Preparing Future Leaders: An Integrated Quality Improvement Residency Curriculum.
The Accreditation Council for Graduate Medical Education (ACGME) has recognized the importance of quality improvement (QI) training and requires that accredited residencies in all specialties demonstrate that residents are "integrated and actively participate in interdisciplinary clinical quality improvement and patient safety activities." However, competing demands in residency training may make this difficult to accomplish. The study's objective is to develop and evaluate a longitudinal curriculum that meets the ACGME requirement for QI and patient safety training and links to patient-centered medical home (PCMH) practices. Residents in the Worcester Family Medicine Residency (WFMR) participated in a faculty-developed quality improvement curriculum that included web-based tutorials, quality improvement projects, and small-group sessions across all 3 years of residency. They completed self-evaluations of knowledge and use of curricular activities annually and at graduation, and comparisons were made between two graduating classes, as well as comparison of end of PGY2 to end of PGY3 for one class. Graduating residents who completed the full 3 years of the curriculum rated themselves as significantly more skilled in nine of 15 areas assessed at end of residency compared to after PGY2 and reported confidence in providing future leadership in a focus group. Five areas were also rated significantly higher than prior-year residents. Involving family medicine residents in a longitudinal curriculum with hands-on practice in implementing QI, patient safety, and chronic illness management activities that are inclusive of PCMH goals increased their self-perceived skills and leadership ability to implement these new and emerging evidence-based practices in primary care.


Comparative genomics of Bordetella pertussis reveals progressive gene loss in Finnish strains.
Bordetella pertussis is a gram-negative bacterium that infects the human respiratory tract and causes pertussis or whooping cough. The disease has resurged in many countries including Finland where the whole-cell pertussis vaccine has been used for more than 50 years. Antigenic divergence has been observed between vaccine strains and clinical isolates in Finland. To better understand genome evolution in B. pertussis circulating in the immunized population, we developed an oligonucleotide-based microarray for comparative genomic analysis of Finnish strains isolated during the period of 50 years. The microarray consisted of 3,582 oligonucleotides (70-mer) and covered 94% of 3,816 ORFs of Tohama I, the strain of which the genome has been sequenced. Twenty isolates from 1953 to 2004 were studied together with two Finnish vaccine strains and two international reference strains. The isolates were selected according to their characteristics, e.g. the year and place of isolation and pulsed-field gel electrophoresis profiles. Genomic DNA of the tested strains, along with reference DNA of Tohama I strain, was labelled and hybridized. The absence of genes as established with microarrays, was confirmed by PCR. Compared with the Tohama I strain, Finnish isolates lost 7 (8.6 kb) to 49 (55.3 kb) genes, clustered in one to four distinct loci. The number of lost genes increased with time, and one third of lost genes had functions related to inorganic ion transport and metabolism, or energy production and conversion. All four loci of lost genes were flanked by the insertion sequence element IS481. Our results showed that the progressive gene loss occurred in Finnish B. pertussis strains isolated during a period of 50 years and confirmed that B. pertussis is dynamic and is continuously evolving, suggesting that the bacterium may use gene loss as one strategy to adapt to highly immunized populations.


Chronic oesophageal stricture due to moniliasis.
A case of persistent oesophageal stricture due to moniliasis, which developed while the patient was symptomatic, is reported. The value and therapeutic implications of performing a repeat barium swallow even if the disease appears to be quiescent are discussed.


Effect of extracorporeal enzymatic deheparinization on formed blood components.
A stirred blood filter containing an immobilized enzyme, heparinase, has been used to neutralize heparin's anticoagulant activity at the outflow of an extracorporeal circuit in dogs. The hematocrit and red blood cell count remained unchanged throughout the 90-min perfusion period. Platelet and white blood cell counts decreased early in the procedure to approximately 20% of the initial levels, but then returned to 30 and 70%, respectively, of their initial values by the end of the procedure. After 24 h normal levels were reestablished. In vitro experiments with human blood were conducted to determine the principal cause of the observed decrease of formed blood components. An unstirred heparinase filter preserved platelets and white blood cells better than stirred filters possessing higher, the same, or no heparin-degrading capacity, suggesting that most of the loss of formed blood components is due to stirring and not to the heparinase or the Sepharose support on which the enzyme is immobilized.


The Lag of the Proliferative Aging Clock Underlies the Lifespan-Extending Effect of Calorie Restriction.
The nature of the life-extending effect of calorie restriction (CR) is an unsolved problem in biology since 30 years of the last century. Furthermore, many different factors that cause analogous life-extending effect, so called CR-mimetic factors, have been found. They increase the lifespan of different animal species (repeatedly in invertebrates) and therefore remain in the forefront of anti-aging researches. The aims of this paper is to find an overarching solution for the nature of CR and all CR-mimetic factors and to analyze the consequences following this phenomenon. The analysis of empirical scientific data, which concern aging process and boundary areas from the point of view of the bioenergetics theory of aging. "Anything that affects a living system that slows (accelerates) the rate of cell division entails extending (reducing) life duration" is this overarching solution. CR is one of such factors that cause a retardation in the rate of cell divisions due to the shortage in 'construction materials' necessary for doubling cell mass during reduplication. This put a brake on realization of the aging program. To draw this conclusion, a new concept of the proliferative aging clock based on bioenergetics theory of aging was put forward. This clock governs the rate of the aging process via programmed, proliferative dependent and stepwise bioenergetics decline. The mechanism of the life-extending effect of CR and CR-mimetic factors is not related to that of natural aging, therefore this unable to be the basis for elaboration of radical remedy for senescence. However, both the CR and some of CR-mimetic factors can undoubtedly lead to human life extension: our organism differs from that of the other mammals only slightly. It is the wellbeing and vulnerability of such extended life that are under consideration. To achieve a healthy and unlimited life it is necessary to reprogram gene expression so that cell bioenergetics levels either remain at a previous level after cell division, which will stop aging, or else grow, which will result in organism rejuvenation.


Integrated clinical workstations for image and text data capture, display, and teleconsultation.
The Department of Veterans Affairs (VA) DHCP Imaging System digitally records clinically significant diagnostic images selected by medical specialists in a variety of hospital departments, including radiology, cardiology, gastroenterology, pathology, dermatology, hematology, surgery, podiatry, dental clinic, and emergency room. These images, which include true color and gray scale images, scanned documents, and electrocardiogram waveforms, are stored on network file servers and displayed on workstations located throughout a medical center. All images are managed by the VA's hospital information system (HIS), allowing integrated displays of text and image data from all medical specialties. Two VA medical centers currently have DHCP Imaging Systems installed, and other installations are underway.


Mutations in Hnrnpa1 cause congenital heart defects.
Incomplete penetrance of congenital heart defects (CHDs) was observed in a mouse model. We hypothesized that the contribution of a major genetic locus modulates the manifestation of the CHDs. After genome-wide linkage mapping, fine mapping, and high-throughput targeted sequencing, a recessive frameshift mutation of the heterogeneous nuclear ribonucleoprotein A1 (Hnrnpa1) gene was confirmed (Hnrnpa1ct). Hnrnpa1 was expressed in both the first heart field (FHF) and second heart field (SHF) at the cardiac crescent stage but was only maintained in SHF progenitors after heart tube formation. Hnrnpa1ct/ct homozygous mutants displayed complete CHD penetrance, including truncated and incomplete looped heart tube at E9.5, ventricular septal defect (VSD) and persistent truncus arteriosus (PTA) at E13.5, and VSD and double outlet right ventricle at P0. Impaired development of the dorsal mesocardium and sinoatrial node progenitors was also observed. Loss of Hnrnpa1 expression leads to dysregulation of cardiac transcription networks and multiple signaling pathways, including BMP, FGF, and Notch in the SHF. Finally, two rare heterozygous mutations of HNRNPA1 were detected in human CHDs. These findings suggest a role of Hnrnpa1 in embryonic heart development in mice and humans.


Development and initial validation of the chronic hepatitis B quality of life instrument (CHBQOL) among Chinese patients.
This study developed and tested preliminary measurement properties of a Chinese scale specifically designed to measure HRQOL in patients with chronic hepatitis B (CHBQOL). We conducted 94 individual interviews with CHB patients to solicit items and five hepatitis expert interviews along with three rounds of cognitive interviews to identify problems with relevance and understanding of content. A cross-sectional validation study was then conducted to evaluate measurement properties (n = 578). Factor analysis was used to determine the latent structure of the scale. Reliability was evaluated through Cronbach's alpha coefficients and intra-class correlation coefficients (ICCs). Measurement model adequacy, convergent, discriminant, and known-groups validity were also examined. A scale of 30 items was drafted. After item reduction, the remaining 23 items were assigned to the CHBQOL Somatic symptoms, Emotional symptoms, Belief and Social stigma domains, which had acceptable goodness of fit (χ2/df = 3.13, GFI = 0.90, AGFI = 0.88, RMSEA = 0.06, SRMR = 0.05). All the CHBQOL domains had satisfactory reliability with Cronbach's α coefficients ranging from 0.73 to 0.91 and ICCs were higher than 0.70 except for Belief domain (ICC = 0.54). Convergent and discriminant validity were acceptable as supported by significant item-domain correlations (0.64-0.90). In general, the correlations between CHBQOL and the SF-36 dimensions met hypotheses. Significant differences were found by mean scores in the subgroups of demographic and clinical variables, supporting the known-groups validity. The CHBQOL instrument proved to be an appropriate tool for assessing HRQOL among Chinese CHB patients.


[Cholera update at the dawn of the millenium].
Cholera is an ancestral disease belonging to the mythology of numerous societies. In the last two centuries, seven pandemias have been recorded, in which the spatial and temporal modalities of disease transmission are related to the major technical revolutions of the period. The now ongoing seventh pandemia is by far the longest and most widespread with specific features that raise new challenges and hopes. The authors present the situation at the dawn of the third millennium based on a review of current epidemiological, clinical, therapeutic, diagnostic and vaccinal data. This update shows that the field is progressing and may indeed be standing on the verge of significant breakthroughs for management of the disease and vibrion endemicity.


Google Trends can improve surveillance of Type 2 diabetes.
Recent studies demonstrate that people are increasingly looking online to assess their health, with reasons varying from personal preferences and beliefs to inability to book a timely appointment with their local medical practice. Records of these activities represent a new source of data about the health of populations, but which is currently unaccounted for by disease surveillance models. This could potentially be useful as evidence of individuals' perception of bodily changes and self-diagnosis of early symptoms of an emerging disease. We make use of the Experian geodemographic Mosaic dataset in order to extract Type 2 diabetes candidate risk variables and compare their temporal relationships with the search keywords, used to describe early symptoms of the disease on Google. Our results demonstrate that Google Trends can detect early signs of diabetes by monitoring combinations of keywords, associated with searches for hypertension treatment and poor living conditions; Combined search semantics, related to obesity, how to quit smoking and improve living conditions (deprivation) can be also employed, however, may lead to less accurate results.


Estimation of glycemic and insulinemic responses to short-grain rice (Japonica) and a short-grain rice-mixed meal in healthy young subjects.
We estimated glycemic and insulinemic responses to short-grain rice (Japonica) and a short-grain rice-mixed meal (i.e. short-grain rice and other ingredients) in three healthy male, and five healthy female subjects aged 22-31 years. A 50 g carbohydrate portion of dry rice was used in this study to estimate the glycemic index (GI) of short-grain rice (Experiment 1). The GI of short-grain rice was 68 (white bread = 100). In Eperiment 2, the subjects took three mixed meals (rice-, bread- and cornflakes-mixed) containing 60 g available carbohydrate, 25-29 g fat, 18-22 g protein, 2331-2486 kJ energy, and 67-123 meal GI in order to detemine whether both the amount and source of carbohydrate consumed determined postprandial glycemic and insulinemic responses of mixed meals. Glycemic response after the rice-mixed meal was significantly lower (p<0.05) than that after the cereal-mixed meal. The predicted glycemic and insulinemic responses, based on GI and the amount of carbohydrate, were related to the observed mean plasma glucose responses. These results suggest that short-grain rice (Japonica) grown in Japan should not be classified as a high GI food and that, in a mixed meal, it is a lower glycemic and insulinemic responder compared with bread or cereal mixed meals. Moreover, both the amount and source of carbohydrate consumed determine the glycemic and insulinemic responses after different mixed meals with variable GI.


Strong inhibition of celastrol towards UDP-glucuronosyl transferase (UGT) 1A6 and 2B7 indicating potential risk of UGT-based herb-drug interaction.
Celastrol, a quinone methide triterpene isolated from Tripterygium wilfordii Hook F., has various biochemical and pharmacological activities, and is now being developed as a promising anti-tumor agent. Inhibitory activity of compounds towards UDP-glucuronosyltransferase (UGT) is an important cause of clinical drug-drug interactions and herb-drug interactions. The aim of the present study is to investigate the inhibition of celastrol towards two important UDP-glucuronosyltransferase (UGT) isoforms UGT1A6 and UGT2B7. Recombinant UGT isoforms and non-specific substrate 4-methylumbelliferone (4-MU) were used. The results showed that celastrol strongly inhibited the UGT1A6 and 2B7-mediated 4-MU glucuronidation reaction, with 0.9 ± 0.1% and 1.8 ± 0.2% residual 4-MU glucuronidation activity at 100 μM of celastrol, respectively. Furthermore, inhibition kinetic study (Dixon plot and Lineweaver-Burk plot) demonstrated that celastrol noncompetitively inhibited the UGT1A1-mediated 4-MU glucuronidation, and competitively inhibited UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameters (Ki) were calculated to be 0.49 μM and 0.045 μM for UGT1A6 and UGT2B7, respectively. At the therapeutic concentration of celastrol for anti-tumor utilization, the possibility of celastrol-drug interaction and celastrol-containing herbs-drug interaction were strongly indicated. However, given the complicated nature of herbs, these results should be viewed with more caution.


Community vulnerability and stratified risk: Hegemonic masculinity, socioeconomic status, and HIV/AIDS in a sex work community in Kampala, Uganda.
This article examines the social patterning of health, economic uncertainty, hegemonic masculinity, and vulnerability among men who live and work in a low-income sex work community in Kampala, Uganda. This problematises the notion that vulnerable communities are homogenous, in demographics, economic status, and risk. This article draws on ethnographic data collected in 2016, including semi-structured interviews and participant observation. This article uses a stratified risk framework to describe the central finding of this study, which is that men's experience in Kataba is characterised by a struggle to fulfil the provider role that constitutes a core aspect of their socially ascribed gender role. In a context of economic scarcity, men's lives are fraught with strain and this intersects with other forms of risk. Finally, by focusing on community vulnerability rather than individual risk, this work contributes to theories of gender and sex work, and informs HIV/AIDS praxis.


Pretreatment serum endostatin as a prognostic indicator in metastatic gastric carcinoma.
Endostatin is the C-terminal antiangiogenic fragment of the extracellular matrix protein collagen XVIII, and is generated by tumor-derived proteases. The presence of serum endostatin in patients with gastric cancer has not been reported. The authors assessed the serum levels of endostatin in patients with gastric carcinoma and evaluated their association with the levels of vascular endothelial growth factor (VEGF) and the clinical outcome. A total of 107 patients with gastric cancer were included in the study. Pretherapeutic serum levels of endostatin and VEGF were measured using an ELISA, and compared with those in 23 healthy controls. The serum levels of endostatin and VEGF were higher in gastric cancer patients than in healthy controls (endostatin, 70.1 +/- 16.6 vs. 52.2 +/- 6.2 ng/mL [p < 0.001]; VEGF, 55.1 +/- 7.6 vs. 32.1 +/- 2.4 ng/mL [p < 0.001]; mean +/- SD). Serum endostatin levels were significantly associated with the presence of distant metastases (r = 0.556, p < 0.001) and VEGF levels (r = 0.335, p < 0.001), but not with the depth of tumor invasion, differentiation, or regional lymph node status. A serum endostatin level above the 75th percentile of the distribution for the patients (79.2 ng/mL) was associated with a poor outcome (last follow-up at 42 months; median survival time, 9 vs. 20 months [log-rank, p = 0.017]; median time to progression, 5 vs. 10 months [log-rank, p = 0.022]) in the patients with metastatic gastric cancer. The results suggest for the first time that an elevated serum level of endostatin at the diagnosis of metastatic gastric cancer could be predictive of a poor outcome.


[The characteristics of the effect of centimeter-range microwaves on drug pharmacokinetics in the body of experimental animals].
The experiments on 130 rat males have shown that the exposure of the animals' liver to centimeter microwaves enhances catalytic activity of P-450p cytochrome, an enzyme of drug microsomal metabolism. However, changes in pharmacokinetic parameters of elimination from the blood of the drugs based on microsomal substrates of hepatic enzymatic system are more dependent on the microwaves' impact on physiological factors modifying drug pharmacokinetics. This implies the necessity of pharmacokinetic investigations in each individual case of combining drugs with microwaves.


Identification of agents targeting FtsZ assembly.
Filamenting temperature-sensitive mutant Z (FtsZ), an essential cell division protein in bacteria, has recently emerged as an important and exploitable antibacterial target. Cytokinesis in bacteria is regulated by the assembly dynamics of this protein, which is ubiquitously present in eubacteria. The perturbation of FtsZ assembly has been found to have a deleterious effect on the cytokinetic machinery and, in turn, upon cell survival. FtsZ is highly conserved among prokaryotes, offering the possibility of broad-spectrum antibacterial agents, while its limited sequence homology with tubulin (an essential protein in eukaryotic mitosis) offers the possibility of selective toxicity. This review aims to summarize current knowledge regarding the mechanism of action of FtsZ, and to highlight existing attempts toward the development of clinically useful inhibitors.


Evolution of Chernobyl Corium in Water: Formation of Secondary Uranyl Phases.
Two crystalline phases, which are analogues of common secondary uranyl minerals, namely, becquerelite (Ca[(UO2)6O4 (OH)6]·8H2O) and phurcalite (Ca2[(UO2)3O2 (PO4)2]·7H2O) were identified on the surface of a Chernobyl corium-containing sample affected by hydrothermal alteration in distilled water at 150 °C for one year. Phases were characterized using Single-Crystal X-ray Diffraction Analysis (SCXRD) as well as optical and scanning electron microscopy. Features of the structural architecture of novel phases, which come from the specific chemical composition of the initial fragment of Chernobyl sample, are reported and discussed. Precise identification of these phases is important for modelling of severe nuclear accidents and their long-term consequences, including expected corium-water interaction processes at three damaged Units of the Nuclear Power Plant Fukushima Daiichi.


Impact of maternal malaria and under-nutrition on intrauterine growth restriction: a prospective ultrasound study in Democratic Republic of Congo.
Maternal malaria and under-nutrition are established risk factors for small-for-gestational-age (SGA) births; however, whether malaria is associated with intrauterine growth restriction (IUGR) is unknown. We investigated IUGR risk among 177 HIV-negative pregnant women enrolled in a longitudinal ultrasound study conducted in Democratic Republic of Congo from May 2005 to May 2006. Malaria infection, maternal anthropometrics, and ultrasound estimated fetal weight were measured monthly. All positive malaria cases were treated and intermittent presumptive therapy (IPTp) provided. Log-binomial regression models for IUGR were fitted using generalized estimating equations to account for statistical clustering of repeat IUGR measurements. Twenty-nine percent of fetuses experienced an episode of IUGR with the majority occurring in the third trimester. The risk of IUGR associated with malaria was greatest after three or more cumulative infections (RR 3.3, 95% CI 1.3-8.2) and was two- to eight-fold higher among women with evidence of under-nutrition. Receiving antimalarial treatment in the previous month (for IPTp or treatment) was significantly protective against IUGR (RR 0.5, 95% CI 0.3-0.7). The interaction observed between malaria and under-nutrition suggests that antenatal programmes in malaria endemic areas should incorporate nutritional screening and supplementation in addition to IPTp.


[Relationship between the expression of heat shock protein 25 and selenium binding protein 1 with ischemia/reperfusion lung injury in vivo: experiment with rats].
To analyze the differential expression proteins of rat ischemia/reperfusion (I/R) lung tissues in vivo and normal lung tissues by comparative proteome analysis, and to study the mechanism of donor lung I/R injury. Forty male SD rats were randomly divided into 2 equal groups: I/R group undergoing mimic orthotopic left lung auto-grafting and harvesting of the left lung five hours after the operation, and control group undergoing isolation of the left hilus of lung and then harvesting of the left lung. The differential proteins in the left ventricle of transplanted heart were separated by means of immobilized pH gradient-based two-dimensional gel electrophoresis (2-DE), identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS), and searched through Matrix Science software system. Western blotting was used to verify part of the differentially expressed proteins. Well-resolved and reproducible 2-DE profile of rat I/R lung tissues and normal lung tissues were obtained. In the I/R lung tissue profile, the average spot number from 3 gels was 489 +/- 52 spots (P > 0.05) with an average matching rate of 89.28% (P > 0.05), and in the control group, the average spot number from 3 gels was 511 +/- 83 spots (P > 0.05) with an average matching rate of 91.22% (P > 0.05). Fourteen differential proteins were identified by peptide mass fingerprinting (PMF) searched in Matrix Science (P < 0.05). Western blotting confirmed that the protein expression of selenium binding protein 1 (SBP-1) and heat shock protein 25 (HSP25) increased at the early stage of I/R group. The protein expression of HSP25 and SBP-1 with stress protection function is upregulated in the early stage of lung I/R injury. Other differentially expressed proteins identified may have important functions in energy metabolism, tissue stress, cell apoptosis, and signal transduction.


[Clinical studies of an ampicillin suppository (KS-R1) in children].
Clinical trials of KS-R1 have been carried out on 28 infections in children, including 8 pharyngitis, 11 tonsillitis, a pharyngolaryngobronchitis, 3 lymphadenitis and 5 urinary tract infections. The following results were obtained. KS-R1 30-50 mg/kg/day, was clinically effective in 27 out of 28 infections. Bacteriologically, the following routine clinical isolates were identified; Enterococci in 1 case, S. viridans 1 case, S. pneumoniae 1 case, S. pyogenes 2 cases, H. parainfluenzae 1 case, E. coli 5 cases and S. aureus + H. influenzae 1 case. Every isolated organism showed +++ sensitivity to the ABPC sensitivity disc in vitro without only 1 case of E. coli. The organisms were eradicated in 11 patients after the administration of KS-R1. Adverse effects did not occur in any patient without case 25, who complained of pollakiuria.


Understanding the Role of Antiviral Cytokines and Chemokines on Neural Stem/Progenitor Cell Activity and Survival.
Viral infections of the central nervous system are accompanied by the expression of cytokines and chemokines that can be critical for the control of viral replication in the brain. The outcomes of cytokine/chemokine signaling in neural cells vary widely, with cell-specific effects on cellular activity, proliferation, and survival. Neural stem/progenitor cells (NSPCs) are often altered during viral infections, through direct infection by the virus or by the influence of immune cell activity or cytokine/chemokine signaling. However, it has been challenging to dissect the contribution of the virus and specific inflammatory mediators during an infection. In addition to initiating an antiviral program in infected NSPCs, cytokines/chemokines can induce multiple changes in NSPC behavior that can perturb NSPC numbers, differentiation into other neural cells, and migration to sites of injury, and ultimately brain development and repair. The focus of this review was to dissect the effects of common antiviral cytokines and chemokines on NSPC activity, and to consider the subsequent pathological consequences for the host from changes in NSPC function.


Structural and functional relationships of toyocamycin on NPM-translocation.
Toyocamycin is an antitumor antibiotic which has a pyrrolo[2,3-D]pyrimidine aglycone with a -CN substituent on the 5-carbon. Treatment of HeLa cells with toyocamycin induces redistribution of the nuclear phosphoprotein nucleophosmin/B23 (NPM) from nucleoli to nucleoplasm (NPM-translocation) which can be detected by immunofluorescence. NPM-translocation is useful in showing drug effects and in detecting drug-resistant cancer cells. To study which structural features of toyocamycin are important for NPM-translocation, we used toyocamycin analogs in which the 5-position -CN was either deleted (tubercidin) or replaced with a -CONH2 (sangivamycin) or -C(NOH)NH2. HeLa cells were incubated with these analogs for 4 h and assayed for NPM-translocation by immunofluorescence. We found that the analog with the deletion of the -CN group (tubercidin) did not induce translocation while those with replacement of the -CN group with -CONH2 or -C(NOH)NH2 retained the NPM-translocation activity. When these or similar modifications were applied to 7-deazaguanosine, none of the guanosine analogs were effective. These results indicate that modifications at the 5-position of the pyrrolo[2,3-D]pyrimidine ring and a structure similar to adenine rather than guanine are essential for NPM-translocation. Since inhibition of RNA synthesis did not induce NPM-translocation, our results suggest that interference with NPM's binding in nucleoli by these analogs causes NPM-translocation.


Characterization of 14-3-3sigma dimerization determinants: requirement of homodimerization for inhibition of cell proliferation.
The seven highly conserved 14-3-3 proteins expressed in mammalian cells form a complex pattern of homo- and hetero-dimers, which is poorly characterized. Among the 14-3-3 proteins 14-3-3sigma is unique as it has tumor suppressive properties. Expression of 14-3-3sigma is induced by DNA damage in a p53-dependent manner and mediates a cell cycle arrest. Here we show that the 14-3-3sigma protein exclusively forms homodimers when it is ectopically expressed at high levels, whereas ectopic 14-3-3zeta formed heterodimers with the five other 14-3-3 isoforms. The x-ray structure of 14-3-3sigma revealed five residues (Ser5, Glu20, Phe25, Q55, Glu80) as candidate determinants of dimerization specificity. Here we converted these amino-acids to residues present in 14-3-3zeta at the analogous positions. Thereby, Ser5, Glu20 and Glu80 were identified as key residues responsible for the selective homodimerization of 14-3-3sigma. Conversion of all five candidate residues was sufficient to switch the dimerization pattern of 14-3-3sigma to a pattern which is very similar to that of 14-3-3zeta. In contrast to wildtype 14-3-3sigma this 14-3-3sigma variant and 14-3-3zeta were unable to mediate inhibition of cell proliferation. Therefore, homodimerization by 14-3-3sigma is required for its unique functions among the seven mammalian 14-3-3 proteins. As inactivation of 14-3-3sigma sensitizes to DNA-damaging drugs, substances designed to interfere with 14-3-3sigma homodimerization may be used to inactivate 14-3-3sigma function for cancer therapeutic purposes.


Effects of general anesthesia on quality of recovery after transaxillary endoscopic breast augmentation: A randomized controlled trial.
Types of general anesthesia may affect the quality of recovery, but few studies have investigated the quality of postoperative recovery, and none has focused on patients undergoing breast augmentation. This prospective, parallel, randomized controlled study enrolled 104 patients undergoing transaxillary endoscopic breast augmentation. Eligible patients were randomly assigned to receive inhalation anesthesia (IH, n = 52) or total intravenous anesthesia (TIVA, n = 52). Quality of recovery was assessed on the first and on the second postoperative days using the 15-item Quality of Recovery questionnaire (QoR-15). Baseline demographic, clinical characteristics, and operative data were also collected. The IH and TIVA groups had similar QoR-15 total scores on the first postoperative day (P = .921) and on the second postoperative day (P = .960), but the IH group had a significantly higher proportion of patients receiving antiemetics than the TIVA group (53.6% vs 23.1%, P = .002). Multivariate analysis revealed that the type of general anesthesia was not significantly associated with QoR-15 total scores on the first postoperative day (β = 0.68, P = .874) and with QoR-15 total scores on the second postoperative day (β = 0.56, P = .892), after adjusting for age, BMI, operation time, steroids use, and antiemetics use. For the patients undergoing transaxillary endoscopic breast augmentation, the type of general anesthesia did not significantly impact the quality of recovery. Both IH or TIVA could provide good quality of recovery demonstrated by high QoR-15 total scores. The results suggested that the type of general anesthesia may not be the most critical factors of quality of recovery in the patients undergoing transaxillary endoscopic breast augmentation.


The therapeutic effect of oral desmopressin lyophilisate formulation in children with central diabetes insipidus.
We aimed to assess the efficacy of oral use of oral desamino-D-arginine-8-vasopressin lyophilisate (OLD) in children with central diabetes insipidus (CDI). Clinical, laboratory, and imaging characteristics of twenty-five children with CDI treated with OLD were evaluated. Fourteen boys and eleven girls with a mean age of 52.37 months were evaluated. These children (mean weight and height at admission, 26.81 ± 14.8 kg vs. 92.52 ± 30 cm) presented with failure to thrive, irritability, prolonged fever, polyuria and hypernatremia (mean sodium level, 143.12 ± 8.6 mEq/L). At the time of hypernatremia, mean serum and urine osmolality were 298.2 ± 18 mOsm/kg and 160.20 ± 8.7 mOsm/kg, respectively. ADH levels were undetectable (<0.5 pmol/L) at admission in all cases. Oral administration of desmopressin lyophilisate (120 µg/tablet) was initiated at a dose of 5 μg/kg/day in two divided doses together with controlled water intake to avoid hyponatremia. Serum sodium levels normalised in a mean duration of 15.2 ± 16.4 h with a mean decline rate of 0.12 ± 0.04 mEq/L/h. Nine children needed rehospitalization because of hypernatremia due to non-compliance. Four episode of hyponatremia was observed. Weight gain and growth were normal during the mean follow-up duration of 37.79 ± 48.2 months. Administration of OLD was practical and safe in the treatment of CDI in children with CNS malformations in this small retrospective series.


Microscale Biomaterials with Bioinspired Complexity of Early Embryo Development and in the Ovary for Tissue Engineering and Regenerative Medicine.
Tissue engineering and regenerative medicine (TERM) are attracting more and more attention for treating various diseases in modern medicine. Various biomaterials including hydrogels and scaffolds have been developed to prepare cells (particularly stem cells) and tissues under 3D conditions for TERM applications. Although these biomaterials are usually homogeneous in early studies, effort has been made recently to generate biomaterials with the spatiotemporal complexities present in the native milieu of the specific cells and tissues under investigation. In this communication, the microfluidic and coaxial electrospray approaches that we used for generating microscale biomaterials with the spatial complexity of both pre-hatching embryos and ovary in the female reproductive system were introduced. This is followed by an overview of our recent work on applying the resultant bioinspired biomaterials for cultivation of normal and cancer stem cells, regeneration of cardiac tissue, and culture of ovarian follicles. The cardiac regeneration studies show the importance of using different biomaterials to engineer stem cells at different stages (i.e., in vitro culture versus in vivo implantation) for tissue regeneration. All the studies demonstrate the merit of accounting for bioinspired complexities in engineering cells and tissues for TERM applications.


Differences in the mechanical strength of dried microcrystalline cellulose pellets are not due to significant changes in the degree of hydrogen bonding.
The mechanical strengths of oven-dried pellets of microcrystalline cellulose, MCC, prepared by extruder/marumerizer technology are weaker when ethanol/water mixtures are used as granulating solutions than when granulated with water. Previously, the difference in the strengths of these pellet systems were thought to be due to changes in the degree of hydrogen bonding within these systems. This work reports the results of studies using magic-angle-spin nuclear magnetic resonance (NMR), x-ray diffraction and degree of crystallinity, and oxygen combustion calorimetry studies of various MCC systems developed to test this hypothesis. Carbon-13 cross polarization magic-angle spin NMR studies of MCC pellets with and without 10% theophylline showed no differences in the spectra of these systems. X-ray diffraction studies and heats of combustion data obtained from oxygen combustion calorimetry of oven-dried pellets of MCC granulated with either water, deuterated water, or a 70/30 ethanol/water mixture were found to have no significant differences in their diffraction patterns, degree of crystallinity, or internal energies. None of these results provide any evidence that a significant net change in the degree of hydrogen bonding is responsible for the observed changes in the strengths of these systems. It is hypothesized that the strength of these dried pellets may, in part, be due to the conversion of some of the intramolecular hydrogen bonded amorphous fibrils at the surface of the MCC particles to intermolecular hydrogen bonded fibrils with other MCC particles.


Morphological re-description and new geographical records for three digenean parasites infecting African sharptooth catfish Clarias gariepinus (Pisces: Clariidae) in Egypt.
Sixty specimens of African sharptooth catfish Clarias gariepinus (Clariidae) were collected during the period of March 2014-February 2015 from boat landing sites and fishermen of the River Nile at Beni Suef Governorate, Egypt, and examined for the presence of digenean parasites. The morphology of these parasites was studied by using light microscopy to describe morphological and morphometrically measurements for different body parts. Three digenean species belonging to three different genera were collected from various organs within the examined fish species. A certain degree of site specificity was also observed, with Thaparotrema botswanensis being found only in the gall bladder of C. gariepinus, while both Pseudoholorchis clarii and Glossidium pedatum were found only in the intestine and thus seem to occupy a certain niche within their host. This study represent as the first record of T. botswanensis and G. pedatum from C. gariepinus, as well as the first report of the genera from the River Nile in Egypt. In addition, re-description of P. clarii clarifies measurements for some body parts.


Opportunistic cervical screening at a sexual health clinic.
Women attending sexual health services may be higher risk for cervical cancer than the general population. In the United Kingdom, where a national cervical screening programme is underway, sexual health clinics no longer routinely offer their attendees cervical smears. Abnormal cervical smears add considerably to the workload of a sexual health service. In the absence of an organised national cervical screening programme in Ireland opportunistic screening is heavily relied upon. Opportunistic screening is performed in primary care, sexual health services and other women's health services. In the absence of this opportunistic cervical screening treatable pre-cancerous lesions may go unrecognised.


A new species of halfbeak, Hyporhamphus naos (Beloniformes: Hemiramphidae), from the tropical eastern Pacific.
The tropical eastern Pacific halfbeak previously considered conspecific with the western Atlantic Hyporhamphus unifasciatus (Ranzani 1842) is described as a new species, H. naos. It resembles H. meeki from the Atlantic and Gulf coasts of the United States in number of gill rakers on the first arch (usually 32-36, mean 33.6), more than in H. unifasciatus (usually 29-32, mean 30.6), but fewer than in other sympatric species of eastern Pacific Hyporhamphus. Results of a three-treatment ANCOVA (H. naos, H. meeki, and H. unifasciatus) show significant differences in slopes and means for all 14 morphometric characters examined, 9 of 14 characters comparing H. naos with H. unifasciatus, and 7 of 14 comparing H. naos with H. meeki. Protein electrophoretic patterns clearly distinguish all three species with a number of fixed allelic differences.


Complementary biological and computational approaches identify distinct mechanisms of chlorpyrifos versus chlorpyrifos-oxon-induced dopaminergic neurotoxicity.
Organophosphate (OP) pesticides are widely used in agriculture. While acute cholinergic toxicity has been extensively studied, chronic effects on other neurons are less understood. Here, we demonstrated that the OP pesticide chlorpyrifos (CPF) and its oxon metabolite are dopaminergic neurotoxicants in Caenorhabditis elegans. CPF treatment led to inhibition of mitochondrial complex II, II + III, and V in rat liver mitochondria, while CPF-oxon did not (complex II + III and IV inhibition observed only at high doses). While the effect on C. elegans cholinergic behavior was mostly reversible with toxicant washout, dopamine-associated deficits persisted, suggesting dopaminergic neurotoxicity was irreversible. CPF reduced the mitochondrial content in a dose-dependent manner and the fat modulatory genes cyp-35A2 and cyp-35A3 were found to have a key role in CPF neurotoxicity. These findings were consistent with in vitro effects of CPF and CPF-oxon on nuclear receptor signaling and fatty acid/steroid metabolism observed in ToxCast assays. Two-way hierarchical analysis revealed in vitro effects on estrogen receptor, pregnane X receptor, and peroxisome proliferator-activated receptor gamma pathways as well as neurotoxicity of CPF, malathion, and diazinon, whereas these effects were not detected in malaoxon and diazoxon. Taken together, our study suggests that mitochondrial toxicity and metabolic effects of CPF, but not CPF-oxon, have a key role of CPF neurotoxicity in the low-dose, chronic exposure. Further mechanistic studies are needed to examine mitochondria as a common target for all OP pesticide parent compounds, because this has important implications on cumulative pesticide risk assessment.


Impact of Malocclusion on Oral Health-Related Quality of Life of 8-12 Years Old Schoolchildren in Southern Brazil.
The aim of this study was to estimate the impact of malocclusion on the oral health-related quality of life (OHRQoL) of schoolchildren aged 8-12 years old in Southern Brazil. A two-stage cluster procedure was used to select 1,199 children in 20 public and private schools in Pelotas/Brazil. Cross-sectional data was collected, consisting of a socioeconomic questionnaire to parents, children's interview and clinical oral examination. The clinical variables were obtained from clinical examination, and the Child Perceptions Questionnaire (CPQ) was assessed during children's interview. To measure malocclusion and orthodontic treatment need the Dental Aesthetic Index was used. For data analysis multiple Poisson regression models estimating the rate ratios (RR) and their respective confidence intervals (95%CI) were used. Among 1,206 participants, 789 were aged 8-10 years and 417 between 11-12 years. The orthodontic treatment need was higher among the younger children (44.6%) than in the older ones (35.0%) (p value ≤0.05). There was a significant association in the CPQ social and emotional domains with malocclusion in the older schoolchildren. In the adjusted analysis (for socioeconomics and clinical variables) the effect of very severe malocclusion on OHRQoL was confirmed in both 8-10 and 11-12 age groups (RR(95%CI) of 1.24(1.02;1.51) and 1.28(1.01;1.62), respectively). The findings demonstrated that children with very severe malocclusion experienced greater negative impact on OHRQoL compared to those with mild or no malocclusion. The results suggest that malocclusion impacts the quality of life. The higher impact occurs in the social and emotional well-being domains.


Differential splicing choices made by neurons and astrocytes and their importance when investigating signal-dependent alternative splicing in neural cells.
A variety of proteins can be encoded by a single gene via the differential splicing of exons. In neurons this form of alternative splicing can be controlled by activity-dependent calcium signaling, leading to the properties of proteins being altered, including ion channels, neurotransmitter receptors and synaptic cell adhesion molecules. The pre-synaptic cell adhesion molecule Neurexin 1 (Nrxn1) is alternatively spliced at splice-site 4 (SS4) which governs exon 22 inclusion (SS4+) and consequently postsynaptic NMDA receptor responses. Nrxn1 was reported to be subject to a delayed-onset shift in Nrxn1 SS4 splicing resulting in increased exon 22 inclusion, involving epigenetic mechanisms which, if disrupted, reduce memory stability. Exon inclusion at SS4 represented one of hundreds of exons reported to be subject to a genome-wide shift in fractional exon inclusion following membrane depolarization with high extracellular K+ that was delayed in onset. We report that high K+ does not increase the SS4+/SS4- ratio in cortical neurons, but does induce a delayed-onset NMDA receptor-dependent neuronal death. In mixed neuronal/astrocyte cultures this neuronal death results in an increase in the astrocyte: neuron ratio, and a misleading increase in SS4+/SS4- ratio attributable to astrocytes having a far higher SS4+/SS4- ratio than neurons, rather than any change in the neurons themselves. We reassessed the previously reported genome-wide delayed-onset shift in fractional exon inclusion after high K+ exposure. This revealed that the reported changes correlated strongly with differences in exon inclusion level between astrocytes and neurons, and was accompanied by a strong decrease in the ratio of neuron-specific: astrocyte-specific gene expression. As such, these changes can be explained by the neurotoxic nature of the stimulation paradigm, underlining the importance of NMDA receptor blockade when using high K+ depolarizing stimuli.


Effects of Diaphragmatic Breathing Patterns on Balance: A Preliminary Clinical Trial.
The purpose of this study was to determine the feasibility of performing a larger study to determine if training in diaphragmatic breathing influences static and dynamic balance. A group of 13 healthy persons (8 men, 5 women), who were staff, faculty, or students at the University of Western States participated in an 8-week breathing and balance study using an uncontrolled clinical trial design. Participants were given a series of breathing exercises to perform weekly in the clinic and at home. Balance and breathing were assessed at the weekly clinic sessions. Breathing was evaluated with Liebenson's breathing assessment, static balance with the Modified Balance Error Scoring System, and dynamic balance with OptoGait's March in Place protocol. Improvement was noted in mean diaphragmatic breathing scores (1.3 to 2.6, P < .001), number of single-leg stance balance errors (7.1 to 3.8, P = .001), and tandem stance balance errors (3.2 to 0.9, P = .039). A decreasing error rate in single-leg stance was associated with improvement in breathing score within participants over the 8 weeks of the study (-1.4 errors/unit breathing score change, P < .001). Tandem stance performance did not reach statistical significance (-0.5 error/unit change, P = .118). Dynamic balance was insensitive to balance change, being error free for all participants throughout the study. This proof-of-concept study indicated that promotion of a costal-diaphragmatic breathing pattern may be associated with improvement in balance and suggests that a study of this phenomenon using an experimental design is feasible.


Emotional dysregulation and attachment dimensions in female patients with bulimia nervosa.
The aim of this study was to examine whether there is a difference in the dimensions of attachment and difference in emotional regulation between the group of female patients suffering from bulimia nervosa (BN) and the control group. We also wanted to examine whether emotional regulation has a mediating role in the relationship between dimensions of attachment and severity of BN symptoms. The study included a total of 100 female participants from 15 to 25 years of age (M=20.40, SD=3.26). The clinical group consisted of 50 patients suffering from BN, and the control group consisted of 50 healthy female subjects. Female patients suffering from BN achieved higher scores in the dimensions of anxiety (t98=-5.12, p=0.00) and avoidance (t98=-4.30, p=0.00). Dimension of attachment related anxiety (β=0.44, p=0.00) proved to be a statistically significant predictor of BN symptoms. Subjects of the clinical group also achieved significantly higher (t98=7.41, p=0.00) emotional dysregulation than participants of the control group. We also found that the mediation effect of emotional regulation on the association between anxiety and BN symptoms was statistically significant (z'=4.43, p=0.00). Patients suffering from BN showed significantly higher levels of attachment related anxiety and avoidance as well as significantly higher level of difficulties in emotional regulation than healthy controls. Attachment anxiety proved to be a significant predictor of symptoms BN, suggesting that the attachment related anxiety is stronger correlate of BN symptoms than avoidance, and may represent a risk factor for more severe BN symptoms. It was also found that the relationship between attachment related anxiety and BN symptoms were mediated by emotional regulation.


Surgical management of squamous cell vulvar cancer without clitoris, urethra or anus involvement.
Vulvar cancers, which constitute 5% of all gynecologic cancers, are the fourth most common female genital cancers, preceded by uterine, ovarian and cervical cancers. The treatment methods employed for vulvar cancers have changed over the years, with previously applied radical surgical approaches, such as en bloc resection, being gradually suspended in favor of treatment approaches that require dissection of less tissue. While the removal of less tissue, which today's approaches have focused on, prevents morbidity, this method seems to result in higher risks of recurrence. It is therefore important that the balance between preventing the recurrence of the disease and forefending against postoperative complications and vulvar deformity be properly understood. As a working assumption, if patients with vulvar cancer are diagnosed at an early stage, properly evaluated and administered appropriate treatment, the most positive results can be obtained. This paper aims to highlight this assumption and demonstrate, through the provision of actual data, how to plan the treatment approach for patients who are diagnosed early. Statements extracted from the National Comprehensive Cancer Network (NCCN) Guidelines Version 1.2016 Sub-Committees on vulvar squamous cell carcinoma and articles by the European Society of Gynaecological Oncology (ESGO) regarding Vulvar Cancer Recommendations were used to obtain updated information.


Single-mutation fitness landscapes for an enzyme on multiple substrates reveal specificity is globally encoded.
Our lack of total understanding of the intricacies of how enzymes behave has constrained our ability to robustly engineer substrate specificity. Furthermore, the mechanisms of natural evolution leading to improved or novel substrate specificities are not wholly defined. Here we generate near-comprehensive single-mutation fitness landscapes comprising >96.3% of all possible single nonsynonymous mutations for hydrolysis activity of an amidase expressed in E. coli with three different substrates. For all three selections, we find that the distribution of beneficial mutations can be described as exponential, supporting a current hypothesis for adaptive molecular evolution. Beneficial mutations in one selection have essentially no correlation with fitness for other selections and are dispersed throughout the protein sequence and structure. Our results further demonstrate the dependence of local fitness landscapes on substrate identity and provide an example of globally distributed sequence-specificity determinants for an enzyme.


Relationship of nuclear appearance to stromal invasion in human breast cancer.
Two biopsies of intraductal and invasive lobular carcinoma of the breast and 11 biopsies of intraductal and invasive carcinoma of the breast were examined by automated micromensurative techniques for mean nuclear area of carcinoma cells in intraductal and in invasive compartments. The nuclei of invasive carcinoma cells tended to be smaller when they invaded stroma as single cells or as "thin strands" than when they invaded as part of large sheets of cells. Cells in direct apposition with the stroma usually had smaller nuclei than cells which were found centrally in large confluent sheets of cells. Intraduct carcinoma cells approached, in size, invasive cells which formed confluent sheets, rather than cancer cells which invaded as single cells. The nuclei of cells which invaded in small groups were usually darker than those of cells in confluent sheets, which were usually more vesicular.


Correlation between size, shape and magnetic anisotropy of CoFe2O4 ferrite nanoparticles.
The present work reports the effect of particle size and shape of CoFe2O4 (CFO) nanoparticles on magnetic properties and their use in device applications as permanent magnets at room temperature. A set of CFO samples with different particle sizes and shapes were synthesized via the polymeric method by sintering at temperatures ranging from 300 °C to 1200 °C. These materials were characterized structurally by x-ray diffraction, morphologically by scanning electron microscopy, and microstructurally by transmission electron microscopy. The morphology of these CFO samples shows size-dependent shapes like spherical, pyramidal, lamellar, octahedral and truncated octahedral shapes for the particle sizes ranging from 7 to 780 nm with increasing sintering temperature. The emergence of magnetic properties was investigated as a function of particle size and shape with a special emphasis on permanent magnet applications at low and room temperatures. The values of saturation and remanent magnetization were found to increase monotonously with a particle size up to 40 nm and from thereafter they were found to remain almost constant. The other magnetic parameters such as coercivity, squareness ratio, anisotropy constant and maximum energy product ([Formula: see text]) were observed to increase up to 40 nm and then decreased thereafter as a function of particle size. The underlying mechanism responsible for the observed behavior of the magnetic parameters as a function of particle size was discussed in the light of coherent rotation, domain wall motion and shape induced demagnetization effects. The significant values of [Formula: see text] - the figure of merit of permanent magnets - observed for single domain particles (particularly, 14 nm and 21 nm) were found to have suitability in permanent magnetic technology.


Extracellular pH modulates the secretion of fibronectin isoforms by human trophoblast.
Differentiation of human trophoblast from the proliferative to the invasive phenotype takes place in a hypoxic and thus likely an acidic microenvironment. During differentiation, the secretion pattern of fibronectin isoforms changes. Therefore, we analysed the relation between extracellular pH, secretion of fibronectin splice variants and invasiveness. By means of immunohistochemistry and biochemistry, cellular non-oncofetal fibronectins were found in placental stroma and around extravillous trophoblast, whereas oncofetal isoforms only marked the extracellular matrix of extravillous trophoblast. In vitro, mesenchymal cells produced non-oncofetal fibronectins only, whereas choriocarcinoma cell lines, extravillous trophoblast and choriocarcinoma/trophoblast hybrid cells secreted both non-oncofetal and oncofetal isoforms. When the pH of the culture medium was either lowered or increased (between 6.0 and 8.0), the trophoblast hybrids, but not choriocarcinoma and mesenchymal cells, responded with increased secretion of fibronectins and a shift towards oncofetal isoforms. These changes were preserved after pH normalisation. Histochemical determination of local tissue acidity revealed that the site of the lowest detectable tissue pK coincided with the starting point of invasion, the proximal part of trophoblastic cell columns. Therefore, it is concluded that the local pH plays an important role as regulator of differentiation of human trophoblast as reflected by the synthesis of oncofetal fibronectins by the invasive phenotype of extravillous trophoblast.


Clinical trial links oncolytic immunoactivation to survival in glioblastoma.
Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).


Persistence of historical population structure in an endangered species despite near-complete biome conversion in California's San Joaquin Desert.
Genomic responses to habitat conversion can be rapid, providing wildlife managers with time-limited opportunities to enact recovery efforts that use population connectivity information that reflects predisturbance landscapes. Despite near-complete biome conversion, such opportunities may still exist for the endemic fauna and flora of California's San Joaquin Desert, but comprehensive genetic data sets are lacking for nearly all species in the region. To fill this knowledge gap, we studied the rangewide population structure of the endangered blunt-nosed leopard lizard Gambelia sila, a San Joaquin Desert endemic, using restriction site-associated DNA (RAD), microsatellite and mtDNA data to test whether admixture patterns and estimates of effective migration surfaces (EEMS) can identify land areas with high population connectivity prior to the conversion of native xeric habitats. Clustering and phylogenetic analyses indicate a recent shared history between numerous isolated populations and EEMS reveals latent signals of corridors and barriers to gene flow over areas now replaced by agriculture and urbanization. Conflicting histories between the mtDNA and nuclear genomes are consistent with hybridization with the sister species G. wislizenii, raising important questions about where legal protection should end at the southern range limit of G. sila. Comparative analysis of different data sets also adds to a growing list of advantages in using RAD loci for genetic studies of rare species. We demonstrate how the results of this work can serve as an evolutionary guidance tool for managing endemic, arid-adapted taxa in one of the world's most compromised landscapes.


Alcohol consumption and coronary heart disease: a causal and protective factor.
Although heavy alcohol consumption is one of the leading causes of preventable deaths, light to moderate consumption of alcohol is associated with a reduced risk of coronary heart disease and total mortality. These benefits have been found in both men and women who consume as little as one to six alcoholic beverages per week regardless of whether the source is wine, beer, or liquor. Further, apparent benefits include a reduced risk for the development of peripheral arterial disease, ischemic stroke, sudden cardiac death, and angina. Even small amounts of alcohol have been associated with increases in blood pressure and increased risks of some cancers, especially breast. The difference between consuming light to moderate and heavy amounts of alcohol may mean the difference between preventing and causing premature death for all causes, especially coronary heart disease.


Hospital-Associated Multidrug-Resistant MRSA Lineages Are Trophic to the Ocular Surface and Cause Severe Microbial Keratitis.
Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of severe and difficult to treat ocular infection. In this study, the population structure of 68 ocular MRSA isolates collected at Massachusetts Eye and Ear between January 2014 and June 2016 was assessed. By using a combination of multilocus sequence typing (MLST) analysis, SCCmec typing and detection of the panton-valentine leukocidin (PVL) gene, we found that the population structure of ocular MRSA is composed of lineages with community and hospital origins. As determined by eBURST analysis of MLST data, the ocular MRSA population consisted of 14 different sequence types (STs) that grouped within two predominant clonal complexes: CC8 (47.0%) and CC5 (41.2%). Most CC8 strains were ST8, harbored type IV SCCmec and were positive for the PVL-toxin (93.7%). The CC5 group was divided between strains carrying SCCmec type II (71.4%) and SCCmec type IV (28.6%). Remaining isolates grouped in 6 different clonal complexes with 3 isolates in CC6 and the other clonal complexes being represented by a single isolate. Interestingly, major MRSA CC5 and CC8 lineages were isolated from discrete ocular niches. Orbital and preseptal abscess/cellulitis were predominantly caused by CC8-SCCmec IV PVL-positive strains. In contrast, infections of the cornea, conjunctiva and lacrimal system were associated with the MDR CC5 lineage, particularly as causes of severe infectious keratitis. This niche specialization of MRSA is consistent with a model where CC8-SCCmec IV PVL-positive strains are better adapted to cause infections of the keratinized and soft adnexal eye tissues, whereas MDR CC5 appear to have greater ability in overcoming innate defense mechanisms of the wet epithelium of the ocular surface.


Invasive pneumococcal disease in England and Wales: what is the true burden and what is the potential for prevention using 7 valent pneumococcal conjugate vaccine?
The annual reported incidence rates for laboratory confirmed invasive pneumococcal disease (IPD) underestimate the true burden of invasive disease attributable to pneumococcal infection. To estimate the proportion of "unspecified" mortality of infectious cause in infants and young children aged 1 month to 4 years reported by the Office for National Statistics (ONS) in England and Wales that could reasonably be attributed to IPD, thereby revising the total number of deaths per year potentially attributable to IPD, and producing a more accurate figure for the number of deaths that may be prevented by a programme of pneumococcal conjugate vaccination. Polymerase chain reaction, latex agglutination, and other alternate methodologies to microbiological culture have been applied in various studies to the detection of Streptococcus pneumoniae. Some of these tests have been shown to be more sensitive indicators of pneumococcal infection. In our analysis the implications of these tests were applied theoretically to the "unspecified" clinical deaths caused by septicaemia, meningitis, and pneumonia reported by the ONS, with a 20% correction/reduction factor for nasopharyngeal carriage which these sensitive tests may coincidentally detect. The ONS reported an average of 13 deaths per year (1989-99) in infants and children aged 1 month to 4 years caused by pneumococcal septicaemia, meningitis, or pneumonia. By applying the rates for the more sensitive tests to the most recent ONS "unspecified" mortality data available (1999), the actual annual number of deaths caused by IPD in the age group 1 month to 4 years is shown to be at least as high as 43. The mortality as a result of IPD in infants and young children may be at least three times the reported rate. The 7 valent pneumococcal conjugate vaccine may have the potential to prevent up to 26 (61%) of the IPD deaths per year in infants and young children in England and Wales alone.


Core Concepts in Human Genetics: Understanding the Complex Phenotype of Sport Performance and Susceptibility to Sport Injury.
High-throughput sequencing of multiple human exomes and genomes is rapidly identifying rare genetic variants that cause or contribute to disease. Microarray-based methodologies have also shed light onto the genes that contribute to common, non-disease human traits such as hair and eye colour. Sport scientists should keep in mind several things when interpreting the literature, and when designing their own genetic studies. First of all, most genetic association methods are more powerful for detecting disease phenotypes (such as susceptibility to injury) than they are for detecting healthy phenotypes (such as sport performance). This is because there are likely to be many more biological factors contributing to the latter, and the effect size of most of these biological factors is likely to be small. Second, implicating a particular gene in a human phenotype like athletic performance or injury susceptibility requires an unbiased population data set. Third, new types of non-coding biological variability continue to be uncovered in the human genome (e.g. epigenetic modifications, microRNAs, etc.). These other types of variability may contribute significantly to differences in athletic performance.


Population genetics and phylogenetics of DNA sequence variation at multiple loci within the Drosophila melanogaster species complex.
Two regions of the genome, a 1-kbp portion of the zeste locus and a 1.1-kbp portion of the yolk protein 2 locus, were sequenced in six individuals from each of four species: Drosophila melanogaster, D. simulans, D. mauritiana, and D. sechellia. The species and strains were the same as those of a previous study of a 1.9-kbp region of the period locus. No evidence was found for recent balancing or directional selection or for the accumulation of selected differences between species. Yolk protein 2 has a high level of amino acid replacement variation and a low level of synonymous variation, while zeste has the opposite pattern. This contrast is consistent with information on gene function and patterns of codon bias. Polymorphism levels are consistent with a ranking of effective population sizes, from low to high, in the following order: D. sechellia, D. melanogaster, D.mauritiana, and D. simulans. The apparent species relationships are very similar to those suggested by the period locus study. In particular, D. simulans appears to be a large population that is still segregating variation that arose before the separation of D. mauritiana and D. sechellia. It is estimated that the separation of ancestral D. melanogaster from the other species occurred 2.5-3.4 Mya. The separations of D. sechellia and D. mauritiana from ancestral D. simulans appear to have occurred 0.58-0.86 Mya, with D. mauritiana having diverged from ancestral D. simulans 0.1 Myr more recently than D. sechellia.


Effect of diet on gentamicin-induced nephrotoxicosis in horses.
Gentamicin sulfate-induced nephrotoxicosis was compared in 2 groups of horses fed different rations. Four horses were fed only alfalfa hay, and 4 other horses were fed only whole oats. Seven days after initiation of the diet, all horses were given gentamicin IV (5 mg/kg of body weight) every 12 hours for 22 days. Urinary gamma-glutamyl-transferase to urinary creatinine (UGGT:UCr) ratio was calculated daily, and serum concentration of gentamicin was measured at 1 and 12 hours after drug administration. Results indicated that horses fed oats had greater renal tubular damage than did horses fed alfalfa. Mean UGGT:UCr for horses fed alfalfa was 47.1 +/- 18.8 and was 100.0 +/- 19.0 for horses fed oats (P = 0.007). The UGGT:UCr in horses fed oats was greater than 100 for a total of 54 days; horses fed alfalfa had UGGT:UCr greater than 100 for only 7 days. Two horses not given gentamicin were fed only oats and 2 were fed only alfalfa. These horses had mean UGGT:UCr of 17.6 +/- 2.2 and 30.5 +/- 3.0, respectively. Mean peak and trough concentrations of gentamicin were statistically different for horses fed oats and those fed alfalfa (peak 23.16 +/- 1.87 and 14.07 +/- 1.79 micrograms/ml, respectively [P = 0.0001], and trough, 1.81 +/- 0.69 and 0.71 +/- 0.70 micrograms/ml, respectively [P = 0.0270]). Mean half-lives of gentamicin (estimated from peak and trough concentrations) for horses fed alfalfa (2.58 +/- 0.26 hours) and horses fed oats (2.88 +/- 0.27 hours) were not significantly different. Horses fed only oats had greater degree of gentamicin-induced nephrotoxicosis than did those fed only alfalfa.


Management of ischiopubic stress fracture in patients with anorexia nervosa and excessive compulsive exercising.
This case report describes a 28-year-old non-athlete female patient with anorexia nervosa who was diagnosed with an ischiopubic ramus stress fracture and treated successfully as an inpatient with a cognitive behaviour-based therapy. The patient's clinical picture, diagnosis and treatment are described, and a brief review of the relevant literature is included. The importance of this case report stems from the rarity of descriptions of this kind of injury in such patients, despite their inherent risk, and the originality of the treatment applied. This, in addition to the usual approach to medical management, exploited specific cognitive and behavioural procedures and strategies to address the patient's excessive compulsive exercising, promoting rest and movement avoidance in order to allow the fracture to heal, while simultaneously addressing the underlying psychopathology.


Pustulotic arthro-osteitis associated with acetabular cartilage lesion in pustulotic arthropathy--implication of bone marrow.
We describe a case of pustulotic arthro-osteitis with hip joint involvement. After right hip joint and walking did not improve despite drugs and physical therapy, total hip replacement was performed. During surgery, brownish degenerated tissue was detected on the surface of the acetabular side. Pathohistological examination revealed that granulation tissue caused by suppurative inflammation of the bone marrow had broken through the cartilage surface, reaching the superficial layer. Our findings suggest that hip joint lesions in pustulotic arthro-osteitis may originate from bone marrow lesions.


Alcohol, White Adipose Tissue, and Brown Adipose Tissue: Mechanistic Links to Lipogenesis and Lipolysis.
According to data from the World Health Organization, there were about 3 million deaths caused by alcohol consumption worldwide in 2016, of which about 50% were related to liver disease. Alcohol consumption interfering with the normal function of adipocytes has an important impact on the pathogenesis of alcoholic liver disease. There has been increasing recognition of the crucial role of adipose tissue in regulating systemic metabolism, far beyond that of an inert energy storage organ in recent years. The endocrine function of adipose tissue is widely recognized, and the significance of the proteins it produces and releases is still being investigated. Alcohol consumption may affect white adipose tissue (WAT) and brown adipose tissue (BAT), which interact with surrounding tissues such as the liver and intestines. This review briefly introduces the basic concept and classification of adipose tissue and summarizes the mechanism of alcohol affecting lipolysis and lipogenesis in WAT and BAT. The adipose tissue-liver axis is crucial in maintaining lipid homeostasis within the body. Therefore, this review also demonstrates the effects of alcohol consumption on the adipose tissue-liver axis to explore the role of alcohol consumption in the crosstalk between adipose tissue and the liver.


Surface-active agents for isolation of the core component of avian myeloblastosis virus.
Sixty-one surface-active agents were evaluated in a procedure designed to assess their ability to remove the envelope from the core component of avian myeloblastosis virus (AMV). The procedure consisted of centrifugation of intact AMV through a series of sucrose gradients each containing an upper layer of agent at one of eight concentrations between 0.01 and 10%. The effectiveness of an agent in producing AMV cores was indicated by (i) the appearance of light-scattering bands in the region of core buoyant density in gradient tubes; (ii) the range of surfactant concentration over which these bands appeared; and (iii) an electron microscopy assessment by the negative-staining technique of the relative proportion of core to non-core material in each of these bands. Six nonionic surfactants were selected by this screening method for comparison in regard to recovery of core protein and endogenous ribonucleic acid (RNA)-dependent deoxyribonucleic acid (DNA) polymerase activity, as well as further morphologic evaluation by electron microscopy. The nonionic surfactants of the polyoxyethylene alcohol class (particularly, Sterox SL) were most effective. Nonionic surfactants of the polyoxyethylene alkylphenol class (particularly, Nonidet P-40) were also effective. Sterox SL and Nonidet P-40 each gave a more than fivefold increase in specific activity of endogenous RNA-dependent DNA polymerase, and each gave a low recovery of core protein. Sterox SL did not interfere to the extent that Nonidet P-40 did in procedures which involved spectrophotometric assay at 260 nm. The use of Sterox SL resulted in the least envelope contamination of core preparations by electron microscopy examination, the most recovery of protein and endogenous RNA-dependent DNA polymerase activity, and a core buoyant density in sucrose of 1.27 g/ml.


A polarized digital shearing speckle pattern interferometry system based on temporal wavelet transformation.
Digital shearing speckle pattern interferometry (DSSPI) has been recognized as a practical tool in testing strain. The DSSPI system which is based on temporal analysis is attractive because of its ability to measure strain dynamically. In this paper, such a DSSPI system with Wollaston prism has been built. The principles and system arrangement are described and the preliminary experimental result of the displacement-derivative test of an aluminum plate is shown with the wavelet transformation method and the Fourier transformation method. The simulations have been conducted with the finite element method. The comparison of the results shows that quantitative measurement of displacement-derivative has been realized.


[Relationship between initial stability and infected loosening of total hip arthroplasty prosthesis].
To investigate the relationship between the initial stability and infected loosening of the total hip arthroplasty (THA) prosthesis. From January 2000 to December 2008, 110 cases (110 hips) were treated with THA revision. Among them, 15 cases (15 hips) were confirmed infected loosening. There were 8 males and 7 females with an average age of 62 years (range 42-75 years). The infected signs were found from 6 months to 2 years after initial THA. All of them had Tsukayama type IV and late infection, including 6 cases of acetabular infected loosening (5 cases of one-stage and 1 case of two-stage acetabular revision), 7 cases of simple infected loosening of femoral prosthesis (4 cases of one-stage and 3 cases of two-stage femoral prosthesis revision), and 2 cases of joint capsule infection and sinus without prosthesis loosening (debridement and continuous irrigation). All incisions healed by first intention. Fifteen patients were followed up for 12 to 36 months (average 24 months). In 13 cases of revision, postoperative X-ray films showed that femoral acetabular prostheses were in good position, and had no clinical and imaging infective signs of loosening. In 2 cases of joint capsule infection, sinus recurred 6 months postoperation without hip joint pain, the function of weight-bearing and walking of hip joint was normal. Harris score increased from preoperative average of 42 to postoperative average of 85; the results were excellent in 4 cases, good in 7 cases, and fair in 4 cases. The infection of THA may occur in the whole joint, half-joint or just in joint capsule. The initial stability of the prosthesis would affect the long-term survival of the prosthesis. If the prosthesis initial stability is obtained, even if there are infective factors, infections would also be limited.


Oat sensitization in children with atopic dermatitis: prevalence, risks and associated factors.
Topical treatments of atopic dermatitis (AD) may be responsible for cutaneous allergies. Percutaneous sensitization to oat used in emollients/moisturizers has already been reported. Our objectives were to measure the prevalence of oat sensitization in AD children, to assess its relevance, and to look at related parameters. We recruited prospectively children with AD referred for allergy testing between June 2001 and December 2004. Atopy patch tests (APT) and skin prick tests (SPT) to oat proteins (1%, 3% and 5%) and to the European standard series were performed followed by oral food challenge (OFC) and repeated open application test (ROAT) in the oat-sensitized group. About 302 children were enrolled. Oat APT and SPT were positive in 14.6% and 19.2% of cases, respectively. Children under 2 years of age were more likely to have positive APT. In oat-sensitized children, OFC and ROAT were positive in 15.6% (five of 32) and 28% (seven of 25) of cases, respectively. Thirty-two percentage of oat cream users had oat-positive atopy patch test (APT) vs 0% in the nonusers group. Oat sensitization in AD children seen for allergy testing is higher than expected. It may be the result of repeated applications of cosmetics with oats on a predisposed impaired epidermal barrier. We suggest avoiding topical-containing oat proteins in infants with AD.


Mechanism of C2-toxin inhibition by fluphenazine and related compounds: investigation of their binding kinetics to the C2II-channel using the current noise analysis.
The binding component C2II of the binary actin ADP-ribosylating C2-toxin from Clostridium botulinum is essential for intoxication of target cells. Activation by a protease leads to channel formation and this is presumably required for the transport of the toxic C2I component into cells. The C2II-channel is cation selective and contains a binding site for fluphenazine and structurally related compounds. Ion transport through C2II and in vivo intoxication is blocked when the sites are occupied by the ligands. C2II was reconstituted into artificial lipid bilayer membranes and formed ion permeable channels. The binding constant of chloroquine, primaquine, quinacrine, chloropromazine and fluphenazine to the C2II-channel was determined using titration experiments, which resulted in its block. The ligand-induced current noise of the C2II-channels was investigated using fast Fourier transformation. The noise of the open channels had a rather small spectral density, which was a function of the inverse frequency up to about 100 Hz. Upon addition of ligands to the aqueous phase the current through C2II decreased in a dose-dependent manner. Simultaneously, the spectral density of the current noise increased drastically and its frequency dependence was of Lorentzian type, which was caused by the on and off-reactions of the ligand-mediated channel block. The ligand-induced current noise of C2II was used for the evaluation of the binding kinetics for different ligands to the channel. The on-rate constant of ligand binding was between 10(7) and 10(9) M(-1) s(-1) and was dependent on the ionic strength of the aqueous phase. The off-rate varied between about 10 s(-1) and 3900 s(-1) and depended on the structure of the ligand. The role of structural requirements for the effective block of C2II by the different ligands is discussed.


Reflex sympathetic dystrophy syndrome of the upper extremity: analysis of total outcome of management of 125 cases.
Case histories of 125 patients with reflex sympathetic dystrophy syndrome of the upper extremity seen from July 1973 to March 1976 were reviewed. There was a 2.9:1 female preponderance. Twenty-four patients had documented litigation pending; however, it did not alter the final outcome significantly. On medical records, progress was noted for 86 patients with 16% having excellent results, 35% good, 26% satisfactory, 6% fair and 17% poor (all subjective evaluations by treating physicians). Median duration of follow-up prior to this study was approximately 2.5 months. Median duration between last clinic visit and follow-up study was 14.5 months. Follow-up letters sent to 123 patients who were believed to be alive showed that 4 patients had died; 77 (63%) replied. The majority of patients (53/77) reported that they still had pain in the shoulder/or hand, but 68% were taking no medications and only 15.3% (12) were taking narcotics. Twenty-eight patients (36%) claimed they were continuing physical therapy at home. Twenty-four (31%) retired or did not go back to the same work. Thirty-five percent were officially disabled, 30% were back at their same jobs and 29/59 female patients (49%) were able to do all the housework. Eighteen patients (23%) were able to return to 100% daily activity, 23 patients (30%) to 75% activity. Eleven patients (14%) had modified their activities considerably and were not able to do well.


Temperature-mediated heteroduplex analysis performed by using denaturing high-performance liquid chromatography to identify sequence polymorphisms in Mycobacterium tuberculosis complex organisms.
PCR products containing sequence polymorphisms were prepared from six mycobacterial genes, denatured, mixed with reference PCR products, and reannealed; the mixtures were then examined with a denaturing high-performance liquid chromatography system (WAVE) equipped with a temperature-controlled alkalated polystyrene divinyl benzene column. Mismatching of bases in heteroduplexes of the PCR products causes elution patterns of the DNA from the column to be altered. The six mycobacterial genes studied were oxyR, in which a specific polymorphism (G(1031)A) is found only in certain species of the Mycobacterium tuberculosis complex, and five genes in which mutations associated with antituberculosis drug resistance have been found. The resistance genes (with affected drug and PCR product sizes given parenthetically) were rpoB (rifampin; 258 bp), katG (isoniazid; 205 bp), pncA (pyrazinamide; 579 bp); rpsL (streptomycin; 196 bp), and embB (ethambutol; 185 bp). Elution patterns of heteroduplexes of all 20 polymorphisms studied shifted detectably at column temperatures ranging from 65.3 to 68 degrees C and elution times of 3.5 to 6 min. These results show that temperature-mediated heteroduplex analysis is a potentially useful genotypic screen for mutations associated with antituberculosis drug resistance and for the G(1031)A polymorphism in oxyR. The method may allow users to detect novel as well as heterogeneous mutations without using expensive kits or detection labels.


The identification and treatment of depression by general practitioners.
To assess the level of recognition and knowledge about treatment of depression by General Practitioners (GPs). Analysis of questionnaires completed by participants commencing a series of workshops aimed at improving their knowledge of the diagnosis and treatment of depression. Of the 3289 GPs involved in the program 2500 (76% respondent rate) completed the questionnaires in a group situation. There was no difference between respondents and nonrespondents in terms of age, gender and year of graduation. The majority of GPs believe they have a satisfactory competence in the recognition and treatment of depression, although a sizeable minority based their diagnosis predominantly on somatic symptoms. The GPs felt confident about their knowledge and skills in counselling and the use of antidepressant medication, but not in dealing with children and suicidal or pregnant patients. The most common symptoms used to identify 'depression' were sleep disorders and only 54% listed depressed mood as a symptom on which the diagnosis is based. Only 28% reported sufficient symptoms to meet criteria for DSM-IV major depressive disorder, which supports views that these criteria are inappropriate for general practice. Fifty-seven percent of doctors used medicine together with nonpharmacological treatment in the majority of patients, and medications doses were almost all within the range recommended in the product information. There is a need to improve GPs knowledge in diagnosing depression, in child psychiatry and in dealing with pregnant and suicidal patients.


Recent advances on the association of apoptosis in chronic non healing diabetic wound.
Generally, wounds are of two categories, such as chronic and acute. Chronic wounds takes time to heal when compared to the acute wounds. Chronic wounds include vasculitis, non healing ulcer, pyoderma gangrenosum, and diseases that cause ischemia. Chronic wounds are rapidly increasing among the elderly population with dysfunctional valves in their lower extremity deep veins, ulcer, neuropathic foot and pressure ulcers. The process of the healing of wounds has several steps with the involvement of immune cells and several other cell types. There are many evidences supporting the hypothesis that apoptosis of immune cells is involved in the wound healing process by ending inflammatory condition. It is also involved in the resolution of various phases of tissue repair. During final steps of wound healing most of the endothelial cells, macrophages and myofibroblasts undergo apoptosis or exit from the wound, leaving a mass that contains few cells and consists mostly of collagen and other extracellular matrix proteins to provide strength to the healing tissue. This review discusses the various phases of wound healing both in the chronic and acute wounds especially during diabetes mellitus and thus support the hypothesis that the oxidative stress, apoptosis, connexins and other molecules involved in the regulation of chronic wound healing in diabetes mellitus and gives proper understanding of the mechanisms controlling apoptosis and tissue repair during diabetes and may eventually develop therapeutic modalities to fasten the healing process in diabetic patients.


Work relative value units and perioperative outcomes in patients undergoing brain tumor surgery.
The work relative value unit (wRVU) is a commonly cited surrogate for surgical complexity; however, it is highly susceptible to subjective interpretation and external forces. Our objective was to evaluate whether wRVU is associated with perioperative outcomes, including complications, after brain tumor surgery. The 2006-2014 American College of Surgeons National Surgical Quality Improvement Program database was queried to identify patients ≥ 18 years who underwent brain tumor resection. Patients were categorized into approximate quintiles based on total wRVU. The relationship between wRVU and several perioperative outcomes was assessed with univariate and multivariate analyses. Subgroup analyses were performed using a Current Procedural Terminology code common to all wRVU groups. The 16,884 patients were categorized into wRVU ranges 0-30.83 (4664 patients), 30.84-34.58 (2548 patients), 34.59-38.04 (3147 patients), 38.05-45.38 (3173 patients), and ≥ 45.39 (3352 patients). In multivariate logistic regression analysis, increasing wRVU did not predict more 30-day postoperative complications, except respiratory complications and need for blood transfusion. Linear regression analysis showed that wRVU was poorly correlated with operative duration and length of stay. On multivariate analysis of the craniectomy subgroup, wRVU was not associated with overall or respiratory complications. The highest wRVU group was still associated with greater risk of requiring blood transfusion (OR 3.01, p < 0.001). Increasing wRVU generally did not correlate with 30 days postoperative complications in patients undergoing any surgery for brain tumor resection; however, the highest wRVU groups may be associated with greater risk of respiratory complications and need for transfusion. These finding suggests that wRVU may be a poor surrogate for case complexity.


Thermodynamics of the hydroxyl radical addition to isoprene.
Oxidation of isoprene by the hydroxyl radical leads to tropospheric ozone formation. Consequently, a more complete understanding of this reaction could lead to better models of regional air quality, a better understanding of aerosol formation, and a better understanding of reaction kinetics and dynamics. The most common first step in the oxidation of isoprene is the formation of an adduct, with the hydroxyl radical adding to one of four unsaturated carbon atoms in isoprene. In this paper, we discuss how the initial conformations of isoprene, s-trans and s-gauche, influences the pathways to adduct formation. We explore the formation of pre-reactive complexes at low and high temperatures, which are often invoked to explain the negative temperature dependence of this reaction's kinetics. We show that at higher temperatures the free energy surface indicates that a pre-reactive complex is unlikely, while at low temperatures the complex exists on two reaction pathways. The theoretical results show that at low temperatures all eight pathways possess negative reaction barriers, and reaction energies that range from -36.7 to -23.0 kcal x mol(-1). At temperatures in the lower atmosphere, all eight pathways possess positive reaction barriers that range from 3.8 to 6.0 kcal x mol(-1) and reaction energies that range from -28.8 to -14.4 kcal x mol(-1).


Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells.
ErbB2 targeted therapies represent an attractive strategy in breast cancer. Herceptin, an anti-ErbB2 monoclonal antibody, is an approved treatment for patients with ErbB2-overexpressing breast cancers. ErbB2 signaling can also be blocked using small molecule tyrosine kinase inhibitors, like Lapatinib, that compete with ATP for binding at the ErbB2 catalytic kinase domain. The principal adverse event attributable to Herceptin is cardiac toxicity. Data from clinical trials show that, unlike Herceptin, Lapatinib may have reduced cardiac toxicity. This study was conducted to elucidate pathways which may contribute to cardiac toxicity or survival using Lapatinib and Herceptin. Our results show that treatments directed to ErbB1/2 receptors using GW-2974 (a generic ErbB1/2 inhibitor) activated AMPK, a key regulator in mitochondrial energy production pathways in human cardiac cells and cancer cells. Although Herceptin downregulates tumor survival pathways, AMPK fails to be activated in tumor and cardiac cells. When treated in combination with TNFalpha, a known cytokine associated with cardiac toxicity, GW-2974 protected cardiac cells from cell death whereas Herceptin contributed to TNFalpha-induced cellular killing. Since activity of AMPK in cardiac cells is associated with stress induced survival in response to cytokines or energy depletion, cardiac toxicity by Herceptin may be a consequence of failure to induce stress-related survival mechanisms. Thus, the ability to activate AMPK after treatment with tyrosine kinase inhibitors may be a crucial factor for increased efficacy against the tumor and decreased risk of cardiomyopathy.


Thrombolytic therapy with tissue plasminogen activator for the treatment of nonstructural malfunction of bileaflet cardiac valve prostheses.
This study was conducted to determine the effect of thrombolytic therapy with tissue plasminogen activator (t-PA) for nonstructural malfunction of bileaflet cardiac valve prostheses. Twenty-seven patients with bileaflet prosthetic valve malfunction diagnosed by a combination of cineradiography and transthoracic echocardiography were treated with the administration of intravenous t-PA. The treatment resulted in complete success in 55.6% (15 of 27), partial success in 22.2% (6 of 27), and no change in 22.2% (6 of 27). In the complete success and partial success groups, the condition of the patients in 85.7% (18 of 21) of the cases improved within 24 h after the administration of t-PA. Six cases in whom thrombolytic therapy was instituted more than 1 month (ranged from 1 to 38 months, mean 14.7 months) after the diagnosis of prosthetic valve malfunction showed significantly less effectiveness of thrombolytic therapy with t-PA. Only one patient (3.7%) had a major complication (thromboembolism) after t-PA treatment. The results suggest that thrombolytic therapy with t-PA in patients with nonstructural malfunction of bileaflet cardiac valve prostheses is effective with low incidence of complication when the treatment is instituted early after the diagnosis.


[Importance of atypical infection in asthma].
The category of atypical respiratory infection involves viruses, bacteria and rickettsia. These micro-organisms can play a marked role in the exacerbation an asthma course but also participate in its development. Authors discuses both aspects, reporting own observations. The knowledge of real importance of atypical infections in asthma remains to be established.


Changes in low-molecular-weight thiol-disulphide redox couples are part of bread wheat seed germination and early seedling growth.
The tripeptide antioxidant glutathione (γ-l-glutamyl-l-cysteinyl-glycine; GSH) essentially contributes to thiol-disulphide conversions, which are involved in the control of seed development, germination, and seedling establishment. However, the relative contribution of GSH metabolism in different seed structures is not fully understood. We studied the GSH/glutathione disulphide (GSSG) redox couple and associated low-molecular-weight (LMW) thiols and disulphides related to GSH metabolism in bread wheat (Triticum aestivum L.) seeds, focussing on redox changes in the embryo and endosperm during germination. In dry seeds, GSH was the predominant LMW thiol and, 15 h after the onset of imbibition, embryos of non-germinated seeds contained 12 times more LMW thiols than the endosperm. In germinated seeds, the embryo contained 17 and 11 times more LMW thiols than the endosperm after 15 and 48 h, respectively. This resulted in the embryo having significantly more reducing half-cell reduction potentials of GSH/GSSG and cysteine (Cys)/cystine (CySS) redox couples (EGSSG/2GSH and ECySS/2Cys, respectively). Upon seed germination and early seedling growth, Cys and CySS concentrations significantly increased in both embryo and endosperm, progressively contributing to the cellular LMW thiol-disulphide redox environment (Ethiol-disulphide). The changes in ECySS/2Cys could be related to the mobilisation of storage proteins in the endosperm during early seedling growth. We suggest that EGSSG/2GSH and ECySS/2Cys can be used as markers of the physiological and developmental stage of embryo and endosperm. We also present a model of interaction between LMW thiols and disulphides with hydrogen peroxide (H2O2) in redox regulation of bread wheat germination and early seedling growth.


Putting the elephant back in the herd: elephant relative quantity judgments match those of other species.
The ability to discriminate between quantities has been observed in many species. Typically, when an animal is given a choice between two sets of food, accurate performance (i.e., choosing the larger amount) decreases as the ratio between two quantities increases. A recent study reported that elephants did not exhibit ratio effects, suggesting that elephants may process quantitative information in a qualitatively different way from all other nonhuman species that have been tested (Irie-Sugimoto et al. in Anim Cogn 12:193-199, 2009). However, the results of this study were confounded by several methodological issues. We tested two African elephants (Loxodonta africana) to more thoroughly investigate relative quantity judgment in this species. In contrast to the previous study, we found evidence of ratio effects for visible and nonvisible sequentially presented sets of food. Thus, elephants appear to represent and compare quantities in much the same way as other species, including humans when they are prevented from counting. Performance supports an accumulator model in which quantities are represented as analog magnitudes. Furthermore, we found no effect of absolute magnitude on performance, providing support against an object-file model explanation of quantity judgment.