Blenderized Tube Feeding Use in Adult Home Enteral Nutrition Patients: A Cross-Sectional Study.
Use of long-term enteral nutrition (EN) has increased dramatically in the United States. It has been the authors' experience that most home EN (HEN) patients use blenderized tube feeding (BTF) in addition to commercial EN. There are limited resources available for patients interested in BTF, and studies evaluating safety and effectiveness are limited. The authors conducted a prospective cross-sectional study (n = 54). age >18 years, follow-up in HEN clinic, prescribed commercial EN. Participants were provided the survey at HEN follow-up appointments after receiving HEN for at least 3 weeks. Median age (range) was 60.5 (22-87) years with 42.6% females (n = 23). BTF was used by 55.5% of patients (n = 30). Most (57%; n = 31) received HEN for >6 months. BTF use was a median of 4 (1-7) days per week. Most common reasons for using BTF were as follows: it is more natural (43%), like eating what their family does (33%), and tolerate BTF better (30%). In patients who use BTF, 80% reported maintaining goal body weight. BTF resulted in significantly less reported nausea, vomiting, bloating, diarrhea, and constipation compared with commercial EN. This is the first study to evaluate BTF use in an adult HEN population. More than 50% of our patients used and approximately 80% expressed a desire to use BTF if provided with adequate information. With new connection tube changes coming in the near future, adequate adapters for BTF need to be developed.


Increased Virulence of Bloodstream Over Peripheral Isolates of P. aeruginosa Identified Through Post-transcriptional Regulation of Virulence Factors.
The factors influencing the virulence of P. aeruginosa in the development of invasive infection remain poorly understood. Here, we investigated the role of the host microenvironment in shaping pathogen virulence and investigated the mechanisms involved. Comparing seven paired genetically indistinguishable clinical bloodstream and peripheral isolates of P. aeruginosa, we demonstrate that isolates derived from bloodstream infections are more virulent than their peripheral counterparts (p = 0.025). Bloodstream and peripheral isolates elicited similar NF-kB responses in a THP-1 monocyte NF-kappaB reporter cell line implicating similar immunogenicity. Proteomic analysis by mass spectrometry identified multiple virulence and virulence-related factors including LecA and RpoN in significantly greater abundance in the bacterial supernatant from the bloodstream isolate in comparison to that from the corresponding peripheral isolate. Investigation by qPCR revealed that control of expression of these virulence factors was not due to altered levels of transcription. Based on these data, we hypothesize a post-transcriptional mechanism of virulence regulation in P. aeruginosa bloodstream infections influenced by surrounding microenvironmental conditions.


Rapid infusion of sodium bicarbonate and albumin into high-risk premature infants soon after birth: a controlled, prospective trial.
We conducted a controlled, prospective trial to evaluate the effectiveness of rapidly infusing sodium bicarbonate (NaHCO3) and salt-poor albumin into high-risk, premature infants in the first 2 hours of life. Fifty-three infants, randomized into one of four treatment groups, received 8 ml. per kilogram of a solution containing either (A) glucose in water, (B) salt-poor albumin, (C) NaHCO3, or (D) a combination of albumin and NaHCO3. After the initial infusion, the babies received no colloid or alkali solutions until 4 hours of age. We managed them supportively with warmth, appropriate oxygen administration, isotonic fluid infusion, and close monitoring. Among the infants who received alkali, 14 of 26 acquired the respiratory distress syndrome (RDS), 11 died, and four had intracranial hemorrhage. Among babies who received no alkali, RDS occurred in 11 of 27, 5 died, and none had intracranial hemorrhage. These results do not support the common practice of rapidly infusing NaHCO3 into high-risk, premature infants, and they suggest that the early management of such infants needs renewed critical evaluation.


Dealloying to nanoporous Au/Pt alloys and their structure sensitive electrocatalytic properties.
A simple and general dealloying method is employed to fabricate nanoporous Au/Pt alloys with pre-determined alloy compositions. Structural characterization by electron microscopes demonstrates that selective etching of Cu from Au/Pt/Cu alloy precursors results in the formation of three-dimensional bicontinuous porous network structures with uniform pores and ligaments less than 10 nm. X-Ray photoelectron spectroscopy and X-ray diffraction demonstrate that nanoporous Au/Pt alloys have a single-phase cubic structure with relatively uniform compositions across the samples. These high surface area alloy nanostructures show much enhanced specific activity and distinct surface reactivity toward the electrooxidation of some small organic molecules, such as methanol and formic acid, as the Au content varies within the structure, thus holding great potential for use in clean energy and environmental applications.


Antioxidant activity of hispidin oligomers from medicinal fungi: a DFT study.
Hispidin oligomers are styrylpyrone pigments isolated from the medicinal fungi Inonotus xeranticus and Phellinus linteus. They exhibit diverse biological activities and strong free radical scavenging activity. To rationalize the antioxidant activity of a series of four hispidin oligomers and determine the favored mechanism involved in free radical scavenging, DFT calculations were carried out at the B3P86/6-31+G (d, p) level of theory in gas and solvent. The results showed that bond dissociation enthalpies of OH groups of hispidin oligomers (ArOH) and spin density delocalization of related radicals (ArO•) are the appropriate parameters to clarify the differences between the observed antioxidant activities for the four oligomers. The effect of the number of hydroxyl groups and presence of a catechol moiety conjugated to a double bond on the antioxidant activity were determined. Thermodynamic and kinetic studies showed that the PC-ET mechanism is the main mechanism involved in free radical scavenging. The spin density distribution over phenoxyl radicals allows a better understanding of the hispidin oligomers formation.


General hospital health professionals' attitudes and perceived dangerousness towards patients with comorbid mental and physical health conditions: Systematic review and meta-analysis.
The stigmatization of mental health is present in general hospital settings impacting quality of care. We hypothesized that health professionals in these areas would elicit negative attitudes and a perceived level of dangerousness across a range of mental health disorders. We aimed to conduct a systematic review and meta-analysis to examine these attitudes and perceptions. We searched the bibliographic databases of CINAHL Complete, MEDLINE Complete, PsycINFO, and Psychology and Behavioral Sciences Collection in May 2017 (no date parameters were set). Quantitative studies investigating generalist health professionals' attitudes towards mental health conditions were selected. Initially, prevalence meta-analyses were conducted to assess the extent of perceived danger, followed by a series of comparative meta-analyses in which the perceived dangerousness of mental health conditions was compared. Of the 653 citations retrieved, eight studies met the inclusion criteria. The overall sample included 2548 health professionals. A majority of health professionals perceived patients with substance use disorder as dangerous 0.60 (95% CI: 0.32-0.88) when compared with patients who had an alcohol-related disorder, schizophrenia, and depression. The results also indicated that a large proportion of staff perceived patients with a diagnosis of schizophrenia as dangerous 0.42 (95% CI: 0.33-0.52). Negative attitudes towards people experiencing mental illness in general hospital settings may be attributed to poor mental health literacy, skills and limited exposure, and social and cultural beliefs about mental illness. Ongoing professional development targeting mental health knowledge is recommended for health professionals working in general hospital settings.


Correlation of renal status with hematologic profile in viperine bite.
Viper venom is mainly hemotoxic and causes coagulation disorders. One of the serious complications of viperine bite is renal failure. Forty adult cases of viper bite with systemic envenomation were studied for renal abnormality. Renal involvement was noted in 13 (32.5%) cases, of which eight (61.5%) had primary fibrinogenolysis and five (38.5%) had disseminated intravascular coagulopathy (DIC). Eight cases (61.5%) with renal dysfunction had incoagulable blood, whereas five (38.5%) had mild coagulation abnormality; however, none of the cases with incoagulable blood who received polyvalent anti-snake venom (ASV) within 8 hr of being bitten developed renal abnormality. In the majority of cases (61.5%), renal dysfunction persisted for more than a week longer than coagulation defects despite adequate treatment. Two cases died. Renal biopsy done in three cases with renal dysfunction revealed acute tubular necrosis. We concluded that renal abnormality correlated well with the degree of coagulation abnormality when left untreated due to late arrival at the hospital. Early administration of ASV prevents renal damage however severe the coagulation abnormality. It appears that DIC is not the cause of renal dysfunction in all cases of acute renal failure, and direct toxicity caused by venom could be responsible for renal dysfunction in certain cases.


Enteric-coated mycophenolate sodium versus mycophenolate mofetil in renal transplant recipients experiencing gastrointestinal intolerance: a multicenter, double-blind, randomized study.
Two open-label studies demonstrated that conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) significantly reduces gastrointestinal (GI) symptom burden and improves GI-specific health-related quality of life. Using a randomized design, this study evaluated changes in GI symptoms and health-related quality of life in patients converted from MMF to EC-MPS versus patients who continued with MMF-based treatment. In this 4-week, multicenter, randomized, prospective, double-blind, parallel-group trial, renal transplant recipients with GI symptoms receiving MMF plus a calcineurin inhibitor ± corticosteroids were randomized to an equimolar dose of EC-MPS+MMF placebo or continue on their MMF-based regimen+EC-MPS placebo. The primary efficacy outcome was a change from baseline in total Gastrointestinal Symptom Rating Scale score of a minimally important difference of more than or equal to 0.3. Three hundred ninety-six patients (EC-MPS group: n=199; MMF group: n=197) were included. A greater proportion of EC-MPS patients (62%) reached the primary efficacy outcome compared with MMF patients (55%); however, the difference was not statistically significant (P=0.15). EC-MPS patients had a significantly greater decrease in the Gastrointestinal Symptom Rating Scale indigestion syndrome dimension versus MMF patients. Within the subgroups of patients with diabetes, patients transplanted 6 to 12 months of study enrollment, and patients on steroids, a statistically significant greater proportion of EC-MPS versus MMF patients reached the primary efficacy outcome. Conversion from MMF to EC-MPS may be associated with improvements in presence and severity of GI symptoms, particularly in patients with indigestion, diabetes, on steroids, and in patients converted between 6 and 12 months posttransplantation.


Acute kidney injury in HIV-infected children: comparison of patients according to the use of highly active antiretroviral therapy.
To assess clinical and laboratory data, and acute kidney injury (AKI) in HIV-infected children using and not using highly active antiretroviral therapy (HAART) prior to admission. A retrospective study was conducted with HIV-infected pediatric patients (<16 years). Children who were using and not using HAART prior to admission were compared. Sixty-three patients were included. Mean age was 5.3±4.27 years; 55.6% were females. AKI was observed in 33 (52.3%) children. Patients on HAART presented lower levels of potassium (3.9±0.8 vs. 4.5±0.7mEq/L, p=0.019) and bicarbonate (19.1±4.9 vs. 23.5±2.2mEq/L, p=0.013) and had a higher estimated glomerular filtration rate (102.2±36.7 vs. 77.0±32.8mL/min/1.73m2, p=0.011) than those not on HAART. In the multivariate analysis, the use of HAART prior to the admission was a protective factor for AKI (p=0.036; OR=0.30; 95% CI=0.097-0.926). AKI is a common complication of pediatric HIV infection. Use of HAART prior to the admission preserved glomerular filtration and was a protective factor for AKI, but increased medication side effects, such as hypokalemia and renal metabolic acidosis.


The H3 chaperone function of NASP is conserved in Arabidopsis.
Histones are abundant cellular proteins but, if not incorporated into chromatin, they are usually bound by histone chaperones. Here, we identify Arabidopsis NASP as a chaperone for histones H3.1 and H3.3. NASP interacts in vitro with monomeric H3.1 and H3.3 as well as with histone H3.1-H4 and H3.3-H4 dimers. However, NASP does not bind to monomeric H4. NASP shifts the equilibrium between histone dimers and tetramers towards tetramers but does not interact with tetramers in vitro. Arabidopsis NASP promotes [H3-H4]2 tetrasome formation, possibly by providing preassembled histone tetramers. However, NASP does not promote disassembly of in vitro preassembled tetrasomes. In contrast to its mammalian homolog, Arabidopsis NASP is a predominantly nuclear protein. In vivo, NASP binds mainly monomeric H3.1 and H3.3. Pulldown experiments indicated that NASP may also interact with the histone chaperone MSI1 and a HSC70 heat shock protein.


Plasma Exosomal miRNAs in Persons with and without Alzheimer Disease: Altered Expression and Prospects for Biomarkers.
To assess the value of exosomal miRNAs as biomarkers for Alzheimer disease (AD), the expression of microRNAs was measured in a plasma fraction enriched in exosomes by differential centrifugation, using Illumina deep sequencing. Samples from 35 persons with a clinical diagnosis of AD dementia were compared to 35 age and sex matched controls. Although these samples contained less than 0.1 microgram of total RNA, deep sequencing gave reliable and informative results. Twenty miRNAs showed significant differences in the AD group in initial screening (miR-23b-3p, miR-24-3p, miR-29b-3p, miR-125b-5p, miR-138-5p, miR-139-5p, miR-141-3p, miR-150-5p, miR-152-3p, miR-185-5p, miR-338-3p, miR-342-3p, miR-342-5p, miR-548at-5p, miR-659-5p, miR-3065-5p, miR-3613-3p, miR-3916, miR-4772-3p, miR-5001-3p), many of which satisfied additional biological and statistical criteria, and among which a panel of seven miRNAs were highly informative in a machine learning model for predicting AD status of individual samples with 83-89% accuracy. This performance is not due to over-fitting, because a) we used separate samples for training and testing, and b) similar performance was achieved when tested on technical replicate data. Perhaps the most interesting single miRNA was miR-342-3p, which was a) expressed in the AD group at about 60% of control levels, b) highly correlated with several of the other miRNAs that were significantly down-regulated in AD, and c) was also reported to be down-regulated in AD in two previous studies. The findings warrant replication and follow-up with a larger cohort of patients and controls who have been carefully characterized in terms of cognitive and imaging data, other biomarkers (e.g., CSF amyloid and tau levels) and risk factors (e.g., apoE4 status), and who are sampled repeatedly over time. Integrating miRNA expression data with other data is likely to provide informative and robust biomarkers in Alzheimer disease.


Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas.
Malignant astrocytomas are a deadly solid tumor in children. Limited understanding of their underlying genetic basis has contributed to modest progress in developing more effective therapies. In an effort to identify such alterations, we performed a genome-wide search for DNA copy number aberrations (CNA) in a panel of 33 tumors encompassing grade 1 through grade 4 tumors. Genomic amplifications of 10-fold or greater were restricted to grade 3 and 4 astrocytomas and included the MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13), and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26), and TP53 (17p3.1) were evident among grade 2 to 4 tumors. BRAF gene rearrangements that were indicated in three tumors prompted the discovery of KIAA1549-BRAF fusion transcripts expressed in 10 of 10 grade 1 astrocytomas and in none of the grade 2 to 4 tumors. In contrast, an oncogenic missense BRAF mutation (BRAF(V600E)) was detected in 7 of 31 grade 2 to 4 tumors but in none of the grade 1 tumors. BRAF(V600E) mutation seems to define a subset of malignant astrocytomas in children, in which there is frequent concomitant homozygous deletion of CDKN2A (five of seven cases). Taken together, these findings highlight BRAF as a frequent mutation target in pediatric astrocytomas, with distinct types of BRAF alteration occurring in grade 1 versus grade 2 to 4 tumors.


Acute effects of serotonergic antidepressants on tryptophan metabolism and corticosterone levels in rats.
The aim of present study is to see the effects of antidepressants in relation to tryptophan metabolism and disposition and to know whether they share any common mechanism of action in this regard. These are the monoamine oxidase inhibitor (moclobemide), atypical tricyclic (tianeptine), selective serotonin reuptake inhibitors (SSRIs) namely sertraline and citalopram and an herbal St John's Wort (SJW). Liver tryptophan pyrrolase activity, serum tryptophan, corticosterone and brain indoles were determined after drug administration in Albino Wistar rats at a dose of 10 mg/kg. All five antidepressants inhibited tryptophan pyrrolase activity. Serum total tryptophan concentrations were increased by 19% and 33% by tianeptine and moclobemide respectively, however 34% decrease in total tryptophan was observed after SJW administration. Free tryptophan was increased by all the drugs being maximum (65% p<0.001) by sertraline and minimum (15%, p>0.05) by tianeptine. Corticosterone levels were significantly (P<0.01) decreased by 52 and 58 percent by citalopram and St John's Wort respectively. By contrast an increase by 16% was observed by tianeptine. It was also observed that all the drugs increase brain tryptophan by 21-61 percent but increases in 5-hydroxytryptamine (5-HT) were observed only by two drugs that is moclobemide and SJW, however in comparison increases were greater (68%) after SJW administration. 5-hydroxyindoleacetic acid (5HIAA) concentrations were increased by 45-64% by all other drugs except tianeptine and moclobemide. It is concluded that attenuation of peripheral tryptophan metabolism and elevation of brain tryptophan contributes to the mechanism of action of antidepressants of different classes and pharmacological profile tested.


The Scientific Foundation for the Physical Activity Guidelines for Americans, 2nd Edition.
The 2018 Physical Activity Guidelines Advisory Committee Scientific Report provides the evidence base for the Physical Activity Guidelines for Americans, 2nd Edition. The 2018 Physical Activity Guidelines Advisory Committee addressed 38 questions and 104 subquestions selected for their public health relevance, potential to inform public policies and programs, maturity of the relevant science, and applicability to the general US population. Rigorous systematic literature searches and literature reviews were performed using standardized methods. Newly described benefits of physical activity include reduced risk of excessive weight gain in children and adults, incidence of 6 types of cancer, and fall-related injuries in older people. Physical activity is associated with enhanced cognitive function and mental health across the life span, plus improved mental health and physical function. There is no threshold that must be exceeded before benefits begin to accrue; the accrual is most rapid for the least active individuals. Sedentary time is directly associated with elevated risk of all-cause and cardiovascular mortality, incident cardiovascular disease and type 2 diabetes, and selected cancer sites. A wide range of intervention strategies have demonstrated success in increasing physical activity. The 2018 Physical Activity Guidelines Advisory Committee Scientific Report provides compelling new evidence to inform physical activity recommendations, practice, and policy.


Regional enhancement of cannabinoid CB₁ receptor desensitization in female adolescent rats following repeated Delta-tetrahydrocannabinol exposure.
Disruption of the substantial re-organization of the brain during adolescence may be induced by persistent abuse of marijuana. The aim of this study was to determine whether adolescent and adult rats exhibit differential adaptation of brain cannabinoid (CB(1)) receptors after repeated exposure to Delta(9)-tetrahydrocannabinol (THC). Rats of both ages and sexes were dosed with 10 mg kg(-1) THC or vehicle twice daily for 9.5 days. Subsequently, CB(1) receptor function and density were assessed. In all brain regions, THC treatment produced desensitization and down-regulation of CB(1) receptors. While the magnitude of down-regulation did not differ across groups, greater desensitization was evident in the brains of THC-treated female adolescent rats for most regions. Adolescent females showed greater desensitization than adult females in the prefrontal cortex, hippocampus, periaqueductal gray (PAG) and ventral midbrain. In contrast, adolescent males exhibited less desensitization in the prefrontal cortex, hippocampus and PAG, an effect opposite to that seen in females. With the exception of the PAG, sex differences were seen only in adolescents, with greater desensitization in the prefrontal cortex, striatum, hippocampus, PAG, and ventral midbrain of females. These results suggest that the brains of adolescent females may be particularly vulnerable to disruption of CB(1) receptor signalling by marijuana abuse. Alternatively, increased desensitization may reflect protective adaptation. Given the extensive re-organization of the brain during adolescence, this disruption has potential long-term consequences for maturation of the endocannabinoid system.


Cancer hallmarks in induced pluripotent cells: new insights.
Studies are beginning to emerge that demonstrate intriguing differences between human-induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). Here, we investigated the expression of key members of the Nodal embryonic signaling pathway, critical to the maintenance of pluripotency in hESCs. Western blot and real-time RT-PCR analyses reveal slightly lower levels of Nodal (a TGF-beta family member) and Cripto-1 (Nodal's co-receptor) and a dramatic decrease in Lefty (Nodal's inhibitor and TGF-beta family member) in hiPSCs compared with hESCs. The noteworthy drop in hiPSC's Lefty expression correlated with an increase in the methylation of Lefty B CpG island. Based on these findings, we addressed a more fundamental question related to the consequences of epigenetically reprogramming hiPSCs, especially with respect to maintaining a stable ESC phenotype. A global comparative analysis of 365 microRNAs (miRs) in two hiPSC versus four hESC lines ultimately identified 10 highly expressed miRs in hiPCSs with >10-fold difference, which have been shown to be cancer related. These data demonstrate cancer hallmarks expressed by hiPSCs, which will require further assessment for their impact on future therapies..


Anatomy and development of the cardiac lymphatic vasculature: Its role in injury and disease.
Lymphatic vessels are present throughout the entire body in all mammals and function to regulate tissue fluid balance, lipid transport and survey the immune system. Despite the presence of an extensive lymphatic plexus within the heart, until recently the importance of the cardiac lymphatic vasculature and its origins were unknown. Several studies have described the basic anatomy of the developing cardiac lymphatic vasculature and more recently the detailed development of the murine cardiac lymphatics has been documented, with important insight into their cellular sources during embryogenesis. In this review we initially describe the development of systemic lymphatic vasculature, to provide the background for a comparative description of the spatiotemporal development of the cardiac lymphatic vessels, including detail of both canonical, typically venous, and noncanonical (hemogenic endothelium) cellular sources. Subsequently, we address the response of the cardiac lymphatic network to myocardial infarction (heart attack) and the therapeutic potential of targeting cardiac lymphangiogenesis.


Understanding the genetics of APOE and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of Alzheimer's disease.
The methodology of Genome-Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two dozen AD GWAS studies to exclude the apolipoprotein E (APOE) region because of its extraordinary statistical support, unique thus far in complex human diseases. New genes associated with AD are proposed frequently based on SNPs associated with odds ratio (OR) < 1.2. Most of these SNPs are not located within the associated gene exons or introns but are located variable distances away. Often pathologic hypotheses for these genes are presented, with little or no experimental support. By eliminating the analyses of the APOE-TOMM40 linkage disequilibrium region, the relationship and data of several genes that are co-located in that LD region have been largely ignored. Early negative interpretations limited the interest of understanding the genetic data derived from GWAS, particularly regarding the TOMM40 gene. This commentary describes the history and problem(s) in interpretation of the genetic interrogation of the "APOE" region and provides insight into a metabolic mitochondrial basis for the etiology of AD using both APOE and TOMM40 genetics.


Altered parasite life-cycle processes characterize Babesia divergens infection in human sickle cell anemia.
Babesia divergens is an intra-erythrocytic parasite that causes malaria-like symptoms in infected people. As the erythrocyte provides the parasite with the infra-structure to grow and multiply, any perturbation to the cell should impact parasite viability. Support for this comes from the multitude of studies that have shown that the sickle trait has in fact been selected because of the protection it provides against a related Apicomplexan parasite, Plasmodium, that causes malaria. In this paper, we examine the impact of both the sickle cell anemia and sickle trait red blood cell (RBC) environment on different aspects of the B. divergens life-cycle, and reveal that multiple aspects of parasite biological processes are altered in the mutant sickle anemia RBC. Such processes include parasite population progression, caused potentially by defective merozoite infectivity and/or defective egress from the sickle cell, resulting in severely lowered parasitemia in these cells with sickle cell anemia. In contrast, the sickle trait RBC provide a supportive environment permitting in vitro infection rates comparable to those of wild-type RBC. The elucidation of these naturally occurring RBC resistance mechanisms is needed to shed light on host-parasite interaction, lend evolutionary insights into these related blood-borne parasites, and to provide new insights into the development of therapies against this disease.


Complete scrotal urinary bladder hernia with both ureters and small intestine presenting as dysuria, bilateral ureterohydronephrosis, and acute renal insufficiency.
We report a case of a complete scrotal bladder hernia with both ureters presenting as dysuria, bilateral ureterohydronephrosis, and acute renal insufficiency. A 37-year-old man with a recurrent large scrotal mass after two surgeries, suffering with small urinary symptoms as a dysuria and nocturia, was examined before the third surgery on an outpatient basis. Urological examination revealed a negative urine, bilateral large ureterohydronephrosis on USG, and serum creatinine 231-250 µmol/l. CT displayed the urinary bladder completely herniated into the scrotum with distal parts of both ureters and small intestine, and bilateral large ureterohydronephrosis. After admission to urological department on retrograde cystography a completely herniation of the urinary bladder with residual urine more than 250 ml was confirmed. A permanent catheter was indwelled. The hernia was explored with urinary bladder repositioning. Because bilateral ureteral obstruction on USG did not retreat, a bilateral percutaneous nephrostomy was done. The patient's serum creatinine markedly improved, also hernia and ureterohydronephrosis was repaired with normally moisten without residual urine (Fig. 2, Ref. 26).


Incidence of testicular germ cell tumors among US men by census region.
The incidence of testicular germ cell tumors (TGCTs) in the United States is notably higher among white men versus other men. Previously, however, it was reported that rates were rising among Hispanics in certain areas. To determine whether this finding was evident in a wider area of the United States, data from 39 US cancer registries were examined. Racial/ethnic-specific incidence rates per 100,000 man-years were calculated overall and by census region for the period of 1998-2011. Annual percentage changes (APCs) were estimated, and joinpoint models were fit. Differences in incidence by region were examined with the Wald test. From 1998 to 2011, 88,993 TGCTs were recorded. The TGCT incidence was highest among non-Hispanic whites (6.57 per 100,000), who were followed by Hispanics (3.88), American Indians/Alaska Natives (2.88), Asians/Pacific Islanders (A/PIs; 1.60), and non-Hispanic blacks (1.20). The incidence significantly increased among Hispanics (APC, 2.31; P < .0001), with rates rising in all regions except the South. Rates rose slightly among non-Hispanic whites (APC, 0.51; P = .0076). Significant differences in rates by region were seen for Hispanics (P = .0001), non-Hispanic whites (P < .0001), and A/PIs (P < .0001), with the highest rates among Hispanics in the West and with the highest rates among non-Hispanic whites and A/PIs in the Northeast. Although the incidence of TGCTs remained highest among non-Hispanic whites between 1998 and 2011, the greatest increase was experienced by Hispanics. Rising rates of TGCTs among Hispanics in the United States suggest that future attention is warranted. Reasons for the increase may include variability in birthplace, changing exposures, genetic susceptibility, and the length of US residence.


Different hereditary contribution of the CFH gene between polypoidal choroidal vasculopathy and age-related macular degeneration in Chinese Han people.
To investigate whether 11 variants in complement factor H gene contributed differently in patients with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) of Chinese descent. We performed a case-control study in a group of Chinese patients with nAMD (n = 344) or PCV (n = 368) and contrasted the results against an independent control group comprising 511 mild cataract patients without any evidence of age-related maculopathy. Association analysis of allele and genotype frequencies was performed for 11 haplotype-tagging single-nucleotide polymorphisms (SNPs) at the CFH locus (rs1061170, rs1329428, rs1410996, rs2284664, rs375396, rs529825, rs551397, rs7540032, rs800292, rs2274700, and rs1065489). Multinomial logistic regression analyses were performed to estimate and compare the effect of these 11 CFH polymorphisms on AMD and PCV, using the wild-type genotype as reference. Differences in the observed genotypic distributions between cases and controls were tested by using χ(2) tests, with age and sex adjusted for using logistic regression. CFH rs1065489 was not significantly associated with the nAMD phenotype in Chinese collections either on univariate or multivariate analysis (P > 0.05 for all comparisons). The other 10 SNPs of CFH were significantly associated with the nAMD phenotype. As for PCV, all 11 SNP markers were significantly associated with risk of PCV before or after correction for age and sex differences. Eight of the 11 SNP markers showed significant evidence of heterogeneity between AMD and PCV (P < 0.05 for all comparisons). Our data suggest that the genetic architecture at the CFH locus is complex with some markers showing significant skewing of the genotypes toward nAMD or PCV in Asians. This further supports the clinical observation that nAMD and PCV could have distinct pathogenesis mechanisms, which will require larger studies to accurately dissect.


Using more activities to address health disparities: local health departments and their "top executives".
Local health departments (LHDs) are expected to address health disparities. Little is known, however, about what factors influence the activities used by an LHD in addressing health disparities. The objective of this study was to examine factors such as an LHD's leader, jurisdiction, and organizational characteristics that could be considered to influence the approaches used within LHDs to address health disparities. We used a cross-sectional, 2-level, mixed linear model with secondary LHD data nested within states. National data were used, depicting activities conducted by LHDs. The sample consisted of the 2332 LHDs that responded to the National Association of County and City Health Officials's 2008 National Profile of LHDs Survey. The activities used by LHDs in addressing health disparities were depicted as respondents indicating that they had employed 0 to 8 types of the activities listed in the Profile Survey in relation to addressing disparities. Local health departments significantly vary in the number of types of activities used in addressing health disparities. Significant associations exist between more types of health disparities activities used by LHDs and LHDs having a "top executive" with more education, clinical training, and/or less than 5 years of experience as the LHD's top executive. Local health departments with a jurisdiction that is urban, with a higher percentage of black residents, with a higher percentage of Hispanic residents, with higher per capita LHD expenditures, and/or that has conducted a community health assessment in last 3 years were also significantly associated with higher numbers of types of health disparities activities used. Local context and the characteristics of an LHD's top executive appear to be important factors related to the activities used to address health disparities across LHDs. A focus on the competencies and development of LHD leaders may be important in promoting LHD engagement in a wider range of approaches toward reducing disparities.


Efficacy and safety of a novel combination of two oral chelators deferasirox/deferiprone over deferoxamine/deferiprone in severely iron overloaded young beta thalassemia major patients.
Minimal data are available on the combined two oral iron chelators in β-thalassemia major (β-TM). Comparison of safety, efficacy, compliance, treatment satisfaction, and quality of life (QoL) of two regimens: deferiprone (DFP) and deferoxamine (DFO) versus DFP and deferasirox (DFX) were studied. A prospective randomized trial (NCT01511848) was conducted on 96 young β-TM patients with severe iron overload. Patients were randomized to receive either DFP with DFO (arm 1) or DFP and DFX (arm 2). Efficacy endpoints were the difference between two groups in the change of serum ferritin (SF), liver iron concentration (LIC), cardiac MRI, and quality of life (QoL). In both arms, SF and LIC at 12 months were significantly lower, and geometric mean cardiac T2* was higher compared to baseline. On regression analysis of change in each studied variable against time, significant difference between slopes of the two groups regarding cardiac T2* (P = 0.001 with more improvement in DFP/DFX patients) was found with no significant difference in the slopes of SF and LIC (P = 0.218 and 0.340). Both iron chelation combination regimens were equally effective in reducing iron overload and improving QoL.DFP/DFX combination proved superior in improving cardiac T2*, treatment compliance, and patients satisfaction with no greater adverse events.


Venlafaxine in Embryos Stimulates Neurogenesis and Disrupts Larval Behavior in Zebrafish.
Venlafaxine, a widely prescribed antidepressant, is a selective serotonin and norepinephrine reuptake inhibitor in humans, and this drug is prevalent in municipal wastewater effluents. While studies have shown that this drug affects juvenile fish behavior, little is known about the developmental impact on nontarget aquatic animals. We tested the hypothesis that venlafaxine deposition in the egg, mimicking maternal transfer of this antidepressant, disrupts developmental programming using zebrafish (Danio rerio) as a model. Embryos (1-4 cell stage) were microinjected with either 1 or 10 ng venlafaxine, which led to a rapid reduction (90%) of this drug in the embryo at hatch. There was a concomitant increase in the concentration of the major metabolite o-desmethylvenlafaxine during the same period. Embryonic exposure to venlafaxine accelerated early development, increased hatching rate and produced larger larvae at 5 days post fertilization. Also, there was an increase in neuronal birth in the hypothalamus, dorsal thalamus, posterior tuberculum, and the preoptic region, and this corresponded with a higher spatial expression of nrd4, a key marker of neurogenesis. The venlafaxine-exposed larvae were less active and covered shorter distance in a light and dark behavioral test compared to the controls. Overall, zygotic exposure to venlafaxine disrupts early development, including brain function, and compromises larval behavior, suggesting impact of this drug on developmental programming in zebrafish.


Surgical outcomes of robotic transanal minimally invasive surgery for selected rectal neoplasms: A single-hospital experience.
Rectal neoplasm is one of the most common malignancies worldwide. Screening programs for rectal neoplasm result in early diagnosis and a decrease in disease-related mortality and morbidity. In selected patients, early rectal cancer may be treated with local excision. Owing to poor exposure during conventional transanal excision, transanal minimally invasive surgery (TAMIS) was developed, and TAMIS is feasible for the local excision of selected rectal neoplasms. However, the limited range of motion is a major disadvantage of this operation. Therefore, robotic TAMIS was developed to resolve this issue. This paper describes the surgical outcomes of robotic TAMIS for selected rectal tumors. The eligibility criteria for robotic TAMIS were as follows: benign neoplasms, early malignancy, complete remission after concurrent chemoradiotherapy, lesions located in the middle or lower rectum, and a lesion size of less than 5 cm. To gain access to the anal canal, a transanal access platform was used, and the da Vinci robotic system was mounted for surgery. Patient characteristics and surgical outcomes were recoded. A total of 23 patients were included, and the median tumor size was 2.5 cm (range: 1.1-4.5 cm) on average. The median tumor location was 5 cm (range: 2-8 cm) from the anal verge. The median length of hospital stay was 3 days (range: 1-10 days). No intraoperative complications were reported, and no patient readmission occurred. The median follow-up period was 9.6 months. No recurrent lesion was found in the follow-up period. Based on the short-term results, robotic TAMIS is a feasible and safe technique for the local excision of selected rectal neoplasms.


Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations.
American Indian-Europeans, Asians, and African Americans have an excess morbidity from systemic lupus erythematosus (SLE) and a higher prevalence of lupus nephritis than do Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and sociodemographic characteristics and clinical features in a large cohort of American Indian-European SLE patients. A total of 2,116 SLE patients of American Indian-European origin and 4,001 SLE patients of European descent for whom we had clinical data were included in the study. Genotyping of 253 continental ancestry-informative markers was performed on the Illumina platform. Structure and Admixture software were used to determine genetic ancestry proportions of each individual. Logistic regression was used to test the association between genetic ancestry and sociodemographic and clinical characteristics. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). The average American Indian genetic ancestry of 2,116 SLE patients was 40.7%. American Indian genetic ancestry conferred increased risks of renal involvement (P < 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P < 0.0001). American Indian ancestry protected against photosensitivity (P < 0.0001, OR 0.58 [95% CI 0.44-0.76]), oral ulcers (P < 0.0001, OR 0.55 [95% CI 0.42-0.72]), and serositis (P < 0.0001, OR 0.56 [95% CI 0.41-0.75]) after adjustment for age, sex, and age at onset. However, age and sex had stronger effects than genetic ancestry on malar rash, discoid rash, arthritis, and neurologic involvement. In general, American Indian genetic ancestry correlates with lower sociodemographic status and increases the risk of developing renal involvement and SLE at an earlier age.


[Frequency of the most common mutations of the CFTR gene in peruvian patients with cystic fibrosis using the ARMS-PCR technique].
To determine the frequency of the ten most common mutations of the CFTR gene reported in Latin Americausing amplification-refractory mutation system-polymerase chain reaction (ARMS-PCR) in patients with cystic fibrosis (CF) in two referral hospitals in Peru during the year 2014. The frequency of the ten most common mutations of the CFTR gene was assessed in patients of the Hospital Nacional Edgardo Rebagliati Martins and the Instituto Nacional de Salud del Niño, both located in Lima, Peru. Blood samples were collected from 36 patients with CF, and the ARMS-PCR technique was used to determine the presence of these mutations. The study group included 73.5% of patients with a known diagnosis of CF in the country when the study was carried out. ARMS-PCR allowed three of the mutations to be identified in a combined 30.6% of the alleles from patients with CF, and 64.9% of the mutated alleles were not identified. The mutations found were p.Phe508del (22,2%), p.Gly542* (6,9%), and p.Arg1162* (1,4%). There is significant variability in both the frequency and type of mutations present in our study population and in what has been reported in other Latin American countries. It is necessary to perform studies that use complete sequencing technology for the CFTR gene to identify other mutations present in our population.


Esculetin Ameliorates Psoriasis-Like Skin Disease in Mice by Inducing CD4+Foxp3+ Regulatory T Cells.
Psoriasis is an autoimmune and inflammatory skin disease affecting around 2-3% of the world's population. Patients with psoriasis need extensive treatments with global immunosuppressive agents that may cause severe side effects. Esculetin, a type of coumarins, is an active ingredient extracted mainly from the bark of Fraxinus rhynchophylla, which has been used to treat inflammatory and autoimmune diseases in China. However, the antipsoriatic effects of esculetin have not been reported. In this study, we aimed to investigate the effects of esculetin on psoriatic skin inflammation in a mouse model and explored the potential molecular mechanisms underlying its action. We found that esculetin ameliorated the skin lesion and reduced PASI scores as well as weight loss in imiquimod-induced psoriasis-like mice, accompanied with weakened proliferation and differentiation of keratinocytes and T cell infiltration in esculetin-treated psoriatic mice. In addition, esculetin reduced the frequency of CD8+CD44highCD62Llow effector T cells in psoriatic mice. In contrast, it increased the frequency of CD4+Foxp3+ Tregs in both lymph nodes and spleens of the psoriatic mice while promoting the differentiation of CD4+CD25- T cells into CD4+Foxp3+ Tregs in vitro. Interestingly, depleting CD4+Foxp3+ Tregs largely reversed esculetin-mediated reduction in PASI scores, indicating that esculetin attenuates murine psoriasis mainly by inducing CD4+Foxp3+ Tregs. Furthermore, the mRNA levels of proinflammatory cytokines in the psoriatic mouse skin, including IL-6, IL-17A, IL-22, IL-23, TNF-α, and IFN-γ, were dramatically decreased by the treatment with esculetin. Finally, we found that esculetin inhibited the phosphorylation of IKKα and P65 in the psoriatic skin, suggesting that it inhibits the activation of NF-κB signaling. Thus, we have demonstrated that esculetin attenuates psoriasis-like skin lesion in mice and may be a potential therapeutic candidate for the treatment of psoriasis in clinic.


Salt-sensitive blood pressure in mice with increased expression of aldosterone synthase.
To study the effects of modestly increased expression of aldosterone synthase (AS), we generated mice (AS(hi/hi)) by replacing the 3' untranslated region of AS mRNA with that from a stable mRNA. AS(hi/hi) mice on a normal-salt diet had 1.5 times the wild-type AS mRNA in adrenals, although their blood pressure and plasma aldosterone did not differ from wild-type mice. Changes in dietary salt did not affect the blood pressure of wild-type mice, but AS(hi/hi) mice had approximately 10-mm Hg higher blood pressure on a high-salt diet than on a low-salt diet and than wild-type mice on either diet. The AS(hi/hi) mice on a high-salt diet also had higher plasma aldosterone, lower plasma potassium, and greater renal expression of the alpha subunit of epithelial sodium channel compared with wild-type mice. The AS(hi/hi) mice on a high-salt diet also had more water intake and urine volume and less urine osmolality than wild-type mice. On a low-salt diet, AS(hi/hi) mice maintained normal blood pressure with less activation of the renin-angiotensin-aldosterone system than wild-type mice. The AS(hi/hi) mice also had less water intake and urine volume and higher urine osmolality than wild-type mice. On a medium high-salt diet, AS(hi/hi) mice were more susceptible than wild-type mice to infusion of angiotensin II, having a higher blood pressure, greater cardiac hypertrophy, and increased oxidative stress. Thus, a modest increase in AS expression makes blood pressure more sensitive to salt, suggesting that genetically increased AS expression in humans may contribute to hypertension and cardiovascular complications in societies with high-salt diets.


Real-time speckle variance swept-source optical coherence tomography using a graphics processing unit.
Advances in swept source laser technology continues to increase the imaging speed of swept-source optical coherence tomography (SS-OCT) systems. These fast imaging speeds are ideal for microvascular detection schemes, such as speckle variance (SV), where interframe motion can cause severe imaging artifacts and loss of vascular contrast. However, full utilization of the laser scan speed has been hindered by the computationally intensive signal processing required by SS-OCT and SV calculations. Using a commercial graphics processing unit that has been optimized for parallel data processing, we report a complete high-speed SS-OCT platform capable of real-time data acquisition, processing, display, and saving at 108,000 lines per second. Subpixel image registration of structural images was performed in real-time prior to SV calculations in order to reduce decorrelation from stationary structures induced by the bulk tissue motion. The viability of the system was successfully demonstrated in a high bulk tissue motion scenario of human fingernail root imaging where SV images (512 × 512 pixels, n = 4) were displayed at 54 frames per second.


Suicide in later life: psychological autopsy findings.
The authors report preliminary data from a psychological autopsy study of completed suicide in late life. Sixteen of 18 victims had diagnosable psychopathology, most commonly major depression of late onset. Symptoms manifest prior to death are described and directions for future investigation discussed. The psychological autopsy is shown to be a viable method for studying suicide in the elderly.


The Hippocratic Method for the Reduction of the Mandibular Dislocation, an Ancient Greek Procedure Still in Use in Maxillofacial Surgery.
Mandibular dislocation remains an acute medical condition in maxillofacial surgery. Since the Hippocratic era its reduction has been performed exactly in the same way it is now performed in modern surgery. We report an example of an elderly female patient with bilateral mandibular dislocation, who came to our department and was treated under sedation using the Hippocratic bimanual intraoral technique by two medical personnel, depicting the timeless usage of the method. Although some characteristics of the procedure were wrongfully attributed to others, such as Barton and Lewis, after a thorough examination of the ancient Greek medical texts, its originality should in fact be attributed solely to the Hippocratic School of Medicine. Furthermore, we recommend the use of the term "mandibular dislocation" instead of the "temporomandibular joint dislocation", as a more accurate medical definition.


TIRAP: an adapter molecule in the Toll signaling pathway.
Mammalian Toll-like receptors (TLRs) recognize conserved products of microbial metabolism and activate NF-kappa B and other signaling pathways through the adapter protein MyD88. Although some cellular responses are completely abolished in MyD88-deficient mice, TLR4, but not TLR9, can activate NF-kappa B and mitogen-activated protein kinases and induce dendritic cell maturation in the absence of MyD88. These differences suggest that another adapter must exist that can mediate MyD88-independent signaling in response to TLR4 ligation. We have identified and characterized a Toll-interleukin 1 receptor (TIR) domain-containing adapter protein (TIRAP) and have shown that it controls activation of MyD88-independent signaling pathways downstream of TLR4. We have also shown that the double-stranded RNA-binding protein kinase PKR is a component of both the TIRAP- and MyD88-dependent signaling pathways.


A silent acute abdomen in a patient with spinal cord injury.
A 52-year-old man with cervical spondylosis sustained a hyperextension injury to the neck and subsequently developed central cord syndrome after 2 weeks. The diagnosis was confirmed clinically and on MRI. During the admission he was febrile from Streptococcus anginosus bacteraemia from a gum infection and was started on penicillin. This resulted in pseudomembranous colitis with abdominal distension and bloody diarrhoea but a lack of expected abdominal complaints. Unfortunately his neurology deteriorated and a repeat MRI showed a discitis at C5-C7 which required a 2-level discectomy, debridement and instrumented fusion. Owing to his spinal cord injury, an abdominal perforation was initially missed owing to the lack of clinical features of an acute abdomen. He underwent a right hemi-colectomy for ascending colon perforation and eventually made a good recovery and was discharged to a spinal rehabilitation unit. By one year follow-up he had returned to full neurological function.


Growth-dependent accumulation of monoalkylglycerol in Madin-Darby canine kidney cells. Evidence for a role in the regulation of protein kinase C.
1-O-Alkyl-sn-glycerol (alkylglycerol) forms the backbone of complex ether-linked glycerolipids, including biologically active lipids such as platelet-activating factor. Synthetic alkylglycerol itself possesses several potent pharmacological activities and has been shown to inhibit protein kinase C (PKC) in vitro. In spite of these properties, free alkylglycerol has been regarded only as a potential product of the inflammatory degradation of complex ether lipids rather than a natural cell constituent. To explore the possibility that endogenous alkylglycerol functions as a physiological regulator in normal cells, we measured its content, along with related monoglycerides and diglycerides, by high performance liquid chromatography and gas-liquid chromatography in Madin-Darby canine kidney (MDCK) cells. The content of free alkylglycerol increased up to 20-fold during the growth of MDCK cell cultures to a confluent density. The increase was greatest during the log phase of growth, in which the content of alkylglycerol rose from 6.0 +/- 1.3 nmol/10(8) cells in preconfluent cultures to 23.6 +/- 3.4 nmol/10(8) cells in confluent cultures. Analysis of the molecular species of alkylglycerol showed that the higher content in quiescent MDCK cells was due primarily to an increase in 1-O-octadecyl-sn-glycerol. In contrast, the levels of monoacylglycerol and the PKC activator diacylglycerol were lower in confluent, quiescent cultures than in preconfluent, proliferating cultures. A similar pattern of changes in the monoglyceride and diglyceride content was observed in interleukin-3-dependent CFTL-12 mast cells when cell proliferation was blocked by growth factor withdrawal. Growth of MDCK cells to a confluent density resulted in a decrease in particulate PKC enzyme activity to a level that was only 6% of that in proliferating cells. To explore whether the accumulation of cellular alkylglycerol contributes to growth-dependent changes in PKC activity, we examined the effects of adding alkylglycerol to the activity and subcellular distribution of the enzyme in MDCK cells. Treatment of cells with 1-O-dodecyl-sn-glycerol resulted in a decrease in the activity of membrane-associated PKC activity and inhibited 12-O-tetradecanoylphorbol-13-acetate-stimulated translocation of PKC from the cytosol to the membrane fraction. Alkylglycerol was also shown to inhibit the activity of purified PKC in vitro when present at levels similar to that of the diacylglycerol activator. We propose that the accumulation of alkylglycerol during the growth of MDCK cells to a confluent density contributes to the decrease in PKC activity. The control of cellular alkylglycerol levels may be a novel mechanism for the regulation of cellular physiology.


Low-dose computed tomography for lung cancer screening in high-risk populations: a systematic review and economic evaluation.
Diagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early. To estimate the clinical effectiveness and cost-effectiveness of LDCT lung cancer screening in high-risk populations. Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library. Clinical effectiveness - a systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programmes [such as chest X-ray (CXR)] was conducted. Bibliographic sources included MEDLINE, EMBASE, Web of Science and The Cochrane Library. Meta-analyses, including network meta-analyses, were performed. Cost-effectiveness - an independent economic model employing discrete event simulation and using a natural history model calibrated to results from a large RCT was developed. There were 12 different population eligibility criteria and four intervention frequencies [(1) single screen, (2) triple screen, (3) annual screening and (4) biennial screening] and a no-screening control arm. Clinical effectiveness - 12 RCTs were included, four of which currently contribute evidence on mortality. Meta-analysis of these demonstrated that LDCT, with ≤ 9.80 years of follow-up, was associated with a non-statistically significant decrease in lung cancer mortality (pooled relative risk 0.94, 95% confidence interval 0.74 to 1.19). The findings also showed that LDCT screening demonstrated a non-statistically significant increase in all-cause mortality. Given the considerable heterogeneity detected between studies for both outcomes, the results should be treated with caution. Network meta-analysis, including six RCTs, was performed to assess the relative clinical effectiveness of LDCT, CXR and usual care. The results showed that LDCT was ranked as the best screening strategy in terms of lung cancer mortality reduction. CXR had a 99.7% probability of being the worst intervention and usual care was ranked second. Cost-effectiveness - screening programmes are predicted to be more effective than no screening, reduce lung cancer mortality and result in more lung cancer diagnoses. Screening programmes also increase costs. Screening for lung cancer is unlikely to be cost-effective at a threshold of £20,000/quality-adjusted life-year (QALY), but may be cost-effective at a threshold of £30,000/QALY. The incremental cost-effectiveness ratio for a single screen in smokers aged 60-75 years with at least a 3% risk of lung cancer is £28,169 per QALY. Sensitivity and scenario analyses were conducted. Screening was only cost-effective at a threshold of £20,000/QALY in only a minority of analyses. Clinical effectiveness - the largest of the included RCTs compared LDCT with CXR screening rather than no screening. Cost-effectiveness - a representative cost to the NHS of lung cancer has not been recently estimated according to key variables such as stage at diagnosis. Certain costs associated with running a screening programme have not been included. LDCT screening may be clinically effective in reducing lung cancer mortality, but there is considerable uncertainty. There is evidence that a single round of screening could be considered cost-effective at conventional thresholds, but there is significant uncertainty about the effect on costs and the magnitude of benefits. Clinical effectiveness and cost-effectiveness estimates should be updated with the anticipated results from several ongoing RCTs [particularly the NEderlands Leuvens Longkanker Screenings ONderzoek (NELSON) screening trial]. This study is registered as PROSPERO CRD42016048530. The National Institute for Health Research Health Technology Assessment programme.


The extracellular chaperone clusterin influences amyloid formation and toxicity by interacting with prefibrillar structures.
Clusterin is an extracellular chaperone present in all disease-associated extracellular amyloid deposits, but its roles in amyloid formation and protein deposition in vivo are poorly understood. The current study initially aimed to characterize the effects of clusterin on amyloid formation in vitro by a panel of eight protein substrates. Two of the substrates (Alzheimer's beta peptide and a PI3-SH3 domain) were then used in further experiments to examine the effects of clusterin on amyloid cytotoxicity and to probe the mechanism of clusterin action. We show that clusterin exerts potent effects on amyloid formation, the nature and extent of which vary greatly with the clusterin:substrate ratio, and provide evidence that these effects are exerted via interactions with prefibrillar species that share common structural features. Proamyloidogenic effects of clusterin appear to be restricted to conditions in which the substrate protein is present at a very large molar excess; under these same conditions, clusterin coincorporates with substrate protein into insoluble aggregates. However, when clusterin is present at much higher but still substoichiometric levels (e.g., a molar ratio of clusterin:substrate=1:10), it potently inhibits amyloid formation and provides substantial cytoprotection. These findings suggest that clusterin is an important element in the control of extracellular protein misfolding.


Alterations in sarcomere function modify the hyperplastic to hypertrophic transition phase of mammalian cardiomyocyte development.
It remains unclear how perturbations in cardiomyocyte sarcomere function alter postnatal heart development. We utilized murine models that allowed manipulation of cardiac myosin-binding protein C (MYBPC3) expression at critical stages of cardiac ontogeny to study the response of the postnatal heart to disrupted sarcomere function. We discovered that the hyperplastic to hypertrophic transition phase of mammalian heart development was altered in mice lacking MYBPC3 and this was the critical period for subsequent development of cardiomyopathy. Specifically, MYBPC3-null hearts developed evidence of increased cardiomyocyte endoreplication, which was accompanied by enhanced expression of cell cycle stimulatory cyclins and increased phosphorylation of retinoblastoma protein. Interestingly, this response was self-limited at later developmental time points by an upregulation of the cyclin-dependent kinase inhibitor p21. These results provide valuable insights into how alterations in sarcomere protein function modify postnatal heart development and highlight the potential for targeting cell cycle regulatory pathways to counteract cardiomyopathic stimuli.


Effects of voice harmonic complexity on ERP responses to pitch-shifted auditory feedback.
The present study investigated the neural mechanisms of voice pitch control for different levels of harmonic complexity in the auditory feedback. Event-related potentials (ERPs) were recorded in response to+200 cents pitch perturbations in the auditory feedback of self-produced natural human vocalizations, complex and pure tone stimuli during active vocalization and passive listening conditions. During active vocal production, ERP amplitudes were largest in response to pitch shifts in the natural voice, moderately large for non-voice complex stimuli and smallest for the pure tones. However, during passive listening, neural responses were equally large for pitch shifts in voice and non-voice complex stimuli but still larger than that for pure tones. These findings suggest that pitch change detection is facilitated for spectrally rich sounds such as natural human voice and non-voice complex stimuli compared with pure tones. Vocalization-induced increase in neural responses for voice feedback suggests that sensory processing of naturally-produced complex sounds such as human voice is enhanced by means of motor-driven mechanisms (e.g. efference copies) during vocal production. This enhancement may enable the audio-vocal system to more effectively detect and correct for vocal errors in the feedback of natural human vocalizations to maintain an intended vocal output for speaking.


Cyp2c44 gene disruption exacerbated pulmonary hypertension and heart failure in female but not male mice.
Epoxyeicosatrienoicacids (EETs), synthesized from arachidonic acid by epoxygenases of the CYP2C and CYP2J gene subfamilies, contribute to hypoxic pulmonary vasoconstriction (HPV) in mice. Despite their roles in HPV, it is controversial whether EETs mediate or ameliorate pulmonary hypertension (PH). A recent study showed that deficiency of Cyp2j did not protect male and female mice from hypoxia-induced PH. Since CYP2C44 is a functionally important epoxygenase, we hypothesized that knockout of the Cyp2c44 gene would protect both sexes of mice from hypoxia-induced PH. We tested this hypothesis in wild-type (WT) and Cyp2c44 knockout (Cyp2c44 (-/-)) mice exposed to normoxia (room air) and hypoxia (10% O2) for 5 weeks. Exposure of WT and Cyp2c44 (-/-) mice to hypoxia resulted in pulmonary vascular remodeling, increased pulmonary artery resistance, and decreased cardiac function in both sexes. However, in female Cyp2c44 (-/-) mice, compared with WT mice, (1) pulmonary artery resistance and right ventricular hypertrophy were greater, (2) cardiac index was lower, (3) left ventricular and arterial stiffness were higher, and (4) plasma aldosterone levels were higher, but (5) there was no difference in levels of EET in lungs and heart. Paradoxically and unexpectedly, we found that Cyp2c44 disruption exacerbated hypoxia-induced PH in female but not male mice. We attribute exacerbated PH in female Cyp2c44 (-/-) mice to elevated aldosterone and as-yet-unknown systemic factors. Therefore, we suggest a role for the human CYP2C genes in protecting women from severe PH and that this could be one of the underlying causes for a better 5-year survival rate in women than in men.


Age- and gender-related ventricular-vascular stiffening: a community-based study.
Increases in vascular (Ea), ventricular systolic (Ees), and ventricular diastolic (Ed) elastance (stiffness) may contribute to the pathogenesis of heart failure (HF) with preserved ejection fraction (HFnlEF). The prevalence of HFnlEF increases strikingly with age, particularly in women. We hypothesized that ventricular-vascular stiffening may occur with age and be more pronounced in women in the general community. In a cross-sectional sample of Olmsted County, Minn, residents > or =45 years old (n=2042), clinical data, Doppler echocardiography, and blood pressure (BP) measurements were obtained. Ea was calculated from stroke volume and systolic BP and indexed to body size (EaI). Ees was calculated by a modified single-beat method using systolic and diastolic BP, stroke volume, ejection fraction, timing intervals, and an estimated normalized ventricular elastance at arterial end diastole. Operant Ed was calculated from Doppler indices reflective of atrial pressures and the diastolic filling volume. EaI, Ees, and Ed all increased with age in men and in women (P<0.0001 for all). Ees increased more steeply with age in women (P=0.002). Adjusted for age, EaI, Ees, and Ed were higher in women than in men (P<0.0001 for all). Findings were similar in those without known or suspected cardiovascular disease (n=623). In the community, advancing age and female gender are associated with increases in vascular and ventricular systolic and diastolic stiffness even in the absence of cardiovascular disease. We speculate that this combined ventricular-vascular stiffening may contribute to the increased prevalence of HFnlEF in elderly persons and particularly in elderly women.


Incremental costs of enrolling cancer patients in clinical trials: a population-based study.
Payment for care provided as part of clinical research has become less predictable as a result of managed care. Because little is known at present about how entry into cancer trials affects the cost of care for cancer patients, we conducted a matched case-control comparison of the incremental medical costs attributable to participation in cancer treatment trials. Case patients were residents of Olmsted County, MN, who entered phase II or phase III cancer treatment trials at the Mayo Clinic from 1988 through 1994. Control patients were patients who did not enter trials but who were eligible on the basis of tumor registry matching and medical record review. Sixty-one matched pairs were followed for up to 5 years after the date of trial entry for case patients or from an equivalent date for control patients. Hospital, physician, and ancillary service costs were estimated from a population-based cost database developed at the Mayo Clinic. Trial enrollees incurred modestly (no more than 10%) higher costs over various follow-up periods. The mean cumulative 5-year cost in 1995 inflation-adjusted U.S. dollars among trial enrollees after adjustment for censoring was $46424 compared with $44 133 for control patients. After 1 year, trial enrollee costs were $24645 compared with $23 964 for control patients. This study suggests that cancer chemotherapy trials may not imply budget-breaking costs. Cancer itself is a high-cost illness. Clinical protocols may add relatively little to that cost.


Quantifying mRNA synthesis and decay rates using small RNAs.
Regulation of mRNA decay is a critical component of global cellular adaptation to changing environments. The corresponding changes in mRNA lifetimes can be coordinated with changes in mRNA transcription rates to fine-tune gene expression. Current approaches for measuring mRNA lifetimes can give rise to secondary effects due to transcription inhibition and require separate experiments to estimate changes in mRNA transcription rates. Here, we propose an approach for simultaneous determination of changes in mRNA transcription rate and lifetime using regulatory small RNAs (sRNAs) to control mRNA decay. We analyze a stochastic model for coupled degradation of mRNAs and sRNAs and derive exact results connecting RNA lifetimes and transcription rates to mean abundances. The results obtained are then generalized to include nonstoichiometric coupled degradation of sRNAs. Our analysis suggests experimental protocols for determining parameters controlling the efficiency of stoichiometric regulation by small RNAs and for analyzing factors and processes regulating changes in mRNA transcription and decay.


Neoantigen-specific CD4+ T-cell response is critical for the therapeutic efficacy of cryo-thermal therapy.
Traditional tumor thermal ablations, such as radiofrequency ablation (RFA) and cryoablation, can result in good local control of tumor, but traditional tumor thermal ablations are limited by poor long-term survival due to the failure of control of distal metastasis. Our previous studies developed a novel cryo-thermal therapy to treat the B16F10 melanoma mouse model. Long-term survival and T-cell-mediated durable antitumor immunity were achieved after cryo-thermal therapy, but whether tumor antigen-specific T-cells were augmented by cryo-thermal therapy was not determined. The long-term antitumor therapeutic efficacy of cryo-thermal therapy was performed in B16F10 murine melanoma models. Splenocytes derived from mice treated with RFA or cryo-thermal therapy were coincubated with tumor antigen peptides to detect the frequency of antigen specific CD4+ and CD8+ T-cells by flow cytometry. Splenocytes were then stimulated and expanded by αCD3 or peptides and adoptive T-cell therapy experiments were performed to identify the antitumor efficacy of T-cells induced by RFA and cryo-thermal therapy. Naïve mice and tumor-bearing mice were used as control groups. Local cryo-thermal therapy generated a stronger systematic antitumor immune response than RFA and a long-lasting antitumor immunity that protected against tumor rechallenge. In vitro studies showed that the antigen-specific CD8+ T-cell response was induced by both cryo-thermal therapy and RFA, but the strong neoantigen-specific CD4+ T-cell response was only induced by cryo-thermal therapy. Cryo-thermal therapy-induced strong antitumor immune response was mainly mediated by CD4+ T-cells, particularly neoantigen-specific CD4+ T-cells. Cryo-thermal therapy induced a stronger and broader antigen-specific memory T-cells. Specifically, cryo-thermal therapy, but not RFA, led to a strong neoantigen-specific CD4+ T-cell response that mediated the resistance to tumor challenge.


Development of a Preliminary Question Prompt List as a Communication Tool for Adults With Gastroesophageal Reflux Disease: A Modified Delphi Study.
Question prompt lists (QPLs) are structured sets of disease-specific questions intended for patient use, encouraging patients to ask questions to facilitate their consultation with their physician. The aim of this study was to develop a QPL specific to adults with gastroesophageal reflux disease (GERD), created by esophageal experts. The QPL content (78 questions) was derived through a modified Delphi method consisting of 2 rounds. In round 1, 18 esophageal experts provided 5 answers to the prompt "What you wish your patients would ask" and "What questions do patients often not ask, that I wish they would ask?" In round 2, the experts rated each question on a 5-point Likert scale, and responses rated as "essential" or "important," determined by an a priori threshold of ≥4.0, were accepted for the QPL. Twelve esophageal experts participated. Of 143 questions from round 1, 110 (76.9%) were accepted for inclusion in the QPL, meeting a median value of ≥4.0, and, subsequently, it reduced to 78, minimizing redundancy. Median values ranged between 4.0 and 5.0, with the highest agreement median (5.0) for questions asking dosing and timing of proton pump inhibitor therapy, and surveillance in Barrett's. Questions were categorized into the following categories: "What does this illness mean," "lifestyle modifications," "general treatment," "treatment with proton pump inhibitors," "What I should expect for my future," and "Barrett's." The largest number of questions covered lifestyle modifications (21.8%), with the highest agreement median (5.0) for "How helpful are lifestyle modifications in GERD?" A preliminary GERD-specific QPL, the first of its kind, was developed by esophageal experts. Modification after more patient consultation and feedback is planned in subsequent versions to create a GERD-QPL for eventual use in clinical gastroenterology.


Germanane synthesis with simultaneous covalent functionalization: towards highly functionalized fluorescent germananes.
Monoelemental 2D-materials beyond graphene are attracting great attention. Although monolayer graphene or phosphorene can be prepared from its layered 3D form, graphite or black phosphorus, by exfoliation of a large van der Waals crystal, this route is not suitable for the preparation of 2D-germanene based materials due to the crystal structure and chemical properties of germanium. Unlike graphene or phosphorene, these materials are prepared by chemical exfoliation from bulk Zintl phases - here represented by calcium germanide. We describe the exfoliation and subsequent modification of calcium germanide, which yields layered germanium materials with alkyl or aryl groups. Different organic functional groups covalently attached to layered germanane exhibit a very intense fluorescence in the blue region, which makes them prospective materials for further application in optoelectronic devices. The described procedure for covalently functionalized germananes represents the way for the production of these materials.


Selective generation of ultracold high-density 1s orthoexcitons in Cu2O with phase-modulated pulse using acousto-optic programmable filter.
Ultracold and high-density 1s orthoexcitons in semiconductor cuprous oxide are prepared via resonant two-photon absorption of a phase-tailored femtosecond pulse, by utilizing an acousto-optic programmable dispersive filter. The stability of the quantum degenerate exciton gas is studied using excitonic Lyman spectroscopy. A density of 10(16) cm(-3) is realized without creating hot carriers, and the Lyman spectrum remains unchanged at this density. This result assures the stability of a spontaneous Bose-Einstein condensate of excitons at sub-Kelvin temperatures.


Restraint of dogs in vehicles in the US, UK and Australia.
Although dogs routinely travel in motor vehicles, there is a lack of evidence on if, how, and why people choose to restrain their dogs when travelling. A lack of restraint is likely to be associated with an increased risk of serious injury or death in the case of an accident, and in some cases may even precipitate an accident. The aim of the present study was to determine the frequency in which dog restraints are used in the US, UK and Australia in a convenience sample, and the factors associated with whether or not a dog is restrained. Online surveys using SurveyMonkey® were distributed in the US, UK and Australia during 2017-2018. The survey consisted of questions related to owning a dog, owner and dog demographics, use of restraint when driving with the dog, reasons for restraining/not restraining the dog, and attitudes to restraint of dogs in vehicles. A logistic regression was used to determine factors associated with the use of restraint. There were 706, 692 and 637 completed surveys from the US, UK and Australia, respectively. A little over half of respondents restrained their dog in the US (55%) compared to 67% in Australia and 72% in the UK. The most common method of restraint in the US and UK was a cage/crate in the cargo area in the back of the vehicle; in Australia it was a harness and tether attached to a seat buckle. In the generalised linear model, country, dog size, owner age, dog age and vehicle type were all significant factors associated with the use of restraint for dogs in cars. Younger dog owners from the US who drove a pickup truck or utility van, had a large dog, and drove with their dogs less frequently were least likely to restrain their dogs. This research highlights the need for improved education and information regarding the use of restraints for dogs traveling in vehicles, although the limitations in the convenience sample used mean further research is needed, including use of a more representative sample.


Genistein protects female nonobese diabetic mice from developing type 1 diabetes when fed a soy- and alfalfa-free diet.
The objective of this study was to determine the effects of the phytoestrogen genistein (GEN) on the time of onset and/or the incidence of type 1 diabetes (T1D) in female nonobese diabetic (NOD) mice, when administered GEN by gavage once every day for up to 180 days. Five groups of mice (approximately 24 animals/group; 6-7 weeks of age) were included: naive control, vehicle control (25 mM Na2CO3 in water), and 3 GEN treatment groups (2 mg/kg, 6 mg/kg, and 20 mg/kg). Mice were maintained on a soy- and alfalfa-free diet (5K96) during the study and were monitored for blood glucose changes every week. When compared to the vehicle control, exposure to 2-mg/kg GEN produced significant decreases ranging from 55 to 79% in the total incidences of diabetes (blood glucose ≥ 250 mg/dl) and severe diabetes (blood glucose ≥ 400 mg/dl) starting at week 14 of the study. However, during the later stages of the study (i.e., after week 23), the 2-mg/kg dose had no effect on disease incidence. In animals treated with 6-mg/kg and 20-mg/kg GEN, significant decreases in the total incidence of diabetes were observed starting at week 16, while the incidence of severe diabetes was significantly decreased with the changes being observed initially at weeks 18 and 17 for the 6-mg/kg and 20-mg/kg GEN treatment groups, respectively. Several lines of evidence, including histopathological analysis, suggested that GEN protected the pancreas from autoimmune destruction. However, this protective effect of GEN was absent when female NOD mice were maintained on NTP-2000 rodent diet, which contained 5% soybean meal and 7.5% alfalfa meal (the total concentrations of phytoestrogens ranged between 95 and 134 mg/kg). In summary, oral dosing of GEN reduced the incidence and increased the time to onset of T1D in female NOD mice but only when fed a soy- and alfalfa-free diet.


Implementation of a teaching programme to improve doctors' awareness of DVLA guidelines: a multicentre study.
Over half of the UK population holds a driver's licence. Driver and Vehicle Licensing Authority (DVLA) guidelines are available for conditions from most specialties. Despite this, no focused training occurs in the undergraduate or postgraduate setting. We evaluate the impact of a teaching programme to improve guideline awareness. A 25-point questionnaire was designed using the current DVLA guidelines. Five questions were included for the following fields: neurology, cardiology, drug and alcohol abuse, visual disorders and respiratory. This was distributed to doctors in training at five hospitals. Four weeks later, a single-session teaching programme was implemented. The questionnaire was redistributed. Preintervention and postintervention scores were compared using the Wilcoxon rank sum test. 139 preteaching and 144 post-teaching questionnaires were completed. Implementation of a single-session teaching programme significantly improved the knowledge of DVLA guidelines in all five areas explored. Median scores: neurology, preteaching 40%, post-teaching 100%, p<0.001; cardiology, 0%, 100%, p<0.001; drug and alcohol misuse, 0%, 100%, p<0.001; visual disorders, 40%, 100%, p<0.001; respiratory disorders, 20%, 100%, p<0.001; and overall, 28%, 92%, p<0.001. Knowledge of DVLA guidelines among our cohort was poor. Implementation of a single-session teaching programme can significantly improve guideline knowledge and awareness, serving as a cost-effective intervention.


Tractography demonstrates dentate-rubro-thalamic tract disruption in an adult with cerebellar mutism.
A 55-year-old female is presented with transient cerebellar mutism caused by a well-circumscribed left pontine infarction due to postoperative basilar perforator occlusion. Although conventional T2 imaging shows a well-demarcated lesion confined to the pontine region, diffusion tensor imaging shows an asymmetry in fractional anisotropy in the superior cerebellar peduncle. This supports the general hypothesis that cerebellar mutism is caused by functional disruption of the dentate-rubro-thalamic tract. Correlating postoperative anatomic changes to a heterogenic clinical syndrome remains challenging, however.


Validation of volatile metabolites of pulmonary oxidative injury: a bench to bedside study.
Changes in exhaled volatile organic compounds (VOCs) can be used to discriminate between respiratory diseases, and increased concentrations of hydrocarbons are commonly linked to oxidative stress. However, the VOCs identified are inconsistent between studies, and translational studies are lacking. In this bench to bedside study, we captured VOCs in the headspace of A549 epithelial cells after exposure to hydrogen peroxide (H2O2), to induce oxidative stress, using high-capacity polydimethylsiloxane sorbent fibres. Exposed and unexposed cells were compared using targeted and untargeted analysis. Breath samples of invasively ventilated intensive care unit patients (n=489) were collected on sorbent tubes and associated with the inspiratory oxygen fraction (F IO2 ) to reflect pulmonary oxidative stress. Headspace samples and breath samples were analysed using gas chromatography and mass spectrometry. In the cell, headspace octane concentration was decreased after oxidative stress (p=0.0013), while the other VOCs were not affected. 2-ethyl-1-hexanol showed an increased concentration in the headspace of cells undergoing oxidative stress in untargeted analysis (p=0.00014). None of the VOCs that were linked to oxidative stress showed a significant correlation with F IO2 (Rs range: -0.015 to -0.065) or discriminated between patients with F IO2 ≥0.6 or below (area under the curve range: 0.48 to 0.55). Despite a comprehensive translational approach, validation of known and novel volatile biomarkers of oxidative stress was not possible in patients at risk of pulmonary oxidative injury. The inconsistencies observed highlight the difficulties faced in VOC biomarker validation, and that caution is warranted in the interpretation of the pathophysiological origin of discovered exhaled breath biomarkers.


Improving medication adherence with adjuvant aromatase inhibitor in women with breast cancer: A randomised controlled trial to evaluate the effect of short message service (SMS) reminder.
Medication adherence is crucial for improving clinical outcomes in the treatment of patients. We evaluate the effect of short message service (SMS) reminder on medication adherence and serum hormones in patients with breast cancer on aromatase inhibitors. An open-label, multi-centre, prospective randomised controlled trial of SMS versus Standard Care was conducted. Medication adherence was assessed via self-report using the Simplified Medication Adherence Questionnaire at baseline, 6 month, and 1 year. Androstenedione, estradiol, and estrone were measured at baseline and 1 year. The χ2 test and mixed effects logistic regression was performed to compare medication adherence between groups. Difference in androstenedione and estrone levels were assessed using analysis of covariance, whereas χ2 test and logistic regression was used for estradiol. Analysis was based on intention-to-treat. A total of 244 patients were randomised to receive weekly SMS reminder (n = 123) or Standard Care (n = 121) between May 2015 and December 2018. The odds of adherence was higher at 6-month in SMS (OR = 1.78, 95% CI 1.04-3.05, p = 0.034), and not significantly different at 1-year (OR = 1.15, 95% CI: 0.67-1.96 p = 0.617). Mixed effects logistic regression analysis showed higher odds of adherence in SMS over the 1-year period (OR = 2.35, 95% CI: 1.01-5.49, p = 0.048). There was no difference in serum hormone levels between groups. SMS reminder improved medication adherence in the short-term but had no effect on serum hormones levels in the longer term. Future studies could investigate the use of tailored SMS intervention according to patient preference to improve its sustainability.


Enhanced glucose uptake via GLUT4 fuels recovery from calcium overload after ischaemia-reperfusion injury in sevoflurane- but not propofol-treated hearts.
So far, no study has explored the effects of sevoflurane, propofol, and Intralipid on metabolic flux rates of fatty acid oxidation (FOX) and glucose oxidation (GOX) in hearts exposed to ischaemia-reperfusion. Isolated paced working rat hearts were exposed to 20 min of ischaemia and 30 min of reperfusion. Peri-ischaemic sevoflurane (2 vol%) and propofol (100 µM) in the formulation of 1% Diprivan(®) were assessed for their effects on oxidative energy metabolism and intracellular diastolic and systolic Ca(2+) concentrations. Substrate flux was measured using [(3)H]palmitate and [(14)C]glucose and [Ca(2+)] using indo-1AM. Western blotting was used to determine the expression of the sarcolemmal glucose transporter GLUT4 in lipid rafts. Biochemical analyses of nucleotides, ceramides, and 32 acylcarnitines were also performed. Sevoflurane, but not propofol, improved the recovery of left ventricular work (P=0.008) and myocardial efficiency (P=0.008) compared with untreated ischaemic hearts. This functional improvement was accompanied by reduced increases in post-ischaemic diastolic and systolic intracellular Ca(2+) concentrations (P=0.008). Sevoflurane, but not propofol, increased GOX (P=0.009) and decreased FOX (P=0.019) in hearts exposed to ischaemia-reperfusion. GLUT4 expression was markedly increased in lipid rafts of sevoflurane-treated hearts (P=0.016). Increased GOX closely correlated with reduced Ca(2+) overload. Intralipid alone decreased energy charge and increased long-chain and hydroxyacylcarnitine tissue levels, whereas sevoflurane decreased toxic ceramide formation. Enhanced glucose uptake via GLUT4 fuels recovery from Ca(2+) overload after ischaemia-reperfusion in sevoflurane- but not propofol-treated hearts. The use of a high propofol concentration (100 µM) did not result in similar protection.


Synergy Pattern of Short Cationic Antimicrobial Peptides Against Multidrug-Resistant Pseudomonas aeruginosa.
With the rise of various multidrug-resistant (MDR) pathogenic bacteria, worldwide health care is under pressure to respond. Conventional antibiotics are failing and the development of novel classes and alternative strategies is a major priority. Antimicrobial peptides (AMPs) cannot only kill MDR bacteria, but also can be used synergistically with conventional antibiotics. We selected 30 short AMPs from different origins and measured their synergy in combination with polymyxin B, piperacillin, ceftazidime, cefepime, meropenem, imipenem, tetracycline, erythromycin, kanamycin, tobramycin, amikacin, gentamycin, and ciprofloxacin. In total, 403 unique combinations were tested against an MDR Pseudomonas aeruginosa isolate (PA910). As a measure of the synergistic effects, fractional inhibitory concentrations (FICs) were determined using microdilution assays with FICs ranges between 0.25 and 2. A high number of combinations between peptides and polymyxin B, erythromycin, and tetracycline were found to be synergistic. Novel variants of indolicidin also showed a high frequency in synergist interaction. Single amino acid substitutions within the peptides can have a very strong effect on the ability to synergize, making it possible to optimize future drugs toward synergistic interaction.


Generalization of perceptual learning of vocoded speech.
Recent work demonstrates that learning to understand noise-vocoded (NV) speech alters sublexical perceptual processes but is enhanced by the simultaneous provision of higher-level, phonological, but not lexical content (Hervais-Adelman, Davis, Johnsrude, & Carlyon, 2008), consistent with top-down learning (Davis, Johnsrude, Hervais-Adelman, Taylor, & McGettigan, 2005; Hervais-Adelman et al., 2008). Here, we investigate whether training listeners with specific types of NV speech improves intelligibility of vocoded speech with different acoustic characteristics. Transfer of perceptual learning would provide evidence for abstraction from variable properties of the speech input. In Experiment 1, we demonstrate that learning of NV speech in one frequency region generalizes to an untrained frequency region. In Experiment 2, we assessed generalization among three carrier signals used to create NV speech: noise bands, pulse trains, and sine waves. Stimuli created using these three carriers possess the same slow, time-varying amplitude information and are equated for naïve intelligibility but differ in their temporal fine structure. Perceptual learning generalized partially, but not completely, among different carrier signals. These results delimit the functional and neural locus of perceptual learning of vocoded speech. Generalization across frequency regions suggests that learning occurs at a stage of processing at which some abstraction from the physical signal has occurred, while incomplete transfer across carriers indicates that learning occurs at a stage of processing that is sensitive to acoustic features critical for speech perception (e.g., noise, periodicity).


Information and communication technology and climate change adaptation: Evidence from selected mining companies in South Africa.
The mining sector is a significant contributor to the gross domestic product of many global economies. Given the increasing trends in climate-induced disasters and the growing desire to find lasting solutions, information and communication technology (ICT) has been introduced into the climate change adaptation mix. Climate change-induced extreme weather events such as flooding, drought, excessive fog, and cyclones have compounded the environmental challenges faced by the mining sector. This article presents the adoption of ICT innovation as part of the adaptation strategies towards reducing the mining sector's vulnerability and exposure to climate change disaster risks. Document analysis and systematic literature review were adopted as the methodology. Findings from the study reflect how ICT intervention orchestrated changes in communication patterns which are tailored towards the reduction in climate change vulnerability and exposure. The research concludes with a proposition that ICT intervention must be part of the bigger and ongoing climate change adaptation agenda in the mining sector.


Differential susceptibility of retroviruses to nucleoside analogues.
Retroviruses may cause diseases in their vertebrate hosts. They are distinguished by their common means of replication involving reverse transcription, a process inhibited by nucleoside reverse transcriptase inhibitors (NRTIs) and other compounds used in antiretroviral chemotherapy. Previous work on NRTIs has been limited to their effect on human immunodeficiency virus (HIV) (for review see Ho & Hitchcock, 1989; Weller, 1999) and little information exists regarding the efficacy and therapeutic potential of these drugs against other retroviruses. We have tested all six NRTIs licensed for HIV treatment [didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), zidovudine (AZT) and abacavir (ABC)] against seven retroviruses representative of the traditional subfamilies: Spumavirinae, Lentivirinae and the Oncovirinae. As expected, each drug showed a range of activities against the panel of retroviruses, some drugs inhibiting other viruses at concentrations well below those required for HIV. Overall, AZT was the most active inhibitor (IC50 range, 0.032-1.0 microM), being most active against the Spuma (foamy) viruses. Abacavir was inhibitory for HIV-1, MN strain (HIV-1 MN), amphotrophic murine leukemia virus (MLV-A) and simian foamy virus type 6 (SFV-6). The least effective inhibitor, 3TC (IC50 range, 0.32->100 microM), was most potent against simian retrovirus types 1 and 2 (SRV-1, SRV-2) and HIV-1, but did not inhibit foamy viruses and MLV-A. Additionally, there were differences in the concentration of drug required to inhibit closely related viruses. Taken together, these data suggest that NRTIs have a wide spectrum of antiretroviral activity and the activity of compounds, even against closely related retroviruses, cannot be predicted.


The recovery of the B-cell population in adult thymectomized, lethally irradiated and bone marrow-reconstituted mice.
The recovery of the B-cell population in adult thymectomized, irradiated and bone marrow-reconstituted mice (T X BM mice was estimated at various times after bone marrow transplantation. The spleen cells to be tested were mixed with dexamethasone-resistant thymocytes (DRT) and sheep red blood cells (SRBC) and transferrred to irradiated recipients. The number of plaque-forming cells (PFC) in the spleen of the recipients was determined 7 days later. Using this functional B-cell assay a sequential appearance of the precursors of IgM-, IgG- and IgA-PFC in the spleen of T X BM mice was observed. The precursors of IgM-PFG (IgM-B cells) were present immediately after transplantation. The first IgG-B cells could be detected at 13-16 days after transplantation and the IgA-B cells finally appeared at 22 days after transplantation. The number of B cells reached a constant and normal level at 30 days after transplantation. The IgM-, IgG- and IgA-B cell development in sham-thymectomized, irradiated and bone narrow-reconstituted mice (ST X BM mice) was virtually the same as in T X BM mice.


The value of arterial spin labelling in adults glioma grading: systematic review and meta-analysis.
This study aimed to evaluate the diagnostic performance of arterial spin labelling (ASL) in grading of adult gliomas. Eighteen studies matched the inclusion criteria and were included after systematic searches through EMBASE and MEDLINE databases. The quality of the included studies was assessed utilizing Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). The quantitative values were extracted and a meta-analysis was subsequently based on a random-effect model with forest plot and joint sensitivity and specificity modelling. Hierarchical summary receiver operating characteristic (HROC) curve analysis was also conducted. The absolute tumour blood flow (TBF) values can differentiate high-grade gliomas (HGGs) from low-grade gliomas (LGGs) and grade II from grade IV tumours. However, it lacked the capacity to differentiate grade II from grade III tumours and grade III from grade IV tumours. In contrast, the relative TBF (rTBF) is effective in differentiating HGG from LGG and in glioma grading. The maximum rTBF (rTBFmax) demonstrated the best results in glioma grading. These results were also reflected in the sensitivity/specificity analysis in which the rTBFmax showed the highest discrimination performance in glioma grading. The estimated effect size for the rTBF was approximately similar between HGGs and LGGs, and grade II and grade III tumours, (-1.46 (-2.00, -0.91), p-value < 0.001), (-1.39 (-1.89, -0.89), p-value < 0.001), respectively; while it exhibited smaller effect size between grade III and grade IV (-1.05 (-1.82, -0.27)), p < 0.05). Sensitivity and specificity analysis replicate these results as well. This meta-analysis suggests that ASL is useful for glioma grading, especially when considering the rTBFmax parameter.


Treatment of hyperglycemia in ischemic stroke (THIS): a randomized pilot trial.
Hyperglycemia may worsen brain injury during acute cerebral infarction. We tested the feasibility and tolerability of aggressive hyperglycemia correction with intravenous insulin compared with usual care during acute cerebral infarction. We conducted a randomized, multicenter, blinded pilot trial for patients with cerebral infarction within 12 hours after onset, a baseline glucose value >or=8.3 mmol/L (>or=150 mg/dL), and a National Institutes of Health Stroke Scale score of 3 to 22. Patients were randomized 2:1 to aggressive treatment with continuous intravenous insulin or subcutaneous insulin QID as needed (usual care). Target glucose levels were <7.2 mmol/L (<130 mg/dL) in the aggressive-treatment group and <11.1 mmol/L (<200 mg/dL) in the usual-care group. Glucose was monitored every 1 to 2 hours, and the protocol treatments continued for up to 72 hours. Final clinical outcomes were assessed at 3 months. We randomized 46 patients (31 to aggressive treatment and 15 to usual care). All patients in the aggressive-treatment group and 11 (73%) in the usual-care group had diabetes (P=0.008). Glucose levels were significantly lower in the aggressive-treatment group throughout protocol treatment (7.4 vs 10.5 mmol/L [133 vs 190 mg/dL], P<0.001). Hypoglycemia <3.3 mmol/L (<60 mg/dL) occurred only in the aggressive-treatment group (11 patients, 35%), 4 (13%) of whom had brief symptoms, including only 1 (3%) neurologic. Final clinical outcomes were nonsignificantly better in the aggressive-treatment group. The intravenous insulin protocol corrected hyperglycemia during acute cerebral infarction significantly better than usual care without major adverse events and should be investigated in a clinical efficacy trial.