A sensitive spectrophotometric method for the determination of H2-receptor antagonists by means of N-bromosuccinimide and p-aminophenol.
A simple, accurate and sensitive spectrophotometric method for determination of H2-receptor antagonists: cimetidine (CIM), famotidine (FAM), nizatidine (NIZ), and ranitidine hydrochloride (RAN) has been fully developed and validated. The method was based on the reaction of these drugs with NBS and subsequent measurement of the excess N-bromosuccinimide by its reaction with p-aminophenol to give a violet colored product (lambda max at 552 nm). Decrease in the absorption intensity (Delta A) of the colored product, due to the presence of the drug, was correlated with its concentration in the sample solution. Different variables affecting the reaction were carefully studied and optimized. Under optimal conditions, linear relationships with good correlation coefficients (0.9988-0.9998) were found between Delta A values and the corresponding concentrations of the drugs in a concentration range of 8-30, 6-22, 6-25, and 4-20 microg mL(-1) for CIM, FAM, NIZ, and RAN, respectively. Limits of detection were 1.22, 1.01, 1.08, and 0.74 microg mL(-1) for CIM, FAM, NIZ, and RAN, respectively. The method was validated in terms of accuracy, precision, ruggedness, and robustness; the results were satisfactory. The proposed method was successfully applied to the analysis of the above mentioned drugs in bulk substance and in pharmaceutical dosage forms; percent recoveries ranged from 98.5 +/- 0.9 to 102.4 +/- 0.8% without interference from the common excipients. The results obtained by the proposed method were comparable with those obtained by the official methods.


In-vivo corneal confocal microscopy: Imaging analysis, biological insights and future directions.
In-vivo corneal confocal microscopy is a powerful imaging technique which provides clinicians and researcher with the capabilities to observe microstructures at the ocular surfaces in significant detail. In this Mini Review, the optics and image analysis methods with the use of corneal confocal microscopy are discussed. While novel insights of neuroanatomy and biology of the eyes, particularly the ocular surface, have been provided by corneal confocal microscopy, some debatable elements observed using this technique remain and these are explored in this Mini Review. Potential improvements in imaging methodology and instrumentation are also suggested.


Enhancement of antifouling properties, metal ions and protein separation of poly(ether-ether-sulfone) ultrafiltration membranes by incorporation of poly ethylene glycol and n-ZnO.
Composite polymeric membranes with enhanced anti-fouling properties, antimicrobial activities and flux were produced via the phase inversion technique using poly (ether-ether-sulfone) (PEES)/polyethylene glycol (PEG) and n-ZnO. SEM and ATR-FTIR spectroscopy were used to study the morphological and chemical properties of the resulting ultrafiltration membranes. PEG and n-ZnO concentration has an effect on membrane morphologies, ultrafiltration performance, thermal characteristics, metal ion separation studies, surface hydrophilicity and anti-fouling capabilities. The permeate flux increased when the PEG concentration was raised. This results revealed that adding PEG and n-ZnO to membranes increased their surface hydrophilicity and anti-fouling properties. The inclusion of 1.5 wt % n-ZnO and 5 wt % PEG to the pristine PEES membrane resulted in a higher flux of 233.76 L m-2 h-1, 70.09 % of water content, 47.46° of contact angle, the porosity of 30.20 %, and hydraulic resistance of 0.22 kPa/Lm-2h-1. Anti-fouling properties of the fabricated membrane were assessed using a model foulant BSA, which revealed a high flux recovery ratio value. As a result, the PEG and n-ZnO incorporated membrane is more hydrophilic than the virgin membrane. In addition, the prepared PEES/PEG/n-ZnO membrane showed a significant increase in metal ions and protein rejection. Furthermore, an antibacterial test of the membrane revealed that the PEG and n-ZnO composite membrane outperformed the bare PEES membrane in terms of antibacterial capabilities. Overall, the findings reveal that combining n-ZnO and PEG resulted in a membrane with improved anti-fouling capabilities and hydrophilicity, making it suitable for water purification.


The role of race in heart failure therapy.
Heart failure in blacks is a unique malady characterized by a different natural history, more worrisome prognosis, and potential variances in the response to current medical therapy for heart failure. The overwhelming burden of hypertension as a putative cause of left ventricular dysfunction identifies this illness. Although differences in the response to medical therapy have been described, angiotensin-converting enzyme inhibitors and beta-blockers remain the most appropriate therapy. Certain genetic polymorphisms may exist that explain the observed differences.


Fifteen-S-hydroxyeicosatetraenoic acid (15-S-HETE) specifically antagonizes the chemotactic action and glomerular synthesis of leukotriene B4 in the rat.
In models of experimental glomerulonephritis, there is temporal concordance between the shift in the glomerular cellular infiltrate from neutrophils (PMN) to macrophages/monocytes and the suppression of glomerular leukotriene B4 (LTB4) generation. Since macrophages are a rich source of 15-lipoxygenase (15-LO) products, we investigated whether the principal product of arachidonate 15-lipoxygenation, 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), was capable of antagonizing the proinflammatory actions of LTB4 in the rat. PMN exhibited chemotaxis to LTB4 in a dose dependent manner with an LC50 of 10(-8) M. When rat neutrophils were pre-treated with 15-S-HETE, chemotaxis to LTB4 was inhibited in a dose dependent manner (maximal at 30 microM 15-S-HETE) but, the same concentration did not inhibit chemotaxis to n-formyl-1-methionyl-1-phenylalanine (FMP). 12-S-HETE (30 microM) did not inhibit chemotaxis to LTB4. Glomeruli from rats injected with nephrotoxic serum three hours earlier generated increased levels of LTB4; prior exposure of such glomeruli to 15-S-HETE totally normalized LTB4 production. The glomerular production of 15-S-HETE and LTB4 was also determined 3 hours, 72 hours and 2 weeks after administration of nephrotoxic serum. Whereas there was an early, short-lived, burst of LTB4 followed by a return to baseline levels, the production of 15-S-HETE increased steadily over the two week period and was present in amounts fivefold greater than LTB4. Thus, these studies assign a role for locally generated 15-LO derivatives in arresting LTB4-promoted PMN infiltration and suppressing LTB4 synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)


Curcumin encapsulated zeolitic imidazolate frameworks as stimuli responsive drug delivery system and their interaction with biomimetic environment.
Metal organic frameworks (MOFs) exhibit unique features of finely tunable pore structures, excellent chemical stability and flexible surface structural functionality, making them advantageous for a wide range of applications including energy storage, compound separation, catalysis, and drug delivery. The present work enlightens a novel approach of single step fabrication of CCM-ZIF-8 as a drug carrier and its application as stimuli responsive drug delivery systems via external stimuli involving change in pH and in presence of biomimetic cell membrane like environment using liposomes and SDS micelles. The methodology is devoid of any post synthesis drug loading steps. The synthesized curcumin encapsulated ZIF-8 frameworks demonstrate ultrahigh drug encapsulation efficiency (ca. 83.33%) and good chemical stability. In vitro drug release of curcumin was three times higher in acidic medium than in physiological pH. Cytotoxicity results demonstrated enhanced therapeutic effect of CCM-ZIF-8 than free curcumin. Confocal microscopy results confirmed the easy cellular internalization of CCM-ZIF-8 in HeLa cells. Intracellular distribution studies at various incubation times confirmed the clathrin-mediated endocytosis to lysosomal pathway of CCM-ZIF-8, but without mitochondria being an intracellular fate. The results signify that CCM-ZIF-8 is an efficient drug carrier for passive tumor therapy in future for cancer treatments.


Dopamine receptors gene overexpression in the microenvironment of invasive gastric cancer and its potential implications.
Gastric cancer (GC) is the fifth most common cancer worldwide and the most commonly diagnosed cancer in Iran. The nervous system provides proximity to tumor cells by releasing neurotransmitters such as dopamine and presenting them to the corresponding receptor-bearing tumors. While nerve fibers infiltrate the tumor microenvironment, little is known about the expression levels of dopamine (DA), dopamine receptors (DRs), and catechol-O-methyltransferase (COMT) in GC patients. DRs and COMT expression were analyzed in 45 peripheral blood mononuclear cells (PBMCs) and 20 paired tumor and adjacent tissue of GC patients by quantitative polymerase chain reaction. DA was measured in plasma specimens using enzyme-linked immunosorbent assay. Protein-protein interaction analysis was carried out to identify GC-related hub genes. Increased expression of DRD1-DRD3 was found in tumor specimens compared with adjacent non-cancerous specimens (P < 0.05). A positive correlation was found between DRD1 and DRD3 expression (P = 0.009); DRD2 and DRD3 expression (P = 0.04). Plasma levels of dopamine were significantly lower in patients (1298 pg/ml) than in controls (4651 pg/ml). DRD1-DRD4 and COMT were up-regulated in PBMCs of patients compared with controls (P < 0.0001). Bioinformatic analyses showed 30 hub genes associated with Protein kinase A and extracellular signal-regulated kinase signaling pathways. The findings indicated dysregulation of DRs and COMT mRNA expression in GC and suggest that the brain- gastrointestinal axis may mediate gastric cancer development. Network analysis revealed that combination treatments could be considered for optimizing and improving the precision treatment of GC.


Giant congenital lower lip nevus restored by local advanced skin flap: a case report.
A congenital lower lip nevus is common, but a lower lip length lesion of more than 40% is hard to excise simply, without any distortion. We designed a lower lip bilateral advanced skin flap to restore the wound surface after completely and successfully removing the nevus. A 13-year-old Mongolian girl was referred to us with a giant congenital lower lip nevus. The lesion covered nearly half of her lower lip. We designed a lower lip bilateral advanced skin flap to restore the wound surface, after completely removing the nevus without advanced repair. This case report demonstrates a case of a lower lip length defect of more than 40%, repaired by direct closure without dysfunction. It was a successful attempt that minimized the subsequent scar and dysfunction.


Effects of G-quadruplex topology on translational inhibition by tRNA fragments in mammalian and plant systems in vitro.
The folding of tRNA fragments (tRFs) into G-quadruplex structures and the implications of G-quadruplexes in translational inhibition have been studied mainly in mammalian systems. To increase our knowledge of these phenomena, we determined the influence of human and plant tRFs and model G-quadruplexes on translation in rabbit reticulocyte lysate and wheat germ extract. The efficiency of translational inhibition in the mammalian system was strongly associated with the type of G-quadruplex topology. In the plant system, the ability of a small RNA to adopt the G-quadruplex conformation was not sufficient to repress translation, indicating the importance of other structural determinants.


Pachyonychia congenita with cutaneous amyloidosis and hyperpigmentation--a distinct variant.
Two kindreds manifesting an unusual form of pachyonychia congenita are described. Clinical involvement consists of nail dystrophy, which tends to improve with age, and moderate palmoplantar hyperkeratosis. In addition, all affected members show a characteristic pattern of cutaneous hyperpigmentation, which resembles macular amyloidosis around the neck and waist, but which confers a dappled appearance to the axillae, popliteal fossae, thighs, buttocks, and lower aspect of the abdomen. With advancing age the pigmentation fades. Histologic and ultrastructural examination of the hyperpigmented skin has revealed pigmentary incontinence and deposition of amyloid within the papillary dermis. These features appear to constitute a distinct variant of pachyonychia congenita.


True Aneurysm of the Left Internal Thoracic Artery.
Aneurysms of the internal thoracic artery (ITA) are rare and can have many etiologies. Hyperflow is an exceptional etiology. We report the case of a 56-year-old woman who presented with a stress-induced ischemia of the left arm. Computed tomography angiography showed occlusion of the subclavian artery and a true aneurysm of the ITA. The ITA aneurysm was resected without restoration of the ITA continuity and a carotid-subclavian bypass was performed. Pathological examination of the aneurysm sac was not specific.


Development and evaluation of the Families, Cultures and Augmentative and Alternative Communication (AAC) multimedia program.
The Families, Cultures and AAC Project was designed to provide professionals and families with accurate, culturally sensitive information about augmentative communication technologies and decision-making strategies through an innovative, user-friendly format. The project resulted in the development of the first interactive bilingual CD-ROM designed to be used by professionals at the pre- or in-service level, and family members from diverse cultures to develop AAC decision-making competencies. The Interactive Health Communication (IHC) model provided an effective structure for conceptualizing, developing and evaluating the program. The program also incorporated universal access design concepts. The program was evaluated in the following 10 categories: usability, visual appearance, consistency, error tolerance, navigation, feedback, user control, redundant formats, content accuracy, and engaging styles. Reviewers of the program indicated that it was well designed and would be useful for the intended purpose.


Feasibility and safety of laparoscopic nephrectomy in uremic patients with end-stage renal disease.
The purpose of this study was to analyse the feasibility and safety of laparoscopic radical nephrectomy (LRN) vs. open radical nephrectomy (ORN), in terms of perioperative and postoperative outcomes, in uremic patients. Between September 2007 and December 2013, 19 patients with end-stage renal disease (ESRD), who underwent LRN or ORN for chronic pyelonephritis, renal calculi, hydronephrosis, renal tumors, complicated cyst, or associated polycystic kidney, were retrospectively analysed. All patients with complete preoperative clinical and intraoperative parameters, including age at surgery, gender, body mass index (BMI), American Society of Anesthesiologists (ASA) score, surgical technique, operation time, complications, were available for further analyses. The 30-day complication rate in both groups was retrospectively review and graded according to the modified Clavien System in five grades. Overall, nine (47.3%) vs. 10 (52.7%) patients underwent LRN vs. ORN, respectively. The mean ASA score (2.7 ± 0.8 vs. 2.9 ± 0.7) did not show statistically significant differences in both groups (p = 0.632). None of the patients in G1 was converted to open surgery for intraoperative complications or CO2 retention. The estimated blood loss was 223 ± 155 mL in G1 and 455 ± 134 mL in G2 (p<0.005). Both groups were comparable with regard to mean operation time. The mean hospital stay was 5.95 ± 1.85 days in G1 and 8.10 ± 1.67 days in G2 (p<0.001). The present study revealed that laparoscopic surgery in uremic patients might be performed safely under the expertise of an experienced laparoscopic team. This surgical technique is a minimally invasive treatment, reduces blood loss, shortens postoperative hospital stay, minimizes wound pain, and encourages an earlier return to normal activity.


Basic helix-loop-helix (bHLH) gene family in Tartary buckwheat (Fagopyrum tataricum): Genome-wide identification, phylogeny, evolutionary expansion and expression analyses.
Tartary buckwheat (Fagopyrum tataricum) a kind of edible and medicinal plant, is of great nutritional value. It is difficult to remove the hull of Tartary buckwheat fruit and breeding new easy-dehulled varieties has been one of the major breeding objectives. The bHLH gene family plays a vital role in plant growth and fruit dehiscence. In order to improve Tartary buckwheat breeding, we need to study the bHLH gene family for excavating genes with potential regulation of fruit development and dehiscence. Here, 164 Fagopyrum tataricum bHLH (FtbHLH) genes were identified. Analyses of gene structure and motif composition illustrate that the members of specific FtbHLH subfamily are relatively conserved. Synteny and phylogenetic analyses of bHLH genes in Tartary buckwheat and other plants lay a foundation for further exploring the evolutionary characteristic of the FtbHLH genes (FtbHLHs). qRT-PCR experiments showed that FtbHLHs expression patterns were different in plant organs, indicating that they may perform diverse functions. In addition, some genes that potentially regulate flower and fruit development and easy dehulling were screened out. Overall, this study will be helpful for further analyzing the biological function of FtbHLHs and provides clues for improving the genetic breeding and economic value of the Tartary buckwheat.


Complete genome sequence of a dahlia common mosaic virus isolate from New Zealand.
Dahlia mosaic disease of the ornamental flowering plant Dahlia is caused by two caulimoviruses, dahlia mosaic virus (DMV) and dahlia common mosaic virus (DCMV). We used a rolling-circle amplification method to amplify, clone and determine for the first time the full genome sequence of a DCMV isolate from New Zealand (DCMV-NZ). Within the 7949-bp circular double-stranded retro-transcribing DCMV-NZ DNA, we identified six putative open reading frames, typical of all genomes in the family Caulimoviridae. The availability of the complete DCMV sequence provides a reference genome against which all others can be compared.


South-east asian ovalocytic (SAO) erythrocytes have a cold sensitive cation leak: implications for in vitro studies on stored SAO red cells.
South-east Asian ovalocytosis (SAO) results from the heterozygous presence of an abnormal band 3, which causes several alterations in the properties of the erythrocytes. Although earlier studies suggested that SAO erythrocytes are refractory to invasion in vitro by the malarial parasite Plasmodium falciparum, a more recent study showed that fresh SAO cells were invaded by the parasites, but became resistant to invasion on storage because intracellular ATP was depleted more rapidly than normal. Here we show that SAO red cells are much more leaky to sodium and potassium than normal red cells when stored in the cold. This leak was much less marked when the cells were stored at 25 or 37 degreesC. Incubation for 3.5 h at 37 degreesC of cold-stored SAO red cells did not restore sodium and potassium to normal levels, probably because the depleted ATP level in cold-stored SAO red cells is further reduced with incubation at 37 degreesC. The increased leakiness of SAO red cells is non-specific and extends to calcium ions, taurine, mannitol and sucrose. These results suggest that SAO red cells undergo a structural change on cooling. Since many of the reports describing altered properties of SAO red cells have used cells which have been stored in the cold, these results need re-evaluation using never-chilled SAO red cells to assess whether the cells have the same abnormal properties under in vivo conditions.


Induction of apoptosis by a stilbene analog involves Bax translocation regulated by p38 MAPK and Akt.
trans-Stilbenes have been reported to induce cytochrome P450 1B1 (CYP1B1) inhibition and cell death, however, the molecular mechanisms of the effects are not fully understood. We report here that (1-(2-{3-[2-(2,4-dimethoxy-phenyl)-vinyl]-5-methoxy-phenoxy}ethyl)-1H-imidazole), a synthetic stilbene analog (SA) significantly suppressed TCDD-stimulated CYP1B1 mRNA expression. In HL-60 cells, SA induced apoptosis through activation of p38 MAPK and inactivation of Akt, which in turn activated Bad and mitochondrial death signaling pathway, as evidenced by Bax translocation and cytochrome c release. Expression of dominant negative p38 MAPK or constitutively active Akt significantly prevented cell death and mitochondrial Bax translocation, implicating that p38 MAPK and Akt signaling pathways play crucial roles in stilbene-induced apoptosis of HL-60 cells. These results suggest that SA induces apoptotic cell death as well as CYP1B1 inhibition and may thus be beneficial in cancer prevention.


Effect of Paclitaxel-eluting versus sirolimus-eluting stents on coronary restenosis in Korean diabetic patients.
With the introduction of drug-eluting stents (DES), the angiographic rates of restenosis have reduced dramatically but less prominently in diabetic patients. We compared the effects of sirolimus-eluting stents (SES) versus paclitaxel-eluting stents (PES) on 6-month angiographic and clinical outcomes in Korean diabetic patients. Diabetic patients with de novo coronary lesions (169 patients with 190 lesions) were randomly assigned to either SES or PES in six different cardiovascular centers from April 2005 to January 2006. Patients with vessel size >2.0 mm and < or =2 vessel diseases requiring < or =2 DES implantation were included in the study. Baseline clinical and angiographic characteristics were similar between the two groups. At 6-month follow-up, the late lumen loss (0.26 +/- 0.76 in the SES group vs. 0.39 +/- 0.92 mm in the PES group, P = 0.356) and the rate of binary restenosis (2.8%[n = 2] in the SES group vs. 6.9%[n = 5] in the PES group, P = 0.441) showed no significant differences. Rates of death (1.2%[n = 1] in the SES group vs. 1.2%[n = 1] in the PES group, P = 1.000), myocardial infarction (1.2%[n = 1] in the SES group vs. 1.2%[n = 1] in the PES group, P = 1.000), and target lesion revascularization (2.4%[n = 2] in the SES group vs. 4.8%[n = 4] in the PES group, P = 0.443) were similar in both groups during 6 months of follow-up. The use of either SES or PES demonstrated similar 6-month angiographic and clinical outcomes in Korean diabetic patients with coronary artery disease.


Influence of Socioeconomic Status and Perceived Barriers on Physical Activity Among Taiwanese Middle-Aged and Older Women.
Physical activity (PA) is associated with cardiovascular health in general populations, particularly in women. Middle-aged and older women are at high risk of less engagement in PA for unknown and complicated reasons. The aim of this study was to investigate whether PA was positively associated with socioeconomic status and psychosocial correlates of PA (self-efficacy and perceived benefits) but inversely correlated with perceived barriers in women (age >40 years). A cross-sectional survey of 326 community-dwelling women was conducted. Data on socioeconomic status, PA, and its psychosocial correlates (ie, perceived benefits/barriers and self-efficacy) were collected using self-report questionnaires. Analyses were performed by multiple linear regressions. Monthly income (β = .35, P = .015), employment status (β = .32, P < .001), and perceived barriers to PA (β = -.19, P = .008) were significantly associated with PA. More highly educated women participated in more (β = .13, P = .033) vigorous PA, women with fewer perceived barriers participated in more (β = -.14, P = .047) moderate-intensity PA, and employed women participated in more (β = .35, P < .001) walking. Significantly higher scores of perceived barriers, including "no trainer," "feeling exhausted," "lack of motivation," and "lack of guidance," were identified in women with low PA compared with those with moderate PA. Socioeconomic status and perceived barriers are associated with PA and its intensity level. Some specific barriers provide insights into the key factors that contribute to low PA in middle-aged and older women. These findings can be considered in future interventions to design PA promotion programs for this population to protect against cardiovascular diseases.


Environmental exposures and pulmonary function among adult residents of rural Appalachian Kentucky.
Estimated residential exposures of adults to roadway density and several metrics of resource extraction, including coal mining and oil and gas drilling, were hypothesized to contribute to the prevalence of respiratory disease in rural Appalachia. Determine how small-area geographic variation in residential environmental exposures impacts measures of pulmonary function among adults in a community-based study. We examined associations between residential environmental respiratory exposures and pulmonary function among 827 adult participants of the "The Mountain Air Project", a community-based, cross-sectional study in Southeastern Kentucky during 2016-2018. Exposures characterized the density of roadways, oil/gas wells, or current/past surface and underground coal mining at the level of 14-digit hydrologic unit code (HUC), or valley "hollow" where participants resided. Each participant completed an in-person interview to obtain extensive background data on risk factors, health history, and occupational and environmental exposures, as well as a spirometry test administered by experienced study staff at their place of residence. Multivariable linear regression was used to model the adjusted association between each environmental exposure and percent predicted forced expiratory volume in one second (FEV1PP) and forced vital capacity (FVCPP). Adjusted regression models indicate persons living in HUCs with the highest level of roadway density experienced a reduction in both FEV1PP (-4.3: 95% CI: -7.44 -1.15;) and FVCPP (-3.8: 95% CI: -6.38, -1.21) versus persons in HUCs with the lowest roadway density. No associations were detected between the metrics associated with mining and oil and gas operations and individual pulmonary function. Our work demonstrates the potential adverse impact of roadway-related exposures on the respiratory health of rural Appalachia residents. We employed a novel method of small-area exposure classification based on the hydrologic unit code (HUC), representing potential exposure levels per hollow occurring in proximity to the residence, and controlled for individual-level risk factors for reduced respiratory health. We highlight an overlooked yet ubiquitous source of residential exposure from motor vehicles that may contribute to the regionally high prevalence of respiratory disease in rural Appalachia.


Changes in plasma histamine during orthotopic liver transplantation in the pig.
Hypotension and cardiac arrhythmia are commonly seen during liver transplantation both in man and in experimental animals. The cardiovascular changes may be explained by release of vasoactive substances, e.g. histamine, into the systemic circulation. Abdominal operations are followed by an increased histamine concentration in portal blood. If the liver clears excess histamine from the splanchnic system, an increased histamine concentration should not be found in the systemic circulation. We measured plasma histamine in peripheral arterial blood, blood from the right atrium and portal blood in different phase of liver transplantation in ten pigs. Histamine concentration increased in the portal vein in the anhepatic phase (basal 15.85 pmol/ml to 34.67 pmol/ml, median, p less than 0.05) but no changes were found in arterial or right atrium samples. Venous and later arterial revascularisation were not followed by any changes in histamine concentration in arteria and right atrium samples. We conclude that the transplanted liver can eliminate splanchnic histamine and that histamine is unlikely to be involved in the cardiovascular changes which are seen after revascularisation of the liver.


Intraoperative Collateral Drainage Evaluation Before Superior Caval Interruption in Partial Anomalous Pulmonary Venous Connection Repair.
A superior sinus venosus atrial septal defect and partial anomalous pulmonary venous connection was corrected by a minimally invasive approach by permanently ligating the superior vena cava and a single pericardial patch for rerouting the flow through the enlarged interatrial communication. The patient had persistency of the left superior vena cava draining in the coronary sinus but no innominate vein. This anatomy poses a risk of developing right-sided superior vena cava syndrome. In this article, we describe our intraoperative strategy to assess the safety of this approach in such cases, which facilitates minimally invasive repair and avoids the most important complications of conventional repair.


SCN2A-Developmental and Epileptic Encephalopathies: Challenges to trial-readiness for non-seizure outcomes.
SCN2A-associated developmental and epileptic encephalopathies (DEEs) present with seizures, developmental impairments, and often both. We sought to characterize the level and pattern of development in children with SCN2A variants, and to address the sensitivity of the Vineland Adaptive Behavior Scales (VABS) in measuring changes over time in children with SCN2A-DEEs. Clinical histories for participants with pathogenic SCN2A variants in the Simons SearchLight project were analyzed for descriptive purposes. VABS scores obtained at study entry and yearly thereafter were analyzed for floor and ceiling effects, change with age, and association with epilepsy through use of regression and longitudinal regression methods. Sixty-four participants (50 with epilepsy, 30 [47%] female, median age 49 months, interquartile range [IQR] 28 to 101) were included. Histories of birth complications (N = 34, 54%), neonatal neurological signs (N = 45, 74%), and other neurological symptoms (N = 31, 48%) were common and similar in epilepsy and nonepilepsy subgroups. Mean standardized VABS scores (Composite 53.5; Motor, 55.8, Communication, 54.1, Socialization, 59.4, and Daily living skills, 55.1) reflected performance ~3 standard deviations below the normative test average. In longitudinal regression analyses, standardized scores decreased between 1.3 and 2.8 points per year, suggesting regression of abilities. Raw score analyses, however, revealed several subdomains with substantial floor effects (eg, community use); other raw scores increased with increasing age. Participants with epilepsy scored 0.6 to 1 SD lower than those without epilepsy (all P's < .05). The VABS, as standardly administered, has shortcomings for addressing growth or regression in individuals with SCN2A-DEEs. Some subdomain raw scores reflected substantial floor effects. Raw scores increased so slowly over time that standardized scores declined. Alternative measures sensitive to incremental meaningful change are required if outcomes such as adaptive behavior are to be primary outcomes in short-term clinical trials.


Design for a study to determine optimal dosage of ascorbic acid and alpha-tocopherol in humans.
Some clinical trials of vitamins C and E have neglected important design features. Our objective was to demonstrate a detailed design that includes essential elements for an effective study of these vitamins in vivo. While taking 400 IU (international units) of vitamin E, subjects took different dosages of vitamin C during three distinct periods. Dosages were 200 mg in food, 500 mg as supplements twice a day (500 × 2), and 1,000 mg as supplements twice a day (1000 × 2). Ten participants spent 3 weeks at each dosage before plasma was drawn on two consecutive days. Final samples were taken after a week with no supplementation. Selected by investigators at four institutions, endpoints were protein carbonyls, TBARs (thiobarbituric reactive substances), and Heinz body formation in RBCs (red blood cells). TBARs and protein carbonyls did not change significantly with dosage. However, Heinz body formation increased at either higher or lower intakes of vitamin C. Even with daily vitamin E, Heinz bodies were significantly fewer at 500 × 2. Results indicate that even with 400 IU vitamin E daily, it is possible to distinguish the effect of different levels of vitamin C with Heinz bodies. This effect may be due to pro-oxidant action of vitamin C or to prolonged survival of RBCs.


Intravenous pamidronate treatment in children with moderate to severe osteogenesis imperfecta: assessment of indices of dual-energy X-ray absorptiometry and bone metabolic markers during the first year of therapy.
Bisphosphonates are now widely used to treat children with osteogenesis imperfecta (OI). However, there are few published data following the initial evolution of changes in bone mass with such treatment. The purpose of the present study was to assess indices of skeletal size and total and regional bone mass in children with OI during the first year of their pamidronate therapy. Twenty-six children [11 males, age median 10.6 (range 3.2-15.5) years] with type III (n=9) or type IV (n=17) OI received intravenous pamidronate 1.0 mg/kg/day on 3 consecutive days, 3-monthly over a 1-year period. Bone mass assessed by dual energy X-ray absorptiometry, serum alkaline phosphatase (ALP) and urine type I collagen N-terminal telopepetide (NTX) were measured at each cycle. Lumbar (L2 to L4) vertebral height increased by median (interquartile range) 4.5% (7.3), area by 11.3% (19.3), bone mineral content (BMC) by 73.7% (50.4), and bone mineral density (BMD) by 48.7% (34.7), P<0.0001 during the first year of therapy. Total body bone area increased by 26.7% (26.3), total body BMC by 41.4% (44.5), and total body BMD by 8.8% (8.3), P<0.0001. Head bone area remained constant whilst head BMC and BMD increased. Pre-infusion U-NTX and S-ALP levels decreased progressively during the follow-up indicating reducing bone turnover rate during pamidronate therapy. Increased bone area and mineral mass were observed during the first year of intravenous pamidronate therapy in children with OI. Increased head bone mass implies a direct effect of pamidronate on skeletal mass accretion, rather than an indirect effect mediated through increased physical activity.


The Heart Club: How Cyanotic Heart Disease Was Reframed.
In April 1948, the thoracic surgeon, Russell Brock, convened a meeting at Guy's Hospital [...].


Synthesis and standardization of an impurity of acetaminophen, development and validation of liquid chromatographic method.
One of the impurities of acetaminophen, N,N'-(oxydi-4,1-phenylene)diacetamide (ODAA), which is not specified in the organic impurities analysis method of acetaminophen by high performance liquid chromatography (HPLC) in American Pharmacopoeia Version 42 (USP 42), was synthesized, characterized and standardized. A new and optimized liquid chromatographic method for the determination of organic impurities of acetaminophen was developed using an ultra-high performance liquid chromatographic (UHPLC) system, which can separate this impurity. This new liquid chromatographic method has been optimized and validated for the simultaneous determination of acetaminophen related compound B, acetaminophen related compound C, acetaminophen related compound D, acetaminophen related compound J and ODAA, the organic impurities in acetaminophen drug substance. Acetaminophen was also subjected to stress-testing under acidic hydrolysis, alkaline hydrolysis, oxidative degradation, thermal degradation and photolytic degradation for 15 days. The impurity molecule, ODAA was synthesized using 4,4'-oxydianiline and acetic anhydride. The chemical structure of the synthesized ODAA molecule was confirmed by characterization studies. The potency of ODAA was found to be 99.64% as a result of the relevant analyses. The chromatographic separation was achieved on a C8 (150 mm × 2.1 mm; 2-µm particle size) reversed-phase column using a gradient elution, being solvent A: methanol-water-glacial acetic acid (50:950:1, v/v/v) and solvent B: methanol-water-glacial acetic acid (500:500:1, v/v/v) flowing at a rate of 0.2 mL/min. The limits of quantitation (S/N 10:1) were 1.248 µg/mL for acetaminophen, 0.373 µg/mL for acetaminophen related compound B, 1.217 µg/mL for acetaminophen related compound C, 0.369 µg/mL for acetaminophen related compound D, 0.125 µg/mL for acetaminophen related compound J and 0.373 µg/mL for ODAA. The individual mean recoveries of each impurity molecule spiked into acetaminophen samples at different concentration levels ranged from 93% to 104%. The method developed for UHPLC instrument was successfully applied to the analyses of different lots of acetaminophen. Thus, the proposed method can be used for determination of this impurity in the presence of other specified impurities of acetaminophen.


Steroid-mediated liver steatosis is CD1d-dependent, while steroid-induced liver necrosis, inflammation, and metabolic changes are CD1d-independent.
Glucocorticoids contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Natural killer T cells play a role in the pathogenesis of NAFLD and response to steroids. The present study aimed to determine the role of CD1d in steroid-mediated metabolic derangement and the steroid-protective effect of glycosphingolipids. Ten groups of mice were studied. Steroids were orally administered to C57BL/6 mice to assess the therapeutic effect of β-glucosylceramide (GC) on the development of steroid-mediated liver damage and metabolic derangements. The role of CD1d in the pathogenesis of steroid-induced liver damage and in mediating the hepatoprotective effect of GC was studied in CD1d-/- mice. A model of oral administration of steroids was established, resulting in insulin resistance, hyperinsulinemia, hypertriglyceridemia, liver steatosis, and hepatocellular injury. Steroid administration to CD1d-/- mice was associated with hyperglycemia and hypertriglyceridemia. However, CD1d-/- mice did not manifest marked steroid-induced steatosis. GC treatment alleviated steroid-associated metabolic derangements and liver injury independent of CD1d expression. A steroid-mediated model of NAFLD and metabolic derangements was established in which steroid-mediated steatosis was CD1d-dependent while steroid-induced liver necrosis, inflammation, and metabolic changes were CD1d-independent, which may support a dichotomy between steatosis and steatohepatitis in NAFLD.


Prediction of evaporation from dam reservoirs under climate change using soft computing techniques.
This study aimed to predict evaporation from dam reservoirs using artificial intelligence considering climate change. Mahabad Dam, near Lake Urmia, in northwestern Iran, is used to investigate the proposed approach. There are three parts to the study presented herein. In the first part, two machine learning models, namely group method of data handling (GMDH) and least squares support vector regression (LS-SVR), were used to model the inflow to the dam reservoir. Temperature, precipitation, and inflow during the previous month from 1990 to 2017 were used as input data. In the second part, the evaporation from the dam reservoir was modeled using the adaptive neuro-fuzzy inference system (ANFIS) and optimized ANFIS using Harris hawks optimization (HHO) and the arithmetic optimization algorithm (AOA) optimization algorithms. The input parameters in this part were temperature, precipitation, inflow to the dam reservoir, along with evaporation from the dam reservoir in the previous month. In the third part, precipitation and temperature were predicted using the fifth report of IPCC based on RCP2.6, RCP4.5, and RCP8.5 scenarios for the period 2020-2040. Out of 28 models presented in the fifth report, EC-ERATH and FIO-ESM had the greatest similarity with observational data of temperature and precipitation, respectively. The results of scatter plots and Taylor's diagram showed the higher performance of LS-SVR (root mean square error (RMSE), mean absolute percentage error (MAPE), and Nash-Sutcliffe efficiency (NSE) of 8.65, 4.69, and 0.96) compared to GMDH (RMSE, MAPE, and NSE of 11.65, 7.81, and 0.93) in modeling the inflow. Moreover, both hybrid modes (AOA-ANFIS and HHO-ANFIS) improved the performance of ANFIS in modeling the evaporation from the dam reservoir. The RMSE, MAPE, and NSE values for ANFIS were 0.56, 0.52, and 0.89, respectively, while these values for the AOA-ANFIS (RMSE, MAPE, and NSE of 0.31, 0.24, and 0.93) and HHO-ANFIS (RMSE, MAPE, and NSE of 0.20, 0.30, and 0.96) were improved remarkably. The impact of climate change reduced the inflow to the dam reservoir by about 0.45, 0.80, and 1.7 MCM in RCP2.6, RCP4.5, and RCP8.5 scenarios, respectively. Also, the effect of climate change caused the evaporation from the dam reservoir to increase by about 0.2, 0.9, and 1 MCM in RCP2.6, RCP4.5, and RCP8.5 scenarios, respectively. The findings of this study show that the correct management of dam reservoirs needs to consider the potential effects of climate change in the future. Moreover, the hybrid machine learning models used in this study can be used to predict the amount of evaporation in other reservoirs.


Sulfo-N-succinimidyl oleate (SSO) inhibits fatty acid uptake and signaling for intracellular calcium via binding CD36 lysine 164: SSO also inhibits oxidized low density lipoprotein uptake by macrophages.
FAT/CD36 is a multifunctional glycoprotein that facilitates long-chain fatty acid (FA) uptake by cardiomyocytes and adipocytes and uptake of oxidized low density lipoproteins (oxLDL) by macrophages. CD36 also mediates FA-induced signaling to increase intracellular calcium in various cell types. The membrane-impermeable sulfo-N-hydroxysuccinimidyl (NHS) ester of oleate (SSO) irreversibly binds CD36 and has been widely used to inhibit CD36-dependent FA uptake and signaling to calcium. The inhibition mechanism and whether SSO modification of CD36 involves the FA-binding site remain unexplored. CHO cells expressing human CD36 were SSO-treated, and the protein was pulled down, deglycosylated, and resolved by electrophoresis. The CD36 band was extracted from the gel and digested for analysis by mass spectrometry. NHS derivatives react with primary or secondary amines on proteins to yield stable amide or imide bonds. Two oleoylated peptides, found only in SSO-treated samples, were identified with high contribution and confidence scores as carrying oleate modification of Lys-164. Lysine 164 lies within a predicted CD36 binding domain for FA and oxLDL. CHO cells expressing CD36 with mutated Lys-164 had impaired CD36 function in FA uptake and FA-induced calcium release from the endoplasmic reticulum, supporting the importance of Lys-164 for both FA effects. Furthermore, consistent with the importance of Lys-164 for oxLDL binding, SSO inhibited oxLDL uptake by macrophages. In conclusion, SSO accesses Lys-164 in the FA-binding site on CD36, and initial modeling of this site is presented. The data suggest competition between FA and oxLDL for access to the CD36 binding pocket.


Expression of Melanocortin-4 Receptor mRNA in Male Rat Hypothalamus During Chronic Stress.
The effects of chronic stress and glucocorticoids receptor antagonist (RU486) on expression of melanocortin 4 receptor (MC4R) mRNA in arcuate nucleus (ARC) of male rats were evaluated. In this study, adult male Sprague Dawley rats were placed into four groups (n=6/group); stress, RU486, stress/RU486, and control groups. In stress group, the rats were restrained, 1 h/day, for 12 days. In RU486 group, the rats were injected RU486 for 12 days. In stress/RU486 group, the rats were injected RU486 1 h before the stress process for 12 days. Relative expression of MC4R mRNA was determined using real-time PCR. Relative expression of MC4R mRNA in the stress group was higher than that of the control rats (P<0.05). Relative expressions of MC4R mRNA were not different between the stress, RU486 and stress/RU486 groups (P>0.05). Chronic restraint stress causes increase in mRNA expression of MC4R in ARC and blockade of glucocorticoid receptors has no effect on this up-regulation.


Electro-Optical Properties of Low-Temperature Growth Indium-tin-oxide Nanowires Using Polystyrene Spheres as Catalyst.
Polystyrene sphere was chosen as a catalyst to fabricate indium-tin-oxide (ITO) nanowires (NWs) with a low-temperature (280-300 °C) electron-beam deposition process, bearing high purity. The ITO NWs with diameter of 20-50 nm and length of ~2 um were obtained. X-ray diffraction and high-resolution transmission electron microscope show high crystal quality. The transmittance is above 90 % at a wavelength 400 nm or more, superior to the ITO bulk film. Owing to the unique morphology gradient of the ITO NWs, the effective refractive index of ITO NWs film is naturally graded from the bottom to the top. The ITO NWs have been used on LED devices (λ = 450 nm), which improved the light output power by 31 % at the current of 150 mA comparing to the one without NWs and did not deteriorate the electrical properties. Such ITO NWs open opportunity in LED devices to further improve light extraction efficiency.


Effects of diets supplemented with lard fat or mackerel oil on plasma lipoprotein lipid concentrations and lipoprotein lipase activities in domestic swine.
Levels of plasma lipoproteins and lipoprotein lipase activities in post-heparin serum were measured in 24-h fasted pigs which were fed a diet containing either 21 energy % mackerel oil or 21 energy % lard fat for 8 weeks. Lipoprotein fractionation was performed separately by density gradient ultracentrifugation and agarose gel chromatography. After 8 weeks levels of plasma triacylglycerol (-62%) and cholesterol (-55%) were lower in the mackerel oil than in the lard fat-fed animals. The triacylglycerol decline was exclusively due to the VLDL fraction, while cholesterol was reduced in all lipoprotein fractions (VLDL, IDL, LDL and HDL). Lipoprotein lipase activity in post-heparin serum, taken 6 h after a meal, was 31% decreased in mackerel oil-fed animals. The results support the hypothesis that regular intake of fish oil reduces VLDL secretion.


Molecular identification of Neospora caninum and co-infection with Toxoplasma gondii in genital apparatus of naturally infected cows in North Tunisia.
The aim of this study was to estimate the molecular prevalence of Toxoplasma gondii, Neospora caninum and the co-infection by both Apicomplexan parasites in uterus tissues of cows. PCR was used to detect T. gondii and N. caninum DNA in uterus from 140 uteri of slaughtered cows in the regional slaughterhouse of Béja (Northwest Tunisia). Positive PCR products were sequenced and used for the phylogenetic analysis. The overall molecular prevalence of T. gondii and N. caninum in cows' uterus was 5 and 15.57%, respectively. Co-infection prevalence by the two parasites was estimated to be 2.85%. Risk factors including the age categories significantly affected the molecular prevalence of T. gondii and N. caninum in cows' uterus. The highest molecular prevalence of T. gondii (11.5 ± 3.1) and N. caninum (21.1 ± 11.1; p = 0.038) was observed in cows aged of more than 8 years. There were no differences depicted according to cow's breeds and localities. Comparison of the partial sequences of the ITS1 gene revealed 100% similarity among our N. caninum sequence (MW136256) and those deposited in GenBank. The T. gondii sequence described in this study (MW260335) was 99.4-100% homologous to T. gondii sequences published in the GenBank.To the best of our knowledge, this is the first molecular evidence of N. caninum and T. gondii co-infection in naturally infected cows in North Africa. This information is pertinent in designing control programmes that would reduce economic losses in the livestock industry.


How cells sense extracellular matrix stiffness: a material's perspective.
The mechanical properties of the extracellular matrix (ECM) in which cells reside have emerged as an important regulator of cell fate. While materials based on natural ECM have been used to implicate the role of substrate stiffness for cell fate decisions, it is difficult in these matrices to isolate mechanics from other structural parameters. In contrast, fully synthetic hydrogels offer independent control over physical and adhesive properties. New synthetic materials that also recreate the fibrous structural hierarchy of natural matrices are now being designed to study substrate mechanics in more complex ECMs. This perspective examines the ways in which new materials are being used to advance our understanding of how ECM stiffness impacts cell function.


Do Politics Matter to an Orthopaedic Surgeon? (They Should!).
Orthopaedic trauma care is intimately tied with health policy, and current changes with health care reform may change how trauma care is delivered. This article offers a brief history of modern health care and the implications of new policies on the practice of orthopaedic trauma.


Refined avian risk assessment for chlorpyrifos in the United States.
Refined risk assessments for birds exposed to flowable and granular formulations ofCPY were conducted for a range of current use patterns in the United States. Overall,the collective evidence from the modeling and field study lines of evidence indicate that flowable and granular CPY do not pose significant risks to the bird communities foraging in agro-ecosystems in the United States. The available information indicates that avian incidents resulting from the legal, registered uses of CPY have been very infrequent since 2002 (see SI Appendix 3). The small number of recent incidents suggests that the current labels for CPY are generally protective of birds.However, incident data are uncertain because of the difficulties associated with finding dead birds in the field and linking any mortality observed to CPY.Plowable CPY is registered for a variety of crops in the United States including alfalfa, brassica vegetables, citrus, corn, cotton, grape, mint, onion, peanut, pome and stone fruits, soybean, sugar beet, sunflower, sweet potato, tree nuts, and wheat under the trade name Lorsban Advanced. The major routes of exposure for birds to flowable CPY were consumption of treated dietary items and drinking water. The Liquid Pesticide Avian Risk Assessment Model (Liquid PARAM) was used to simulate avian ingestion of CPY by these routes of exposure. For acute exposure,Liquid PARAM estimated the maximum retained dose in each of 20 birds on each of1,000 fields that were treated with CPY over the 60-d period following initial application.The model used a 1-h time step. For species lacking acceptable acute oral toxicity data (all focal species except northern bobwhite (C. virginianus) and redwinged blackbird (A. phoeniceus)), a species sensitivity distribution (SSD) approach was used to generate hypothetical dose-response curves assuming high, median and low sensitivity to CPY. For acute risk, risk curves were generated for each use pattern and exposure scenario. The risk curves show the relationship between exceedence probability and percent mortality. The results of the Liquid PARAM modeling exercise indicate that flow able CPY poses an acute risk to some bird species, particularly those species that are highly sensitive and that forage extensively in crops with high maximum application rates (e.g., grapefruit, orange). Overall, most bird species would not experience significant mortality as a result of exposure to flowable CPY.The results of a number of field studies conducted at application rates comparable to those on the Lorsban Advanced label indicate that flowable CPY rarely causes avian mortality. The results of the field studies suggest that Liquid PARAM is likely over-estimating acute risk to birds for flowable CPY.For chronic exposure, Liquid PARAM estimated the maximum total daily intake (TDI) over a user-specified exposure duration (28-d in the case of CPY).The maximum average TDI was compared to the chronic NOEL and LOEL from the most sensitive species tested for CPY, the mallard. This comparison was done for each of the 20 birds in each of the 1000 fields simulated in Liquid PARAM.The outpu· ~ are estimates of the probabilities of exceeding the NOEL and LOEL.Liquid PAkAM did not predict significant adverse effects resulting from chronic exposure to flowable CPY. The small number of incidents (2) involving CPY reported since 2002 suggests that the current labels for CPY are generally protective of birds.Granular CPY is registered for a wide variety of crops including brassica vegetables, corn, onion, peanut, sugar beet, sunflower, and tobacco under the trade name Lorsban 15G. Consumption of grit is required by many birds to aid in digestion of hard dietary items such as seeds and insects. Because CPY granules are in the same size range as natural grit particles consumed by birds, there is a potential for birds to mistakenly ingest granular CPY instead of natural grit. We developed the Granular Pesticide Avian Risk Model (GranPARAM) to simulate grit ingestion behavior by birds. The model accounts for proportion of time that birds forage for grit in treated fields, relative proportions of natural grit versus pesticide granules onthe surface of treated fields, rates of ingestion of grit, attractiveness of pesticide granules relative to natural grit and so on. For CPY, each model simulation included20 birds on each of 1,000 fields to capture variability in rates of ingestion of grit and for aging behavior between birds within a focal species, and variability in soil composition between fields for the selected use pattern. The estimated dose for each birdwas compared with randomly chosen doses from relevant dose-response curves forCPY. Our analysis for a wide variety of use patterns on the Lorsban 15G label found that granular CPY poses little risk of causing mortality to bird species that frequent treated fields immediately after application. The predictions of the model have been confirmed in several avian field studies conducted with Lorsban 15G at application rates similar to or exceeding maximum application rates on the Lorsban 15G label.


Oxygen uptake transients at the onset and offset of arm and leg work.
The halftimes (t1/2) of the VO2 on-and off-responses have been determined on 4 moderately active subjects (1) in arm cranking (VO2 congruent to 1 1/min). (2) in leg pedaling at 4 graded submaximal (VO2 congruent to 0.8 to 2.51/min) work loads, and (3) when superimposing arm cranking on preexisting leg pedaling, both in the supine and in the upright position. In supine experiments the mean t1/2 of the VO2 on-response was longer for arm cranking than for leg pedaling (64 vs 44-49 sec) at equal VO2; however, at the same percentage of arm and leg VO2 max the respective t1/2 were similar. In sitting experiments all t1/2 of the VO2 on-response were shorter than when supine, but the t1/2 for the arms were still slightly longer than those for the legs. When arm cranking was superimposed on preexisting leg pedaling, the t1/4 for arms was reduced both in supine (from 64 to 35-38 sec) and in the sitting position (from 44 to 40 sec). The halftime of the VO2 off-response were much shorter (20-32 sec) than those of the on-response and similar in all experiments. In all conditions the O2 deficits at work onset were considerably larger than the fast component of the corresponding O2 debts during the first minutes of recovery. The difference was totally accounted for by anaerobic glycolysis occurring early during the VO2 on-response, particularly in arm exercise. It is concluded that at submaximal work loads the O2 deficit is accounted for the fast component of the O2 debt plus the O2 equivalent of the early lactate production.


Molecular cloning and expression of cDNAs encoding alcohol dehydrogenases from Vitis vinifera L. during berry development.
Three full-length cDNAs (VvAdh1, VvAdh2, and VvAdh3) encoding alcohol dehydrogenases (EC 184.108.40.206) were obtained from grape berries (Vitis vinifera L.) by means of PCR and RACE. Pairwise comparisons at the nucleotide level showed that the three cDNAs displayed strong homology in the coding region, but were highly divergent in the 5' and 3' untranslated regions. VvAdh1 and VvAdh2 corresponded to the two previously characterised Adh genes from grapevine, but VvAdh3 was unrelated to known grapevine Adh sequences. The two first cDNAs presented a single ORF of 380 amino acids, whereas the last one has two additional residues. Moreover, the three encoded polypeptides possessed the 22 residues strictly conserved between Adh from different kingdoms. Expression pattern of the individual isogenes was investigated during fruit development. Specific primers were designed, and quantitative RT-PCR experiments were performed to increase the sensitivity of detecting isogenes with a low expression level. Results presented here revealed different developmental regulation of the three Adh isogenes during fruit ripening. VvAdh1 and VvAdh3 transcripts were temporarily accumulated in young, developing berry, whereas VvAdh2 was overexpressed later in fruit development, from the onset of ripening (véraison). Expression analysis also indicated that VvAdh2 accounted for most of the Adh mRNAs present in berries during development. The increased ADH activity detected in berries correlated with the expression pattern of VvAdh2 transcripts. The VvAdh2 and VvAdh3 encoded enzymes were purified from overexpressing E. coli cells. Comparison of kinetic properties of the two ADH enzymes showed a difference in affinity with either ethanol or acetaldehyde as substrates. Significance of multiple Adh expressed in berries is discussed.


Geographic pathology of thyroid diseases.
The thyroid is one of the organs which demonstrates clearly the influence of extrinsic and especially geographically determined influences in the development of diseases. Endemic goiter and cretinism are the most typical examples. The question as to whether thyroid cancer arises more frequently in goiters that in normal thyroids, cannot be answered definitely as yet. But without doubt, the relative frequency of different types of thyroid neoplasms in goiter areas is not the same as in region without endemic goiter. The most common type of thyroid carcinoma observed in a nonendemic region is papillary carcinoma. Follicular and anaplastic carcinomas, however, are more often associated with goiter. Under the influence of iodine prophylaxis, the relative frequency of the different types of thyroid carcinoma approaches that of these carcinomas in nongoiter regions. The malignant hemangioendothelioma is observed nearly exclusively in some Alpine goiter areas. Since the introduction of preventive measures in Switzerland, its occurrence has diminished progressively. In contrast to endemic goiter, focal thyroiditis and even Hashimoto's disease seem to be on the increase since institution of iodine prophylaxis of endemic goiter. As the development of malignant lymphoma may be related to thyroiditis, a possible increase of such tumors should be considered.


Impairment of Akt activity by CYP2E1 mediated oxidative stress is involved in chronic ethanol-induced fatty liver.
Protein kinase B (PKB/Akt) plays important roles in the regulation of lipid homeostasis, and impairment of Akt activity has been demonstrated to be involved in the development of non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that cytochrome P4502E1 (CYP2E1) plays causal roles in the pathogenesis of alcoholic fatty liver (AFL). We hypothesized that Akt activity might be impaired due to CYP2E1-induced oxidative stress in chronic ethanol-induced hepatic steatosis. In this study, we found that chronic ethanol-induced hepatic steatosis was accompanied with reduced phosphorylation of Akt at Thr308 in mice liver. Chronic ethanol exposure had no effects on the protein levels of phosphatidylinositol 3 kinase (PI3K) and phosphatase and tensin homologue deleted on chromosome ten (PTEN), and led to a slight decrease of phosphoinositide-dependent protein kinase 1 (PDK-1) protein level. Ethanol exposure resulted in increased levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE)-Akt adducts, which was significantly inhibited by chlormethiazole (CMZ), an efficient CYP2E1 inhibitor. Interestingly, N-acetyl-L-cysteine (NAC) significantly attenuated chronic ethanol-induced hepatic fat accumulation and the decline of Akt phosphorylation at Thr308. In the in vitro studies, Akt phosphorylation was suppressed in CYP2E1-expressing HepG2 (CYP2E1-HepG2) cells compared with the negative control HepG2 (NC-HepG2) cells, and 4-HNE treatment led to significant decrease of Akt phosphorylation at Thr308 in wild type HepG2 cells. Lastly, pharmacological activation of Akt by insulin-like growth factor-1 (IGF-1) significantly alleviated chronic ethanol-induced fatty liver in mice. Collectively, these results indicate that CYP2E1-induced oxidative stress may be responsible for ethanol-induced suppression of Akt phosphorylation and pharmacological modulation of Akt in liver may be an effective strategy for the treatment of ethanol-induced fatty liver.


Activity-Dependent Transcription Collaborates with Local Dendritic Translation to Encode Stimulus-Specificity in the Genome Binding of NPAS4.
A new study in Cell (Brigidi et al., 2019) shows that local dendritic versus somatic translation of the neuronal activity-inducible transcription factor NPAS4 drives the formation of distinct heterodimers that enable stimulus-specificity to be encoded into the pattern of NPAS4 binding across the genome.


[Diagnostic criteria: OCT angiography for retinal angiomatous proliferation (RAP lesions, type 3 neovascularization)].
Multimodal imaging of retinal angiomatous proliferation (RAP) lesions (type 3 neovascularization) and the diagnostic significance of optical coherence tomography angiography (OCT-A). Confirmation of the diagnosis in six case reports with fundus photography, optical coherence tomography (OCT), fluorescein angiography (FLA), indocyanine green angiography (ICGA) and optical coherence tomography angiography (OCT‑A). The use of OCT‑A is helpful for the diagnosis and follow-up examinations of RAP lesions (type 3 neovascularization). It enables the detailed visualization of intraretinal and choroidal microcirculation. Furthermore, it is possible to evaluate the progression, classify the stages and comprehend the treatment strategy.


Outcomes and survival after laparoscopic gastrectomy for adenocarcinoma. Analysis on 65 patients operated on by conventional or robot-assisted minimal access procedures.
Despite laparoscopic surgery for gastric cancer has gained worldwide acceptance, long term results and survival are seldom reported. This study was designed to assess long term outcomes after laparoscopic gastrectomy with D2 dissection. The short term results of conventional and robot-assisted minimally invasive procedures were also examined. The charts of 65 patients who underwent laparoscopic surgery for non-metastatic adenocarcinoma were reviewed retrospectively. This series included 35 patients with early gastric cancer (EGC) and 30 with advanced gastric cancer (AGC). A 4/5 laparoscopic subtotal gastrectomy (LSG) with D2 nodal clearance was the procedure of choice for distal cancers. Laparoscopic total gastrectomy (LTG) with modified D1 lymphadenectomy was performed for mid-proximal EGC. Sixty gastrectomies were carried out laparoscopically, 56 LSG and 4 LTG. Conversion to laparotomy was required in 5 patients with distal cancer. No intraoperative complication was registered. Morbidity included 2 duodenal leaks that healed conservatively. Two postoperative deaths were registered. An average number 31.3+/-8.8 lymph nodes were collected. The mean hospital stay was 10 days (range 7-24). The mean follow up was 30 months (range 2-86) and the cumulative overall 5 year survival rate was 78%. Survival at 5 years for EGC was 94% and survival at 4 years for AGC was 53% (57% for non-converted patients). Laparoscopic gastrectomy for cancer represents a valid alternative to open surgery with minimal morbidity and acceptable long term survival. Considering the risk of preoperative under diagnoses a D2 lymphadenectomy is suggested also for EGC. This study validated the effectiveness of minimally invasive technique in the management of gastric cancer.


Human Phenotypic Diversity: An Evolutionary Perspective.
As humans migrated across the world, they encountered new environments requiring them to adapt to new challenges that presented themselves. The distribution of human phenotypes observed today is the result of this continuous adaptation, via biological/physiological and cultural means, and also by the modification of cultural practices, which leads to biological changes. In this chapter, we examine a number of adaptive traits and the roles played by their genetic and environmental determinants. We have selected a few traits used for human identification purposes (externally visible characteristics), associated with human metabolism and linked to a shift in subsistence method and food consumption. We discuss the evolutionary processes that have affected the temporal and spatial distribution of these traits, including natural, sexual, and cultural selection.


[Clinical aspects and pathogenesis of infarction of the brain stem].
Clinical and hemodynamic studies were carried out in 75 patients with stem brain infarction in the acute period, including repeated infarctions. The total rupture of the autoregulatory mechanisms of the brain blood flow was discovered, leading to the development of different phenomena of "brain steal" determining the clinical course of stem brain infarction. In the given pathology, the acute period is characterized by the development of the vicious circle of hemodynamic disorders, which is coupled with pathological dissociation in coagulation hemostasis. The progression of the hemodynamic changes requires pathogenetic correction of central and cerebral circulation.


A Most Enantioselective Chiral Surface: Tartaric Acid on All Surfaces Vicinal to Cu(110).
Enantioselective chemistry on intrinsically chiral surfaces is the quintessential form of structure-sensitive surface chemistry, arising purely from the dissymmetry of the surface structure. Identification or design of chiral surface structures that maximize enantioselectivity for a given processes is extremely challenging because of the limited magnitude of the enantiospecific interaction energetics of chiral molecules with chiral surfaces. Using spherical Cu single crystals exposing surfaces with a continuous two-dimensional distribution of crystallographic orientations, we mapped the enantiospecific surface reaction kinetics of tartaric acid decomposition across the surface orientation space. These measurements reveal both the mechanistic origin of enantioselectivity and identify the structural features of the most enantiospecific surface orientation.


High molecular protein of Helicobacter pylori responsible for inhibition of ornithine decarboxylase activity of human gastric cultured cells.
Ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, mediates epithelial cell proliferation and plays a critical role in the optimal repair of gastric mucosal damage. Several studies have shown that Helicobacter pylori inhibits the growth and proliferation of gastric cells in vitro. To test whether H. pylori extract affects ODC mRNA expression and its enzyme activity in gastric cells and to examine the partial characterization of the molecule responsible for this effect. Human gastric cells (MKN-45) were used. Bacterial extracts from various E. coli or H. pylori strains, namely (1) cagA+, vacA+, CagA+, VacA+; (2) cagA+, vacA+, CagA+ VacA-; or (3) cagA-, vacA+, CagA-, VacA- were added to the cells. Cell proliferation was assessed by [3H]-thymidine incorporation, viability by MTT assay and LDH release test, ODC enzyme activity by 14CO2 counts from L-[1(14)C]ornithine, and ODC mRNA by Northern blotting. H. pylori and E. coli extract did not affect viability of gastric cells. H. pylori extract, especially extracts containing a protein greater than 50 kDa, significantly inhibited proliferation and ODC activity of gastric cells while E. coli extract had no effect. Inhibition of ODC activity was found in extracts of all H. pylori strains, irrespective of CagA and VacA protein expression. Serum stimulation induces an increase in ODC mRNA while H. pylori extract did not affect ODC mRNA expression. High molecular weight (greater than 50 kDa) proteins of H. pylori extract without CagA or VacA protein inhibited proliferation and ODC activity of human gastric cells, but did not affect ODC mRNA expression, suggesting that inhibition of ODC activity is regulated at the post-transcriptional level.


Pimobendan increases calcium sensitivity of skinned human papillary muscle fibers.
The calcium sensitizing effects of the cardiotonic agent pimobendan on force production were investigated on chemically skinned human papillary muscle fibres. The papillary muscles were obtained from patients undergoing mitral valve replacement operations. Tension was produced by different free calcium concentrations and 100 mumol/l of pimobendan shifted the pCa-tension relationship significantly to the left. The effects of pimobendan were concentration dependent (10-300 mumol/l) but additionally also correlated with the state of left ventricular performance of the patients. Skinned papillary muscle fibres obtained from patients with reduced ventricular performance were more sensitive to calcium as well as pimobendan compared with fibres from patients with normal left ventricular performance. No differences in response to pimobendan were observed between fibres from NYHA II and NYHA III heart failure patients.


Alternatives to amputation.
Amputation of the digit of valuable animals is an inappropriate technique for resolving the serious infective processes that involve the important structures of the distal interphalangeal region. Surgeons should be able to recognize the early clinical signs and radiographic indications of three distinct, but interrelated, phenomena--the septic joint, the retroarticular abscess, and the complication of tenovaginitis. Tenovaginitis depends on either the septic joint or retroarticular abscess for its etiology. In any of these complications, the effective treatment will be based on the removal of diseased tissue and on irrigation with drainage of the area, followed by the elimination of mechanical forces or movement in the affected region.


Constructing core competency indicators for clinical teachers in Taiwan: a qualitative analysis and an analytic hierarchy process.
The objective of this study was to construct a framework of core competency indicators of medical doctors who teach in the clinical setting in Taiwan and to evaluate the relative importance of the indicators among these clinical teachers. The preliminary framework of the indicators was developed from an in-depth interview conducted with 12 clinical teachers who had previously been recognized and awarded for their teaching excellence in university hospitals. The framework was categorized into 4 dimensions: 1) Expertise (i.e., professional knowledge and skill); 2) Teaching Ability; 3) Attitudes and Traits; and 4) Beliefs and Values. These areas were further divided into 11 sub-dimensions and 40 indicators. Subsequently, a questionnaire built upon this qualitative analysis was distributed to another group of 17 clinical teachers. Saaty's eigenvector approach, or the so-called analytic hierarchy process (AHP), was applied to perform the pairwise comparisons between indicators and to determine the ranking and relative importance of the indicators. Fourteen questionnaires were deemed valid for AHP assessment due to completeness of data input. The relative contribution of the four main dimensions was 31% for Attitudes and Traits, 30% for Beliefs and Values, 22% for Expertise, and 17% for Teaching Ability. Specifically, 9 out of the 10 top-ranked indicators belonged to the "Attitudes and Traits" or "Beliefs and Values" dimensions, indicating that inner characteristics (i.e., attitudes, traits, beliefs, and values) were perceived as more important than surface ones (i.e., professional knowledge, skills, and teaching competency). We performed a qualitative analysis and developed a questionnaire based upon an interview with experienced clinical teachers in Taiwan, and used this tool to construct the key features for the role model. The application has also demonstrated the relative importance in the dimensions of the core competencies for clinical teachers in Taiwan.


Mesoscale eddies and Trichodesmium spp. distributions in the southwestern North Atlantic.
Trichodesmium abundance was elevated in certain cyclonic and anticyclonic eddiesEnhancement in cyclonic eddies could be driven by Ekman convergenceAnticyclonic eddies with elevated abundance were anomalously fresh.


The evolution and current use of invasive hemodynamic monitoring for predicting volume responsiveness during resuscitation, perioperative, and critical care.
Traditional hemodynamic monitors such as pulmonary artery and central venous catheters provide continuous data and secure intravenous access, but their diagnostic efficacy has been criticized. Dynamic arterial waveform monitoring is promising, but studies suggest it is reliable only within narrow ventilation and rhythm parameters. Newer algorithm-based hemodynamic monitors have emerged; they, too, are limited in their accuracy and applicability. Intravascular monitors are used to predict fluid responsiveness and need for alternative therapies, such as vasomotor or inotropic support. Recent efficacy data, along with other important clinical findings, are reviewed with regard to invasive monitors. We caution against over-generalizing from existing studies, and provide guidance for clinicians wishing to target monitoring techniques for appropriate patients.


Carnitine deficiency in surgical neonates receiving total parenteral nutrition.
Carnitine plays a key role in the oxidation of fatty acids. Most solutions for parenteral nutrition do not contain carnitine. Because endogenous carnitine synthesis is insufficient in newborns, they are prone to developing a carnitine deficiency when they are dependent on total parenteral nutrition (TPN). Stimulated by the clinical observation of manifest clinical symptoms of carnitine deficiency in one patient, a study of 13 consecutive neonates who received TPN for over 2 weeks was begun. Their plasma carnitine levels before and during carnitine supplementation were determined. All patients had a carnitine intake far below the recommended minimal need of 11 mumol/kg per day. Although only three of them clearly showed clinical symptoms described as carnitine deficiency, carnitine supplementation for all neonates receiving TPN for over 2 weeks is recommended.


Suppression of levels of phenobarbital-inducible rat liver cytochrome P-450 by pituitary hormone.
The effect of pituitary factor on the constitutive and inducible levels of hepatic phenobarbital (PB)-inducible major cytochrome P-450, P-450b and P-450e, in male and female rat livers was studied by immunoblot analyses. Although only trace amounts (approximately 4 pmol/mg protein) of P-450b and P-450e were detected in untreated adult rats, hypophysectomy increased the contents of P-450b and P-450e 58- and 14-fold, respectively, in male rats and 118- and 30-fold, respectively, in female rats. The increases were also observed in treatment with dexamethasone, which suppressed the pituitary function. Treatment with PB increased more effectively the hepatic contents of P-450b and P-450e, but their contents were still 4-fold higher in the male than the female. Treatment of hypophysectomized female rats with PB increased the contents of P-450b and P-450e 4-fold higher than the contents in PB-treated nonhypophysectomized female rats. Consequently, the sex-related difference in their contents was reduced less than 1.4-fold in the hypophysectomized rats treated with PB. Similar results were also obtained from the quantitation of microsomal O-pentylresorufin O-depentylation and testosterone 16 beta-hydroxylation. Either intermittent injection or continuous infusion of human growth hormone, but not of ovine prolactin, into hypophysectomized male and female rats decreased the contents of both cytochromes. These results indicate that growth hormone acts as a repressive factor for the constitutive and inducible levels of P-450b and P-450e in a manner different from the regulation of P-450-male and P-450-female.


[Multidimensional analysis of the relation between the resources of the psychiatric service and the detection and prevalence of mental patients in regions of Siberia and the Far East].
The article deals with the assessment of the main components and canonic correlations reflecting the relationship between the resources of psychiatric care (a number of beds and psychiatrists providing medical care in hospitals and in other settings) and the rate of identification and incidence of psychoses, schizophrenia, epilepsy, alcoholism, neuroses and oligophrenia in Siberia and Far East over a period of 16 years (from 1965 to 1981 excluding 1978). The first main component covered up to 80.1% of the dispersion range of the identification rate and 94.5% of the incidence rate, the second component covered up to 37.1% and 21% respectively. Canonic correlations proved higher for the incidence rate as against the identification rate. Although there were substantial differences in the studied interrelationship with regard to a number of territories, the main tendency was expressed in a marked linear correlation between a growth in the resources of psychiatric service and the time-course of the rates of the studied pathology.


Microdose intravaginal levonorgestrel contraception: a multicentre clinical trial. III. The relationship between pregnancy rate and body weight. World Health Organization. Task Force on Long-Acting Systemic Agents for Fertility Regulation.
This paper investigates the relationship between pregnancy rates and body weight of 1005 women using a vaginal ring releasing 20 micrograms levonorgestrel per 24 hours. While the overall pregnancy rate at one year was 3.7%, it was found that women have an increasing risk of pregnancy with increasing body weight. For example, a woman of 40 kg has an estimated pregnancy rate of 1.7% in contrast to 9.8% for a woman of 80 kg weight.


Evaluation of COD effect on anammox process and microbial communities in the anaerobic baffled reactor (ABR).
Nitrogen removal with different organic carbon effect was investigated using anaerobic baffled reactor (ABR) anammox reactor. Results indicated that organic carbon exert an important effect on nitrogen removal through anammox process. When the feeding COD concentration was lower than 99.7mgL(-1), nitrogen removal could be enhanced via the coexistence of denitrification and anammox. Elevated COD could further deteriorate the anammox activity with almost complete inhibition at the COD concentration of 284.1mgL(-1). The nitrogen removal contribution rate of anammox was varied from 92.7% to 6.9%. However, the anammox activity was recovered when the COD/TN was decreased from 2.33 to 1.25 with influent nitrite addition. And, the anammox process was again intensified from 27.0 to 51.2%. High-throughput Miseq sequencing analyses revealed that the predominant phylum changed from Chloroflexi to Proteobacteria with the elevated COD addition, which indicated COD concentration was the most important factor regulating the bacterial community structure.


Extract of Lycopus europaeus L. reduces cardiac signs of hyperthyroidism in rats.
Extracts from the plant Lycopus europaeus L. are traditionally used in mild forms of hyperthyroidism. High doses caused a reduction of TSH or thyroid hormone levels in animal experiments, whereas in hyperthyroid patients treated with low doses of Lycopus an improvement of cardiac symptoms was reported without major changes in TSH or thyroid hormone concentrations. Lycopus extract was tested in thyroxine treated hyperthyroid rats (0.7 mg/kg BW i.p.). Co-treatment with an hydroethanolic extract from L. europaeus L. started one week later than T4-application and lasted 5.5 weeks. As reference substance atenolol was used. The raised body temperature was reduced very effectively even by the low dose of the plant extract, whereas the reduced gain of body weight and the increased food intake remained unaffected by any treatment. No significant changes of thyroid hormone concentrations or TSH levels were observed. Lycopus extract and atenolol reduced the increased heart rate and blood pressure. The cardiac hypertrophy was alleviated significantly by both treatment regimes. beta-Adrenoceptor density in heart tissue was significantly reduced by the Lycopus extract or the beta-blocking agent showing an almost equal efficacy. Although the mode of action remains unclear, these organo-specific anti-T4-effects seem to be of practical interest, for example in patients with latent hyperthyroidism.


A comparative study of ventrolateral and recurrent excitatory postsynaptic potentials in large pyramidal tract cells in the cat.
In acute cats deeply anesthetized with Nembutal, monosynaptic excitatory postsynaptic potentials (EPSPs) triggered by stimulation of the ventrolateral (VL) thalamic nucleus and the pes pedunculus were recorded in large pyramidal tract cells (PT cells). Deep anesthesia, low intensities of stimulation and an averaging technique were used in order to get VL and recurrent EPSPs free of polysynaptic potentials. Comparison of the time course of both EPSPs revealed a much faster rise time and shorter half-width for VL EPSPs than for recurrent EPSPs. This would suggest a more proximal location for VL synaptic contacts than for recurrent ones with respect to the soma of PT cells. The separation of the sites of origin of both EPSPs is further suggested by their almost perfect linear summation. It is suggested that VL EPSPs are produced on the apical dendritic tree, while recurrent EPSPs could originate on the basilar dendritic branches.


Progress on materials and scaffold fabrications applied to esophageal tissue engineering.
The mortality rate from esophageal disease like atresia, carcinoma, tracheoesophageal fistula, etc. is increasing rapidly all over the world. Traditional therapies such as surgery, radiotherapy or chemotherapy have been met with very limited success resulting in reduced survival rate and quality of patients' life. Tissue-engineered esophagus, a novel substitute possessing structure and function similar to native tissue, is believed to be an effective therapy and a promising replacement in the future. However, research on esophageal tissue engineering is still at an early stage. Considerable research has been focused on developing ideal scaffolds with optimal materials and methods of fabrication. This article gives a review of materials and scaffold fabrications currently applied in esophageal tissue engineering research.


Cysteamine as a Future Intervention in Cystic Fibrosis Against Current and Emerging Pathogens: A Patient-based ex vivo Study Confirming its Antimicrobial and Mucoactive Potential in Sputum.
Cysteamine has recently been shown to have in vitro properties potentially therapeutically beneficial in cystic fibrosis (CF). In this study we investigated the antimicrobial and mucolytic activity of cysteamine against the complex biologic matrix of CF sputum. Sputum samples were obtained from 23 CF adults. Sputum polymicrobial content after in vitro exposure to cysteamine and standard CF antibiotics was assessed after a single exposure and after 14 days low-dose exposure. The effect of cysteamine on sputum spinnbarkeit was assessed. Cysteamine reduced sputum polymicrobial burden by 3.18 (95% CI 2.30-4. 07, p < 0.001) log10 units after 24 h incubation. Combined cysteamine and tobramycin reduced polymicrobial burden by a further 3.75 (95% CI 2.63-5.07, p < 0 · 001) log10 units above that seen with tobramycin. Repeated low dosing with cysteamine reduced sputum polymicrobial load from day 10 onwards (p = 0.032). Cysteamine reduced CF sputum viscoelasticity, sputum spinnbarkeit cysteamine 11.1 mm/s (95% CI 3.95-18.2) vs DNAse 1.69 mm/s (95% CI 0.73-2.65), p = 0.016. Cysteamine was active against Mycobacterium abscessus as a monotherapy and also potentiated the effects of amikacin and azithromycin. Further investigation is required into the therapeutic potential of cysteamine in CF to treat emerging as well as established microbial pathogens and as a mucolytic agent.


Replication: key to research application.
Replication of research is critical to expanding the sample size and demonstrating applicability of research findings for different critical care patients or units. This author describes several options for developing a replication study in critical care.


Aberrant modulation of the BRCA1 and G1/S cell cycle pathways in alcoholic hepatitis patients with Mallory Denk Bodies revealed by RNA sequencing.
Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. Liver injury from alcohol administration causes balloon hepatocytes and MDB formation impeding liver regeneration. By comparing AH livers where MDBs had formed with normal liver transcriptomes obtained by RNA sequencing (RNA-Seq), there was significant upregulation of BRCA1-mediated signaling and G1/S cell cycle checkpoint pathways. The transcriptional architecture of differentially expressed genes from AH livers reflected step-wise transcriptional changes progressing to AH. Key molecules such as BRCA1, p15 and p21 were significantly upregulated both in AH livers and in the livers of the DDC re-fed mice model where MDBs had formed. The increase of G1/S cell cycle checkpoint inhibitors p15 and p21 results in cell cycle arrest and inhibition of liver regeneration, implying that p15 and p21 could be exploited for the identification of specific targets for the treatment of liver disease. Provided here for the first time is the RNA-Seq data that represents the fully annotated catalogue of the expression of mRNAs. The most prominent alterations observed were the changes in BRCA1-mediated signaling and G1/S cell cycle checkpoint pathways. These new findings expand previous and related knowledge in the search for gene changes that might be critical in the understanding of the underlying progression to the development of AH.


Effects of hexamethonium and other ganglionic blocking agents on electrical activity of the esophagus induced by vagal stimulation in the dog.
Electrical activity of the dog's esophagus was evoked by electrical stimulation of the vagus nerve and recorded by using a suction electrode placed on the serosal surface of the esophagus. Neuromuscular blocking agents (d-tubocurarine and succinylcholine) blocked this activity, while atropine had no effect. Hexamethonium (in doses which did not effect neuromuscular transmission in the diaphragm) and high doses of nicotine significantly depressed the evoked esophageal electrical activity, while lower doses of nicotine facilitated the response. The results suggest that a certain proportion of the striated muscle of the esophagus is innervated by processes from the intermediate ganglion cells in the Auerbach plexus.


Identification and partial characterization of phospholipid methylation in rat small-intestinal brush-border membranes.
An earlier study (Biochim. Biophys. Acta 46 (1961) 205-216) failed to detect the enzymatic synthesis of phosphatidylcholine (PC) from phosphatidylethanolamine (PE) via a transmethylation pathway in rat small-intestinal microsomal membranes. This pathway was therefore assumed to be absent from this organ. Recently, however, in our laboratory it has been demonstrated that this pathway for the synthesis of phosphatidylcholine is present in rat colonic brush-border and basolateral membranes. It was therefore of interest to examine whether phospholipid methylation activity was present in rat small-intestinal brush-border membranes. The results of the present experiments demonstrate for the first time that this pathway for the synthesis of phosphatidylcholine exists in these plasma membranes. Evidence to support the enzymatic nature of this reaction include: loss of activity by heat denaturation and at 0 degree C, significant inhibition by S-adenosyl-L-homocysteine and saturation kinetics. The predominant product of this brush-border membrane phospholipid methyltransferase is phosphatidyl-N-monomethylethanolamine. This enzymatic activity has an apparent Km for S-adenosyl-L-methionine of 40 microM, a Vmax of 8.4 pmol/mg protein per 5 min, and a pH optimum of 8.0.


Screening for Lung Cancer.
Lung cancer is a global health burden and is among the most common and deadliest of all malignancies worldwide. The goal of screening programs is to detect tumors in earlier, curable stages, consequently reducing disease-specific mortality. The issue of screening has great relevance to thoracic surgeons, who should play a leading role in the debate over screening and its consequences. The burden is on thoracic surgeons to work in a multidisciplinary setting to guide and treat these patients safely and responsibly, ensuring low morbidity and mortality of potential diagnostic or therapeutic interventions.


Strategic green marketing orientation and environmental sustainability in sub-Saharan Africa: Does green absorptive capacity moderate? Evidence from Tanzania.
Small and medium-sized enterprises are increasingly promoting environmental sustainability, a trend that has raised environmental awareness and inspired individuals and organizations to work together to create a more sustainable and greener future by implementing environmentally friendly practices. This study examines the influence of strategic green marketing orientation on environmental sustainability. Also, the study examines the moderating effect of green absorptive capacity on the relationship between strategic green marketing orientation and environmental sustainability. We used partial least squares structural equation modelling to test hypotheses with data obtained from 391 manufacturing enterprises in Tanzania via structured questionnaires. Our study's main findings show that strategic green marketing orientation has a significant and positive influence on environmental sustainability, and green absorptive capacity strengthens the positive effect of strategic green marketing orientation on environmental sustainability. Although there is scholarly interest in incorporating environmental considerations into business endeavors, there is little evidence on ways that a strategic green marketing orientation promotes environmental sustainability in a manufacturing context. Thus, our findings add to the literature on understanding environmental sustainability for manufacturing enterprises by revealing the role of strategic green marketing orientation and green absorptive capacity in explaining environmental sustainability. The study suggests that manufacturing enterprises should integrate environmental considerations into their strategic resources and endeavors to improve eco-friendly outcomes.


Genetic variants in 2q31 and 5p15 are associated with aggressive benign prostatic hyperplasia in a Chinese population.
Benign prostatic hyperplasia (BPH) is a common disease prevalent in elderly men. However, the genetic determinants of BPH remain unclear. Because BPH and prostate cancer (PCa) share some common pathological characteristics, we investigated whether susceptibility loci for PCa contributed to BPH risk and BPH aggressiveness in Chinese men. Fourteen SNPs associated with PCa risk in a Chinese population were genotyped in 426 BPH cases (184 aggressive and 242 non-aggressive BPH cases) and 1,008 controls. The association between the SNPs and BPH risk/aggressiveness was estimated using logistic regression analysis. In addition, effects of the 14 SNPs on BPH related clinical traits, including International Prostate Symptom Score (IPSS), prostate volume, total PSA, and free PSA were evaluated using linear regression analysis. Two SNPs, rs12621278 in ITGA6 at 2q31 (OR = 0.82, P = 0.05) and rs339331 in RFX6 at 6q22 (OR = 1.22, P = 0.04) were significantly associated with BPH. In addition, rs12621278 (OR = 0.73, P = 0.05) and rs12653946, 13 kb upstream of IRX4 at 5p15 (OR = 1.40, 0.03), were significantly associated with aggressive BPH. Moreover, the risk allele of rs12621278 (G) and rs12653946 (T) for aggressive BPH were significantly associated with elevated IPSS after treatment (P = 0.01). This is the first systematic investigation on the contributions of PCa susceptibility loci to risk and aggressiveness of BPH. Our findings advance our understanding of the genetic basis of BPH, especially aggressive BPH. In addition, our results provide new insights into the genetic determinants shared between BPH and PCa.


Short hairpin RNA-mediated knockdown of VEGFA in Müller cells reduces intravitreal neovascularization in a rat model of retinopathy of prematurity.
Vascular endothelial growth factor (VEGF) A is implicated in aberrant angiogenesis and intravitreous neovascularization (IVNV) in retinopathy of prematurity (ROP). However, VEGFA also regulates retinal vascular development and functions as a retinal neural survival factor. By using a relevant ROP model, the 50/10 oxygen-induced retinopathy (OIR) model, we previously found that broad inhibition of VEGFA bioactivity using a neutralizing antibody to rat VEGF significantly reduced IVNV area compared with control IgG but also significantly reduced body weight gain in the pups, suggesting an adverse effect. Therefore, we propose that knockdown of up-regulated VEGFA in cells that overexpress it under pathological conditions would reduce IVNV without affecting physiological retinal vascular development or overall pup growth. Herein, we determined first that the VEGFA mRNA signal was located within the inner nuclear layer corresponding to CRALBP-labeled Müller cells of pups in the 50/10 OIR model. We then developed a lentiviral-delivered miR-30eembedded shRNA against VEGFA that targeted Müller cells. Reduction of VEGFA by lentivector VEGFA-shRNAetargeting Müller cells efficiently reduced 50/10 OIR up-regulated VEGFA and IVNV in the model, without adversely affecting physiological retinal vascular development or pup weight gain. Knockdown of VEGFA in rat Müller cells by lentivector VEGFA-shRNA significantly reduced VEGFR2 phosphorylation in retinal vascular endothelial cells. Our results suggest that targeted knockdown of overexpressed VEGFA in Müller cells safely reduces IVNV in a relevant ROP model.


Safe Use of Defibrillators: A Case Study in Greek Registered Nurses.
International literature reveals the deficit of nurses' knowledge on the defibrillator and the need to implement continuing education training courses relative to clinical issues.The purpose of this study was the evaluation of Greek registered nurses' knowledge on the safe use of the defibrillator before and after a 2-h workshop. Anonymous self-administered validated questionnaire consisted of two parts was used to collect the data, after the written consent of the participants. The sample consisted of 65 participants (12 men and 53 women) and the output data were analyzed with SPSS v. 19.0 (SPSS Inc., Chicago, IL). The quantitative variables are expressed as mean values (SD) or as median values (interquartile range = IQR) while the qualitative variables are expressed as absolute and relative frequencies. For the comparison of the proportions of the correct answers before and after the intervention, McNemar tests were used. A knowledge score was computed for every participant from all correct answers and converted to a scale from 0 to 100 (where 0 = none correct answer and 100 = all answers were correct). Paired Student's t-tests were used for the comparison of the knowledge score before and after the intervention. All reported p values are two-tailed and the statistical significance was set at p < 0.05. The mean knowledge score increased significantly from 66.7% to 91.3% after the intervention. The study showed that the implementation of educational programs contributes positively to update registered nurses' knowledge on clinical issues, which cannot be replenished only through undergraduate education and experience.


Decreased cardiovagal regulation in exfoliation syndrome.
To investigate the parasympathetic cardiovascular regulation, baroreflex sensitivity (BRS), and pulse wave velocity (PWV) in exfoliation syndrome (XFS). Heart rate variability indices [standard deviation of all RR intervals (SDNN); the mean of absolute successive differences (RMSSD); the percentage of intervals differing by >50 ms from the preceding interval (pNN50); low frequency power, and high frequency power], as well as BRS and PWV, were determined on 27 consecutive white XFS patients and 20 white control subjects under standard circumstances, with controlled breath rate of 0.25 Hz. The paired t test, the Mann-Whitney U test, and the Fisher exact test were used for comparisons. There was no significant difference between the XFS and control groups in sex distribution, age, heart rate, blood pressure, body mass index, systemic diseases, or medication. But in XFS patients, SDNN (mean+/-SD, 24+/-7.3 vs. 49+/-16.5 ms), RMSSD (17+/-7.3 vs. 45+/-29.1 ms), pNN50 (1.6%+/-2.5% vs. 17.7%+/-25.9%), high frequency (112+/-109 vs. 479+/-554 ms), and BRS (4.64+/-2.12 vs. 9.49+/-4.76 ms/mm Hg for BRS+ and 5.28+/-2.16 vs. 10.29+/-4.62 ms/mm Hg for BRS-) were all significantly lower than in the control group (P<0.01 for each parameter). Low frequency was also reduced in XFS (72+/-55 vs. 253+/-241 ms) (P=0.027). In XFS, PWV was significantly increased compared with the control group (11.6+/-4.1 vs. 9.3+/-2.2 m/s) (P=0.023). Our results suggest a clinically and statistically significant impairment of cardiovagal regulation and impairment of conduit artery function in XFS patients.