeconomic group using multivariate Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI). There were 117,914 patient years of follow-up (median 16.8 years) from 7527 participants. Eighty-seven had undetected coeliac disease, their all-cause mortality rate was 9.4 per 1000 person years (95% CI 5.4-16.1) compared with 12.7 (95% CI 12.1-13.4) in EMA-negative participants. The adjusted all-cause mortality HR was 0.98 (95% CI 0.57-1.69). Death due to cancer and circulatory diseases was not increased, adjusted HR were 1.27 (95% CI 0.57-2.85) and 1.39 (95% CI 0.66-2.92) respectively. We observed no excess overall mortality in people aged over 45 years with undetected coeliac disease compared with the general population, nor any increase in deaths related to circulatory disease or cancer. Our findings do not support screening the general population aged over 45 years, for coeliac disease for the purpose of improving life expectancy.


Epidemiología, consumo de recursos y costos del manejo médico de la Hepatitis C en Argentina, Colombia, Uruguay y Venezuela.
To describe the epidemiology, the consumption of resources and the relevant costs in the management of hepatitis C in four Latin American countries: Argentina, Colombia, Uruguay and Venezuela. Bibliographic review, study of costs and elicitation by experts METHODS: A literature search was carried out to collect epidemiological and cost data for the management of the disease. Information was additionally elicited with hepatologists from each country using the modified Delphi Panel technique. For the estimation of costs, the perspective of the health system was adopted. The direct medical costs of the different stages associated with the natural history of the disease were considered through micro-costing. Extensive epidemiological and economic information is provided for the four countries under study. The age range between 40 and 60 years was the most affected. The frequency of genotypes showed a predominance of genotype 1 (68 to 88%), genotype 1b having been reported as the most prevalent in Argentina and Colombia and 1a in Uruguay and Venezuela. The costs of drug regimens, associated health events and adverse events present important differences in the four selected countries of Latin America. Hepatitis C presents a high burden of disease in the countries under study, and its management imposes significant costs on health systems.


Adapting a Patient-Reported Outcome Measure to Digital Outpatient Specialist Health Care Services for Type 1 Diabetes: User Involvement Study.
Diabetes self-management is crucial for patients with type 1 diabetes, and digital services can support their self-management and facilitate flexible follow-up. The potential of using digital patient-reported outcome (PRO) measures in routine outpatient care is not fully used owing to a lack of adapted PRO measures. This study presents the process of identifying and adapting a digital PRO measure for use in clinical diabetes practice and describes the preferred item topics of the adapted PRO measure, as reported by patients and diabetes specialist nurses. With the involvement of patients, diabetes specialist nurses, management, and researchers, we hosted a series of workshops and 2 dialogue conferences. Scoping searches to identify relevant PRO measures formed the foundation for the process. An in-person dialogue conference was conducted with diabetes specialist nurses as participants, and a digital dialogue conference was conducted with patients with type 1 diabetes as participants. A diabetes-specific PRO measure was translated and adapted to our digital platform. Notes and summaries from the dialogue conferences were imported into NVivo (QSR International) and thematically analyzed as a single combined data set. The thematic analysis of the 2 dialogue conferences aimed to explore the views of patients with type 1 diabetes and diabetes specialist nurses on the outcomes necessary to measure. An overarching theme, Ensuring that the PRO measure captures the patients' needs precisely and accurately, in a way that facilitates care and communication with health care personnel, was identified and supported with data from both the patients and diabetes specialist nurses. This theme contained four categories: The need for explanatory text after questions to ensure understanding and accurate response, Capturing individual needs in standardized questions, getting to the heart of the patient's problem, and The questions increase patient reflection. We successfully conducted an iterative process that identified a PRO measure aligned with the topics raised by the diabetes specialist nurses. Similarly, the patients found the PRO measure to be relevant and one that was addressing their needs. Only minor adjustments were necessary when programming the PRO measure in the digital platform. Our management, patients, and diabetes specialist nurses had a valuable impact on the results. User involvement facilitated a specific focus on the clinical requests to be met by PRO measures and how they must be adapted to local and digital platforms. Overall, this has facilitated the current implementation of the adapted digital PRO measure.


Cellular Mechanisms of Action of Drug Abuse on Olfactory Neurons.
Cannabinoids (Δ9-tetrahydrocannabinol) are the active ingredient of marijuana (cannabis) which is the most commonly abused illicit drug in the USA. In addition to being known and used as recreational drugs, cannabinoids are produced endogenously by neurons in the brain (endocannabinoids) and serve as important signaling molecules in the nervous system and the rest of the body. Cannabinoids have been implicated in bodily processes both in health and disease. Recent pharmacological and physiological experiments have described novel aspects of classic brain signaling mechanisms or revealed unknown mechanisms of cellular communication involving the endocannabinoid system. While several forms of signaling have been described for endocannabinoids, the most distinguishing feature of endocannabinoids is their ability to act as retrograde messengers in neural circuits. Neurons in the main olfactory bulb express high levels of cannabinoid receptors. Here, we describe the cellular mechanisms and function of this novel brain signaling system in regulating neural activity at synapses in olfactory circuits. Results from basic research have the potential to provide the groundwork for translating the neurobiology of drug abuse to the realm of the pharmacotherapeutic treatment of addiction, specifically marijuana substance use disorder.


Differential cytolocation and functional assays of the two major human SLC30A8 (ZnT8) isoforms.
The non-synonymous single nucleotide polymorphism (SNP) rs13266634 in human zinc transporter 8, ZnT8 (SLC30A8), leads to a R325 variant, which is associated with an increased risk of developing Type 2 Diabetes (T2D). Although the molecular details remain unknown, the mutation is thought to alter the kinetics of zinc transport into insulin granules in pancreatic β-cells. Nevertheless, analysis of ZnT8 sequences from several animals shows that the amino acid at position 325 is poorly conserved. Apart from this particular SNP, human ZnT8 also has two isoforms (splice variants) that differ in length regarding a 49 amino acid N-terminal extension. When expressed in human embryonic kidney (HEK293) cells, the long isoform was present in the plasma membrane in addition to internal membranes, whereas the short isoform was localized mostly to internal membranes. Our observation that human ZnT8 variants and isoforms expressed in Xenopus laevis oocytes are all localized at the cell surface allowed us to develop a zinc transport assay using the radioactive isotope 65Zn. We found no detectable differences in zinc transport between W and R variants and no statistically significant differences between long and short isoforms of the W325 variant. Our findings of differential cytolocation of ZnT8 isoforms could be relevant for β-cell zinc metabolism in health and disease.


Harmonization of legislation and regulations to achieve food safety: US and Canada perspective.
Trade in food and food ingredients among the nations of the world is rapidly expanding and, with this expansion, new supply chain partners, from globally disparate geographic regions, are being enrolled. Food and food ingredients are progressively sourced more from lesser developed nations. Food safety incidents in the USA and Canada show a high unfavorable correlation between illness outbreaks and imported foods. In the USA, for example, foodborne disease outbreaks caused by imported food appeared to rise in 2009 and 2010, and nearly half of the outbreaks, associated with imported food, implicated foods imported from areas which previously had not been associated with outbreaks. Projecting supply chains into new geographical regions raises serious questions about the capacity of the new supply chain partners to provide the requisite regulatory framework and sufficiently robust public health measures for ensuring the safety of the foods and foodstuffs offered for international trade. The laws, regulation and legislation among the many nations participating in the global food trade are, at best, inconsistent. These inconsistencies frequently give rise to trade disputes and cause large quantities of food to be at risk of destruction on the often dubious pretext that they are not safe. Food safety is often viewed through a political or normative lens. Often as not, this lens has been wrought absent scientific precision. Harmonization of food safety legislation around sound scientific principles, as advocated by the US Food Safety Modernization Act (FSMA), would ultimately promote trade and likely provide for incremental improvement in public health. Among the priority roles of most national governments are the advancement of commerce and trade, preservation of public health and ensuring domestic tranquility. Achieving these priorities is fundamental to creating and preserving the wealth of nations. Countries such as the Netherlands, Canada, Germany, Japan and the USA, for example, have very stable governments, are leaders in trade and commerce and enjoy high standards of public health. It is not by accident or coincidence that these nations are also among the world's wealthiest. Attainment of national priorities, especially those related to promoting trade in foodstuffs and also in preserving public health (food safety), would benefit greatly from international efforts in harmonizing food safety regulations and legislation.


Feasibility study: honey for treatment of cough in children.
Respiratory tract infections are an important health problem because of high incidence and economic costs. The World Health Organization identifies honey as a potential demulcent treatment for cough. The aim of this study is to determine: i) patient public perceptions towards a proposed randomized controlled trial (RCT) comparing the effects of honey to placebo for treatment of cough in children; ii) potential participation rates for proposed trial; iii) whether age and gender of parent or child impacts on proposed cough assessment tools. Forty adult participants with children age 1-6 years presenting with an upper respiratory tract infection were enrolled. They underwent a structured interview regarding the proposed trial and assessed their child's cough using two validated questionnaires. Eighty-eight percent of those recruited were willing to participate in the proposed trial. The two independently validated cough scores correlated well. A relationship between age and gender of child or parent with cough assessment score was not found. We conclude that a RCT to determine the effects of honey versus placebo is feasible. The public find the outcome measures and trial design acceptable.


Epigenetic Mechanisms of Nicotine Dependence.
Smoking continues to be a leading cause of preventable disease and death worldwide. Nicotine dependence generates a lifelong propensity towards cravings and relapse, presenting an ongoing challenge for the development of treatments. Accumulating evidence supports a role for epigenetics in the development and maintenance of addiction to many drugs of abuse, however, the involvement of epigenetics in nicotine dependence is less clear. Here we review evidence that nicotine interacts with epigenetic mechanisms to enable the maintenance of nicotine-seeking across time. Research across species suggests that nicotine increases permissive histone acetylation, decreases repressive histone methylation, and modulates levels of DNA methylation and noncoding RNA expression throughout the brain. These changes are linked to the promoter regions of genes critical for learning and memory, reward processing and addiction. Pharmacological manipulation of enzymes that catalyze core epigenetic modifications regulate nicotine reward and associative learning, demonstrating a functional role of epigenetic modifications in nicotine dependence. These findings are consistent with nicotine promoting an overall permissive chromatin state at genes important for learning, memory and reward. By exploring these links through next-generation sequencing technologies, epigenetics provides a promising avenue for future interventions to treat nicotine dependence.


Selectivity of pharmacological tools: implications for use in cell physiology. A review in the theme: Cell signaling: proteins, pathways and mechanisms.
Pharmacological inhibitors are frequently used to identify the receptors, receptor subtypes, and associated signaling pathways involved in physiological cell responses. Based on the effects of such inhibitors conclusions are drawn about the involvement of their assumed target or lack thereof. While such inhibitors can be useful tools for a better physiological understanding, their uncritical use can lead to incorrect conclusions. This article reviews the concept of inhibitor selectivity and its implication for cell physiology. Specifically, we discuss the implications of using inhibitor vs. activator approaches, issues of direct vs. indirect pathway modulation, implications of inverse agonism and biased signaling, and those of orthosteric vs. allosteric, competitive vs. noncompetitive, and reversible vs. irreversible inhibition. Additional problems can result from inconsistent estimates of inhibitor potency and differences in potency between cell-free systems and intact cells. These concepts are illustrated by several examples of inhibitors displaying affinity for related but distinct targets or even unrelated targets. Of note, many of the issues being addressed are also applicable to genetic inhibition strategies. The main practical conclusion following from these concepts is that investigators should be critical in the choice of inhibitor, its concentrations, and its mode of application. When this advice is adhered to, small-molecule pharmacological inhibitors can be important experimental tools in the hand of physiologists.


The effect of basic training on aerobic capacity and body fat in New Zealand army recruits.
Physical fitness levels were assessed in 50 males recruits at the beginning, the middle and the end of ten weeks basic army training. Aerobic capacity was predicted indirectly from a timed 2.4 km run. Body fat levels were estimated from three skinfold measurements. Estimated VO2 max increased from 48.7 ml.kg-1 min-1 to 56.6 ml.kg-1 min-1, ie, 16.2 percent rise. Accompanying this increase was a decline in percent body fat from 12.4 percent to 10.2 percent, with no change in total body weight. It was concluded that the level of training intensity at 58 ml.kg-1 min-1, was effective in reducing body fat and increasing aerobic capacity.


Serum Vitamins and Minerals at Diagnosis and Follow-up in Children With Celiac Disease.
Children with celiac disease (CD) may experience deficiencies of several micronutrients. The objectives of the present study were to determine the prevalence of micronutrient deficiencies in children with CD at diagnosis, 6 months, and 18 months after the start of a gluten-free diet (GFD), and examine any correlation between micronutrient deficiencies, serum tissue transglutaminase (TtG) immunoglobulin A (IgA) antibody titers, and the degree of mucosal damage at diagnosis. Children (<17 years) with CD had their serum vitamins, minerals, and anti-TtG IgA antibodies measured at diagnosis, 6 and 18 months after starting a GFD. Histopathological changes of duodenal biopsies at diagnosis were documented using modified MARSH classification. The medical records of 140 children (mean age at diagnosis 7.8 ± 4.01 years, 87 girls [621%]) with CD were examined. At diagnosis, serum vitamin D was the most commonly deficient vitamin in 70% of children. Serum ferritin was subnormal in 34.5% with zinc in 18.6% children but only 12 (10.9%) children had iron deficiency anemia. There was no correlation between micronutrient deficiencies at diagnosis and serum TtG IgA antibody titers or the degree of villous atrophy. The majority of serum levels of measured micronutrients had normalized after 6 months of starting GFD except for vitamin D, which improved but remained subnormal. At diagnosis, most children with CD have vitamin D deficiency. The degree of micronutrient deficiencies does not correlate with the degree of villous atrophy or serum titers of anti-TtG IgA antibodies.


Monocyte Function in Parkinson's Disease and the Impact of Autologous Serum on Phagocytosis.
Background: Increasing evidence implicates involvement of the innate immune system in the initiation and progression of Parkinson's disease (PD). Monocytes and monocyte-derived cells perform a number of functions, such as phagocytosis, chemotaxis, and cytokine secretion, which may be particularly relevant to PD pathology. The behavior of these cells in early-moderate disease, in conditions more similar to the in-vivo environment has not been fully evaluated. Research Question: Does monocyte function, including phagocytosis, chemotaxis and cytokine secretion, differ in early-moderate PD compared to age and gender-matched controls? Methods: Participants included PD patients (n = 41) with early-moderate stage disease (Hoehn and Yahr ≤2) and age and gender matched controls (n = 41). Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and monocytes were further separated using CD14 magnetic beads. Functional assays, including bead phagocytosis (in standard medium and autologous serum), Boyden chamber trans-well chemotaxis, and cytokine secretion on lipopolysaccharide stimulation were performed. Monocyte surface markers relating to chemotaxis were measured using immunohistochemistry and flow cytometry. Between-group analysis was performed using paired t-tests. Results: An autologous serum environment significantly increased bead phagocytosis compared to standard medium as expected, in both patients and controls. When in autologous serum, PD monocytes demonstrated enhanced phagocytosis compared to control monocytes (p = 0.029). The level of serum-based phagocytosis was influenced by complement inactivation and the origin of the serum. There were no significant differences between PD and controls in terms of standard medium based monocyte migration or cytokine secretion in this cohort. Conclusions: Autologous serum has a significant influence on monocyte phagocytosis and reveals increased phagocytic capacity in early-moderate PD compared to controls. These conditions may better reflect the function of monocytes in-vivo in PD patients than standard medium based phagocytosis assays. Further studies will be required to replicate these results in larger cohorts, including earlier and later stages of disease, and to understand which serum factors are responsible for this observation and the potential mechanistic relevance to PD pathogenesis.


Thiopurine metabolite ratios for monitoring therapy in pediatric Crohn disease.
Thiopurines (azathioprine, 6-mercaptopurine) are a mainstay of treatment in Crohn disease (CD). Monitoring intracellular metabolite (6-thioguanine nucleotides [6-TGN] and 6-methylmercaptopurine [6-MMP]) levels can help optimize therapeutic efficacy and minimize potential toxicity. Determination of 6-MMP/6-TGN ratios may provide additional useful information, such as the identification of individuals with excessive thiopurine methyltransferase activity and disadvantageous 6-MMP overproduction. These patients are at increased risk of therapeutic failure and hepatotoxicity. The aim of the study was to evaluate the correlation of 6-MMP/6-TGN ratios with therapeutic efficacy and risk of hepatotoxicity in CD. The present study was a single-center cross-sectional study including pediatric patients with CD studied prospectively with clinical and laboratory assessments along with serial measurements of 6-MMP and 6-TGN. Clinical response was determined using established clinical indices. The study included 238 pediatric patients with CD with a total of 1648 evaluation points. The patients were in steroid-free remission at 59.1% of the evaluation points. 6-MMP/6-TGN ratios of 4 to 24 were protective against relapse (odds ratio [OR] 0.52, 95% confidence interval [CI] -0.39 to 0.69, P = 0.001). Hepatotoxicity was associated with high 6-MMP levels (>3919 pmol/8 × 10 red blood cell count: OR 7.65, 95% CI 3.7-15.9, P = 0.001) and high 6-MMP/6-TGN ratios (>24: OR 5.35, 95% CI -3.43 to 8.43, P = 0.001). We observed significant associations between 6-MMP/6-TGN ratios and clinical response, and risk of hepatotoxicity. Our results suggest that determination of thiopurine metabolite ratios is a valuable tool for identification of patients at increased risk of therapeutic failure and hepatotoxicity.


PPAR agonists for the treatment of neuroinflammatory diseases.
Peroxisome proliferator-activated receptors [PPARs; PPARα, PPARβ/δ (also known as PPARδ), and PPARγ] widely recognized for their important role in glucose/lipid homeostasis, have recently received significant attention due to their additional anti-inflammatory and neuroprotective effects. Several newly developed PPAR agonists have shown high selectivity for specific PPAR isoforms in vitro and in vivo, offering the potential to achieve desired therapeutic outcomes while reducing the risk of adverse effects. In this review, we discuss the latest preclinical and clinical studies of the activation of PPARs by synthetic, natural, and isoform-specific (full, partial, and dual) agonists for the treatment of neuroinflammatory diseases, including HIV-associated neurocognitive disorders (HAND), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and cerebral ischemia.


Nano-curcumin safely prevents streptozotocin-induced inflammation and apoptosis in pancreatic beta cells for effective management of Type 1 diabetes mellitus.
Approaches to prevent selective and progressive loss of insulin-producing beta cells in Type 1 diabetes mellitus (T1DM) will help to manage this prevalent and devastating disease. Curcumin (CUR), a natural anti-inflammatory substance, suppresses diabetes-associated inflammation and cell death. However, very high doses need to be used because of poor oral bioavailability, making it difficult to translate the anti-inflammatory actions to clinical situations. We have prepared biodegradable nanosystems encapsulating curcumin (nCUR), resulting in at least nine-fold improvement in oral bioavailability. Here, we tested the ability of nCUR to prevent streptozotocin (STZ)-induced inflammation and apoptosis in pancreatic islets and beta cells, in rats. Non-fasted rats pretreated with 10 or 50 mg·kg-1 nCUR 6 h prior to STZ challenge had up to 37% reduction in the glucose levels, while plain CUR (50 mg·kg-1 ) results in 12% reduction. This treatment with nCUR was accompanied by decreased islet or beta cell death, as shown by TUNEL assay and H&E staining. Both CUR and nCUR significantly decreased levels of inflammatory cytokines in pancreatic tissue homogenates that correlated well with minimal histiocytic infiltration. Pre-treatment with nCUR, but not CUR, decreased 8-oxo-2'-deoxyguanosine, a sensitive biomarker of ROS-induced DNA damage, in pancreas. In normal rodents, daily dosing for 28 days, with nCUR (25-100 mg·kg-1 ) did not cause any deleterious health issues by the carrier. Together, these data indicate a potentially translatable dose of nCUR that is safe and efficacious in improving beta cell function, which could prevent T1DM.


High fat programming of beta cell compensation, exhaustion, death and dysfunction.
Programming refers to events during critical developmental windows that shape progeny health outcomes. Fetal programming refers to the effects of intrauterine (in utero) events. Lactational programming refers to the effects of events during suckling (weaning). Developmental programming refers to the effects of events during both fetal and lactational life. Postnatal programming refers to the effects of events either from birth (lactational life) to adolescence or from weaning (end of lactation) to adolescence. Islets are most plastic during the early life course; hence programming during fetal and lactational life is most potent. High fat (HF) programming is the maintenance on a HF diet (HFD) during critical developmental life stages that alters progeny metabolism and physiology. HF programming induces variable diabetogenic phenotypes dependent on the timing and duration of the dietary insult. Maternal obesity reinforces HF programming effects in progeny. HF programming, through acute hyperglycemia, initiates beta cell compensation. However, HF programming eventually leads to chronic hyperglycemia that triggers beta cell exhaustion, death and dysfunction. In HF programming, beta cell dysfunction often co-presents with insulin resistance. Balanced, healthy nutrition during developmental windows is critical for preserving beta cell structure and function. Thus early positive nutritional interventions that coincide with the development of beta cells may reduce the overwhelming burden of diabetes and metabolic disease.


Tubular Adenoma of the Breast: A Clinicopathologic Study of a Series of 9 Cases.
Tubular adenoma of the breast is one of the most rare benign neoplasms, accounting for only 0.13% to 1.7% of all breast benign tumors. Little is known about this rare neoplasm as the current literature offers only some case reports or a few number of small series. The aim of our study is to provide some clinicopathologic features of the breast tubular adenoma. We retrospectively analyzed at our department of pathology all cases of breast tubular adenomas confirmed by immunohistochemistry over a period of 9 years (2009-2017). Nine cases of breast tubular adenoma have been recorded, with an average age of 31.44 years. Five tumors were located at the right side (55.55%), and most cases had suspicious aspects on imaging techniques (6 cases out of 9). The diagnosis has been made on 5 resected specimens (lumpectomy) and on 4 core needle biopsies. The tumor size ranged from 0.9 to 7 cm (mean size of 3.08 cm) and had well-circumscribed margins with elastic consistency. The histopathologic analysis showed a typical pattern of proliferating round and uniform tubules lined by regular epithelial cells surrounded by myoepithelial cells, packed in a small amount of stroma, highlighted by CD34 immunostaining. Tubular adenoma is a rare breast benign neoplasm of young premenopausal women. The radiologic aspects are often worrisome and only the histopathologic analysis can achieve the correct definitive diagnosis by excluding all potential differential diagnoses.


Post-Processing of FDM 3D-Printed Polylactic Acid Parts by Laser Beam Cutting.
In this paper, the post-processing of 3D-printed poly lactic acid (PLA) parts is investigated. Workpieces are manufactured by fused deposition modeling (FDM) 3D printing, while they may have defects in some areas such as edges. A post-processing is introduced here for 3D-printed samples by low power CO2 laser. The thickness of the FDM samples are 3.2 mm and printed by optimum conditions. Effects of process parameters such as focal plane position (-3.2-3.2 mm), laser power (20-40 W), and laser cutting speed (1-13 mm/s) are examined based on the design of experiments (DOE). Geometrical features of the kerf; top and bottom kerf; taper; ratio of top to the bottom kerf are considered as output responses. An analysis of the experimental results by statistical software is conducted to survey the effects of process parameters and to obtain regression equations. By optimizing of the laser cutting process; an appropriate kerf quality is obtained and also optimum input parameters are suggested. Experimental verification tests show a good agreement between empirical results and statistical predictions. The best optimum sample with 1.19 mm/s cutting speed, 36.49 W power and 0.53 mm focal plane position shows excellent physical features after the laser cutting process when 276.9 μm top and 261.5 μm bottom kerf width is cut by laser.


Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma.
Previous studies have shown that mithramycin A (MIT) is a promising candidate for the treatment of pancreatic carcinoma through inhibiting transcription factor Sp1. However, systemic toxicities may limit its clinical application. Here, we report a rationally designed formulation of MIT-loaded nanoparticles (MIT-NPs) with a small size and sustained release for improved passive targeting and enhanced therapeutic efficacy. Nearly spherical MIT-NPs with a mean particle size of 25.0±4.6 nm were prepared by encapsulating MIT into methoxy poly(ethylene glycol)-block-poly(d,l-lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) with drug loading of 2.11%±0.51%. The in vitro release of the MIT-NPs lasted for >48 h with a sustained-release pattern. The cytotoxicity of MIT-NPs to human pancreatic cancer BxPC-3 and MIA Paca-2 cells was comparable to that of free MIT. Determined by flow cytometry and confocal microscopy, the NPs internalized into the cells quickly and efficiently, reaching the peak level at 1-2 h. In vivo fluorescence imaging showed that the prepared NPs were gradually accumulated in BxPC-3 and MIA Paca-2 xenografts and retained for 168 h. The fluorescence intensity in both BxPC-3 and MIA Paca-2 tumors was much stronger than that of various tested organs. Therapeutic efficacy was evaluated with the poorly permeable BxPC-3 pancreatic carcinoma xenograft model. At a well-tolerated dose of 2 mg/kg, MIT-NPs suppressed BxPC-3 tumor growth by 96%. Compared at an equivalent dose, MIT-NPs exerted significantly higher therapeutic effect than free MIT (86% versus 51%, P<0.01). Moreover, the treatment of MIT and MIT-NPs reduced the expression level of oncogene c-Myc regulated by Sp1, and notably, both of them decreased the protein level of CD47. In summary, the novel formulation of MIT-NPs shows highly therapeutic efficacy against pancreatic carcinoma xenograft. In addition, MIT-NPs can downregulate CD47 expression, implying that it might play a positive role in cancer immunotherapy.


Development and initial characterization of a Bos taurus x B. gaurus interspecific hybrid backcross panel.
A panel of 40 Bos taurus x B. gaurus (gaur) interspecific hybrid backcross off spring was constructed for use as a tool in refining and improving the resolution of the bovine gene map. The gaur (2n = 58) is characterized karyotypically by a 2; 28 Robertsonian translocation with respect to the cattle karyotype (2n = 60). This translocation was used as a centromeric marker to directionally orient linkage maps of B. taurus (BTA) chromosomes 2 and 28. The initial linkage analysis of this panel consisted primarily of genes or DNA segments containing microsatellites previously placed on bovine maps. Two new markers, NRAMP1 and ACTA1, were added to the linkage maps on BTA2 and BTA28, respectively. Additionally, fibroblast cultures from fetal tissue of each offspring were analyzed cytogenetically at early passages. In all cases, the translocation chromosome was inherited in a balanced condition, and only one cell line possessed a chromosome abnormality. This aberrant line was determined to be trisomic, 61,XXX.


Carbon monoxide protects against liver failure through nitric oxide-induced heme oxygenase 1.
Carbon monoxide (CO) and nitric oxide (NO) each have mechanistically unique roles in various inflammatory disorders. Although it is known that CO can induce production of NO and that NO can induce expression of the cytoprotective enzyme heme oxygenase 1 (HO-1), there is no information whether the protective effect of CO ever requires NO production or whether either gas must induce expression of HO-1 to exert its functional effects. Using in vitro and in vivo models of tumor necrosis factor alpha-induced hepatocyte cell death in mice, we find that activation of nuclear factor kappaB and increased expression of inducible NO are required for the protective effects of CO, whereas the protective effects of NO require up-regulation of HO-1 expression. When protection from cell death is initiated by CO, NO production and HO-1 activity are each required for the protective effect showing for the first time an essential synergy between these two molecules in tandem providing potent cytoprotection.


Raised intracranial pressure in Apert syndrome.
Raised intracranial pressure is a well-known complication of Apert syndrome. The current policy in the authors' unit is to monitor these patients and only perform surgery when raised intracranial pressure has been diagnosed. The authors present their experience with this protocol, as it allows a more accurate picture of the natural history of raised intracranial pressure in Apert syndrome. The records of 24 patients, aged between 7 and 14 years, with Apert syndrome who had been managed expectantly (i.e., with no routine "automatic" early surgery) were reviewed. Data were collected on the incidence, timing, and management of raised intracranial pressure. Twenty of 24 patients (83 percent) developed raised intracranial pressure. The average age of the first episode was 18 months (range, 1 month to 4 years 5 months). Raised intracranial pressure was managed with surgery in 18 patients, including two patients who underwent shunt procedures for hydrocephalus. Two patients had their raised intracranial pressure treated successfully by correcting coexisting upper airway obstruction alone. Seven of the 20 patients (35 percent) developed a second episode of raised intracranial pressure, on average 3 years 4 months later (range, 1 year 11 months to 5 years 9 months). In Apert syndrome, there is a high incidence of raised intracranial pressure, which can first occur at any age up to 5 years and may recur despite initial successful treatment. Causes of raised intracranial pressure include craniocerebral disproportion, venous hypertension, upper airway obstruction, and hydrocephalus. Careful clinical, ophthalmologic, respiratory, and radiologic monitoring will allow raised intracranial pressure to be diagnosed accurately when it occurs and then treated most appropriately.


Thicker than blood: conserved mechanisms in Drosophila and vertebrate hematopoiesis.
Blood development in Drosophila melanogaster shares several interesting features with hematopoiesis in vertebrates, including spatiotemporal regulation as well as the use of similar transcriptional regulators and signaling pathways. In this review, we describe what is known about hematopoietic development in Drosophila and the various cell types generated and their functions. Additionally, the molecular genetic mechanisms of hematopoietic cell fate determination and commitment within Drosophila blood cell lineages are discussed and compared to vertebrate mechanisms.


Rhythm and Synchrony in a Cortical Network Model.
We studied mechanisms for cortical gamma-band activity in the cerebral cortex and identified neurobiological factors that affect such activity. This was done by analyzing the behavior of a previously developed, data-driven, large-scale network model that simulated many visual functions of monkey V1 cortex (Chariker et al., 2016). Gamma activity was an emergent property of the model. The model's gamma activity, like that of the real cortex, was (1) episodic, (2) variable in frequency and phase, and (3) graded in power with stimulus variables like orientation. The spike firing of the model's neuronal population was only partially synchronous during multiple firing events (MFEs) that occurred at gamma rates. Detailed analysis of the model's MFEs showed that gamma-band activity was multidimensional in its sources. Most spikes were evoked by excitatory inputs. A large fraction of these inputs came from recurrent excitation within the local circuit, but feedforward and feedback excitation also contributed, either through direct pulsing or by raising the overall baseline. Inhibition was responsible for ending MFEs, but disinhibition led directly to only a small minority of the synchronized spikes. As a potential explanation for the wide range of gamma characteristics observed in different parts of cortex, we found that the relative rise times of AMPA and GABA synaptic conductances have a strong effect on the degree of synchrony in gamma.SIGNIFICANCE STATEMENT Canonical computations used throughout the cerebral cortex are performed in primary visual cortex (V1). Providing theoretical mechanisms for these computations will advance understanding of computation throughout cortex. We studied one dynamical feature, gamma-band rhythms, in a large-scale, data-driven, computational model of monkey V1. Our most significant conclusion is that the sources of gamma band activity are multidimensional. A second major finding is that the relative rise times of excitatory and inhibitory synaptic potentials have strong effects on spike synchrony and peak gamma band power. Insight gained from studying our V1 model can shed light on the functions of other cortical regions.


Is gout a risk equivalent to diabetes for stroke and myocardial infarction? A retrospective claims database study.
Gout is a risk factor for cardiovascular disease, but associations with specific cardiovascular outcomes, myocardial infarction (MI), and stroke are unclear. Our objective in the present study was to assess whether gout is as strong a risk factor as diabetes mellitus (DM) for incident MI and incident stroke. In this retrospective study, we used U.S. claims data from 2007 to 2010 that included a mix of private and public health plans. Four mutually exclusive cohorts were identified: (1) DM only, (2) gout only, (3) gout and DM, and (4) neither gout nor DM. Outcomes were acute MI or stroke with hospitalization. We compared the age- and sex-specific rates of incident MI and stroke across the four cohorts and assessed multivariable-adjusted HRs. In this study, 232,592 patients had DM, 71,755 had gout, 23,261 had both, and 1,010,893 had neither. The incidence of acute MI was lowest in patients with neither gout nor DM, followed by patients with gout alone, DM alone, and both. Among men >80 years of age, the respective rates/1000 person-years were 14.6, 25.4, 27.7, and 37.4. Similar trends were noted for stroke and in women. Compared with DM only, gout was associated with a significantly lower adjusted HR of incident MI (HR 0.81, 95% CI 0.76-0.87) but a similar risk of stroke (HR 1.02, 95% CI 0.95-1.10). Compared with patients with DM only, patients with both gout and DM had higher HRs for incident MI and stroke (respectively, HR 1.35, 95% CI 1.25-1.47; HR 1.42, 95% CI 1.29-1.56). Gout is a risk equivalent to DM for incident stroke but not for incident MI. Having both gout and DM confers incremental risk compared with DM alone for both incident MI and stroke.


Structural Colors Enabled by Lattice Resonance on Silicon Nitride Metasurfaces.
Artificial color pixels based on dielectric Mie resonators are appealing for scientific research as well as practical design. Vivid colors are imperative for displays and imaging. Dielectric metasurface-based artificial pixels are promising candidates for developing flat, flexible, and/or wearable displays. Considering the application feasibility of artificial color pixels, wide color gamuts are crucial for contemporary display technology. To achieve a wide color gamut, ensuring the purity and efficiency of nanostructure resonance peaks in the visible spectrum is necessary for structural color design. Low-loss dielectric materials are suitable for achieving vivid colors with structural color pixels. However, high-order Mie resonances prevent color pixels based on dielectric metasurfaces from efficiently generating highly saturated colors. In particular, fundamental Mie resonances (electric/magnetic dipole) for red can result in not only a strong resonance peak at 650 nm but also high-order Mie resonances at shorter wavelengths, which reduces the saturation of the target color. To address these problems, we fabricated silicon nitride metasurfaces on quartz substrates and applied Rayleigh anomalies at relatively short wavelengths to successfully suppress high-order Mie resonances, thus creating vivid color pixels. We performed numerical design, semianalytic considerations, and experimental proof-of-concept examinations to demonstrate the performance of the silicon nitride metasurfaces. Apart from traditional metasurface designs that involve transmission and reflection modes, we determined that lateral light incidence on silicon nitride metasurfaces can provide vivid colors through long-range dipole interactions; this can thus extend the applications of such surfaces to eyewear displays and guided-wave illumination techniques.


Chemical characterization of urinary glycopeptides.
We prepared human urinary glycopeptides from the supernatant liquid remaining after precipitation of the nondialyzable fraction with cetylpyridinium chloride. Using cation exchange and affinity chromatographies and gel filtration, we obtained 28 glycopeptide subfractions. By compositional analyses of sugar and amino acid, and by reducing-terminal analyses after reduction with NaBH4, we determined the size of the carbohydrate moiety and the types of carbohydrate-peptide linkage involved. We isolated several glycopeptides not previously described: six with sialic acid, two with fucose, two with glucose, and one with N-acetylgalactosamine. The sialic acid glycopeptides had a short carbohydrate chain of the O-glycoside type. The fucose-containing glycopeptides were fucosyllactosaminoglycans. The glucose glycopeptides were polymers linked to a small peptide moiety. The N-acetylgalactosamine-rich glycopeptide was found in an N-glycoside-type fraction, with N-acetylgalactosamine at the nonreducing terminal.


Intrathecal neostigmine for post-cesarean section analgesia: dose response.
Intrathecal (IT) neostigmine produces analgesia in animals and humans and enhances systemic opioid analgesia. To examine the safety of IT neostigmine for eventual use in obstetrics, we studied 24 healthy, term pregnant patients scheduled to receive elective cesarean section using a combined spinal-epidural anesthetic. Using an open-label, dose-ranging design, patients received either IT placebo or neostigmine 10, 30, or 100 microg in a 1-mL solution of 5% glucose in normal saline followed in 15 min by 2% epidural lidocaine for cesarean section. Neostigmine did not affect fetal heart rate tracings or Apgar scores. The women received patient-controlled analgesia intravenous morphine postoperatively. Compared with the glucose control, neostigmine produced a dose-independent reduction in postoperative morphine use. Cumulative average 24-h morphine use was 82 +/- 7 mg for women receiving IT placebo and 50 +/- 8 mg for women receiving IT neostigmine (P < 0.003). Hourly morphine use was significantly reduced in the neostigmine groups for 10 h postoperatively. These data indicate that IT neostigmine can produce 10 h of post-cesarean section analgesia without adverse fetal effects and support cautious further prospective study.