Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder.
Aripiprazole, a quinolinone derivative, is an atypical antipsychotic drug indicated for the treatment of adult patients with schizophrenia. Aripiprazole 10 or 15 mg once daily is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. Although aripiprazole has only been directly compared with haloperidol and olanzapine in treatment-responsive patients to date, current data generally indicate that aripiprazole has a beneficial profile in terms of a low potential for bodyweight gain. Dosage titration is not necessary and the drug is effective in the first few weeks of treatment. Head-to-head comparative trials with atypical antipsychotic agents are required, as are long-term (> or =1 year) studies, to fully define the position of aripiprazole in relation to other antipsychotic drugs. Aripiprazole is a valuable new therapeutic option in the management of patients with schizophrenia. PHARMACOLOGICAL PROPERTIES: Aripiprazole is a quinolinone derivative with a high affinity for dopamine D2 and D3 receptors, and serotonin 5-HT1A, 5-HT2A and 5-HT2B receptors. The mechanism of action of aripiprazole is not yet known, but evidence suggests that its efficacy in the treatment of the positive and negative symptoms of schizophrenia and its lower propensity for extrapyramidal symptoms (EPS) may be attributable to aripiprazole's partial agonist activity at dopamine D2 receptors. At serotonin 5-HT1A receptors, in vitro studies have shown that aripiprazole acts as a partial agonist whereas at serotonin 5-HT2A receptors aripiprazole is an antagonist. The main active metabolite, dehydro-aripiprazole, has affinity for dopamine D2 receptors and thus has some pharmacological activity similar to that of the parent compound. Aripiprazole is rapidly absorbed after oral administration. The mean time to peak plasma concentration is 3 hours following multiple-dose administration of aripiprazole 10 or 15 mg and the absolute oral bioavailability of the drug is 87%. Steady-state plasma drug concentrations are achieved by 14 days; however, the drug appears to accumulate over this period, since mean peak plasma concentration and mean area under the plasma concentration-time curve values of aripiprazole 10 or 15 mg/day are 4-fold greater on day 14 than on day 1. This accumulation may be expected, since the mean elimination half-life of a single dose of aripiprazole is about 75 hours. Aripiprazole has extensive extravascular distribution and more than 99% of aripiprazole and dehydro-aripiprazole (the main active metabolite of aripiprazole) is bound to plasma protein. Elimination of the drug is primarily hepatic; the cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems transform aripiprazole to dehydro-aripiprazole, with the latter enzyme system subject to genetic polymorphism. Thus, dosage adjustment of aripiprazole is necessary when it is coadministered with CYP3A4 and CYP2D6 inhibitors (since aripiprazole concentration is increased) and with inducers of CYP3A4 (since aripiprazole concentration is decreased). THERAPEUTIC EFFICACY: The efficacy of aripiprazole has been demonstrated in patients with schizophrenia or schizoaffective disorder. In general, significant reductions from baseline in mean Positive and Negative Syndrome Scale total, positive and negative symptom scores, and Clinical Global Impression Severity of Illness scores were observed in patients with acute relapse of chronic schizophrenia or schizoaffective disorder receiving recommended (10 or 15 mg/day) or higher-than-recommended (20 or 30 mg/day) dosages of aripiprazole versus those receiving placebo in three well controlled, short-term trials. No additional therapeutic benefit was observed at the higher-than-recommended dosages. The drug is effective as early as the first or second week of treatment. The efficacy of aripiprazole was maintained for up to 52 weeks. The drug was significantly more effective than placebo in preventing relapse in patients with stable chronic schizophrenia in a 26-week, randomised trial. In a 52-week trial in patients with acute relapse of schizophrenia, the percentage of responders maintaining a response at study end was 77% of aripiprazole versus 73% of haloperidol recipients. Aripiprazole may improve cognitive function. In a nonblind, 26-week trial, patients with chronic schizophrenia receiving aripiprazole 30 mg/day experienced similar (general cognitive function) or better (verbal learning) changes from baseline in the neurocognitive parameters evaluated compared with recipients of olanzapine 10-15 mg/day. Aripiprazole 10-30 mg/day was generally well tolerated. The tolerability profile of aripiprazole was broadly similar to that observed with placebo in a meta-analysis of short-term trials in patients with acute relapse of schizophrenia or schizoaffective disorder and in a 26-week trial in patients with chronic stable schizophrenia. The most frequent treatment-emergent adverse events included insomnia and anxiety, and additionally, headache and agitation (in short-term trials) or akathisia and psychosis (in a 52-week trial). In general, the drug was associated with a placebo-level incidence of EPS and EPS-related adverse events. Significantly fewer aripiprazole recipients experienced EPS-related adverse events than haloperidol recipients in a 52-week trial. Changes in severity of EPS were minimal and usually no different from those observed with placebo. Moreover, there was less severe EPS in the aripiprazole group than the haloperidol group in a long-term trial. Treatment-emergent tardive dyskinesia was reported in only 0.2% of patients receiving aripiprazole (short-term trials), an incidence similar to that seen in placebo recipients (0.2%). Aripiprazole has a low propensity to cause clinically significant bodyweight gain, hyperprolactinaemia or corrected QT interval prolongation in patients with schizophrenia or schizoaffective disorder. In addition, there were no clinically relevant differences in mean changes from baseline in measures of diabetes and dyslipidaemia between the aripiprazole or placebo groups in a 26-week, placebo-controlled trial.


A review of kinases implicated in pancreatic cancer.
The current 5-year survival rate of pancreatic cancer is about 3% and the median survival less than 6 months because the chemotherapy and radiation therapy presently available provide only marginal benefit. Clearly, pancreatic cancer requires new therapeutic concepts. Recently, the kinase inhibitors imatinib and gefitinib, developed to treat chronic myelogenous leukaemia and breast cancer, respectively, gave very good results. Kinases are deregulated in many diseases, including cancer. Given that phosphorylation controls cell survival signalling, strategies targeting kinases should obviously improve cancer treatment. The purpose of this review is to summarize the present knowledge on kinases potentially usable as therapeutic targets in the treatment of pancreatic cancer. All clinical trials using available kinase inhibitors in monotherapy or in combination with chemotherapeutic drugs failed to improve survival of patients with pancreatic cancer. To detect kinases relevant to this disease, we undertook a systematic screening of the human kinome to define a 'survival kinase' catalogue for pancreatic cells. We selected 56 kinases that are potential therapeutic targets in pancreatic cancer. Preclinical studies using combined inhibition of PAK7, MAP3K7 and CK2 survival kinases in vitro and in vivo showed a cumulative effect on apoptosis induction. We also observed that these three kinases are rather specific of pancreatic cancer cells. In conclusion, if kinase inhibitors presently available are unfortunately not efficient for treating pancreatic cancer, recent data suggest that inhibitors of other kinases, involved more specifically in pancreatic cancer development, might, in the future, become interesting therapeutic targets.


Combined Lid Crease and Endoscopic Approach to Lateral Frontal Sinus Disease With Orbital Extension.
Functional endoscopic sinus surgery for frontal sinus disease has obviated the need for external approaches. Special circumstances such as acute infection with orbital involvement or significant lateral sinus disease frequently require adjunct access. We describe the clinical outcomes of a combined upper eyelid crease and endoscopic approach for lateral frontal sinus disease with orbital extension. A retrospective case series of 7 patients who underwent a combined lid crease approach for frontal sinus disease with orbital extension between April 2012 and October 2016 was performed. All patients had the presence of lateral frontal sinus disease as well as orbital extension as seen on a preoperative computed tomography (CT) scan. Patient demographics, indications for surgery, and perioperative findings were examined. Six of the 7 patients were male. Mean age was 61 years, and the indication for surgery was primarily drainage of mucopyocele and inverting papilloma (IP) in 1 patient. The frontal sinus and orbit were successfully accessed, and the respective pathology was addressed in both locations. No intraoperative or postoperative complications were encountered. There was no postoperative or cosmetic complications. The combined lid crease and endoscopic approach is a safe and effective technique for accessing the lateral frontal sinus and orbit.


Patient safety events in out-of-hospital paediatric airway management: a medical record review by the CSI-EMS.
To describe the frequency and characterise the nature of patient safety events in paediatric out-of-hospital airway management. We conducted a retrospective cross-sectional medical record review of all 'lights and sirens' emergency medicine services transports from 2008 to 2011 in patients <18 years of age in the Portland Oregon metropolitan area. A chart review tool (see online supplementary appendix) was adapted from landmark patient safety studies and revised after pilot testing. Expert panels of physicians and paramedics performed blinded reviews of each chart, identified safety events and described their nature. The primary outcomes were presence and severity of patient safety events related to airway management including oxygen administration, bag-valve-mask ventilation (BVM), airway adjuncts and endotracheal intubation (ETI).DC1SM110.1136/bmjopen-2016-012259.supp1supplementary appendix RESULTS: From the 11 328 paediatric transports during the study period, there were 497 'lights and sirens' (code 3) transports (4.4%). 7 transports were excluded due to missing data. Of the 490 transports included in the analysis, 329 had a total of 338 airway management procedures (some had more than 1 procedure): 61.6% were treated with oxygen, 15.3% with BVM, 8.6% with ETI and 2% with airway adjuncts. The frequency of errors was: 21% (71/338) related to oxygen use, 9.8% (33/338) related to BVM, 9.5% (32/338) related to intubation and 0.9% (3/338) related to airway adjunct use. 58% of intubations required 3 or more attempts or failed altogether. Cardiac arrest was associated with higher odds of a severe error. Errors in paediatric out-of-hospital airway management are common, especially in the context of intubations and during cardiac arrest.


Long-term benefit of bilateral subthalamic deep brain stimulation on camptocormia in Parkinson's disease.
We report the case of a 63-year-old female with a long history of severe Parkinson's disease (PD) and subsequent onset of debilitating camptocormia who underwent successful bilateral subthalamic nucleus deep brain stimulation surgery (STN DBS). The literature and previous reports are reviewed. The patient history and details of the surgical procedure are reported including the implantable pulse generator (IPG) settings and response to stimulation. The results of her PD symptom and camptocormia improvements are discussed. Five year postoperatively, the patient has enjoyed good results for both her PD symptoms as well as significant and sustained improvement in her thoracolumbar flexion deformity. She remains on minimal medications and no longer requires any assistive devices for ambulation. Comparison and contrast of the current world literature on DBS for camptocormia is reviewed. We discuss the current targets used for DBS in the setting of camptocormia in the cases reported, both PD associated and not associated. The optimal target has yet to be defined and further work on appropriate patient selection is needed.


Prevalence and diagnostic challenges of thyroid lymphoma: a multi-institutional study in non-Western countries.
Research on the primary thyroid lymphoma (PTL) diagnosis is limited, with only a few large sample size studies, reported from Asian countries. The aim of the present study was to clarify the current prevalence and challenges in PTL diagnosis, and recommended ancillary studies for PTL in non-Western countries. PTL (n = 153) cases were retrieved from 10 institutions in non-Western countries and analyzed. Ultrasound examination (UE) and fine needle aspiration cytology (FNAC) were used as main preoperative diagnostic tools in all participating institutions. Flow cytometry (FCM) was performed in the 5 institutions (50%). Lobectomy was the most common histological procedure to confirm the PTL diagnosis. All institutions routinely performed immuno-histochemical analysis. PTL was 0.54% of malignant thyroid tumor cases, with mucosa-associated lymphoid tissue lymphoma (MALTL) and diffuse large B-cell lymphoma (DLBCL) being 54.9% and 38.6%, respectively. Kuma Hospital, where the frequency of MALTL was highest (83.7%), routinely performed FCM using the materials obtained by FNAC. UE and FNAC sensitivities were 62.5% and 57.8%, respectively. In both UE and FNAC, sensitivity of MALTL was lower than of DLBCL. The study elucidated that the prevalence of PTL in non-Western countries was lower than previously reported. We propose that FCM should be more actively used to improve the preoperative diagnosis of MALTL. Our data predicted that the MALTL proportion will increase with improved diagnostic tools, while observation of PTL-suspected nodules without histological examination remains a viable option.


ER stress and hexosamine pathway during tumourigenesis: A pas de deux?
Both the hexosamine biosynthetic pathway (HBP) and the endoplasmic reticulum (ER) are considered sensors for the nutritional state of the cell. The former is a branch of the glucose metabolic pathway that provides donor molecules for glycosylation processes, whereas the second requires co-translational N-glycosylation to ensure proper protein folding. It has become clear that the microenvironment of solid tumours, characterised by poor oxygen and nutrient supply, challenges optimal functions of the ER and the HBP. Here, we review recent advances demonstrating that the ER stress (ERS) response and HBP pathways are interconnected to promote cell viability. We then develop the idea that communication between ER and HBP is a survival feature of neoplastic cells that plays a prominent role during tumourigenesis.


Betaine homocysteine methyl transferase 1, a novel auto-antigen associated with anti-Golgi immune reactivity.
Anti-Golgi antibodies are rare autoantibodies that have been described in systemic autoimmune diseases. Not all Golgi auto-antigens are known. The objective of this study was to identify a novel auto-antigen associated with anti-Golgi immune reactivity. Sera from a patient with Golgi immune reactivity and from a control individual were used for Western blotting after 2-dimensional gel separation of a rat Golgi-enriched extract. Betaine homocysteine S-methyltransferase 1 (BHMT1) was identified as an auto-antigen by MALDI-TOF/TOF mass spectrometry. Using human recombinant BHMT1, a strong positive blotting signal was obtained with serum from the patient but not from a control. Pre-absorption of the serum sample with reactivity to BHMT1 with recombinant human BHMT1 resulted in decreased reactivity on Western blotting and in disappearance of the Golgi-like pattern on indirect immunofluorescence. Using immunocytochemistry, we confirmed the subcellular localization of BHMT1 to the Golgi apparatus. Antibodies to BHMT1 were found in four of 80 samples with a Golgi-pattern on indirect immunofluorescence. The antibodies were not associated with a specific clinical condition. We identified BHMT1 as a novel auto-antigen associated with anti-Golgi immune reactivity.


Consumption of dairy products and death from cardiovascular disease in the Japanese general population: the NIPPON DATA80.
Recent Western studies show an inverse association between milk and dairy product intake and cardiovascular disease (CVD). We studied the association between consumption of milk and dairy products and CVD death in Japan. Men and women aged 30 years or older were followed for 24 years. All had participated in a national nutrition survey in 300 health districts throughout Japan in 1980. The Cox proportional hazards model was used to assess mortality risk according to tertiles of milk and dairy product intake, with the high consumption group as reference. Hazard ratios (HRs) per 100-g/day increase in consumption were also estimated. During the 24-year follow-up period, there were 893 CVD deaths, 174 deaths from coronary heart disease (CHD), and 417 stroke deaths among 9243 participants. For women, the HRs for death from CVD, CHD, and stroke in the low consumption group were 1.27 (95% CI: 0.99-1.58; P for trend = 0.045), 1.67 (0.99-2.80; P = 0.02), and 1.34 (0.94-1.90; P = 0.08), respectively, after adjustment for age, body mass index, smoking status, alcohol drinking habits, history of diabetes, use of antihypertensives, work category, and total energy intake. With each 100-g/day increase in consumption of milk and dairy products, HRs tended to decrease for deaths from CVD (HR, 0.86; 95% CI, 0.74-0.99), CHD (0.73; 0.52-1.03), and stroke (0.81; 0.65-1.01) in women. No significant association was observed in men. Consumption of milk and dairy products was inversely associated with CVD death among women in Japan.


Population and clinical genetics of human transposable elements in the (post) genomic era.
Recent technological developments-in genomics, bioinformatics and high-throughput experimental techniques-are providing opportunities to study ongoing human transposable element (TE) activity at an unprecedented level of detail. It is now possible to characterize genome-wide collections of TE insertion sites for multiple human individuals, within and between populations, and for a variety of tissue types. Comparison of TE insertion site profiles between individuals captures the germline activity of TEs and reveals insertion site variants that segregate as polymorphisms among human populations, whereas comparison among tissue types ascertains somatic TE activity that generates cellular heterogeneity. In this review, we provide an overview of these new technologies and explore their implications for population and clinical genetic studies of human TEs. We cover both recent published results on human TE insertion activity as well as the prospects for future TE studies related to human evolution and health.


The Wikipedia Gender Gap Revisited: Characterizing Survey Response Bias with Propensity Score Estimation.
Opt-in surveys are the most widespread method used to study participation in online communities, but produce biased results in the absence of adjustments for non-response. A 2008 survey conducted by the Wikimedia Foundation and United Nations University at Maastricht is the source of a frequently cited statistic that less than 13% of Wikipedia contributors are female. However, the same study suggested that only 39.9% of Wikipedia readers in the US were female - a finding contradicted by a representative survey of American adults by the Pew Research Center conducted less than two months later. Combining these two datasets through an application and extension of a propensity score estimation technique used to model survey non-response bias, we construct revised estimates, contingent on explicit assumptions, for several of the Wikimedia Foundation and United Nations University at Maastricht claims about Wikipedia editors. We estimate that the proportion of female US adult editors was 27.5% higher than the original study reported (22.7%, versus 17.8%), and that the total proportion of female editors was 26.8% higher (16.1%, versus 12.7%).


Hedonic analysis of the price of UHT-treated milk in Italy.
The Italian market for UHT milk has been growing thanks to both consumers' interest in products with an extended shelf life and to the lower prices of these products compared with refrigerated, pasteurized milk. However, because the lower prices of UHT milk can hinder producers' margins, manufacturers have introduced new versions of UHT milk products such as lactose-free options, vitamin-enriched products, and milk for infants, with the goal of differentiating their products, escaping the price competition, and gaining higher margins. In this paper, we estimated the contribution of different attributes to UHT milk prices in Italy by using a database of Italian UHT milk sales and a hedonic price model. In our analysis, we considered 2 UHT milk market segments: products for infants and those for the general population. We found premiums varied with the milk's attributes as well as between the segments analyzed: n-3 fatty acids, organic, and added calcium were the most valuable product features in the general population segment, whereas in the infant segment fiber, glass packaging, and the targeting of newborns delivered the highest premiums. Finally, we present recommendations for UHT milk manufacturers.


A new member of the HCO3(-) transporter superfamily is an apical anion exchanger of beta-intercalated cells in the kidney.
The kidneys play pivotal roles in acid-base homeostasis, and the acid-secreting (alpha-type) and bicarbonate-secreting (beta-type) intercalated cells in the collecting ducts are major sites for the final modulation of urinary acid secretion. Since the H(+)-ATPase and anion exchanger activities in these two types of intercalated cells exhibit opposite polarities, it has been suggested that the alpha- and beta-intercalated cells are interchangeable via a cell polarity change. Immunohistological studies, however, have failed to confirm that the apical anion exchanger of beta-intercalated cells is the band 3 protein localized to the basolateral membrane of alpha-intercalated cells. In the present study, we show the evidence that a novel member of the anion exchanger and sodium bicarbonate cotransporter superfamily is an apical anion exchanger of beta-intercalated cells. Cloned cDNA from the beta-intercalated cells shows about 30% homology with anion exchanger types 1-3, and functional expression of this protein in COS-7 cells and Xenopus oocytes showed sodium-independent and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid-insensitive anion exchanger activity. Furthermore, immunohistological studies revealed that this novel anion exchanger is present on the apical membrane of beta-intercalated cells, although some beta-intercalated cells were negative for AE4 staining. We conclude that our newly cloned transporter is an apical anion exchanger of the beta-intercalated cells, whereas our data do not exclude the possibility that there may be another form of anion exchanger in these cells.


Genotyping reveals a wide heterogeneity of Tropheryma whipplei.
Tropheryma whipplei, the causative agent of Whipple's disease, is associated with various clinical manifestations as well as an asymptomatic carrier status, and it exhibits genetic heterogeneity. However, relationships that may exist between environmental and clinical strains are unknown. Herein, we developed an efficient genotyping system based on four highly variable genomic sequences (HVGSs) selected on the basis of genome comparison. We analysed 39 samples from 39 patients with Whipple's disease and 10 samples from 10 asymptomatic carriers. Twenty-six classic gastrointestinal Whipple's disease associated with additional manifestations, six relapses of classic Whipple's disease (three gastrointestinal and three neurological relapses), and seven isolated infections due to T. whipplei without digestive involvement (five endocarditis, one spondylodiscitis and one neurological infection) were included in the study. We identified 24 HVGS genotypes among 39 T. whipplei DNA samples from the patients and 10 T. whipplei DNA samples from the asymptomatic carriers. No significant correlation between HVGS genotypes and clinical manifestations of Whipple's disease, or asymptomatic carriers, was found for the 49 samples tested. Our observations revealed a high genetic diversity of T. whipplei strains that is apparently independent of geographical distribution and unrelated to bacterial pathogenicity. Genotyping in Whipple's disease may, however, be useful in epidemiological studies.


[Subjective parental stress as indicator for child abuse risk: the role of emotional regulation and attachment].
The Child Abuse Potential Inventory (CAPI) is an evidence-based procedure for the assessment of the risk for child abuse in parents. In this study, a German translation of the CAPI was applied to a normal sample of German parents (N = 944). Descriptive analysis of the CAPI scores in the German provides findings comparable to the original standardization sample. The subjects' child abuse risk score was associated with demographic characteristics like education, marital status, occupation and gender. Long-term stability of the child abuse risk score and associations with individual differences in emotional regulation and attachment were investigated in a sub-sample of mothers with high and low child abuse risk scores (N = 69). The findings proved long-term stability. Furthermore associations between the child abuse risk score and anger dispositions were found which, however, were moderated by attachment differences. The findings suggest attachment security as a protective factor against child abuse.


Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage.
The International Stem Cell Initiative analyzed 125 human embryonic stem (ES) cell lines and 11 induced pluripotent stem (iPS) cell lines, from 38 laboratories worldwide, for genetic changes occurring during culture. Most lines were analyzed at an early and late passage. Single-nucleotide polymorphism (SNP) analysis revealed that they included representatives of most major ethnic groups. Most lines remained karyotypically normal, but there was a progressive tendency to acquire changes on prolonged culture, commonly affecting chromosomes 1, 12, 17 and 20. DNA methylation patterns changed haphazardly with no link to time in culture. Structural variants, determined from the SNP arrays, also appeared sporadically. No common variants related to culture were observed on chromosomes 1, 12 and 17, but a minimal amplicon in chromosome 20q11.21, including three genes expressed in human ES cells, ID1, BCL2L1 and HM13, occurred in >20% of the lines. Of these genes, BCL2L1 is a strong candidate for driving culture adaptation of ES cells.


Incremental benefit of computer-aided detection when used as a second and concurrent reader of CT colonographic data: multiobserver study.
To quantify the changes in reader performance levels, if any, during interpretation of computed tomographic (CT) colonographic data when a computer-aided detection (CAD) system is used as a second or concurrent reader. After institutional review board approval was obtained, 16 experienced radiologists searched for polyps in 112 patients, 56 of whom had 132 polyps. Each case was interpreted on three separate occasions by using an unassisted (without CAD), second-read CAD, or concurrent CAD reading paradigm. The reading paradigm and case order were randomized, with a minimal interval of 1 month between consecutive interpretations. The readers' findings were compared with the reference-truth interpretation. The mean per-patient sensitivity and mean per-patient specificity with CAD were compared with those achieved with unassisted reading. An increase in per-patient sensitivity was considered to be clinically more important than an equivalent decrease in specificity. The mean per-patient sensitivity for identification of patients with polyps of any size increased significantly with use of second-read CAD (mean increase, 7.0%; 95% confidence interval [CI]: 4.0%, 9.8%) and concurrent CAD (mean increase, 4.5%; 95% CI: 0.8%, 8.2%). The mean per-patient specificity did not decrease significantly with use of second-read CAD (mean decrease, -2.5%; 95% CI: -5.2%, 0.1%) or concurrent CAD (mean decrease, -2.2%; 95% CI: -4.6%, 0.2%). With analysis restricted to patients with polyps 6 mm or larger, the benefit in sensitivity with second-read CAD remained (mean increase, 7.1%; 95% CI: 3.0%, 11.1%), whereas the increase with concurrent CAD was not significant (mean increase, 4.2%; 95% CI: -0.5%, 8.9%). Use of second-read CAD significantly increased the per-polyp sensitivity for polyps 6 mm or larger (mean increase, 9.0%; 98.3% CI: 4.9%, 12.8%) and polyps 5 mm or smaller (mean increase, 5.9%; 98.3% CI: 3.2%, 9.1%), but use of concurrent CAD increased the per-polyp sensitivity for only those polyps 5 mm or smaller (mean increase, 4.8%; 98.3% CI: 2.2%, 7.9%). Use of second-read CAD significantly improves readers' per-patient and per-polyp detection. Concurrent CAD is less effective. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100354/-/DC1.


Severe reactions associated with diphtheria-tetanus-pertussis vaccine: detailed study of children with seizures, hypotonic-hyporesponsive episodes, high fevers, and persistent crying.
The pathophysiology of severe reactions to diphtheria-tetanus-pertussis (DTP)vaccine is not well understood. Active pertussis toxin in DTP vaccine has been proposed to cause severe DTP vaccine reactions. Large doses of pertussis toxin cause hyperinsulinemia and hypoglycemia as well as leukocytosis with a predominant lymphocytosis in animal models. To learn more about the causes of and risk factors for severe DTP vaccine reactions, children experiencing severe DTP vaccine reactions were studied. Prospective, referral-based surveillance. Los Angeles, CA. Children experiencing severe reactions within 48 hours of DTP immunization and evaluated within 24 hours of the reaction. Severe reactions included encephalopathy, persistent crying > or = 3 hours, hypotonic-hyporesponsive episodes (collapse episodes), fever > or = 40.5 degrees C, or seizures. Some comparisons were made between children with DTP vaccine-associated seizures and a comparison group of children experiencing febrile seizures unrelated to immunization. A history and physical examination were performed. Follow-up examinations were performed 1 month later. Blood was collected for complete blood cell count with leukocyte differential count, serum chemistry measurements, and insulin and glucose values. Serum was assayed for active pertussis toxin, both in free and immune-complex masked states. Sixty children experienced severe reactions within 48 hours of DTP immunization: 32 children had seizures only, 14 subjects had hypotonic-hyporesponsive episodes, 2 subjects had fever > or = 40.5 degrees C only, 4 subjects had persistent crying > or = 3 hours, 6 children had seizures and fever > or = 40.5 degrees C, and 2 children had persistent crying and seizures. The children with seizures had a high rate of personal and family histories of seizures, and 90% had documented fevers (> or = 38 degrees C). Persistent crying was associated with painful local reactions. Effects that may have been due to vaccine pertussis toxin were not found. Lymphocytosis did not occur, nor did hypoglycemia. Some relatively elevated insulin values were noted; however, this finding was also noted in the comparison group of children experiencing febrile seizures unrelated to immunization. No biologically active pertussis toxin was found in the acute sera of children experiencing severe DTP vaccine reactions. Seizures associated with DTP vaccine have similar clinical characteristics as febrile seizures, and persistent crying is initiated by painful local reactions. Vaccine endotoxin is a cause of febrile DTP vaccine reactions. We found no evidence that DTP vaccine pertussis toxin plays a role in severe DTP vaccine reactions.


Comparative epigenomics in the Brassicaceae reveals two evolutionarily conserved modes of PRC2-mediated gene regulation.
Polycomb Repressive Complexes 2 (PRC2) are multi-protein chromatin modifiers that are evolutionarily conserved among eukaryotes and play key roles in the regulation of gene expression, notably through the trimethylation of lysine 27 of histone H3 (H3K27me3). Although PRC2-mediated gene regulation has been studied in many organisms, few studies have explored in depth the evolutionary conservation of PRC2 targets. Here, we compare the H3K27me3 epigenomic profiles for the two closely related species Arabidopsis thaliana and Arabidopsis lyrata and the more distant species Arabis alpina, three Brassicaceae that diverged from each other within the past 24 million years. Using a robust set of gene orthologs present in the three species, we identify two classes of evolutionarily conserved PRC2 targets, which are characterized by either developmentally plastic or developmentally constrained H3K27me3 marking across species. Constrained H3K27me3 marking is associated with higher conservation of promoter sequence information content and higher nucleosome occupancy compared to plastic H3K27me3 marking. Moreover, gene orthologs with constrained H3K27me3 marking exhibit a higher degree of tissue specificity and tend to be involved in developmental functions, whereas gene orthologs with plastic H3K27me3 marking preferentially encode proteins associated with metabolism and stress responses. In addition, gene orthologs with constrained H3K27me3 marking are the predominant contributors to higher-order chromosome organization. Our findings indicate that developmentally plastic and constrained H3K27me3 marking define two evolutionarily conserved modes of PRC2-mediated gene regulation that are associated with distinct selective pressures operating at multiple scales, from DNA sequence to gene function and chromosome architecture.


Right hemihepatectomy by suprahilar intrahepatic transection of the right hemipedicle using a vascular stapler.
Successful hepatic resection requires profound anatomical knowledge and delicate surgical technique. Hemihepatectomies are mostly performed after preparing the extrahepatic hilar structures within the hepatoduodenal ligament, even in benign tumours or liver metastasis.(1-5). Regional extrahepatic lymphadenectomy is an oncological standard in hilar cholangiocarcinoma, intrahepatic cholangio-cellular carcinoma and hepatocellular carcinoma, whereas lymph node metastases in the hepatic hilus in patients with liver metastasis are rarely occult. Major disadvantages of these procedures are the complex preparation of the hilus with the risk of injuring contralateral structures and the possibility of bleeding from portal vein side-branches or impaired perfusion of bile ducts. We developed a technique of right hemihepatectomy or resection of the left lateral segments with intrahepatic transection of the pedicle that leaves the hepatoduodenal ligament completely untouched. (6) However, if intraoperative visualization or palpation of the ligament is suspicious for tumor infiltration or lymph node metastasis, the hilus should be explored and a lymphadenectomy performed.


Viral vector-induced amygdala NPY overexpression reverses increased alcohol intake caused by repeated deprivations in Wistar rats.
Acute administration of neuropeptide Y (NPY) modulates alcohol intake in genetic and chemical models of high intake, while leaving intake unaffected during 'normal' or baseline conditions. In non-selected, normal rat lines, alcohol consumption can be increased by prolonged exposure to alcohol, and it is unclear what effect a constitutive increase in NPY function will have on alcohol intake. The purpose of the present study was to examine the effects on alcohol intake of an inducible, constitutive overexpression of NPY, one of the most abundant neuropeptides in the central nervous system. A liquid diet was used in combination with repeated alcohol deprivation sessions to increase alcohol intake in normal Wistar rats. We then examined the effect of NPY overexpression in the amygdala on excessive alcohol intake produced by prolonged exposure to alcohol and alcohol deprivation. Repeated withdrawal increased alcohol consumption in a 24-h continuous access two-bottle choice model. Both the number of withdrawals as well as the length of the withdrawal periods affected alcohol consumption with an increased intake resulting from multiple withdrawals and the alcohol deprivation effect being enhanced by longer periods of abstinence. The increase in intake following repeated abstinence was blunted by intra-amygdala administration of a Sindbis viral vector containing NPY cDNA. Amygdala NPY overexpression also was demonstrated to be anxiolytic in the open field test. Repeated withdrawal in combination with a history of alcohol consumption significantly elevated alcohol intake, and the amygdala may mediate the transition to high-drinking states in this model.


Effects of Moringa oleifera on Insulin Levels and Folliculogenesis in Polycystic Ovary Syndrome Model with Insulin Resistance.
Insulin resistance is a frequent metabolic disorder in Polycystic Ovary Syndrome (PCOS). Moringa oleifera has been shown to increase insulin expres-sion and decrease the degree of insulin in diabetes mellitus, therefore it is expected that Moringa oleifera could decrease insulin levels and increase folliculogenesis in PCOS. To prove the effect of Moringa oleifera leaf extract in various doses might decrease the insulin levels and increase folliculogenesis in female PCOS-insulin resistant rats. The three month old white rat of Wistar strain (Rattus norvegicus) 100-130 grams were divided into five groups (n=8) including normal control, PCOS-insulin re-sistance, PCOS-insulin resistance given metformin and PCOS-resistance insulin were giv-en Moringa oleifera leaf extract in two doses. Then, the PCOS model-insulin resistance by injection of testosterone propionate for 28 days. After 14 days treatment, we analysed insulin levels and folliculogenesis. The PCOS control group showed a significant increase in insulin levels compared to the normal control group. The insulin levels from group treatment with Moringa oleifera leaf extract of 250 mg/kgBW was significantly lower than the PCOS control group. Ovarian histology analysis found that the number and diameter of follicle of PCOS control group showed a significant decrease compared to normal control group. In addition, the treatment with metformin and leaf Moringa oleifera dose 250 mg/kgBW and 500 mg/kgBW showed significant increase of folliculogenesis compared to PCOS control group. Moringa oleifera could lowering the blood insulin levels, subsequently decreasing the androgen thus allowed the increasing of folliculogenesis in PCOS.


Can response time be trained with bilateral limb training in children with Down syndrome?
Response time (RT), that is, the time taken to respond is known to be delayed in children with Down syndrome (DS). We performed a pilot study to evaluate whether bilateral limb training can be used to train RT, in children with DS. 10 children with DS (5 males) were recruited from a special school in a suburban region using convenience sampling. Response time was measured using an indigenously developed RT Analyzer, before and after intervention, from right and left hand. Structured bilateral limb training was given for a period of 4 weeks, using low-cost, locally available materials, in community settings. The Wilcoxon signed ranks test was used for statistical analysis. Significant improvements in RT following 4 weeks of intervention were seen in the left hand (P = 0.006) but not in the right hand (P = 0.104). Response time can be trained in children with DS using 4 weeks of bilateral limb training activities using low-cost, locally available materials.


Designing coastal conservation to deliver ecosystem and human well-being benefits.
Conservation scientists increasingly recognize that incorporating human values into conservation planning increases the chances for success by garnering broader project acceptance. However, methods for defining quantitative targets for the spatial representation of human well-being priorities are less developed. In this study we employ an approach for identifying regionally important human values and establishing specific spatial targets for their representation based on stakeholder outreach. Our primary objective was to develop a spatially-explicit conservation plan that identifies the most efficient locations for conservation actions to meet ecological goals while sustaining or enhancing human well-being values within the coastal and nearshore areas of the western Lake Erie basin (WLEB). We conducted an optimization analysis using 26 features representing ecological and human well-being priorities (13 of each), and included seven cost layers. The influence that including human well-being had on project results was tested by running five scenarios and setting targets for human well-being at different levels in each scenario. The most important areas for conservation to achieve multiple goals are clustered along the coast, reflecting a concentration of existing or potentially restorable coastal wetlands, coastal landbird stopover habitat and terrestrial biodiversity, as well as important recreational activities. Inland important areas tended to cluster around trails and high quality inland landbird stopover habitat. Most concentrated areas of importance also are centered on lands that are already conserved, reflecting the lower costs and higher benefits of enlarging these conserved areas rather than conserving isolated, dispersed areas. Including human well-being features in the analysis only influenced the solution at the highest target levels.


Anti-inflammatory and cytoprotective effects of selected Pakistani medicinal plants in Helicobacter pylori-infected gastric epithelial cells.
Helicobacter pylori infection is associated with gastritis, peptic ulcer, and gastric cancer. Due to its high global prevalence and uprising resistance to available antibiotics, efforts are now directed to identify alternative source to treat and prevent associated disorders. In the present study, effect of selected indigenous medicinal plants of Pakistan was evaluated on the secretion of interleukin-8 (IL-8) and generation of reactive oxygen species (ROS) in a bid to rationalize their medicinal use and to examine the anti-inflammatory and cytoprotective effects in gastric epithelial cells. AGS cells and clinically isolated Helicobacter pylori strain (193C) were employed for co-culture experiments. Anti-Helicobacter pylori activity and cytotoxic effects of the selected plants were determined by serial dilution method and DNA fragmentation assay respectively. ELISA and flow cytometry were performed to evaluate the effect on IL-8 secretion and ROS generation in Helicobacter pylori-infected cells. At 100μg/ml, extracts of Alpinia galangal, Cinnamomum cassia, Cinnamomum tamala, Mentha arvensis, Myrtus communis, Oligochaeta ramose, Polygonum bistorta, Rosa damascena, Ruta graveolens, Syzygium aromaticum, Tamarix dioica, and Terminalia chebula exhibited strong inhibitory activity against IL-8 secretion. Of these, four extracts of Cinnamomum cassia, Myrtus communis, Syzygium aromaticum, and Terminalia chebula markedly inhibited IL-8 secretion at both 50 and 100μg/ml. Cinnamomum cassia was further assessed at different concentrations against Helicobacter pylori and TNF-α stimulated IL-8 secretion, which displayed significant suppression of IL-8 in a concentration-dependent-manner. Among the plants examined against ROS generation, Achillea millefolium, Berberis aristata, Coriandrum sativum, Foeniculum vulgare, Matricaria chamomilla and Prunus domestica demonstrated significant suppression of ROS from Helicobacter pylori-infected cells (p<0.01). Results of the study revealed anti-inflammatory and cytoprotective effects of selected medicinal plants which could partially validate the traditional use of these plants in GI disorders particularly associated with Helicobacter pylori. Furthermore, results obtained may lead to possible future candidates of chemoprevention against peptic ulcer or gastric cancer.


Endoscopic middle ear and mastoid surgery for cholesteatoma.
To reduce incidence of residual cholesteatoma following ear surgery; and to reduce the need for second look "open" mastoidectomy using endoscopic mastoidotomy. Ten-year retrospective chart review of 249 primary cholesteatoma cases (1994-2004) with a minimum follow-up of two years. The first objective was to evaluate the effectiveness of otoendoscopy in reducing the incidence of "cholesteatoma remnant" at the time of primary surgery. The second investigation was to evaluate the effectiveness of otoendoscopy in reducing the need to open the mastoid cavities during "second look operations". Endoscopes were used on all cases as an adjunct to standard microscopic methods. Once all visible cholesteatoma was removed with standard microscopic techniques, endoscopes were utilized in order to identify any "remnants" of cholesteatoma. Endoscopes were also employed during revision second look cases in order to allow the evaluation of intact canal wall mastoid cavities without an open Mastoidectomy approach. Endoscopy at time of primary operations revealed a 22% incidence of hidden cholesteatoma "remnants" despite apparent total microscopic eradication in closed cavity cases, and 10% in open cavity patients. Endoscopic removal of cholesteatoma remnants reduced the long term cholesteatoma "residual" to 9.7% in closed cavity patients. Furthermore, endoscopic surgery significantly reduced the need to open the mastoids during second look operations. Otoendoscopy is a very effective adjunctive method in ear surgery. It allows significant reduction in cholesteatoma residual rate in both closed cavity and open cavity cases. Furthermore, the great majority of second look mastoids can be evaluated endoscopically and thus avoid an open revision Mastoidectomy.


Royal jelly improves hyperglycemia in obese/diabetic KK-Ay mice.
The study examined whether royal jelly (RJ) can prevent obesity and ameliorate hyperglycemia in type 2 diabetes. This study utilized obese/diabetic KK-Ay mice. RJ (10 mg/kg) was administered by oral gavage. Body weight, plasma glucose and insulin levels were measured. mRNA and protein levels were determined using quantitative reverse transcription polymerase chain reaction and western blotting, respectively. Four weeks of RJ administration improved hyperglycemia and partially suppressed body weight gain, although the latter effect did not reach statistical significance. In addition, RJ administration did not improve insulin resistance. RJ administration suppressed the mRNA expression of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, in the liver. Simultaneously, RJ administration induced adiponectin (AdipoQ) expression in abdominal fat, adiponectin receptor-1 (AdipoR1) expression in the liver and phosphorylated AMP-activated protein kinase (pAMPK) expression, which suppressed G6Pase levels in the livers of KK-Ay mice. pAMPK levels were also increased in skeletal muscle, but glucose transporter-4 (Glut4) translocation was not increased in the RJ supplementation group. The improvement in hyperglycemia due to long-term RJ administration may be because of the suppression of G6Pase expression through the upregulation of AdipoQ and AdipoR1 mRNA and pAMPK protein expressions.


Neuroprotective properties of cannabigerol in Huntington's disease: studies in R6/2 mice and 3-nitropropionate-lesioned mice.
Different plant-derived and synthetic cannabinoids have shown to be neuroprotective in experimental models of Huntington's disease (HD) through cannabinoid receptor-dependent and/or independent mechanisms. Herein, we studied the effects of cannabigerol (CBG), a nonpsychotropic phytocannabinoid, in 2 different in vivo models of HD. CBG was extremely active as neuroprotectant in mice intoxicated with 3-nitropropionate (3NP), improving motor deficits and preserving striatal neurons against 3NP toxicity. In addition, CBG attenuated the reactive microgliosis and the upregulation of proinflammatory markers induced by 3NP, and improved the levels of antioxidant defenses that were also significantly reduced by 3NP. We also investigated the neuroprotective properties of CBG in R6/2 mice. Treatment with this phytocannabinoid produced a much lower, but significant, recovery in the deteriorated rotarod performance typical of R6/2 mice. Using HD array analysis, we were able to identify a series of genes linked to this disease (e.g., symplekin, Sin3a, Rcor1, histone deacetylase 2, huntingtin-associated protein 1, δ subunit of the gamma-aminobutyric acid-A receptor (GABA-A), and hippocalcin), whose expression was altered in R6/2 mice but partially normalized by CBG treatment. We also observed a modest improvement in the gene expression for brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and peroxisome proliferator-activated receptor-γ (PPARγ), which is altered in these mice, as well as a small, but significant, reduction in the aggregation of mutant huntingtin in the striatal parenchyma in CBG-treated animals. In conclusion, our results open new research avenues for the use of CBG, alone or in combination with other phytocannabinoids or therapies, for the treatment of neurodegenerative diseases such as HD.


Oral immunogenicity of the plant proteinase bromelain.
Bromelain is a natural mixture of proteolytic enzymes derived from pineapple stem that has been shown to have anti-inflammatory activity when administered orally. Although most proteins given orally without adjuvant (e.g., food) result in tolerance, we previously reported that long-term oral exposure to bromelain stimulated the development of high serum anti-bromelain antibody titers. The purpose of these studies was to further investigate the mechanisms responsible for the immunogenicity of oral bromelain. Results showed that repeated exposure was required for development of anti-bromelain antibodies, with strong antibody responses in all mice that received at least 12 doses of bromelain either orally or intragastrically over 3-6 weeks. Proteolytic activity was required for strong oral immunogenicity in the absence of conventional adjuvant, with strong serum antibody responses generated against proteolytically active bromelain and trypsin, but not against ovalbumin, lysozyme, or inactivated bromelain. Significantly higher anti-bromelain antibody titers were seen in IL-10-deficient versus wild-type mice, suggesting that simultaneous treatments that decrease IL-10 activity may further enhance systemic antibody responses following oral exposure. The antibodies generated did not affect the proteolytic activity of bromelain. The data demonstrate that proteolytically active antigens such as bromelain can stimulate both systemic and mucosal immune responses following repeated oral exposure. Further studies of the mechanisms involved in generation of immune responses following oral exposure to proteolytically active antigens can lead to a better understanding of mechanisms of oral tolerance and to the development of novel adjuvants for oral vaccines.


Neoadjuvant 5-FU or Capecitabine Plus Radiation With or Without Oxaliplatin in Rectal Cancer Patients: A Phase III Randomized Clinical Trial.
National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidine capecitabine could be substituted for continuous infusion 5-FU in the curative setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation. Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided. Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3-4 diarrhea (P < .0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm. Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity.


Blood RNA biomarkers in prodromal PARK4 and rapid eye movement sleep behavior disorder show role of complexin 1 loss for risk of Parkinson's disease.
Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinson's disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3'-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction.


Microbial Nanoculture as an Artificial Microniche.
Microbes self-organize in microcolonies while transitioning to a sessile form within a protective biofilm matrix. To enable the detailed study of microbial dynamics within these microcolonies, new sessile culture systems are needed that sequester cells and mimic their complex growth conditions and interactions. We present a new nanoliter-scale sessile culture system that is easily implemented via microfluidics-enabled fabrication. Hundreds of thousands of these nanocultures can be easily generated and imaged using conventional or confocal microscopy. Each nanoculture begins as a several nanoliter droplet of suspended cells, encapsulated by a polydimethylsiloxane (PDMS) membrane. The PDMS shell provides long-lasting mechanical support, enabling long term study, and is selectively permeable to small molecules including antibiotics, signaling molecules and functional fluorescent probes. Thus, as microcolonies mature within the nanocultures, they can be stressed or interrogated using selected probes to characterize cell physiological properties, antibiotic susceptibilities, and antagonistic interactions. We demonstrate this platform by investigating broad ranges of microcolony dynamics, including direct and indirect bacterial-fungal interactions. This versatile new tool has broad potential for addressing biological questions associated with drug resistance, chronic infections, microbiome dynamics, and antibiotic discovery.


Recovery of clinical but not radiographic outcomes by the delayed addition of adalimumab to methotrexate-treated Japanese patients with early rheumatoid arthritis: 52-week results of the HOPEFUL-1 trial.
The aim of this study was to compare efficacy outcomes of initial treatment with adalimumab + MTX vs adalimumab addition following 26 weeks of MTX monotherapy in Japanese early RA patients naive to MTX with high disease activity. Patients completing the 26-week, randomized, placebo-controlled trial of adalimumab + MTX were eligible to receive 26 weeks of open-label adalimumab + MTX. Patients were assessed for mean change from baseline in the 28-joint DAS with ESR (DAS28-ESR) and modified total Sharp score (mTSS), and for the proportions of patients achieving clinical, functional or radiographic remission. Of 333 patients assessed, 278 (137 from the initial adalimumab + MTX and 141 from the initial placebo + MTX groups) completed the 52-week study. Significant differences in clinical and functional parameters observed during the 26-week blinded period were not apparent following the addition of open-label adalimumab to MTX. Open-label adalimumab + MTX slowed radiographic progression through week 52 in both groups, but patients who received adalimumab + MTX throughout the study exhibited less radiographic progression than those who received placebo + MTX during the first 26 weeks (mean ΔmTSS at week 52 = 2.56 vs 3.30, P < 0.001). Delayed addition of adalimumab in Japanese MTX-naive early RA patients did not impact clinical and functional outcomes at week 52 compared with the earlier addition of adalimumab. However, the accrual of significant structural damage during blinded placebo + MTX therapy contributed to the persistence of differences between the treatment strategies, suggesting that Japanese patients at risk for aggressive disease should benefit from the early inclusion of adalimumab + MTX combination therapy. Trial registration. ClinicalTrials.gov (http://clinicaltrials.gov/), NCT00870467.


How is implementation research applied to advance health in low-income and middle-income countries?
This paper examines the characteristics of implementation research (IR) efforts in low-income and middle-income countries (LMICs) by describing how key IR principles and concepts have been used in published health research in LMICs between 1998 and 2016, with focus on how to better apply these principles and concepts to support large-scale impact of health interventions in LMICs. There is a stark discrepancy between principles of IR and what has been published. Most IR studies have been conducted under conditions where the researchers have considerable influence over implementation and with extra resources, rather than in 'real world' conditions. IR researchers tend to focus on research questions that test a proof of concept, such as whether a new intervention is feasible or can improve implementation. They also tend to use traditional fixed research designs, yet the usual conditions for managing programmes demand continuous learning and change. More IR in LMICs should be conducted under usual management conditions, employ pragmatic research paradigm and address critical implementation issues such as scale-up and sustainability of evidence-informed interventions. This paper describes some positive examples that address these concerns and identifies how better reporting of IR studies in LMICs would include more complete descriptions of strategies, contexts, concepts, methods and outcomes of IR activities. This will help practitioners, policy-makers and other researchers to better learn how to implement large-scale change in their own settings.


Functions of the MDM2 oncoprotein.
The p53 protein is activated in response to physiological stress resulting in either a G1 arrest of cells or apoptosis. As such, p53 must be tightly regulated, and the MDM2 oncoprotein plays a central role in that regulatory process. The transcription of the Mdm2 oncogene is induced by the p53 protein after DNA damage, and the MDM2 protein then binds to p53 and blocks its activities as a tumour suppressor and promotes its degradation. These two proteins thus form an autoregulatory feedback loop in which p53 positively regulates MDM2 levels and MDM2 negatively regulates p53 levels and activity. Immediately after ultraviolet (UV) irradiation MDM2 messenger RNA and protein levels fall in a p53-independent fashion, resulting in increased p53 levels. The p53 protein is then activated as a transcription factor by posttranslational modification permitting p53 to initiate its cell-cycle arrest or apoptotic (programmed cell death) functions. At later times, after the repair of DNA, MDM2 levels increase in a p53-dependent fashion. This induction of MDM2 results in the inhibition of p53 transcriptional activity and the degradation of p53 protein. MDM2-p53 complexes in the nucleus are transported to the cytoplasm via signals present in the MDM2 protein, where p53 is degraded in the proteasome. Thus MDM2 acts as a nuclear-cytoplasmic shuttle for the p53 protein. There are many levels at which this process is regulated, and as such there are many places for chemotherapeutic interventions. The amino-terminal domain of the MDM2 protein is all that is required to bind the p53 protein. The MDM2 protein has additional domains and therefore may have additional functions. Any of these MDM2 domains may contribute to MDM2's activities as an oncogene independent of its inhibition of the tumour suppressor functions of p53. Thus MDM2 itself could be a target for cancer therapeutic intervention.


Bayesian inference on the effect of density dependence and weather on a guanaco population from Chile.
Understanding the mechanisms that drive population dynamics is fundamental for management of wild populations. The guanaco (Lama guanicoe) is one of two wild camelid species in South America. We evaluated the effects of density dependence and weather variables on population regulation based on a time series of 36 years of population sampling of guanacos in Tierra del Fuego, Chile. The population density varied between 2.7 and 30.7 guanaco/km2, with an apparent monotonic growth during the first 25 years; however, in the last 10 years the population has shown large fluctuations, suggesting that it might have reached its carrying capacity. We used a Bayesian state-space framework and model selection to determine the effect of density and environmental variables on guanaco population dynamics. Our results show that the population is under density dependent regulation and that it is currently fluctuating around an average carrying capacity of 45,000 guanacos. We also found a significant positive effect of previous winter temperature while sheep density has a strong negative effect on the guanaco population growth. We conclude that there are significant density dependent processes and that climate as well as competition with domestic species have important effects determining the population size of guanacos, with important implications for management and conservation.


Fault Diagnosis of Planetary Gearbox Based on Adaptive Order Bispectrum Slice and Fault Characteristics Energy Ratio Analysis.
The vibration of a planetary gearbox (PG) is complex and mutually modulated, which makes the weak features of incipient fault difficult to detect. To target this problem, a novel method, based on an adaptive order bispectrum slice (AOBS) and the fault characteristics energy ratio (FCER), is proposed. The order bispectrum (OB) method has shown its effectiveness in the feature extraction of bearings and fixed-shaft gearboxes. However, the effectiveness of the PG still needs to be explored. The FCER is developed to sum up the fault information, which is scattered by mutual modulation. In this method, the raw vibration signal is firstly converted to that in the angle domain. Secondly, the characteristic slice of AOBS is extracted. Different from the conventional OB method, the AOBS is extracted by searching for a characteristic carrier frequency adaptively in the sensitive range of signal coupling. Finally, the FCER is summed up and calculated from the fault features that were dispersed in the characteristic slice. Experimental data was processed, using both the AOBS-FCER method, and the method that combines order spectrum analysis with sideband energy ratio (OSA-SER), respectively. Results indicated that the new method is effective in incipient fault feature extraction, compared with the methods of OB and OSA-SER.


Fluid lavage of open wounds (FLOW): a multicenter, blinded, factorial pilot trial comparing alternative irrigating solutions and pressures in patients with open fractures.
Open fractures are an important source of morbidity and are associated with delayed union, nonunion, and infection. Preventing infection through meticulous irrigation and debridement is an important goal in management, and different lavage fluids and irrigation techniques (e.g., high- or low-pressure lavage) have been described for this purpose. However, there are a limited number of randomized trials comparing irrigating solutions or irrigating technique. We compared the use of castile soap versus normal saline and high- versus low-pressure pulsatile lavage on the rates of reoperations and complications in patients with open fracture wounds. We conducted a multicenter, blinded, randomized 2 × 2 factorial pilot trial of 111 patients in whom an open fracture wound was treated with either castile soap solution or normal saline and either high- or low-pressure pulsatile lavage. The primary composite outcome of reoperation, measured at 12 months after initial operative procedure, included infection, wound healing problems, and nonunion. Planned reoperations were not included. Secondary outcomes included all infection, all wound healing problems, and nonunion as well as functional outcomes scores (EuroQol-5 dimensions and short form-12). Eighty-nine patients completed the 1-year follow-up. Among all patients, 13 (23%) in the castile soap group and 13 (24%) in the saline group had a primary outcome event (hazard ratio, 0.91, 95% confidence interval: 0.42-2.00, p = 0.52). Sixteen patients (28%) in the high-pressure group and 10 patients (19%) in the low-pressure group had a primary outcome event (hazard ratio 0.55, 95% confidence interval: 0.24-1.27, p = 0.17). Functional outcome scores showed no significant differences at any time point between groups. The fluid lavage of open wounds pilot randomized controlled trial demonstrated the possibility that the use of low pressure may decrease the reoperation rate for infection, wound healing problems, or nonunion. We have demonstrated the desirability and feasibility of a definitive trial examining the effects of alternative irrigation approaches.


Immediate and Delayed Procedural Stroke or Death in Stenting Versus Endarterectomy for Symptomatic Carotid Stenosis.
Background and Purpose- Stenting for symptomatic carotid stenosis (carotid artery stenting [CAS]) carries a higher risk of procedural stroke or death than carotid endarterectomy (CEA). It is unclear whether this extra risk is present both on the day of procedure and within 1 to 30 days thereafter and whether clinical risk factors differ between these periods. Methods- We analyzed the risk of stroke or death occurring on the day of procedure (immediate procedural events) and within 1 to 30 days thereafter (delayed procedural events) in 4597 individual patients with symptomatic carotid stenosis who underwent CAS (n=2326) or CEA (n=2271) in 4 randomized trials. Results- Compared with CEA, patients treated with CAS were at greater risk for immediate procedural events (110 versus 42; 4.7% versus 1.9%; odds ratio, 2.6; 95% CI, 1.9-3.8) but not for delayed procedural events (59 versus 46; 2.5% versus 2.0%; odds ratio, 1.3; 95% CI, 0.9-1.9; interaction P=0.006). In patients treated with CAS, age increased the risk for both immediate and delayed events while qualifying event severity only increased the risk of delayed events. In patients treated with CEA, we found no risk factors for immediate events while a higher level of disability at baseline and known history of hypertension were associated with delayed procedural events. Conclusions- The increased procedural stroke or death risk associated with CAS compared with CEA was caused by an excess of events occurring on the day of procedure. This finding demonstrates the need to enhance the procedural safety of CAS by technical improvements of the procedure and increased operator skill. Higher age increased the risk for both immediate and delayed procedural events in CAS, mechanisms of which remain to be elucidated. Clinical Trial Registration- URL: https://clinicaltrials.gov . Unique identifier: NCT00190398. URL: http://www.isrctn.com . Unique identifier: ISRCTN57874028. URL: http://www.isrctn.com . Unique identifier: ISRCTN25337470. URL: https://clinicaltrials.gov . Unique identifier: NCT00004732.


Minimum variance control structure for adaptive optics systems.
The adaptive optics minimum variance control problem is formulated as a linear-quadratic-Gaussian optimization. The formulation incorporates the wavefront sensor frame integration in discrete-time models of the deformable mirror and incident wavefront. It shows that, under nearly ideal conditions, the resulting minimum variance controller approaches the integral controller commonly used in adaptive optics systems. The inputs to the controller dynamics are obtained from a reconstructor with the maximum a posteriori structure that uses the estimation error covariance of the wavefront error. The ideal conditions assumed to obtain the integral controller are as follows; isotropic first-order (but nonstationary) temporal atmospheric aberrations, no computational loop delay, and no deformable mirror dynamics. The effects of variations in these conditions are examined.


The networks of care surrounding cancer palliative care patients.
This paper explicates the nature and extent of the networks of care surrounding patients with cancer palliative care needs. Twenty-four patients with 15 different types/sites of cancer were recruited in one city in England, UK. During one in-depth interview patients identified who was 'involved in their care' and any known pathways of communication between them. One hundred of these people (35 doctors, 32 nurses, 17 professions allied to medicine, 8 family members and 8 others) were also interviewed. Maps of people/teams and the connections between them for each patient were then reconstructed using social networking software (PAJEK). The 24 patients identified a total of 619 people or teams (mean 26, median 22, range 9-45 per patient) contributing to their care. Selected care network maps are displayed, illustrating the extent and nature of the care networks supporting palliative care patients. Common members of care networks for patients with palliative care needs are revealed, but their individual and unique nature is also apparent. The possible clinical utility and challenges of mapping care networks are discussed. Exploring the care networks surrounding individual patients can be useful for illuminating the extent and complexity of individual patient's care networks; clarifying who is involved and who they communicate with; providing opportunities to see interaction routes that may otherwise be hidden, revealing potentially missing or weak connections; and highlighting overlaps or gaps in provision.


Homeopathy for anxiety and anxiety disorders: a systematic review of the research.
To conduct a systematic review of the clinical research evidence on homeopathy in the treatment of anxiety and anxiety disorders. A comprehensive search of major biomedical databases: MEDLINE, EMBASE, ClNAHL, PsycINFO, Cochrane Library; and of specialist complementary and alternative medicine (CAM) databases: AMED, CISCOM and Hom-Inform was conducted. Efforts were made to identify unpublished and ongoing research using relevant sources and experts in the field. Relevant research was categorised by study type and appraised according to study design. Clinical commentaries were obtained for studies reporting clinical outcomes. Eight randomised controlled studies were identified. The types of anxiety and anxiety disorders studied were test anxiety, generalised anxiety disorder and anxiety related to medical or physical conditions such as cancer or surgical procedures. Single case reports/studies were the most frequently encountered study type but other study types including uncontrolled trials/case series and surveys were also found. No relevant qualitative research was identified. A comprehensive search demonstrates that the evidence on the benefit of homeopathy in anxiety and anxiety disorders is limited. A number of studies of homeopathy in such conditions were located but the randomised controlled trials report contradictory results, are underpowered or provide insufficient details of methodology. Several uncontrolled and observational studies reported positive results including high levels of patient satisfaction but because of the lack of a control group, it is difficult to assess the extent to which any response is due to homeopathy. Adverse effects reported appear limited to 'remedy reactions' and included temporary worsening of symptoms and reappearance of old symptoms. On the basis of this review it is not possible to draw firm conclusions on the efficacy or effectiveness of homeopathy for anxiety. However, surveys suggest that homeopathy is quite frequently used by people suffering from anxiety. If shown to be effective, it is possible that homeopathy may have benefits in terms of adverse effects and acceptability to patients. Consequently, further investigation is indicated. Future research should be of pragmatic design and include qualitative studies.


Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy.
We demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abrogates the G2 DNA damage checkpoint in both normal and malignant cells. Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitors persist suggesting that sequential administration of PARP and WEE1 inhibitors could maintain efficacy while ameliorating toxicity. Strikingly, while sequential administration mirrored concurrent therapy in cancer cells that have high basal replication stress, low basal replication stress in normal cells protected them from DNA damage and toxicity, thus improving tolerability while preserving efficacy in ovarian cancer xenograft and patient-derived xenograft models.


Cavity-enhanced generation of 6 W cw second-harmonic power at 532 nm in periodically-poled MgO:LiTaO3.
We report on efficient cw high-power second harmonic generation in a periodically poled LiTaO3 crystal placed in a resonant enhancement cavity. We tested three configurations, differing in the coupling mirror reflectivity, and a maximum conversion efficiency of about 76%, corresponding to 6.1 W of green light with 8.0 W of fundamental power, was achieved. This is, to the best of our knowledge, the highest cw power ever reported using a periodically-poled crystal in an external cavity. We observed photo-thermal effect induced by photon absorption at the mirrors and in the crystal, which however does not affect stable operation of the cavity. A further effect arises for two out of the three configurations, at higher values of the input power, which degrades the performance of the locked cavity. We suggest this effect is due to the onset of competing nonlinearities in the same crystal.


Apps seeking theories: results of a study on the use of health behavior change theories in cancer survivorship mobile apps.
Thousands of mobile health apps are now available for use on mobile phones for a variety of uses and conditions, including cancer survivorship. Many of these apps appear to deliver health behavior interventions but may fail to consider design considerations based in human computer interface and health behavior change theories. This study is designed to assess the presence of and manner in which health behavior change and health communication theories are applied in mobile phone cancer survivorship apps. The research team selected a set of criteria-based health apps for mobile phones and assessed each app using qualitative coding methods to assess the application of health behavior change and communication theories. Each app was assessed using a coding derived from the taxonomy of 26 health behavior change techniques by Abraham and Michie with a few important changes based on the characteristics of mHealth apps that are specific to information processing and human computer interaction such as control theory and feedback systems. A total of 68 mobile phone apps and games built on the iOS and Android platforms were coded, with 65 being unique. Using a Cohen's kappa analysis statistic, the inter-rater reliability for the iOS apps was 86.1 (P<.001) and for the Android apps, 77.4 (P<.001). For the most part, the scores for inclusion of theory-based health behavior change characteristics in the iOS platform cancer survivorship apps were consistently higher than those of the Android platform apps. For personalization and tailoring, 67% of the iOS apps (24/36) had these elements as compared to 38% of the Android apps (12/32). In the area of prompting for intention formation, 67% of the iOS apps (34/36) indicated these elements as compared to 16% (5/32) of the Android apps. Mobile apps are rapidly emerging as a way to deliver health behavior change interventions that can be tailored or personalized for individuals. As these apps and games continue to evolve and include interactive and adaptive sensors and other forms of dynamic feedback, their content and interventional elements need to be grounded in human computer interface design and health behavior and communication theory and practice.


Highly superporous cholesterol-modified poly(2-hydroxyethyl methacrylate) scaffolds for spinal cord injury repair.
Modifications of poly(2-hydroxyethyl methacrylate) (PHEMA) with cholesterol and the introduction of large pores have been developed to create highly superporous hydrogels that promote cell-surface interactions and that can serve as a permissive scaffold for spinal cord injury (SCI) treatment. Highly superporous cholesterol-modified PHEMA scaffolds have been prepared by the bulk radical copolymerization of 2-hydroxyethyl methacrylate (HEMA), cholesterol methacrylate (CHLMA), and ethylene dimethacrylate (EDMA) cross-linking agent in the presence of ammonium oxalate crystals to establish interconnected pores in the scaffold. Moreover, 2-[(methoxycarbonyl)methoxy]ethyl methacrylate (MCMEMA) was incorporated in the polymerization recipe and hydrolyzed, thus introducing carboxyl groups in the hydrogel to control its swelling and softness. The hydrogels supported the in vitro adhesion and proliferation of rat mesenchymal stem cells. In an in vivo study of acute rat SCI, hydrogels were implanted to bridge a hemisection cavity. Histological evaluation was done 4 weeks after implantation and revealed the good incorporation of the implanted hydrogels into the surrounding tissue, the progressive infiltration of connective tissue and the ingrowth of neurofilaments, Schwann cells, and blood vessels into the hydrogel pores. The results show that highly superporous cholesterol-modified PHEMA hydrogels have bioadhesive properties and are able to bridge a spinal cord lesion.


Disrupted Circadian Control of Hormonal Rhythms and Anticipatory Thirst by Dim Light at Night.
Our study addresses underlying mechanisms of disruption of the circadian timing system by low-intensity artificial light at night (ALAN), which is a growing global problem, associated with serious health consequences. Rats were exposed to low-intensity (∼2 lx) ALAN for 2 weeks. Using in situ hybridization, we assessed 24-h profiles of clock and clock-controlled genes in the suprachiasmatic nuclei (SCN) and other hypothalamic regions, which receive input from the master clock. Moreover, we measured the daily rhythms of hormones within the main neuroendocrine axes as well as the detailed daily pattern of feeding and drinking behavior in metabolic cages. ALAN strongly suppressed the molecular clockwork in the SCN, as indicated by the suppressed rhythmicity in the clock (Per1, Per2, and Nr1d1) and clock output (arginine vasopressin) genes. ALAN disturbed rhythmic Per1 expression in the paraventricular and dorsomedial hypothalamic nuclei, which convey the circadian signals from the master clock to endocrine and behavioral rhythms. Disruption of hormonal output pathways was manifested by the suppressed and phase-advanced corticosterone rhythm and lost daily variations in plasma melatonin, testosterone, and vasopressin. Importantly, ALAN altered the daily profile in food and water intake and eliminated the clock-controlled surge of drinking 2 h prior to the onset of the rest period, indicating disturbed circadian control of anticipatory thirst and fluid balance during sleep. Our findings highlight compromised time-keeping function of the central clock and multiple circadian outputs, through which ALAN disturbs the temporal organization of physiology and behavior.


Fat-soluble vitamin deficiency in children and adolescents with cystic fibrosis.
Determine the prevalence of fat-soluble vitamin deficiency in children with cystic fibrosis (CF) aged ≤18 years in New South Wales (NSW), Australia, from 2007 to 2010. A retrospective analysis of fat-soluble vitamin levels in children aged ≤18 years who lived in NSW and attended any of the three paediatric CF centres from 2007 to 2010. An audit of demographic and clinical data during the first vitamin level measurement of the study period was performed. Deficiency of one or more fat-soluble vitamins was present in 240/530 children (45%) on their first vitamin level test in the study period. The prevalence of vitamins D and E deficiency fell from 22.11% in 2007 to 15.54% in 2010, and 20.22% to 13.89%, respectively. The prevalence of vitamin A deficiency increased from 11.17% to 13.13%. Low vitamin K was present in 29% in 2007, and prevalence of prolonged prothrombin time increased from 19.21% to 22.62%. Fat-soluble vitamin deficiency is present in 10%-35% of children with pancreatic insufficiency, but only a very small proportion of children who are pancreatic-sufficient. This is one of few studies of fat-soluble vitamin deficiency in children with CF in Australia. Fat-soluble vitamin testing is essential to identify deficiency in pancreatic-insufficient children who may be non-compliant to supplementation or require a higher supplement dose, and pancreatic-sufficient children who may be progressing to insufficiency. Testing of vitamin K-dependent factors needs consideration. Further studies are needed to monitor rates of vitamin deficiency in the CF community.


Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction.
Renin-angiotensin system inhibitors are recommended for treating hypertension with chronic kidney disease. The addition of a mineralocorticoid receptor blocker may be one option to achieve target blood pressure. We investigated the efficacy and safety of esaxerenone, a mineralocorticoid receptor blocker, in Japanese hypertensive patients with moderate kidney dysfunction. Two multicenter, open-label, nonrandomized dose escalation studies were conducted to investigate esaxerenone monotherapy and add-on therapy to renin-angiotensin system inhibitor treatment. Esaxerenone therapy was initiated at 1.25 mg/day and titrated to 2.5 and then 5 mg/day for a treatment duration of 12 weeks. Primary endpoints were changes from baseline in sitting systolic and diastolic blood pressure. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also assessed. Thirty-three patients received monotherapy, and 58 received add-on therapy; the mean baseline estimated glomerular filtration rates were 51.9 and 50.9 mL/min/1.73 m2, respectively. The esaxerenone dosage was increased to ≥2.5 mg/day in 100% (n = 33) and 93.1% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. Reductions in sitting blood pressure from baseline to the end of treatment were similar (monotherapy: -18.5/-8.8 mmHg; add-on therapy: -17.8/-8.1 mmHg; both P < 0.001). The antihypertensive effects of esaxerenone were consistent across patient subgroups. A serum K+ level ≥5.5 mEq/L was observed in seven patients (12.1%) receiving add-on therapy but in none receiving monotherapy. All increases in serum K+ levels were transient, and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment owing to kidney function decline. Esaxerenone was effective and well tolerated in hypertensive patients with moderate kidney dysfunction.


Centralization of radical prostatectomy in the United States.
Radical prostatectomy is a common treatment for organ confined prostate cancer and its use is increasing. We examined how the increased volume is being distributed and what hospital characteristics are associated with increasing volume. We identified all men age 40 to less than 80 years who underwent radical prostatectomy for prostate cancer from 2000 to 2008 in the NIS (Nationwide Inpatient Sample) (586,429). Ownership of a surgical robot was determined using the 2007 AHA (American Hospital Association) Annual Survey. The association between hospital radical prostatectomy volume and hospital characteristics, including ownership of a robot, was explored using multivariate linear regression. From 2000 to 2008 there was a 74% increase in the number of radical prostatectomies performed (p = 0.05) along with a 19% decrease in the number of hospitals performing radical prostatectomy (p <0.001), resulting in an increase in annual hospital radical prostatectomy volume (p = 0.009). Several hospital variables were associated with greater radical prostatectomy volume including teaching status, urban location, large bed size and ownership of a robot in 2007. On multivariate analysis the year, teaching status, large bed size, urban location and presence of a robot were associated with higher hospital radical prostatectomy volume. Use of radical prostatectomy increased significantly between 2000 and 2008, most notably after 2005. The increase in radical prostatectomy resulted in centralization to select hospitals, particularly those in the top radical prostatectomy volume quartile and those investing in robotic technology. Our findings support the hypothesis that hospitals with the greatest volume increases are specialty centers already performing a high volume of radical prostatectomy procedures.


The social-emotional processing stream: five core constructs and their translational potential for schizophrenia and beyond.
Cognitive neuroscience approaches to translational research have made great strides toward understanding basic mechanisms of dysfunction and their relation to cognitive deficits, such as thought disorder in schizophrenia. The recent emergence of Social Cognitive and Affective Neuroscience has paved the way for similar progress to be made in explaining the mechanisms underlying the social and emotional dysfunctions (i.e., negative symptoms) of schizophrenia and that characterize virtually all DSM Axis I and II disorders more broadly. This article aims to provide a roadmap for this work by distilling from the emerging literature on the neural bases of social and emotional abilities a set of key constructs that can be used to generate questions about the mechanisms of clinical dysfunction in general and schizophrenia in particular. To achieve these aims, the first part of this article sketches a framework of five constructs that comprise a social-emotional processing stream. The second part considers how future basic research might flesh out this framework and translational work might relate it to schizophrenia and other clinical populations. Although the review suggests there is more basic research needed for each construct, two in particular--one involving the bottom-up recognition of social and emotional cues, the second involving the use of top-down processes to draw mental state inferences--are most ready for translational work.


Functionalized Multi-Walled Carbon Nanotube Paper for Monitoring Chemical Vapors.
The multi-walled carbon nanotube paper is prepared by vacuum filtration of pure nanotubes and their functionalized forms prepared by KMnO4 and H2O2 oxidation or by grafting with Poly(methyl methacrylate) (PMMA) and polypyrrole to form sensory nanotubes layer for detection of volatile organic compounds in air. The selected compounds for experimentation (acetone, diethyl ether, isopentane, methanol, tetrahydrofuran) have different polarities and volume fractions of saturated vapors. The sensing is measured by electrical resistance of the paper, which increases when exposed to vapors. A reversible reaction is observed when the paper is removed from the vapors. The functionalized nanotubes differ in their sensitivity to selected organics solvents. For example, KMnO4 oxidized paper has differentiated response to all used vapors, so the measured data may indicate clearly the type of the vapor. On the other hand, the MWCNT/PMMA composite has nearly the same response to acetone, diethyl ether and tetrahydrofuran and different response to isopentane and methanol. The investigation can lead to construction of sensory unit which could be capable of detecting and identifying different vapors in the air.


Evoked potentials in the assessment of neurotoxicity in humans.
The present paper reviews strengths and weaknesses of evoked potentials (EPs) as an index of toxic insult to the nervous system. EPs are obtained by averaging successive samples of EEG time-locked to the presentation of stimuli. Components of the resulting waveform can be measured for amplitude, latency, and distribution. Normal ranges of these parameters have been characterized for auditory, visual and somatosensory stimuli. Auditory EPs have been studied in humans exposed to lead, trichloroethylene, and carbon monoxide. Changes in timing of short latency components and in amplitude of later cortical components have been reported. Methyl mercury, n-hexane and carbon monoxide cause complex changes in the waveshape of flash and patterned visual EPs. Similarly, specific components of somatosensory EPs are altered following exposure to carbon monoxide, lead and acrylamide. The current lack of standardized recording and analysis techniques has sometimes generated contradictory results, but the evidence thus far supports the ultimate usefulness of EPs as a neurotoxicological screening tool.


Reducing Gastroschisis Mortality: A Quality Improvement Initiative at a Ugandan Pediatric Surgery Unit.
With modern treatment, survival of gastroschisis exceeds 90% in high-income countries. Survival in these countries has been largely attributed to prenatal diagnosis, delivery at tertiary facilities with timely resuscitation, timely intervention, parenteral nutrition and intensive care facilities. In sub-Saharan Africa, due to lack of these facilities, mortality rates are still alarmingly high ranging from 75 to 100%. In Uganda the mortality is 98%. The aim of this study was to reduce gastroschisis mortality in a feasible, sustainable way using a locally derived gastroschisis care protocol at a referring hospital in Western Uganda. Data collection was performed from January to October 2018. Nursing staff were interviewed regarding the survival and management of gastroschisis babies. A locally derived protocol was created with staff input and commitment from all the team members. Four mothers absconded and 17 babies were cared for using the newly designed protocol. Seven survived and were well at one month post discharge follow-up, reducing the mortality for this condition from 98 to 59%. A dedicated team with minimal resources can significantly reduce the mortality in gastroschisis by almost 40% using a locally derived protocol.


Widening the effective field of view of adaptive-optics telescopes by deconvolution from wave-front sensing: average and signal-to-noise ratio performance.
A fundamental problem of adaptive-optics systems is the very narrow corrected field of view that can be obtained because turbulence is extended in altitude throughout the atmosphere. The correctable field of view is of the order of 5-10 µrad at visible wavelengths and increases as the wavelength increases. Previous concepts to broaden the corrected field of view have been hardware oriented, requiring multiple wave-front sensor (WFS) measurements to control multiple deformable mirrors. We analyze the average and the signal-to-noise-ratio performance of an image measurement and postprocessing technique that uses simultaneous measurements of a short-exposure compensated image measured in an off-axis direction; an additional WFS measurement is taken in the off-axis direction. Results are presented for infinite-altitude WFS beacons driving both the WFS for the adaptive optics and the WFS looking in the off-axis direction, a variety of seeing and WFS light-level conditions, and off-axis angles from two to six times the isoplanatic angle. This technique improves the average effective transfer function out to a field angle of at least six times the isoplanatic angle while providing a higher signal-to-noise ratio in the spatial frequency domain.


[The cerebral protection technique in angioplasty plus stenting of carotid: an effective procedure against cerebral embolism].
To describe the cerebral protection technique used in the angioplasty and stenting to treat stenotic lesions of carotid artery bifurcation, showing its efficiency in avoiding cerebral emboli during the procedure. Forty two patients (47 arteries) were treated with the cerebral protection technique, which consists in the temporary occlusion of the internal carotid artery, above the stenotic lesion, performing the aspiration and flushing of glucose solution into the internal carotid artery after the delivery of the stent and the angioplasty, to remove any atherosclerotic plaque's fragments. The angioplasty was efficient in all cases. There were no cerebral emboli in the patients in whom the complete cerebral protection technique was used, showing its efficiency. Distal embolism occurred in one patient, during pre angioplasty and before the use of cerebral protection. The cerebral protection technique was efficient to avoid cerebral emboli in the procedures performed. This data is in agreement with the literature and the use of this technique increases the indications of carotid angioplasty.


Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with isolated growth hormone deficiency due to organic causes.
To determine characteristics of children initially diagnosed with isolated growth hormone deficiency (IGHD) of organic aetiology, who later developed multiple pituitary hormone deficiencies (MPHD). Data were analysed for 716 growth hormone-treated children with organic IGHD, who were growth hormone-naïve at baseline in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study. Development of MPHD was ascertained from investigator-provided diagnoses, adverse events and concomitant medications. Analyses were performed for all patients and separately for those who developed MPHD within 4.5 years or had >3.5 years follow-up and continued to have IGHD (4-year cohort). MPHD developed in 71/716 (9.9%) children overall, and in 60/290 (20.7%) in the 4-year cohort. The most frequent additional deficiencies were thyroid-stimulating hormone (47 patients) and gonadotropins (23 patients). Compared with those who remained with IGHD, children who developed MPHD had more severe GHD at study entry, significantly lower baseline insulin-like growth factor1, peak stimulated growth hormone, and more frequent diagnosis of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Multivariate logistic regression analyses identified female gender, longer follow-up, higher baseline age and lower peak stimulated growth hormone as predictors of MPHD development. MPHD is more likely to develop in patients with severe organic IGHD, especially those with history of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Older baseline age, female gender and longer follow-up duration were also associated with higher incidence of MPHD. Long-term monitoring of pituitary function is recommended, irrespective of the aetiology of GHD.