Enhanced Thermal Conductivity in a Diamine-Appended Metal-Organic Framework as a Result of Cooperative CO2 Adsorption.
Diamine-appended variants of the metal-organic framework M2(dobpdc) (M = Mg, Mn, Fe, Co, Zn; dobpdc4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) exhibit exceptional CO2 capture properties owing to a unique cooperative adsorption mechanism, and thus hold promise for use in the development of energy- and cost-efficient CO2 separations. Understanding the nature of thermal transport in these materials is essential for such practical applications, however, as temperature rises resulting from exothermic CO2 uptake could potentially offset the energy savings offered by such cooperative adsorbents. Here, molecular dynamics (MD) simulations are employed in investigating thermal transport in bare and e-2-appended Zn2(dobpdc) (e-2 = N-ethylethylenediamine), both with and without CO2 as a guest. In the absence of CO2, the appended diamines function to enhance thermal conductivity in the ab-plane of e-2-Zn2(dobpdc) relative to the bare framework, as a result of noncovalent interactions between adjacent diamines that provide additional heat transfer pathways across the pore channel. Upon introduction of CO2, the thermal conductivity along the pore channel (the c-axis) increases due to the cooperative formation of metal-bound ammonium carbamates, which serve to create additional heat transfer pathways. In contrast, the thermal conductivity of the bare framework remains unchanged in the presence of zinc-bound CO2 but decreases in the presence of additional adsorbed CO2.


Circulating microvesicles across a population with various degree of cardiovascular burden are associated with systolic blood pressure.
Circulating microvesicles (MVs) have been studied in heterogeneous, divergent, and rather small patient populations with cardiovascular risk . Therefore, we measured endothelial (EMVs), platelet (PMVs) and erythrocyte (RMVs) MVs in patients with divergent cardiovascular risk. We then compared them to coronary artery disease (CAD) and healthy subjects and identified independent MVs' predictors. We enrolled consecutive patients from our Cardiology, Hypertension, Diabetic, Rheumatic, and Nephrology Outpatient Units with MVs measurements. Central blood pressure (BP) was measured by either applanation tonometry or Mobil-O-graph device, while MVs by a standardized flow cytometry protocol. We studied 369 participants with increased cardiovascular risk: 63 with high cardiovascular risk (47 diabetes mellitus type II/DM and 16 end-stage renal disease/ESRD), 92 with chronic inflammatory disorders and 73 with untreated essential hypertension/UEH. We further included 53 subjects with CAD and 87 otherwise healthy individuals. All MVs were lower in patients with increased cardiovascular risk compared to CAD, showing predictive value with high sensitivity and specificity. Furthermore, PMVs and EMVs were increased in patients with cardiovascular risk compared to healthy individuals. DM and ESRD patients had increased EMVs versus UEH and chronic inflammatory disorders. In the whole study population, RMVs were associated only with history of essential hypertension. In multivariate analysis, systolic BP predicted PMVs. Aage, systolic BP, and DM predicted EMVs. In a large population of patients with divergent cardiovascular risk, MVs are independently associated with systolic blood pressure.


Research note: utilizing hazelnut kernel oil meal in layer diets.
The present study was conducted in order to investigate the possibility of utilizing hazelnut kernel oil meal (HKOM) in layer diets as a replacement for soybean oil meal (SBM). Two hundred and sixteen brown egg layers raised in contiguous wire cages were used. The duration of the experiment was 24 wk consisting of six periods of 4 wk. In the trial, six diets containing different levels of HKOM replacing 0, 20, 40, 60, 80, and 100% of SBM protein, respectively, were utilized as the treatments. Differences among the diets in terms of egg yield, feed consumption, feed efficiency ratio, egg weight, egg yolk and albumen ratios, shell thickness, shell weight, and Roche color values of the yolk were not statistically significant (P greater than .01). Results indicated that SBM could be replaced totally by HKOM in layer diets. However, replacement of more than 40% of SBM with HKOM is not recommended.


Cyclic Progesterone Therapy in Androgenic Polycystic Ovary Syndrome (PCOS)-A 6-Month Pilot Study of a Single Woman's Experience Changes.
Background and Objectives: Women with androgenic Polycystic Ovary Syndrome (PCOS) have increased endometrial cancer risk that cyclic progesterone will prevent; it may also reverse PCOS's neuroendocrine origins. This pilot study's purpose was to document 6-month experience changes in a woman with PCOS taking cyclic progesterone therapy because she was intolerant of combined hormonal contraceptive therapy, the current PCOS standard of care. A 31-year-old normal-weight woman with PCOS had heavy flow, irregular cycles, and was combined hormonal contraceptives-intolerant. She was prescribed cyclic oral micronized progesterone (OMP) (300 mg/h.s. cycle days 14-27). She kept Menstrual Cycle Diary© (Diary) records, starting with the 1st treatment cycle for six cycles; she was on no other therapy. Statistical analysis a priori hypothesized progesterone decreases high estradiol (E2) experiences (flow, cervical mucus, fluid retention, front-of-the-breast tenderness and anxiety); analysis focused on these. Our objectives: (1) changes from cycles 1 to 6 in E2-related experiences; and (2) follicular phase E2-related changes from cycle 1 (no therapy) to cycles 3 and 6. Materials and Methods: Data from consecutive Diaries were entered into an SPSS database and analyzed by Wilcoxon Signed Rank Test (Objective #1) within-person whole cycle ordinal data, and (Objective #2 follicular phase) repeated measures ANOVA. Results: Cyclic OMP was associated with regular, shorter cycles (±SD) (28.2 ± 0.8 days). Comparison of cycles 1-6 showed decreased fluid retention (p = 0.001), breast tenderness (p = 0.002), and cervical mucus (p = 0.048); there were no changes in flow or anxiety. Fluid retention in the follicular phase also significantly decreased over time (F (1.2, 14.7) = 6.7, p = 0.017). Conclusions: Pilot daily Diary data suggest women with PCOS have improved everyday experiences on cyclic progesterone therapy. Larger prospective studies with more objective outcomes and randomized controlled trials of this innovative PCOS therapy are needed.


Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Tumor Cells.
PARP inhibitors (PARPis) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success. We hypothesized that RAD52-mediated DNA repair remains active in PARPi-treated BRCA-deficient tumor cells and that targeting RAD52 should enhance the synthetic lethal effect of PARPi. We show that RAD52 inhibitors (RAD52is) attenuated single-strand annealing (SSA) and residual homologous recombination (HR) in BRCA-deficient cells. Simultaneous targeting of PARP1 and RAD52 with inhibitors or dominant-negative mutants caused synergistic accumulation of DSBs and eradication of BRCA-deficient but not BRCA-proficient tumor cells. Remarkably, Parp1-/-;Rad52-/- mice are normal and display prolonged latency of BRCA1-deficient leukemia compared with Parp1-/- and Rad52-/- counterparts. Finally, PARPi+RAD52i exerted synergistic activity against BRCA1-deficient tumors in immunodeficient mice with minimal toxicity to normal cells and tissues. In conclusion, our data indicate that addition of RAD52i will improve therapeutic outcome of BRCA-deficient malignancies treated with PARPi.


Long-term assessment of systemic inflammation and the cumulative incidence of age-related hearing impairment in the epidemiology of hearing loss study.
Although research has linked systemic inflammation to various diseases of aging, few studies have examined the potential role it may play in the development of age-related hearing impairment. Among 1,073 participants free of hearing impairment (pure-tone average 0.5, 1, 2, 4kHz ≤ 25 dB HL) in the population-based Epidemiology of Hearing Loss Study (1998-2000), serum C-reactive protein, and interleukin-6 were measured at three time points (1988-1990, 1998-2000, and 2009-2010), and tumor necrosis factor-α was measured at one time point (1998-2000), whereas hearing impairment was measured again in 2003-2005 and 2009-2010 to determine the 10-year cumulative incidence. Inflammatory marker levels from a single time point (1998-2000) were not associated with an increased risk of developing hearing impairment. Associations between long-term serum C-reactive protein levels and incident hearing impairment differed by age (p = .031). Participants less than 60 years with consistently high (>3 mg/L) or increasing levels of serum C-reactive protein over 10 years were nearly two times (hazard ratio: 1.96, 95% confidence interval: 1.19, 3.23) as likely to develop hearing impairment over the subsequent 10-year period, an association not seen in participants more than or equal to 60 years. A statistically significant association (p-trend = .041) was also observed between number of markers in the highest group at baseline and incident hearing impairment in this younger age group. Associations between long-term serum C-reactive protein levels and incident hearing impairment were observed in the cohort as a whole, but differed significantly by age group, with statistically significant associations observed in adults less than 60 years, participants moving through the peak risk period for hearing impairment over the course of the study.


Chemokine and cytokine levels in the lumbar cerebrospinal fluid of preterm infants with post-hemorrhagic hydrocephalus.
Neuroinflammation has been implicated in the pathophysiology of post-hemorrhagic hydrocephalus (PHH) of prematurity, but no comprehensive analysis of signaling molecules has been performed using human cerebrospinal fluid (CSF). Lumbar CSF levels of key cytokines (IL-1α, IL-1β, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, TGF-β1, IFN-γ) and chemokines (XCL-1, CCL-2, CCL-3, CCL-19, CXCL-10, CXCL-11, CXCL-12) were measured using conventional and multiplexed Enzyme-linked Immunosorbent Assays and compared between preterm infants with PHH and those with no known neurological injury. The relationships between individual biomarker levels and specific CSF cell counts were examined. Total protein (TP) CSF levels were elevated in the PHH subjects compared to controls. CSF levels of IL-1α, IL-4, IL-6, IL-12, TNF-α, CCL-3, CCL-19, and CXCL-10 were significantly increased in PHH whereas XCL-1 was significantly decreased in PHH. When normalizing by TP, IL-1α, IL-1β, IL-10, IL-12, CCL-3, and CCL-19 levels were significantly elevated compared to controls, while XCL-1 levels remained significantly decreased. Among those with significantly different levels in both absolute and normalized levels, only absolute CCL-19 levels showed a significant correlation with CSF nucleated cells, neutrophils, and lymphocytes. IL-1β and CXCL-10 also were correlated with total cell count, nucleated cells, red blood cells, and neutrophils. Neuroinflammation is likely to be an important process in the pathophysiology of PHH. To our knowledge, this is the first study to investigate CSF levels of chemokines in PHH as well as the only one to show XCL-1 selectively decreased in a diseased state. Additionally, CCL-19 was the only analyte studied that showed significant differences between groups and had significant correlation with cell count analysis. The selectivity of CCL-19 and XCL-1 should be further investigated. Future studies will further delineate the role of these cytokines and chemokines in PHH.


Efficacy of a recombinant equine influenza vaccine against challenge with an American lineage H3N8 influenza virus responsible for the 2003 outbreak in the United Kingdom.
Fifteen influenza-naive Welsh mountain ponies were randomly assigned to three groups of five. A single dose of a recombinant ALVAC vaccine was administered intramuscularly to five of the ponies, two doses, administered five weeks apart, were administered to five, and the other five served as unvaccinated, challenge controls. Two weeks after the completion of the vaccination programme, the ponies were all challenged by exposure to an aerosol of influenza virus A/eq/Newmarket/5/03. Their clinical signs were scored daily for 14 days according to a standardised scoring protocol, and nasal swabs were taken daily for 10 days to monitor the excretion of virus. The challenge produced severe clinical signs of influenza (fever, coughing, nasal discharge and dyspnoea) in all five control ponies, but the vaccinated ponies developed only mild disease, consisting of a serous nasal discharge lasting for only one day. The excretion of virus was almost completely suppressed in the vaccinated ponies, but the control ponies shed the virus for up to seven days after the challenge.


Design, synthesis, and biological studies of dual URAT1 inhibitor and FXR agonist based on benzbromarone.
With increased unhealthy dietary patterns and a sedentary lifestyle, the prevalence of hyperuricemia is growing rapidly, placing a tremendous burden on the public health system. Persistent hyperuricemia in extreme cases induces gout, gouty arthritis, and other metabolic diseases. Benzbromarone is a potent human urate transporter 1 (URAT1) inhibitor that is widely used as a uric acid-lowering drug. Recent studies indicated that benzbromarone can also activate farnesoid X receptor (FXR), whereas its agonistic activity on FXR is rather poor. Mounting evidence suggested that the etiology of gout is directly related to NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasomes, and FXR suppresses the expression of NLRP3 in various ways. Therefore, the dual URAT1 inhibitor and FXR agonist may exert synergistic effects on decreasing uric acid (UA) levels and inhibiting inflammation. To obtain a better dual URAT1 inhibitor and FXR agonist, we performed the structure-based drug design (SBDD) strategy to improve the FXR activation of benzbromarone by forming strong interactions with ARG331 in FXR binding pocket. All of these efforts lead to the identification of compound 4, which exerts better activity on FXR and uric acid-lowering effect than benzbromarone.


Coenonia anatina gen. nov., sp. nov., a novel bacterium associated with respiratory disease in ducks and geese.
Taxon 1502 was originally described as a Riemerella anatipestifer-like bacterium causing exudative septicaemia in ducks and geese. In the present study, an integrated genotypic and phenotypic approach was used to elucidate the phylogenetic affiliation and taxonomic relationships of 12 strains of taxon 1502. Whole-cell protein and fatty acid analyses and an extensive biochemical examination by using conventional tests and several API microtest systems indicated that all isolates formed a homogeneous taxon, which was confirmed by DNA-DNA hybridizations. 16S rDNA sequence analysis of a representative strain (LMG 14382T) indicated that this taxon belongs to the Cytophaga-Flavobacterium-Bacteroides phylum and revealed a moderate but distinct relationship to species of the genus Capnocytophaga (overall 16S rDNA sequence identities were 88.8-90.2%). Taxon 1502 is concluded to represent a single species that should be allocated to a novel genus, and the name Coenonia anatina gen. nov., sp. nov. is proposed. The DNA G + C content of representative strains was 35-36 mol% and the type strain is LMG 14382T.


Visual outcomes following lensectomy and vitrectomy for combined anterior and posterior persistent hyperplastic primary vitreous.
To determine the visual outcome after surgery for persistent hyperplastic primary vitreous using modern vitreoretinal techniques. Retrospective medical record review during a 5-year period (June 1992 to June 1997). Information recorded for each patient included age, medical history, sex, results of preoperative ocular examination, age at diagnosis, procedure performed, intraoperative and postoperative complications, location and number of sclerotomy sites, type of aphakic rehabilitation, amblyopic therapy given, final visual acuity, and length of follow-up. Fourteen patients who underwent surgical management of combined anterior and posterior persistent hyperplastic primary vitreous were identified. Eleven patients underwent aphakic rehabilitation and aggressive amblyopic therapy consisting of occlusive therapy for several waking hours each day. One additional older patient received aphakic rehabilitation only. Ten eyes (71%) achieved a visual acuity of 20/300 or better, and 8 (57%) obtained a final visual acuity of 20/100 or better. Average length of follow-up was 22 months (range, 4-57 months). Nine patients were fitted with an aphakic soft contact lens, 2 older patients had a posterior chamber intraocular lens placed at the time of vitrectomy, and 1 patient wore aphakic spectacles. With modern vitreoretinal techniques, aphakic rehabilitation, and aggressive amblyopic therapy, useful vision can be obtained in the majority of patients with combined anterior and posterior persistent hyperplastic primary vitreous.


Injected histone antibodies interfere with transcription of lampbrush chromosome loops in oocytes of Pleurodeles.
Antibodies to calf thymus histone H2B were purified by chromatography on DEAE-cellulose and injected into oocyte nuclei of Pleurodeles waltlii. As shown by indirect immunofluorescence these antibodies cross-reacted strongly with corresponding histones associated with lampbrush chromosomes. Shortly after injection the lateral loops of the chromosomes retracted into the chromomeres and by 3 h postinjection the 'lampbrush' appearance was completely lost and the chromosomes appeared in light-microscopic preparations as rod-like structures consisting of longitudinally coalesced chromomeres. In control oocytes injected with non-immune immunoglobulins or antibodies against a ubiquitous transcript-associated protein no morphological alterations of the lampbrush chromosomes could be observed. Electron microscopic spreads of chromosomes prepared at various times after injection of anti-H2B revealed a progressive loss of transcriptional complexes from the loop axes. Finally, higher-order chromatin configurations, like supranucleosomal globules ('superbeads') or cable-like chromatin strands 50-60 nm thick predominated, indicating complete transcriptional inactivation of all chromosomal regions. The results indicate that H2B antibodies react specifically with histones associated with the transcribed DNA of lateral loops in their native state. The resulting antigen-antibody complexes seem to inhibit progression of the RNA polymerases along the template, thus causing the premature release of transcripts, a process analogous to the stripping effect of actinomycin D. The demonstration of histones associated with heavily transcribed regions, which are not compacted into nucleosomes but largely extended, supports the current concept that unfolding of nucleosomes to allow transcription of the DNA does not involve dissociation of histones. In contrast, amplified ribosomal RNA genes are unaffected by injected H2B antibodies. This does not necessarily indicate absence of histones from nucleolar chromatin, since we do not know whether it is accessible in vivo to antibodies or whether the histone antigenic determinants are masked by the presence of other proteins. The technique of injecting specific antibodies should be widely applicable when analysing the in vivo distribution of chromosomal components at the electron-microscopic level and when studying complex metabolic processes, like the cleavage and modification of RNA, by selective inhibition of defined enzymic steps.


Histochemical changes in livers from portacaval-shunted rats.
Portacaval shunt (PCS) operations were performed on male inbred SD rats. The activity of liver gamma-glutamyltranspeptidase (GGT) increased a few days after the operation and remained high after several months. However, the activity was only present in periportal areas of liver lobules and was mainly restricted to the endothelial lining cells of periportal blood vessels. Phenobarbital sodium (CAS: 57-03-7) administration did not change the distribution of GGT. The activity of liver glucose-6-phosphatase disappeared in the centrilobular areas a few days after the operation but was present in the periportal areas. The distribution of this activity returned to normal after several months. The capacity of liver cells to store glycogen was significantly decreased following the PCS operation. Morphologic changes in hepatocytes observed after the PCS operation did not show similarities to those seen in preneoplastic livers. The nuclei of the small compact hepatocytes found in the animals with PCS were irregular in shape and stained intensively with hematoxylin and eosin. The large pale-staining cells in the periphery of liver lobes were GGT negative and their nuclei had a normal morphology. Neither morphologic nor histochemical changes consistent with preneoplastic and/or neoplastic stage were observed after 10 months in the liver when the PCS operation was performed on rats having received an ip dose (10 mg/kg) of diethylnitrosamine (CAS: 55-18-5) 2 weeks prior to the operation.


Symptoms experiences and attitudes towards menstruation among adolescent girls.
The study aimed to analyse the factors affecting menstrual symptoms and attitudes among adolescent girls and the relationship between them. The sample of the cross-sectional, descriptive and analytical research was composed of 604 adolescent girls studying at a university. Individual Information Form, Menstruation Symptom Questionnaire (MSQ) and Menstrual Attitude Questionnaire (MAQ) were used as data collection tool in the research. Average age of the students was 21.22 ± 1.71, and average menstrual cycle length was 29.3 ± 7.85 days. MSQ mean score was 69.84 ± 15.48 and MAQ mean score was 103.10 ± 9.84. These results are important for showing that students perceive menstruation as a natural phenomenon, despite significant menstrual symptoms.Impact statementWhat is already known on this subject? The intensity of menstrual symptoms is associated with negative menstrual attitudes. But, there have been few studies on the relationship between menstruation symptoms and attitudes and their impact on menstrual problems in Turkish adolescents.What the results of this study add? Adolescents' menstrual complaints are common, but their attitudes towards menstruation are positive. The lack of a significant relationship between menstrual symptoms and attitudes were more likely to be explained by the fact that young girls perceive menstruation as a natural phenomenon even though they have so many symptoms.What the implications are of these findings for clinical practice and/or further research? Further study should be extended to various cultures and destinations to understand the effect of culture on menstruation that rural areas may be surrounded by taboos and myths which might affect the negative attitude.


Self-complementary AAV virus (scAAV) safe and long-term gene transfer in the trabecular meshwork of living rats and monkeys.
AAV vectors produce stable transgene expression and elicit low immune response in many tissues. AAVs have been the vectors of choice for gene therapy for the eye, in particular the retina. scAAVs are modified AAVs that bypass the required second-strand DNA synthesis to achieve transcription of the transgene. The goal was to investigate the ability of AAV vectors to induce long-term, safe delivery of transgenes to the trabecular meshwork of living animals. Single doses of AAV2.GFP and AAV2.RGD.GFP/Ad5.LacZ were injected intracamerally (IC) into rats (n = 28 eyes). A single dose of scAAV.GFP was IC-injected into rats (n = 72 eyes) and cynomolgus monkeys (n = 3). GFP expression was evaluated by fluorescence, immunohistochemistry, and noninvasive gonioscopy. Intraocular pressure (IOP) was measured with calibrated tonometer (rats) and Goldmann tonometer (monkeys). Differential expression of scAAV-infected human trabecular meshwork cells (HTM) was determined by microarrays. Humoral and cell-mediated immune responses were evaluated by ELISA and peripheral blood proliferation assays. No GFP transduction was observed on the anterior segment tissues of AAV-injected rats up to 27 days after injection. In contrast, scAAV2 transduced the trabecular meshwork very efficiently, with a fast onset (4 days). Eyes remained clear and no adverse effects were observed. Transgene expression lasted >3.5 months in rats and >2.35 years in monkeys. The scAAV viral vector provides prolonged and safe transduction in the trabecular meshwork of rats and monkeys. The stable expression and safe properties of this vector could facilitate the development of trabecular meshwork drugs for gene therapy for glaucoma.


The value of ascites adenosine deaminase activity and interferon gamma level in discriminating tuberculous from non-tuberculous ascites.
The diagnosis of tuberculous ascites is often difficult because of the subtle clinical clues, poorly discriminative biochemical assays, delayed results of bacteriological studies and hazards of laparoscopy. Therefore, the role of ascites adenosine deaminase (ADA) activity and interferon-gamma (IFN-delta) level in distinguishing tuberculous from other causes of ascites was examined in 50 patients with ascites. Following bacteriologic culture, seventeen (34%) patients were found to have tuberculous ascites; nine (59.9%) of them had also schistosomal hepatic fibrosis (SHF). Therefore, 36% (9 out of 25) of all patients with SHF included in the study, had coexistent peritoneal tuberculosis despite the presence of transudative ascites and unrecognized clinical features. Ascites ADA activity was significantly higher in tuberculous than in other causes of ascites (P < 0.001) regardless of the presence of an underlying liver disease. A cut-off of 28 U/L reached a sensitivity of 94.4% and a specificity of 100%. A direct correlation was found between ascites ADA activity and total proteins in the tuberculous group (r = 0.613) and the only false-negative result occurred in a patient with SHF and low-ascites protein. Ascites IFN-delta level was also significantly higher in tuberculous ascites with or without SHF than in other causes of ascites (P < 0.05). A cut-off of 26 pg/ml reached a sensitivity of 81% and a specificity of 100%. There was no correlation between ascites ADA activity and IFN-delta level in the tuberculous group (r = 0.329). Based on the results of the present study, it can be concluded that tuberculous ascites should be considered as an important cause of ascites particularly in patients with underlying liver disease. Ascites ADA activity was more sensitive than ascites IFN-delta in diagnosing tuberculosis (TB). It has proved to be an easy, rapid, safe and reliable method for routine use in the early diagnosis of tuberculous ascites.


Hypertriglyceridemia is associated with stroke after non-cardiac, non-neurological surgery in the older patients: A nested case-control study.
Geriatric postoperative stroke is a rare but serious complication after surgery. The association between hypertriglyceridemia and postoperative stroke remains controversial, especially in older patients undergoing non-cardiac, non-neurological surgery. The study aims to address this clinical dilemma. We conducted a nested case-control study among 9601 aged patients undergoing non-cardiac non-neurological surgery from October 2015 to 2021. A total of 22 positive cases were matched for the surgical type and time, to 88 control patients by a ratio of 1:4. The effect of hypertriglyceridemia on the occurrence of postoperative stroke within 30 days after surgery was estimated using conditional logistic regression analysis by adjusting to various potential confounders. A total of 22 cases developed ischemia stroke after surgery, and compared with the non-stroke group, they had more postoperative ICU admission, longer postoperative hospitalization and higher total cost (all p < 0.05), and more patients were presenting with preoperative hypertriglyceridemia [8 (36.4%) vs. 15 (17.0%), p = 0.045]. There was a significant association between hypertriglyceridemia and postoperative stroke, with adjusted odds ratios of 6.618 (95% CI 1.286, 34.064) (p = 0.024). The above results remained robust in the sensitivity analyses. Among older patients undergoing non-cardiac and non-neurological surgery, hypertriglyceridemia was associated with significant increased risk of postoperative stroke.


Association between polymorphisms of the renin angiotensin system and carotid stenosis.
Carotid stenosis is a common manifestation of systemic atherosclerosis. Apart from traditional risk factors, genetic determinants, such as polymorphisms of the renin angiotensin system (RAS), may be relevant in modulating the atherosclerotic process leading to carotid stenosis. In this study, we investigated the role of angiotensin-converting enzyme (ACE) I/D and -240A>T, angiotensinogen (AGT) M235T, and angiotensin type 1 receptor (AGTR1) 1166A > C polymorphisms in modulating the susceptibility to the disease. Eight hundred twenty-one consecutive patients with severe carotid stenosis (≥70%) and 847 control subjects were investigated. A significant difference in genotype distribution (P < .0001) and allele frequency (P < .0001) between patients and controls for the ACE I/D polymorphism, but not for the other single-nucleotide polymorphisms investigated, was observed. The ACE D allele frequency was significantly higher in patients without traditional risk factors in comparison with that observed in those with at least one risk factor (0.71 vs 0.61; P = .04). The ACE D allele significantly influenced carotid stenosis under dominant, recessive, and additive model of inheritance at both univariate (P < .0001) and multivariate analysis (P < .0001). When the combined effect of RAS unfavorable alleles was considered, patients carrying less than three alleles had a lower risk of carotid stenosis (odds ratio [OR], 0.79 [0.63-0.99]; P = .05), while carriers of more than four unfavorable alleles had an increased risk (OR, 1.44 [1.12-1.84]; P = .004), in comparison with subjects carrying three or four unfavorable alleles. ACE D allele frequency was similar in patients with and without additional atherosclerotic localizations (0.61 vs 0.62, respectively). Our findings evidence a role for ACE I/D polymorphism in influencing the susceptibility to carotid stenosis, even in the absence of traditional risk factors. Interestingly, our findings provided further information concerning the role of this polymorphism in modulating the atherosclerotic process apart from its different localizations.


Effects of FDP and Danshen on renal cortical Na-K-ATPase activity in rats after treatment with renal ischemia and gentamicin.
The main purpose of our study is to investigate the possible protective effects of Fructose 1-6 diphosphate (FDP) and Danshen (Salvia Miltiozzhiza Bunze) on renal cortical Na-K-ATPase activity after renal ischemia and gentamicin nephrotoxicity. An 18.6% reduction in renal cortical Na-K-ATPase activity was shown after 30 min of renal pedicle clamping and 60 min of reflow, and a 32.5% reduction after 90 min of single injection of 100 mg/kg gentamicin. Light and electronic microscopy revealed no significant morphologic changes in both groups in the experiment. 4g/kg FDP and 18g/kg Danshen were infused 60 min after reflow in the ischemic group, 90 min after injection of gentamicin in the gentamicin-treated group and 90 min in the sham-operated group separately. The enzyme activity in the FDP-treated groups was found to be higher than that in the control kidneys while in the Danshen-treated groups no significant difference could be found. Our study showed that FDP and Danshen could prevent the decline of renal cortical Na-K-ATPase activity induced by ischemia and gentamicin. FDP could increase this enzyme activity while Danshen showed no such direct effect.


Impact of inoculum acclimation on energy recovery and investigation of microbial community changes during anaerobic digestion of the chicken manure.
The aim of this study was to assess the effect of inoculum adaptation on biogas recovery from two identical lab-scale semi-continuous anaerobic digesters (AD) treating chicken waste (i.e. TS and VS contents of ca. 6.2% and 2.9%, respectively) at mesophilic condition (35°C). For the first two months; one of the AD was run with adapted whereas the second AD was run with unadapted granular sludge to chicken manure which was further operated for about 100 more days. In this scope, qPCR analysis and Illumina sequencing were also used to detect microbial community changes inside anaerobic reactors. Molecular analyses revealed that the number of archaea was significantly higher than that of overall archaea compared to the values obtained at the start-up time and methanogens also increased as the operation continued. On the other hand, although average daily biogas production was about 25% higher in adapted AD compared to the unadapted AD (i.e. biogas yields were ca. 0.6 and 0.7 m3/kg VSfeed, respectively), there was not a meaningful change in archaea numbers at the end of the operation. These suggest that changes in the structure of a microbial community lead to changes in biogas production and controlling ultimate methanogenic archaeal community may promote successful methane production in anaerobic reactors.


BCL10 as a useful marker for pancreatic acinar cell carcinoma, especially using endoscopic ultrasound cytology specimens.
Acinar cell carcinomas (ACCs) of the pancreas are characterized by the histological and immunohistochemical features of acinar cell differentiation. Recently, BCL10, originally identified as a recurrent t(1;14)(p22;q32) translocation in MALT B-cell lymphoma, was found to be immunohistochemically positive in some solid tumors, including ACC. To evaluate its diagnostic efficacy, we performed BCL10 immunohistochemistry and evaluated molecular markers correlated to pancreatic tumor lineages (neuroendocrine markers and a mutation analysis of KRAS and GNAS) using samples from 126 pancreatic tumors (17 ACCs, 24 pancreatic ductal adenocarcinomas, 4 adenosquamous carcinomas, 9 intraductal papillary mucinous neoplasms, 10 mucinous cystic neoplasms, 44 neuroendocrine tumors, 9 serous cystic tumors and 10 solid-pseudopapillary neoplasms). BCL10 was exclusively expressed in normal acini. In pancreatic tumors, 14 of 17 (82%) ACCs and 2 of 4 (50%) adenosquamous carcinomas were positive, while the other subtypes were almost negative. We subsequently examined the diagnostic utility of BCL10 in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens using 57 pancreatic tumors. BLC10 correctly identified ACCs (9/13) and adenosquamous carcinomas (2/4) but none of the other subtypes (n = 41). Therefore, we suggested that BCL10 expression is a useful marker for acinar cell differentiation, particularly in the diagnosis of EUS-FNA specimens.


Transvaginal color flow Doppler sonography in the assessment of gestational trophoblastic disease.
The aim of this study was to evaluate the blood flow characteristics of the uterine artery and intratumoral vessels in patients with GTD. Twelve patients with GTD were evaluated with TVS, and 11 also had CFD sonography performed. Spectral analysis of both uterine artery and samples intratumoral and intramyometrial vessels revealed systolic frequencies and PI that were significantly higher in the uterine artery than in sampled intratumoral vessels (P < 0.05). Uterine artery PI correlated significantly with age (P = 0.043), uterine size (P = 0.003), and beta-HCG titer (P = 0.03). Intratumoral PI correlated significantly with uterine size (P = 0.05). Intratumoral PI did not correlate with patient age, the shape or orientation of the uterus, presence or absence of subendometrial halo, endometrial thickness or echogenicity, or impression of myometrial invasion. Regression analysis of beta-HCG titers on uterine artery and intratumoral PI revealed a linear association. TVS and color flow Doppler sonography are useful in the assessment of patients with GTD. The PI is strongly associated with prognosis and correlates with beta-HCG titers.


Astaxanthin anticancer effects are mediated through multiple molecular mechanisms: A systematic review.
During the latest decades, the interest on the effectiveness of natural compounds and their impact on human health constantly increased, especially on those demonstrating to be effective on cancer. Molecules coming from nature are currently used in chemotherapy like Taxol, Vincristine or Vinblastine, and several other natural substances have been showed to be active in reducing cancer cell progression and migration. Among them, astaxanthin, a xanthophyll red colored carotenoid, displayed different biological activities including, antinflammatory, antioxidant, proapoptotic, and anticancer effects. It can induce apoptosis through downregulation of antiapoptotic protein (Bcl-2, p-Bad, and survivin) expression and upregulation of proapoptotic ones (Bax/Bad and PARP). Thanks to these mechanisms, it can exert anticancer effects towards colorectal cancer, melanoma, or gastric carcinoma cell lines. Moreover, it possesses antiproliferative activity in many experimental models and enhances the effectiveness of conventional chemotherapic drugs on tumor cells underling its potential future use. This review provides an overview of the current knowledge on the anticancer potential of astaxanthin by modulating several molecular targets. While it has been clearly demonstrated its multitarget activity in the prevention and regression of malignant cells in in vitro or in preclinical investigations, further clinical studies are needed to assess its real potential as anticancer in humans.


Transgenic expression of IGF-1 modifies the proliferative potential of human retinal pigment epithelial cells.
To induce the expression of insulin-like growth factor (IGF)-1, by using gene transfer methods, to modify the growth characteristics of human retinal pigment epithelial cells. Human retinal pigment epithelial cells were transfected in vitro with plasmid vector pcDNA:IGF-1, which encodes an epitope-tagged human IGF-1 fusion protein and a selectable neomycin resistance gene. Transduced cells were cloned in G418 and expanded for analysis of IGF-1 transgene expression and its effect on the cell phenotype. The expression of the IGF-1 transgene in cloned cells was confirmed by reverse transcription-polymerase chain reaction and quantified by Western blot analysis. The growth characteristics of transduced clones were compared with the control by spectrophotometric and flow cytometric cell proliferation assays. Cloned retinal pigment epithelial cells expressed the IGF-1 transgene and secreted the IGF-1 fusion protein into the tissue culture medium. Transduced clones demonstrated a dose-dependent, enhanced ability to proliferate in low serum conditions, compared with the control. Clones that expressed moderate and high levels of the IGF-1 fusion protein were isolated and grew at a significantly faster rate and showed a statistically significant increase in the number of cells after 6 days, compared with the control (P < 0.002, paired samples, t-test). Expression of the IGF-1 transgene in synchronized clones enhanced cell cycle kinetics by increasing recruitment of the G(0)-G(1)-phase cells into the proliferative phase of the cell cycle. The human IGF-1 fusion protein encoded by the pcDNA:IGF-1 vector demonstrates paracrine biological activity in human retinal pigment epithelial cells in vitro. Expression and secretion of the IGF-1 transgene enhances growth characteristics in a dose-dependent manner and can modulate the proliferative potential of the retinal pigment epithelial cell.


Parent Satisfaction With Communication Is Associated With Physician's Patient-Centered Communication Patterns During Family Conferences.
To evaluate the association between physician's patient-centered communication patterns and parental satisfaction during decision-making family conferences in the PICU. Single-site, cross-sectional study. Forty-four-bed PICUs in a free-standing children's hospital. Sixty-seven English-speaking parents of 39 children who participated in an audiorecorded family conference with 11 critical care attending physicians. Thirty-nine family conferences were audiorecorded. Sixty-seven of 77 (92%) eligible parents were enrolled. The conference recordings were coded using the Roter Interaction Analysis System and a Roter Interaction Analysis System-based patient-centeredness score, which quantitatively evaluates the conversations for physician verbal dominance and discussion of psychosocial elements, such as a family's goals and preferences. Higher patient-centeredness scores reflect higher proportionate dialogue focused on psychosocial, lifestyle, and socioemotional topics relative to medically focused talk. Parents completed satisfaction surveys within 24 hours of the conference. Conferences averaged 45 minutes in length (SD, 19 min), during which the medical team contributed 73% of the dialogue compared with parental contribution of 27%. Physicians dominated the medical team, contributing 89% of the team contribution to the dialogue. The majority of physician speech was medically focused (79%). A patient-centeredness score more than 0.75 predicted parental satisfaction (β = 12.05; p < 0.0001), controlling for the length of conference, child severity of illness, parent race, and socioeconomic status. Parent satisfaction was negatively influenced by severity of illness of the patient (β = -4.34; p = 0.0003), controlling for previously mentioned factors in the model. Parent-physician interactions with more patient-centered elements, such as increased proportions of empathetic statements, question asking, and emotional talk, positively influence parent satisfaction despite the child's severity of illness.


Tandem synthesis and in vitro antiplasmodial evaluation of new naphtho[2,1-d]thiazole derivatives.
A series of naphtho[2,1-d]thiazoles was prepared in good yields under microwave irradiation with an original protocol combining tandem direct arylation and intramolecular Knoevenagel reaction on 1,3-thiazole derivatives. Antiplasmodial evaluation of this series highlighted two hit compounds (compounds 11 and 13) displaying promising in vitro activity on the multiresistant K1 Plasmodium falciparum strain. Structure-toxicity and structure-activity relationships are also discussed and reveal the importance of the R(1) and R(4) substituents of the naphthyl moiety for the biological profile of the series.


[The computed tomography of colorectal tumors with water as the contrast medium].
The diagnosis of colorectal carcinoma is based on double-contrast barium enema and endoscopy. However, in contrast to computed tomography (CT), these modalities do not permit a precise preoperative prediction wether a tumour is limited to the bowel wall or has spread into surrounding tissue. To improve the detection of colorectal neoplasms by CT we prospectively studied the use of intrarectally administered water for CT scan in 16 patients with colorectal cancer proved by barium enema and endoscopy. The water repletion technique allowed an improved depiction of the large bowel wall, and the primary tumour was demonstrated by CT in all cases. Furthermore the use of water prevented artifacts which was helpful in the evaluation of the liver for suspected metastases.


An unusual renal accessory artery originating from the thoracic aorta and its potential clinical implications.
We report a case of an unsual anatomical vascular blood supply to the right kidney. In an analysis of kidneys, by dissection of 39 foetuses, additional renal arteries were found in 18 cases (46.15%). In only one case (2.5%) was it noticed that the right kidney was supplied with blood by three renal arteries, one main and two additional arteries. One of the additional arteries, marked as the upper pole artery of aortic origin, separated from the thoracic aorta at the level of T11 (the eleventh thoracic rib), 1.5 cm above the truncus coeliacus. This artery, after passing through the diaphragm, entered the renal hilus at its upper part and served to vasculate that part of the kidney. The importance of this study is seen in the fact that anatomic knowledge of variations in the vascularization of the kidneys is of exceptional practical importance. Also, this information may concern transplant surgeons involved in living donor nephrectomies.


Retrospective diagnosis of congenital cytomegalovirus infection using umbilical cord.
Approximately 90% of infants congenitally infected with cytomegalovirus are asymptomatic at birth, but a number of them later develop central nervous system disorders. However, diagnosis of congenital infection with virologic or serologic evidence had been almost impossible beyond the neonatal period. Recently, dried blood spots on Guthrie cards have been demonstrated to be useful for retrospective diagnosis of congenital cytomegalovirus infection; however, they are usually stored for only 1 year. In Japan, the umbilical cord is kept clean and dry as a symbol of the mother-to-child bond, and in recent studies, cytomegalovirus deoxyribonucleic acid was successfully detected from dried umbilical cord of two 1-year-old children who were clinically suspected of having had congenital cytomegalovirus infection. This report describes a 4-year-old male with various central nervous system disorders who was diagnosed with congenital cytomegalovirus infection by detecting cytomegalovirus deoxyribonucleic acid from dried umbilical cord.


Flexible flatfoot treatment in children with mechanical sound vibration therapy.
The flat foot can be defined as a syndrome with multiple etiopathogenesis, characterized by an altered structure of the longitudinal arch of the plantar vault with its reduction in height. The plantar arch collapse can be counteracted by strengthening the muscles involved; for many years, specific physical exercises have been proposed with this purpose in physical and rehabilitation medicine. The aim of our work was to improve the plantar arch muscles' tone using high focal vibration therapy (300Hz) 10 children with a 4th degree flat foot (age: 8,7±2,2; height: 132±15cm; weight: 35,2±12,3Kg) underwent 10 sessions, 2 days/wk, of 30 min of focused high vibratory therapy at a frequency of 300 Hz (Vissman, Italy). Before and after treatment stabilometry (StT), static and dynamic baropodometry tests were performed. Evaluation of StT showed an improvement of stability, a decrease of sway area and ellipse area. Baropodometry tests showed a decrease in foot surface. Also dynamic tests showed a decrease in both foot surfaces. The results lead us to consider this method as a method of first choice to a conservative approach in the rehabilitation of flat foot syndrome also for the 4th grade in children.


A survey of speech-language therapy provision for people with post-stroke dysarthria in the UK.
A large number of people who experience a stroke are affected by dysarthria. This may be in isolation or in association with aphasia and/or dysphagia. Despite evidence highlighting the psychological and social impact of having post-stroke dysarthria and a number of clinical guidelines that make recommendations for appropriate management, little is known currently about UK service delivery issues relating to speech and language therapy (SLT) assessment and treatment for this group. Such evidence is necessary in order to plan, develop and research services for people with post-stroke dysarthria. To gain an overview of SLT practices in the management of people with dysarthria after stroke in the UK. SLTs in the UK were asked to complete an online survey addressing referral patterns, caseload profiles, and their assessment and intervention methods for post-stroke dysarthria. In the absence of a national register of clinicians working with people with acquired dysarthria, a snowballing method was used to facilitate participant recruitment. Results were analysed using descriptive statistics. A total of 146 SLTs responded. The majority were employed by the National Health Service (NHS). Most patients were referred within 1 week post-stroke. Almost half the respondents did not regularly use formal assessments and the use of instrumentation was rare, including the use of video recording. The focus of therapy for mild, moderate and severe dysarthria did not differ significantly for clinicians. A little under half the respondents endorsed non-verbal oral exercises in rehabilitation. The survey demonstrated some appreciation of the centrality of regular intensive practice to effect change, but this was in a minority. Through this research it became clear that basic information regarding post-stroke dysarthria incidence, prevalence and core demographics is currently unavailable. More embedded NHS SLT reporting systems would make a significant contribution to this area. A more in-depth examination is required of the natural history of dysarthria over the months and years following stroke, of SLT practices in relation to post-stroke dysarthria, with investigations to understand more fully the choices SLTs make and how this relates to available evidence to support their clinical decision-making.


Prion replication alters the distribution of synaptophysin and caveolin 1 in neuronal lipid rafts.
The main event in the pathogenesis of prion diseases is the conversion of the cellular prion protein (PrP(C)) into the abnormal, protease-resistant prion protein (PrP(res)). PrP(C) is a GPI-anchored protein located in lipid rafts or detergent-resistant membranes (DRMs). Here we describe the association of PrP with DRMs in neuronal cell bodies and axons during the course of murine scrapie and its relation with the distribution of the PrP-interacting proteins caveolin 1 and synaptophysin. Scrapie infection triggered the accumulation of PrP(res) in DRMs from retinas and optic nerves from early stages of the disease before evidence of neuronal cell loss. Most of the PrP(res) remained associated with lipid rafts throughout different stages in disease progression. In contrast to PrP(res), caveolin 1 and synaptophysin in retina and optic nerves shifted to non-DRM fractions during the course of scrapie infection. The accumulation of PrP(res) in DRMs was not associated with a general alteration in their composition, because no change in the total protein distribution across the sucrose gradient or in the flotation characteristics of the glycosphingolipid GM1 or Thy-1 were observed until advanced stages of the disease. However, an increase in total cholesterol levels was observed in optic nerve and retinas. Only during late stages of the disease was a decrease in the number of neuronal cell bodies observed, suggesting that synaptic abnormalities are the earliest sign of neuronal dysfunction that ultimately results in neuronal death. These results indicate that prion replication triggers an abnormal localization of caveolin 1 and synaptophysin, which in turn may alter neuronal function.


[Assessment of fiberoptic bronchoscopic examination in inhalation injury--analysis of 32 cases].
68 times of fiberoptic bronchoscopic serial examinations in 32 patients with inhalation injury were performed at early stage after injury. Bronchoscopic abnormalities including congestion, erythema, edema and necrosis were observed. Patients were divided into three groups according to the degree of damage: mild, moderate and severe. 8 patients with mild inhalation injury, their bronchoscopic abnormalities included slight congestion and edema, these changes extended to the carina with disappearance of the trachea rings, airway lumen was slight narrowed, carina was blunted, these lesions were resolved within one week after injury. The fiberoptic bronchoscopy of patients with moderate injury showed moderate congestion and edema of mucosa of the trachea, disappearance of the trachea rings, the lumen was more narrowed as compared with mild injury. The blunted carina widen to 0.5 cm due to swelling, the mucosa of primary bronchus showed slight congestion and edema. These lesions were resolved 2 weeks after injury. The fiberoptic bronchoscopic abnormalities of 13 patients with severe inhalation injury were extreme congestion and edema of the trachea mucosa with necrosis; hemorrhage and ulceration of the mucosa were seen. The trachea lumen was significantly narrowed, the carina widened to 1 cm, and even the primary bronchus mucosa manifested moderate congestion and edema with necrosis. However, secondary bronchus mucosa was only slightly damaged. All lesions resolved about three weeks after injury. The results of the fiberoptic bronchoscopy correlated with the clinical course, blood gas analysis, as well as the prognosis.


Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance.
In breast cancer, overexpression of the transmembrane tyrosine kinase ERBB2 is an adverse prognostic marker, and occurs in almost 30% of the patients. For therapeutic intervention, ERBB2 is targeted by monoclonal antibody trastuzumab in adjuvant settings; however, de novo resistance to this antibody is still a serious issue, requiring the identification of additional targets to overcome resistance. In this study, we have combined computational simulations, experimental testing of simulation results, and finally reverse engineering of a protein interaction network to define potential therapeutic strategies for de novo trastuzumab resistant breast cancer. First, we employed Boolean logic to model regulatory interactions and simulated single and multiple protein loss-of-functions. Then, our simulation results were tested experimentally by producing single and double knockdowns of the network components and measuring their effects on G1/S transition during cell cycle progression. Combinatorial targeting of ERBB2 and EGFR did not affect the response to trastuzumab in de novo resistant cells, which might be due to decoupling of receptor activation and cell cycle progression. Furthermore, examination of c-MYC in resistant as well as in sensitive cell lines, using a specific chemical inhibitor of c-MYC (alone or in combination with trastuzumab), demonstrated that both trastuzumab sensitive and resistant cells responded to c-MYC perturbation. In this study, we connected ERBB signaling with G1/S transition of the cell cycle via two major cell signaling pathways and two key transcription factors, to model an interaction network that allows for the identification of novel targets in the treatment of trastuzumab resistant breast cancer. Applying this new strategy, we found that, in contrast to trastuzumab sensitive breast cancer cells, combinatorial targeting of ERBB receptors or of key signaling intermediates does not have potential for treatment of de novo trastuzumab resistant cells. Instead, c-MYC was identified as a novel potential target protein in breast cancer cells.


The facilitatory effects of intravenous dexmedetomidine on the duration of spinal anesthesia: a systematic review and meta-analysis.
Central mechanisms have been proposed to explain the prolongation of effect reported with the off-label use of dexmedetomidine as an adjuvant in local anesthetic admixtures. We evaluated whether IV dexmedetomidine can prolong the duration of sensory block associated with spinal anesthesia. The authors searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases for randomized controlled trials investigating the facilitatory effects of IV administration of dexmedetomidine (dexmedetomidine group) compared with placebo (control group) on single-injection local anesthetic-based spinal anesthesia. Durations of sensory and motor block, sensory and motor block onset times, postoperative pain scores, time to first analgesic request, analgesic consumption, and dexmedetomidine-related side effects were evaluated. Results were combined using random effects modeling when appropriate. A total of 364 patients were analyzed from 7 intermediate to high-quality randomized controlled trials. When IV dexmedetomidine accompanied spinal anesthesia, sensory block duration was prolonged by at least 34% (point estimate: 38%), P < 0.00001, motor block duration was prolonged by at least 17% (point estimate: 21%), P < 0.00001, and time to first analgesic request was increased by at least 53% (point estimate: 60%), P < 0.00001. The use of dexmedetomidine was associated with a 3.7-fold increase (95% confidence interval, 1.53-8.82, P = 0.004) in transient reversible bradycardia. There was no difference in the incidence of hypotension or postoperative sedation, and none of the patients experienced respiratory depression. IV dexmedetomidine can prolong the duration of sensory block, motor block, and time to first analgesic request associated with spinal anesthesia.


Rate of preventable early unplanned intensive care unit transfer for direct admissions and emergency department admissions.
Appropriate patient placement at the time of admission to avoid unplanned transfers to the ICU and codes outside of the ICU is an important safety goal for many institutions. The objective of this study was to determine if the overall rate of unplanned ICU transfers within 12 hours of admission to the inpatient medical/surgical unit was higher for direct admissions compared with emergency department (ED) admissions. This was a retrospective cohort study of all unplanned ICU transfers within 12 hours of admission to an inpatient unit at a tertiary care children's hospital from January 2010 to December 2012. Proportions of preventable unplanned transfers from the ED and from direct admission were calculated and compared. Over the study period, there were a total of 46,998 admissions; 279 unplanned ICU transfers occurred during the study period of which 101 (36%) were preventable. Preventable unplanned transfers from each portal of entry were calculated and compared with the total number of admissions from those portals. The portals of entry evaluated included admissions from our internal ED versus all outside facility transfers. The rates of early unplanned transfer (per 1000 admissions) by portal of entry were 3.50 for direct admissions and 3.18 for ED. There was no difference between direct admissions and ED admissions resulting in preventable unplanned transfers to the ICU (P=.64). Rates of unplanned ICU transfers within 12 hours of admission to an inpatient unit are not higher for direct admissions compared with ED admissions. Further studies are required to determine clinical risk factors associated with unplanned ICU transfer after admission, thus allowing for more accurate initial patient placement.


The New York Sepsis Severity Score: Development of a Risk-Adjusted Severity Model for Sepsis.
In accordance with Rory's Regulations, hospitals across New York State developed and implemented protocols for sepsis recognition and treatment to reduce variations in evidence informed care and preventable mortality. The New York Department of Health sought to develop a risk assessment model for accurate and standardized hospital mortality comparisons of adult septic patients across institutions using case-mix adjustment. Retrospective evaluation of prospectively collected data. Data from 43,204 severe sepsis and septic shock patients from 179 hospitals across New York State were evaluated. Prospective data were submitted to a database from January 1, 2015, to December 31, 2015. None. Maximum likelihood logistic regression was used to estimate model coefficients used in the New York State risk model. The mortality probability was estimated using a logistic regression model. Variables to be included in the model were determined as part of the model-building process. Interactions between variables were included if they made clinical sense and if their p values were less than 0.05. Model development used a random sample of 90% of available patients and was validated using the remaining 10%. Hosmer-Lemeshow goodness of fit p values were considerably greater than 0.05, suggesting good calibration. Areas under the receiver operator curve in the developmental and validation subsets were 0.770 (95% CI, 0.765-0.775) and 0.773 (95% CI, 0.758-0.787), respectively, indicating good discrimination. Development and validation datasets had similar distributions of estimated mortality probabilities. Mortality increased with rising age, comorbidities, and lactate. The New York Sepsis Severity Score accurately estimated the probability of hospital mortality in severe sepsis and septic shock patients. It performed well with respect to calibration and discrimination. This sepsis-specific model provides an accurate, comprehensive method for standardized mortality comparison of adult patients with severe sepsis and septic shock.


Grip and Muscle Strength Dynamometry Are Reliable and Valid in Patients With Unhealed Minor Burn Wounds.
Small burns are common and can cause disproportionate levels of disability. The ability to measure muscle impairment and consequent functional disability is a necessity during rehabilitation of patients. This study aimed to determine the reliability and validity of grip and muscle strength dynamometry in patients with unhealed, minor burn wounds. Grip and muscle strength were assessed three times on each side. Assessment occurred at presentation for the initial injury and again every other day (or every 5 days beyond 10 days post injury) until discharge from the service. Reliability was assessed using intraclass correlation. Minimum detectable differences were calculated for each muscle group. Validity was assessed using regression analysis, incorporating appropriate burn severity measures and patient demographics. Thirty patients with TBSA ≤15% were assessed. Both grip and muscle strength demonstrated very good reliability (intraclass correlation coefficient: 0.85-0.96). Minimum detectable differences ranged from 3.8 to 8.0 kg. Validity of both forms of dynamometry was confirmed through associations with gender for all muscle groups (P < .001). In addition, grip strength was associated with the dominant hand (P = .002) and time to assessment (P < .001). Strength was seen to improve over time in all muscle groups. Grip and muscle strength dynamometry are reliable and valid assessments of strength and are applicable for clinical use in patients who have unhealed, minor burn wounds.


Impaired conduction of vasodilation along arterioles in connexin40-deficient mice.
Connexins have been hypothesized to play an important role in intercellular communication within the vascular wall and may provide a mechanistic explanation for conduction of vasomotor responses. To test this hypothesis, we studied the transmission of vasomotor responses in the intact skeletal muscle microcirculation of connexin40-deficient mice (Cx40(-/-)). Arterioles were locally stimulated with hyperpolarizing dilators (acetylcholine [ACh] as well as bradykinin [Bk]) or depolarizing K(+) solution, and the resulting changes in diameter were measured using a videomicroscopy technique at the site of application and up to 1.32 mm upstream. Arterial pressure was elevated 25% in Cx40(-/-) mice (94+/-5 versus 75+/-4 mm Hg). Vessels selected for study had equivalent basal diameter and vasomotor tone in both genotypes of mice. Vasomotion was present in small arterioles of both genotypes, but its intensity was exaggerated in Cx40(-/-) mice. ACh and Bk induced dilation (33% and 53%, respectively, of maximal response) at the site of application that was of similar magnitude in both genotypes. These dilations were observed to spread upstream within <1 second without significant attenuation in Cx40(+/+) mice. However, spreading was severely attenuated in Cx40(-/-) animals (11+/-4% versus 35+/-7% with ACh and 38+/-5% versus 60+/-7% with Bk in Cx40(-/-) and Cx40(+/+), respectively; P<0.05). In contrast, conducted vasoconstrictions, induced by K(+) solution decreased equally with distance in both genotypes. These results support a significant role for Cx40 in vascular intercellular communication. Our observations indicate that Cx40 is required for normal transmission of endothelium-dependent vasodilator responses and may underlie altered vasomotion patterns.


Natural organic matter quantification in the waters of a semiarid freshwater wetland (Tablas de Daimiel, Spain).
Dissolved organic matter (DOM) concentrations have been measured in the waters of a semiarid freshwater wetland, the Tablas de Daimiel, Spain, when the system-characterised by variable hydroperiodicity conditions, was completely flooded (February 2011). Fluxes of DOM from the wetland soils to the overlying waters were measured by using a passive diffusion sampler (peeper). Not only dissolved organic carbon (DOC) concentrations were measured but refractory organic matter (ROM, usually known as humic substances) was also quantified using a novel voltammetric method. Fluorescence spectra were recorded to help in selecting the appropriate standard for ROM quantification, test the homogeneity of DOM in the waters and get an indication of their source. The results obtained show a 7-fold increase in measured ROM concentrations from the Gigüela River to the outlet, which points to a net exportation of ROM from the wetland and to the existence of an internal source of ROM in the system, probably diffusion from the wetland soils. This hypothesis is confirmed by the flux of ROM from the soils to the water column measured with the peeper and by the common fluorescence characteristics of column and interstitial waters. The smaller increase in DOC concentrations along the wetland, in spite of the higher DOC fluxes from soils, suggests that there is significant turnover of organic carbon (OC) in the water column. The system acts as a major carbon sink but, when flooded, exports OC as DOM.


Reduction of shunt dependency rates following aneurysmal subarachnoid hemorrhage by tandem fenestration of the lamina terminalis and membrane of Liliequist during microsurgical aneurysm repair.
OBJECTIVEShunt-dependent hydrocephalus is an important cause of morbidity following aneurysmal subarachnoid hemorrhage (aSAH) in excess of 20% of cases. Hydrocephalus leads to prolonged hospital and ICU stays, well as to repeated surgical interventions, readmissions, and complications associated with ventriculoperitoneal (VP) shunts, including shunt failure and infection. Whether variations in surgical technique at the time of aneurysm treatment may modify rates of shunt dependency remains a matter of debate. Here, the authors report on their experience with tandem fenestration of the lamina terminalis (LT) and membrane of Liliequist (MoL) at the time of open microsurgical repair of the ruptured aneurysm.METHODSThe authors conducted a retrospective review of 663 consecutive patients with aSAH treated from 2005 to 2015 by open microsurgery via a pterional or orbitozygomatic craniotomy by the senior author (M.T.L.). Data collected from review of the electronic medical record included age, Hunt and Hess grade, Fisher grade, need for an external ventricular drain, and opening pressure. Patients were stratified into those undergoing no fenestration and those undergoing tandem fenestration of the LT and MoL at the time of surgical repair. Outcome variables, including VP shunt placement and timing of shunt placement, were recorded and statistically analyzed.RESULTSIn total, shunt-dependent hydrocephalus was observed in 15.8% of patients undergoing open surgical repair following aSAH. Tandem microsurgical fenestration of the LT and MoL was associated with a statistically significant reduction in shunt dependency (17.9% vs 3.2%, p < 0.01). This effect was confirmed with multivariate analysis of collected variables (multivariate OR 0.09, 95% CI 0.03-0.30). Number-needed-to-treat analysis demonstrated that tandem fenestration was required in approximately 6.8 patients to prevent a single VP shunt placement. A statistically significant prolongation in days to VP shunt surgery was also observed in patients treated with tandem fenestration (26.6 ± 19.4 days vs 54.0 ± 36.5 days, p < 0.05).CONCLUSIONSTandem fenestration of the LT and MoL at the time of open microsurgical clipping and/or bypass to secure ruptured anterior and posterior circulation aneurysms is associated with reductions in shunt-dependent hydrocephalus following aSAH. Future prospective randomized multicenter studies are needed to confirm this result.


Metatranscriptomics reveals mycoviral populations in the ovine rumen.
The rumen is known to contain DNA-based viruses, although it is not known whether RNA-based viruses that infect fungi (mycoviruses) are also present. Analysis of publicly available rumen metatranscriptome sequence data from sheep rumen samples (n = 20) was used to assess whether RNA-based viruses exist within the ovine rumen. A total of 2466 unique RNA viral contigs were identified that had homology to nine viral families. The Partitiviridae was the most consistently observed mycoviral family. High variation in the abundance of each detected mycovirus suggests that rumen mycoviral populations vary greatly between individual sheep. Functional analysis of the genes within the assembled mycoviral contigs suggests that the mycoviruses detected had simple genomes, often only carrying the machinery required for replication. The fungal population of the ovine rumen was also assessed using metagenomics data from the same samples, and was consistently dominated by the phyla Ascomycota and Basidomycota. The strictly anaerobic phyla Neocallimastigomycota were also present in all samples but at a low abundance. This preliminary investigation has provided clear evidence that mycoviruses with RNA genomes exist in the rumen, with further in-depth studies now required to characterise this mycoviral community and determine its role in the rumen.


An artificial-vision- and statistical-learning-based method for studying the biodegradation of type I collagen scaffolds in bone regeneration systems.
This work proposes a method based on image analysis and machine and statistical learning to model and estimate osteocyte growth (in type I collagen scaffolds for bone regeneration systems) and the collagen degradation degree due to cellular growth. To achieve these aims, the mass of collagen -subjected to the action of osteocyte growth and differentiation from stem cells- was measured on 3 days during each of 2 months, under conditions simulating a tissue in the human body. In addition, optical microscopy was applied to obtain information about cellular growth, cellular differentiation, and collagen degradation. Our first contribution consists of the application of a supervised classification random forest algorithm to image texture features (the structure tensor and entropy) for estimating the different regions of interest in an image obtained by optical microscopy: the extracellular matrix, collagen, and image background, and nuclei. Then, extracellular-matrix and collagen regions of interest were determined by the extraction of features related to the progression of the cellular growth and collagen degradation (e.g., mean area of objects and the mode of an intensity histogram). Finally, these critical features were statistically modeled depending on time via nonparametric and parametric linear and nonlinear models such as those based on logistic functions. Namely, the parametric logistic mixture models provided a way to identify and model the degradation due to biological activity by estimating the corresponding proportion of mass loss. The relation between osteocyte growth and differentiation from stem cells, on the one hand, and collagen degradation, on the other hand, was determined too and modeled through analysis of image objects' circularity and area, in addition to collagen mass loss. This set of imaging techniques, machine learning procedures, and statistical tools allowed us to characterize and parameterize type I collagen biodegradation when collagen acts as a scaffold in bone regeneration tasks. Namely, the parametric logistic mixture models provided a way to identify and model the degradation due to biological activity and thus to estimate the corresponding proportion of mass loss. Moreover, the proposed methodology can help to estimate the degradation degree of scaffolds from the information obtained by optical microscopy.


Validation of a body condition scoring system in rhesus macaques (Macaca mulatta): assessment of body composition by using dual-energy X-ray absorptiometry.
Body condition scoring (BCS) is a subjective semiquantitative method of assessing body fat and muscle by palpation of key anatomic features. A previously published BCS system for rhesus macaques (Macaca mulatta) uses a scale comprising both whole and half units, in which the midrange represents optimal body condition (3.0), lower values represent emaciated to lean conditions (1.0 to 2.0), and higher values (4.0 to 5.0) indicate excessive body fat. A valid BCS system is well described, relevant to the species, has agreement within and between raters, and is consistent with objective measures. Here we correlate the subjective BCS assigned during physical exam with percentage body fat as determined by dual-energy X-ray absorptiometry (DEXA). Adult rhesus monkeys from an indoor-housed breeding colony were evaluated by the veterinary staff and assigned to 1 of 9 BCS score groups to give a minimum of 6 animals in each group. DEXA was used to obtain objective body composition measurements for macaques in each BCS group. Animals in the 'optimal' BCS group (3.0) had 25% body fat on average. Each full unit change in BCS was associated with an approximate 10% change in body fat percentage for macaques in the 2.0-to-5.0 BCS range. Absolute body fat in animals with BCS of 1.0 or 1.5 may be too low for accurate assessment by DEXA.


Unsupervised AER Object Recognition Based on Multiscale Spatio-Temporal Features and Spiking Neurons.
This article proposes an unsupervised address event representation (AER) object recognition approach. The proposed approach consists of a novel multiscale spatio-temporal feature (MuST) representation of input AER events and a spiking neural network (SNN) using spike-timing-dependent plasticity (STDP) for object recognition with MuST. MuST extracts the features contained in both the spatial and temporal information of AER event flow, and forms an informative and compact feature spike representation. We show not only how MuST exploits spikes to convey information more effectively, but also how it benefits the recognition using SNN. The recognition process is performed in an unsupervised manner, which does not need to specify the desired status of every single neuron of SNN, and thus can be flexibly applied in real-world recognition tasks. The experiments are performed on five AER datasets including a new one named GESTURE-DVS. Extensive experimental results show the effectiveness and advantages of the proposed approach.


Structure of a slow CLC Cl⁻/H+ antiporter from a cyanobacterium.
X-ray crystal structures have been previously determined for three CLC-type transporter homologues, but the absolute unitary transport rate is known for only one of these. The Escherichia coli Cl(-)/H(+) antiporter (EC) moves ∼2000 Cl(-) ions/s, an exceptionally high rate among membrane-transport proteins. It is not known whether such rapid turnover is characteristic of ClCs in general or if the E. coli homologue represents a functional outlier. Here, we characterize a CLC Cl(-)/H(+) antiporter from the cyanobacterium Synechocystis sp. PCC6803 (SY) and determine its crystal structure at 3.2 Å resolution. The structure of SY is nearly identical to that of EC, with all residues involved in Cl(-) binding and proton coupling structurally similar to their equivalents in EC. SY actively pumps protons into liposomes against a gradient and moves Cl(-) at ∼20 s(-1), 1% of the EC rate. Electrostatic calculations, used to identify residues contributing to ion binding energetics in SY and EC, highlight two residues flanking the external binding site that are destabilizing for Cl(-) binding in SY and stabilizing in EC. Mutation of these two residues in SY to their counterparts in EC accelerates transport to ∼150 s(-1), allowing measurement of Cl(-)/H(+) stoichiometry of 2/1. SY thus shares a similar structure and a common transport mechanism to EC, but it is by comparison slow, a result that refutes the idea that the transport mechanism of CLCs leads to intrinsically high rates.


Residual psychomotor effects following reversal of midazolam sedation with flumazenil.
The ability of flumazenil to reverse the effects of midazolam sedation was examined in a randomised, crossover, placebo controlled study in six male volunteers. Subjects received intravenous injections of either (a) midazolam 10 mg followed 10 minutes later by flumazenil 1.0 mg or (b) midazolam 10 mg followed after 10 minutes by flumazenil 4 mg or (c) placebo followed after 10 minutes by placebo. Post reversal drug effects were examined using a psychomotor battery (critical flicker fusion, digit symbol substitution, tapping test, ball-bearing test, number recall, reflex time) and linear analogue mood scales. It was found that a residual psychomotor deficit was present following flumazenil and that this persisted for up to 125 minutes after the 1.0 mg dose and 65 minutes following 4 mg. A small deterioration in performance was apparent after initial reversal with 1.0 mg, the peak deterioration occurring at 35 minutes.


Euarchontan Opsin Variation Brings New Focus to Primate Origins.
Debate on the adaptive origins of primates has long focused on the functional ecology of the primate visual system. For example, it is hypothesized that variable expression of short- (SWS1) and middle-to-long-wavelength sensitive (M/LWS) opsins, which confer color vision, can be used to infer ancestral activity patterns and therefore selective ecological pressures. A problem with this approach is that opsin gene variation is incompletely known in the grandorder Euarchonta, that is, the orders Scandentia (treeshrews), Dermoptera (colugos), and Primates. The ancestral state of primate color vision is therefore uncertain. Here, we report on the genes (OPN1SW and OPN1LW) that encode SWS1 and M/LWS opsins in seven species of treeshrew, including the sole nocturnal scandentian Ptilocercus lowii. In addition, we examined the opsin genes of the Central American woolly opossum (Caluromys derbianus), an enduring ecological analogue in the debate on primate origins. Our results indicate: 1) retention of ultraviolet (UV) visual sensitivity in C. derbianus and a shift from UV to blue spectral sensitivities at the base of Euarchonta; 2) ancient pseudogenization of OPN1SW in the ancestors of P. lowii, but a signature of purifying selection in those of C. derbianus; and, 3) the absence of OPN1LW polymorphism among diurnal treeshrews. These findings suggest functional variation in the color vision of nocturnal mammals and a distinctive visual ecology of early primates, perhaps one that demanded greater spatial resolution under light levels that could support cone-mediated color discrimination.


A comparison of intracellular changes in porcine eggs after fertilization and electroactivation.
The experiments compare intracellular changes in porcine eggs induced by electrical activation with those induced by sperm penetration. Adequate electrostimulation induces changes in both cortical granule exocytosis and protein synthesis similar to those induced by sperm during fertilization. However, ionic changes induced by electrostimulation differ markedly from those initiated at fertilization. Thus, dynamic video imaging using Fura-2 as a Ca2+ probe provides evidence that parthenogenetic activation induced by electrostimulation is initiated by a single sharp rise in the concentration of intracellular free calcium ([Ca2+]i) in the egg. The intracellular Ca2+ transient increase is triggered by an influx of extracellular Ca2+ immediately after electrostimulation. The amplitude of the intracellular Ca2+ transient increase is a function both of the extracellular Ca2+ concentration and of electric field parameters (field strength and pulse duration). Imaging demonstrates further that a single electrical pulse can only induce a single Ca2+ transient which usually lasts three to five minutes; no further Ca2+ transients are observed unless additional electrical stimuli are applied. By contrast, sperm-induced activation is characterised by a series of Ca2+ spikes which continue for at least 3 hours after sperm-egg fusion. The pattern of Ca2+ spiking after fertilization is not consistent during this period but changes both in frequency and amplitude. Overall, the results demonstrate that, although electrostimulation induces both cortical granule exocytosis and protein reprogramming in porcine eggs, it does not reproduce the pattern of [Ca2+]i changes induced by sperm entry at fertilization.


Evaluation of a fluoride-containing sealant by SEM, microleakage, and fluoride release.
A fluoride-containing sealant (FluroShield) was evaluated in vitro and compared to a sealant without fluoride (Helio-Seal). Both materials were applied to the occlusal surface of extracted teeth and microscopically evaluated for their ability to penetrate pits and fissures. Additional specimens were subjected to dye immersion and evaluated for resistance to microleakage. Disc-shaped samples of the fluoride-containing sealant were immersed in distilled water and analyzed daily for seven days for fluoride release. All specimens of FluroShield released fluoride during the evaluation period, but there were differences between the materials in resistance to microleakage.


[A possible therapeutic improvement of the antibacterial effect by monitoring the production of leukocyte free oxygen radicals during antibiotic treatment of infertile patients with chronic bacterial prostatitis].
In the male chronic accessory gland bacterial infections (AGBI), antibiotic treatment (AT) efficacy usually evaluates the antimicrobial outcome through one or more spermiocolture (SC) become negative. Recently, bacterial olipeptide fMPL has been used to detect a specific Radical Oxygen Species production by leukocytes (L-RLO), even when they are present at low concentrations in sperm fractions specimens. In the male AGBI could be present endogenous fMLP at sufficient levels to produce L chemiotaxis in the semen, and secondly active their specific L-RLO production, till when bacteriospermia remained positive. In the Percoll 50% (Pc50%) fraction, at higher L concentrations, from 22 infertile patients affected by chronic bacterial prostatitis (BP) and enrolled to a randomly AT treatment with a Quinolone (n = 12) or a Macrolide (n = 10), through two secondary milestones (possible elevated basal L-RLO in the pre-treatment, T0; significant changes in the basal and fMLP-stimulated L-RLO production within each treatment group and between groups), we would verify if a normalized L-RLO production could be taken as break-point for the AT withdrawal before checking SC for control. Indeed, in T0 all patients had positive SC and exhibited both basal and fMLP-stimulated L-RLO levels higher than those observed in 2 control groups (group cA = 10 fertile men, without chronic BP; group cB = 10 patients affected by chronic abacterial prostatitis (AP). On the 3rd AT cycle for 14 days, together in 20/22 AT-treated patients, basal and fMLP-stimulated L-RLO levels become low or normal, as well as their SCs become negative (CFU/ml = 0), whilst in a third control group (group cC) of 10 not-AT-treated BP patients, through matched-follow-up observations, these L-RLO values were always elevated and their SC remained positive (CFU/ml > or = 10(5)). In chronic BP patients, AT seems to demonstrate both antimicrobial effectiveness and reduction of L-RLO production with values similar to those of control group cA. The monitored L-RLO values during AT could be useful in order to ottimize antimicrobial effect: this tool being able to previse SC outcome, could be assumed to define clearly AT break-point and/or cycle numbers.


Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy.
Angiogenesis is fundamental for tumor development and progression. Hence, anti-angiogenic drugs have been developed to target VEGF and its receptors (VEGFRs). Several tyrosine kinase inhibitors (TKIs) have been developed over the years and others are still under investigation, each anti-VEGFR TKI showing a different cardiotoxic profile. Knowledge of the cardiac side-effects of each drug and the magnitude of their expression and frequency can lead to a specific approach. This work reviews the mechanism of action of anti-VEGFR TKIs and the pathophysiological mechanisms leading to cardiotoxicity, followed by close examination of the most important drugs individually. A literature search was conducted on PubMed selecting review articles, original studies and clinical trials, with a focus on Phase III studies. Side-effects on the cardiovascular system could lead both to the worsening of general health status of cancer patients and to the discontinuation of the cancer treatment affecting its efficacy. Cardiologists often have to face new triggers of heart disease in these patients. They need a specific approach, which must be carried out in cooperation with oncologists. It must start before cancer treatment, continue during it and extend after its completion.


[Neurofibromatosis type 2 and auditory brainstem implantation].
Neurofibromatosis type 2 (NF2) is a rare and severe autosomal dominant disorder caused by mutations in a tumour suppressor gene. This article reviews NF2 and its treatment with auditory brainstem implantation. The review is based on the authors' experience with the disease and literature identified through a non-systematic search of PubMed. NF2 is caused by loss-of-normal function of the tumour suppressor protein merlin. Merlin normally suppresses cell growth and proliferation. The clinical picture is dominated by neurological symptoms, caused by multiple tumours - mainly schwannomas and meningeomas. The hallmark of the disease is development of bilateral vestibular schwannomas, and the most common presenting symptom in adults is progressive hearing loss. Presenile cataract, ocular motility disorders, peripheral neuropathy and skin tumours are other common findings. The majority of patients become deaf, many patients become severely disabled and life expectancy is reduced. The goal of management is conservation of function and maintenance of quality of life. Auditory brainstem implants stimulate the cochlear nucleus directly and provide substantial auditory benefits to patients with NF2. A multidisciplinary approach in specialty centres is recommended. Management by an experienced team reduces mortality and improves outcome after surgery. Auditory brainstem implantation is an important part of the hearing rehabilitation in these patients. Emerging knowledge of the molecular disease mechanisms offers hope for new therapeutic strategies.


4-Aminopyridine, A Blocker of Voltage-Dependent K+ Channels, Restores Blood Pressure and Improves Survival in the Wistar Rat Model of Anaphylactic Shock.
Anaphylactic shock is associated with severe hypotension. Potassium channel blockers, such as 4-aminopyridine, induce vasoconstriction. The objective of this study was to test the ability of 4-aminopyridine to restore blood pressure and increase survival in anaphylactic shock. Experimental study. Physiology laboratory. Adult male Wistar rats. Rats were sensitized with ovalbumin (1 mg SC), and anaphylactic shock was induced by IV injection of ovalbumin (1 mg). Experimental groups included non-allergic rats (NA) (n = 6); allergic rats (Controls) (n = 6); allergic rats treated with 4-aminopyridine (4-aminopyridine) (1 mg/kg) (n = 6); and allergic rats treated with epinephrine (EPI) (10 µg/kg) (n = 6). Treatments were administered 1 minute after induction of anaphylactic shock. Mean arterial blood pressure, heart rate, and survival were measured for 60 minutes. Plasma levels of histamine, leukotriene B4, prostaglandin E2, prostaglandin F2, pH, and HCO3 were measured. Mean arterial blood pressure was normal in the NA group; severe hypotension and high mortality were observed in controls; normalization of mean arterial blood pressure, heart rate, and increased survival were observed in 4-aminopyridine and EPI groups. All allergic 4-aminopyridine-treated rats survived after the induction of anaphylactic shock. Histamine level was higher in controls and the 4-aminopyridine group but reduced in the EPI group. Prostaglandin E2 increased in controls and EPI group and decreased in 4-aminopyridine group; prostaglandin F2 increased in controls but decreased in 4-aminopyridine and EPI groups. Leukotriene B4 decreased in 4-aminopyridine and EPI groups. Metabolic acidosis was prevented in the 4-aminopyridine group. Our data suggest that voltage-dependent K+ channel inhibition with 4-aminopyridine treatment restores blood pressure and increases survival in the Wistar rat model of anaphylactic shock. 4-aminopyridine or related voltage-dependent K channel blockers could be a useful additional therapeutic approach to treatment of refractory anaphylactic shock.


Hepatic glucose output in humans measured with labeled glucose to reduce negative errors.
Steele and others have suggested that minimizing changes in glucose specific activity when estimating hepatic glucose output (HGO) during glucose infusions could reduce non-steady-state errors. This approach was assessed in nondiabetic and type II diabetic subjects during constant low dose [27 mumol.kg ideal body wt (IBW)-1.min-1] glucose infusion followed by a 12 mmol/l hyperglycemic clamp. Eight subjects had paired tests with and without labeled infusions. Labeled infusion was used to compare HGO in 11 nondiabetic and 15 diabetic subjects. Whereas unlabeled infusions produced negative values for endogenous glucose output, labeled infusions largely eliminated this error and reduced the dependence of the Steele model on the pool fraction in the paired tests. By use of labeled infusions, 11 nondiabetic subjects suppressed HGO from 10.2 +/- 0.6 (SE) fasting to 0.8 +/- 0.9 mumol.kg IBW-1.min-1 after 90 min of glucose infusion and to -1.9 +/- 0.5 mumol.kg IBW-1.min-1 after 90 min of a 12 mmol/l glucose clamp, but 15 diabetic subjects suppressed only partially from 13.0 +/- 0.9 fasting to 5.7 +/- 1.2 at the end of the glucose infusion and 5.6 +/- 1.0 mumol.kg IBW-1.min-1 in the clamp (P = 0.02, 0.002, and less than 0.001, respectively).


Activation of the complete mouse metallothionein gene locus in the maternal deciduum.
The mouse metallothionein (MT) gene family consists of four known members (MT-I through IV) clustered on chromosome 8. Studies reported herein examine the expression and regulation of the MT-III and MT-IV genes in specific cell types in the maternal reproductive tract, developing embryo, and fetus known to express the MT-I and -II genes. MT-III and MT-IV mRNAs were absent from the visceral yolk sac, placenta, and fetal liver, tissues with high levels of MT-I and MT-II mRNAs. In contrast, MT-III and MT-IV mRNAs were both abundant in the maternal deciduum, and in experimentally induced deciduoma on 7 and 8 days postcoitum (1 dpc = vaginal plug), as are MT-I and -II mRNAs. The abundance of each of these MT mRNAs increased coordinately during development of the deciduum (6-8 dpc), and in situ hybridization localized MT-I, MT-III, and MT-IV mRNAs to the secondary decidual zone of the antimesometrial region on 8 dpc, where in some regions all of the cells were apparently positive. Thus, all of the known mouse MT genes are co-expressed in at least some of the cells in the secondary decidual zone. Electrophoretic analysis of decidual MT suggested that the MT-I, -II, and -III isoforms are abundant proteins in the secondary deciduum. Bacterial endotoxin-lipopolysaccharide (LPS) and Zn are powerful inducers of MT-I and MT-II gene expression in many adult organs, whereas these agents apparently have little effect on MT-III and MT-IV gene expression. Neither of these agents significantly effected levels of decidual MT-III or MT-IV mRNAs in vivo or in primary cultures of decidual cells in vitro, and only modest effects of Zn on MT-I mRNA levels were noted. During 2 days of in vitro culture, decidual cell MT-I and MT-III mRNA levels remained elevated while MT-IV mRNA levels decreased. Thus, expression of the mouse MT gene locus in the deciduum appears to be developmentally regulated, and in this tissue, the MT genes are refractory to induction by Zn or inflammation.


Adolescent Emotion Regulation and Future Psychopathology: A Prospective Transdiagnostic Analysis.
Transdiagnostic frameworks posit a causal link between emotion regulation (ER) ability and psychopathology. However, there is little supporting longitudinal evidence for such frameworks. Among N = 1,262 adolescents, we examined the prospective bidirectional relationship between ER and future pathological anxiety, depression, and substance dependence symptoms in 10 assessment waves over 7 years. In Random-intercept cross-lagged panel models, within-person results do not reveal prospective lag-1 effects of either ER or symptoms. However, between-person analyses showed that dispositional ER ability at baseline predicted greater risk for developing clinically significant depression, anxiety, and substance dependence over the 7-year follow-up period. These findings provide some of the first direct evidence of prospective effects of ER on future symptom risk across affect-related disorders, and should strengthen existing claims that ER ability represents a key transdiagnostic risk factor.


Epithelial transport and bioavailability of intranasally administered human growth hormone formulated with the absorption enhancers didecanoyl-L-alpha-phosphatidylcholine and alpha-cyclodextrin in rabbits.
The transepithelial transport of biosynthetic human growth hormone (hGH) formulated with the absorption enhancers didecanoyl-L-alpha-phosphatidylcholine (DDPC) and alpha-cyclodextrin (alpha-CD) was studied after intranasal administration to rabbits. Plasma concentrations of the hormone were determined until 240 min post administration by ELISA, and the absolute bioavailability was estimated to be in the vicinity of 20%. The localization of hGH was studied 15 min after application of the powder formulation in the initial absorptive phase. To visualize the hormone, a two-step indirect immuno-gold technique was used on semithin and ultrathin cryosections and Epon sections. Polyclonal rabbit anti-hGH was used as primary antibody and gold-conjugated goat anti-rabbit IgG as secondary antibody, succeeded by silver enhancement. Growth hormone was mainly found in the cytoplasm and nuclei of ciliated cells, showing distinct morphological signs of early necrosis, and in lamina propria, including the venules. Minute amounts of hGH were found in endocytotic vesicles in morphologically normal epithelial cells and in the intercellular compartment. We conclude that the major transport route of hGH formulated with absorption enhancers DDPC and alpha-CD was transcellular through lethally damaged ciliated cells.


Editorial: Basic research in bladder cancer - refining the tools. 3rd IBCN seminars series1.
This editorial highlights submissions to part II of the 3rd IBCN Seminars Series particularly focusing on the tools required for conduction of translational research in bladder cancer. One of the submissions describe the ex vivo culture of primary tumor cells from N-methyl-N-nitrosourea-induced bladder tumors in rats and subsequent establishment of an immortalized cell line. In a next step the authors thoroughly characterize this cell line. They conclude that differentiation marker expression patterns observed in the original tumors are largely retained in the spheroids. Although new cancer models, such as organoid tissue cultures, hold great promise for studying cancer progression and might have a potential for development and selection of an optimal treatment, their limitations must be kept in mind. The second submission, therefore, critically questions the current role of organoid tissue culture as a predictive tool in urothelial cancer patients. The third manuscript of this series provides a broader overview of post-translational modification in bladder cancer is presented and how PTMs can be exploited as potential therapeutic targets. The 3 manuscripts featured in this issue demonstrate especially how basic research is being channeled to inform clinically actionable discoveries.


Solid- and solution-phase organics dictate copper distribution and speciation in multicomponent systems containing ferrihydrite, organic matter, and montmorillonite.
Copper retention by ferrihydrite, leaf compost, and montmorillonite was studied over 8 months in systems that emulate a natural soil where different solid phases compete for Cu through a common solution in a compartmentalized batch reactor. Copper speciation in solution (total dissolved, DPASV-labile, and free) and exchangeable and total Cu in individual solid phases were determined. Organic carbon in solution (DOC) and that retained by the mineral phases were also determined. Cu sorption reached steady-state after 4 months and accounted for 80% of the Cu initially added to the system (0.15 mg L(-1)). The remaining 20% stayed in solution as nonlabile (82.8%), labile (17%), and free (0.2%) Cu species. Copper sorption followed the order organic matter > silicate clays > iron oxides. Within each solid phase, exchangeable Cu was < or = 10% of the total Cu sorbed. DOC reached steady state (22 mg L(-1)) after 4 months and seemed to control Cu solubility and sorption behavior by the formation of soluble Cu-DOC complexes and by sorbing onto the mineral phases. DOC sorption onto ferrihydrite prevented Cu retention by this solid phase. Using a multicomponent system and 8 months equilibrations, we were able to capture some of the more important aspects of the complexity of soil environments bytaking into account diffusion processes and competition among solid- and solution-phase soil constituents in the retention of a metal cation.