Effects of different positive end-expiratory pressure titration strategies on mechanical power during ultraprotective ventilation in ARDS patients treated with veno-venous extracorporeal membrane oxygenation: A prospective interventional study.
Ultraprotective ventilation in acute respiratory distress syndrome (ARDS) patients with veno-venous extracorporeal membrane oxygenation (VV ECMO) reduces mechanical power (MP) through changes in positive end-expiratory pressure (PEEP); however, the optimal approach to titrate PEEP is unknown. This study assesses the effects of three PEEP titration strategies on MP, hemodynamic parameters, and oxygen delivery in twenty ARDS patients with VV ECMO. PEEP was titrated according to: (A) a PEEP of 10 cmH2O representing the lowest recommendation by the Extracorporeal Life Support Organization (PEEPELSO), (B) the highest static compliance of the respiratory system (PEEPCstat,RS), and (C) a target end-expiratory transpulmonary pressure of 0 cmH2O (PEEPPtpexp). PEEPELSO was lower compared to PEEPCstat,RS and PEEPPtpexp (10.0 ± 0.0 vs. 16.2 ± 4.7 cmH2O and 17.3 ± 4.0 cmH2O, p < 0.001 each, respectively). PEEPELSO reduced MP compared to PEEPCstat,RS and PEEPPtpexp (5.3 ± 1.3 vs. 6.8 ± 2.0 and 6.9 ± 2.3 J/min, p < 0.001 each, respectively). PEEPELSO resulted in less lung stress compared to PEEPCstat,RS (p = 0.011) and PEEPPtpexp (p < 0.001) and increased cardiac output and oxygen delivery (p < 0.001 each). An empirical PEEP of 10 cmH2O minimized MP, provided favorable hemodynamics, and increased oxygen delivery in ARDS patients treated with VV ECMO. German Clinical Trials Register (DRKS00013967). Registered 02/09/2018https://drks.de/search/en/trial/DRKS00013967.


The association between malnutrition and psychological distress in patients with advanced head-and-neck cancer.
Malnutrition and psychological distress are often seen in patients with head-and-neck cancer, but little is known about the interrelationships between those two symptoms. The present study examined the relationship between malnutrition and psychological distress in patients with advanced head-and-neck cancer. Using the Patient-Generated Subjective Global Assessment, 99 patients with advanced-stage head-and-neck cancer were screened for nutrition status. The patients were also screened for psychosocial distress (using the Distress Thermometer) and for psychosocial issues (using the Problem Checklist). Any relationship between malnutrition and psychosocial distress was determined by regression and correlation analysis. We also used t-tests to compare distress levels for patients with and without specific nutrition-related symptoms. The study group included 80 men and 19 women [mean age: 58.4 ± 10.9 years (range: 23-85 years)]. The correlation between poorer nutrition status and level of psychological distress was significant r = 0.37 (p < 0.001). Specifically, reduced food intake and symptoms were both positively associated with distress: r = 0.27 and r = 0.29 respectively, both significant at p < 0.01. After controlling for the effects of psychosocial problems and pain, nutrition status remained a significant predictor of distress, explaining 3.8% of the variance in the distress scores of the patients (p < 0.05). Malnutrition and symptoms were strongly related to distress in patients with advanced head-and-neck cancer. Our results suggest the need for further research into the complex relationship between nutrition status and distress and into the management of both nutrition and distress in cancer care.


Knife inflicted penetrating injuries of the maxillofacial region: a descriptive, record-based study.
Penetrating knife injuries of the face are more common in South Africa than the rest of the world. These injuries can be life-threatening, especially where the major blood vessels of the face are involved. The approach to treatment should be multidisciplinary, beginning with the trauma unit to provide airway maintenance and haemodynamic stabilisation. An interventional radiologist may be consulted for angiography. The aim of the present study was to retrospectively analyse all cases of knife-inflicted penetrating injuries to the maxillofacial region with the knife in situ and subsequently develop a management protocol to be used by maxillofacial surgery registrars when presented with such cases. It was a retrospective, cross-sectional and record-based study, analysing all penetrating knife injuries reported at various hospitals for a period of 11 years. In this study, 24 cases of knife injuries were analysed. Twenty-one patients (87.5%) in this series were male and three (12.5%) were female. Of these 24 patients, 13 (54.2%) were coloured and 11 (45.8%) were black. There were no white or Indian patients. Post-surgical recovery of all patients was rapid and uneventful, and there were no fatalities. Patients with knife injuries to the face with no definite signs of vascular injury can thus be safely and accurately managed on the basis of physical examination and plain-film radiography. An angiogram is mandatory if the patient presents with excessive bleeding, an expanding haematoma or if the knife blade is in the region of any large vessels.


Long-Term Outcomes of Genetic Parkinson's Disease.
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects 1-2% of people by the age of 70 years. Age is the most important risk factor, and most cases are sporadic without any known environmental or genetic causes. Since the late 1990s, mutations in the genes SNCA, PRKN, LRRK2, PINK1, DJ-1, VPS35, and GBA have been shown to be important risk factors for PD. In addition, common variants with small effect sizes are now recognized to modulate the risk for PD. Most studies in genetic PD have focused on finding new genes, but few have studied the long-term outcome of patients with the specific genetic PD forms. Patients with known genetic PD have now been followed for more than 20 years, and we see that they may have distinct and different prognoses. New therapeutic possibilities are emerging based on the genetic cause underlying the disease. Future medication may be based on the pathophysiology individualized to the patient's genetic background. The challenge is to find the biological consequences of different genetic variants. In this review, the clinical patterns and long-term prognoses of the most common genetic PD variants are presented.


Safety and Activity of PolyPEPI1018 Combined with Maintenance Therapy in Metastatic Colorectal Cancer: an Open-Label, Multicenter, Phase Ib Study.
Although chemotherapy is standard of care for metastatic colorectal cancer (mCRC), immunotherapy has no role in microsatellite stable (MSS) mCRC, a "cold" tumor. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine derived from 7 tumor-associated antigens (TAA) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in patients with MSS mCRC. Eleven patients with MSS mCRC received PolyPEPI1018 and Montanide ISA51VG adjuvant subcutaneously, combined with fluoropyrimidine/biologic following first-line induction with chemotherapy and a biologic (NCT03391232). In Part A of the study, 5 patients received a single dose; in Part B, 6 patients received up to three doses of PolyPEPI1018 every 12 weeks. The primary objective was safety; secondary objectives were preliminary efficacy, immunogenicity at peripheral and tumor level, and immune correlates. PolyPEPI1018 vaccination was safe and well tolerated. No vaccine-related serious adverse event occurred. Eighty percent of patients had CD8+ T-cell responses against ≥3 TAAs. Increased density of tumor-infiltrating lymphocytes were detected post-treatment for 3 of 4 patients' liver biopsies, combined with increased expression of immune-related gene signatures. Three patients had objective response according to RECISTv1.1, and 2 patients qualified for curative surgery. Longer median progression-free survival for patients receiving multiple doses compared with a single dose (12.5 vs. 4.6 months; P = 0.017) suggested a dose-efficacy correlation. The host HLA genotype predicted multi-antigen-specific T-cell responses (P = 0.01) indicative of clinical outcome. PolyPEPI1018 added to maintenance chemotherapy for patients with unresectable, MSS mCRC was safe and associated with specific immune responses and antitumor activity warranting further confirmation in a randomized, controlled setting.


Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses.
CD8 T-cell responses to liver-expressed antigens range from deletional tolerance to full effector differentiation resulting in overt hepatotoxicity. The reasons for these heterogeneous outcomes are not well understood. To identify factors that govern the fate of CD8 T cells activated by hepatocyte-expressed antigen, we exploited recombinant adenoassociated viral vectors that enabled us to vary potential parameters determining these outcomes in vivo. Our findings reveal a threshold of antigen expression within the liver as the dominant factor determining T-cell fate, irrespective of T-cell receptor affinity or antigen cross-presentation. Thus, when a low percentage of hepatocytes expressed cognate antigen, high-affinity T cells developed and maintained effector function, whereas, at a high percentage, they became functionally exhausted and silenced. Exhaustion was not irreversibly determined by initial activation, but was maintained by high intrahepatic antigen load during the early phase of the response; cytolytic function was restored when T cells primed under high antigen load conditions were transferred into an environment of low-level antigen expression. Our study reveals a hierarchy of factors dictating the fate of CD8 T cells during hepatic immune responses, and provides an explanation for the different immune outcomes observed in a variety of immune-mediated liver pathologic conditions.


Towards Educational Electronic Health Records (EHRs): A Design Process for Integrating EHRs, Simulation, and Video Tutorials.
Electronic health records (EHRs) are becoming ubiquitous in healthcare practice. However, their use in medical education has been slower to catch on and a new category of EHRs is beginning to emerge known as eduEHRs. These systems allow learners to explore and experiment with EHRs in the context of medical education. However, current eduEHRs have limitations, such as a lack of dynamic interaction built-in that would mimic real-world use of these tools. To overcome this, the integration of eduEHRs with software and tools such as video simulations and tutorials has considerable promise. In this paper we describe a new design process for integrating EHRs, simulations, and video tutorials.


Thallium toxicity and the role of Prussian blue in therapy.
Thallium salts have been used as medicinal agents, as key ingredients in a variety of manufacturing processes, and as a potent rodenticide. Additionally, environmental concerns are growing, as thallium is a waste product of coal combustion and the manufacturing of cement. Thallium salts are rapidly and nearly completely absorbed by virtually all routes, with gastrointestinal exposure being the most common route to produce toxicity. Thallium enters cells by a unique process governed by its similarity in charge and ionic radius to potassium. Although the exact mechanism of toxicity has not been established, thallium interferes with energy production at essential steps in glycolysis, the Krebs cycle, and oxidative phosphorylation. Additional effects include inhibition of sodium-potassium-adenosine triphosphatase and binding to sulfhydryl groups. The major manifestations of toxicity consist of a rapidly progressive, ascending, extremely painful sensory neuropathy and alopecia. Unlike exposure to most metal salts, gastrointestinal symptoms of thallium toxicity are relatively minor, and constipation is more characteristic than diarrhoea. Many other findings such as an autonomic neuropathy, cranial nerve abnormalities, altered mental status, motor weakness, cardiac, hepatic, and renal effects are described, but are less specific. Thallium also crosses the placenta freely and produces abnormalities in animals as well as fetal demise, overt toxicity and congenital abnormalities in humans. There are no controlled trials of treatments in thallium-poisoned patients. Thus, the literature is predominated by very small animal studies and case reports with very limited data. Strong evidence speaks against the use of traditional metal chelators such as dimercaprol (British Anti-Lewisite) and penicillamine, and the latter may cause redistribution of thallium into the central nervous system. Likewise, forced potassium diuresis appears harmful. The use of single- or multiple-dose activated charcoal is supported by in vitro binding experiments and some animal data, and charcoal haemoperfusion may be a useful adjunct. Multiple animal studies give evidence for enhanced elimination and improved survival with Prussian blue. Unfortunately, despite the fact that many humans have been treated with Prussian blue, the data presented are insufficient to comment definitively on its efficacy. However, Prussian blue's safety profile is superior to that of other proposed therapies and it should be considered the drug of choice in acute thallium poisoning. Public health efforts should focus on greater restrictions on access to, and use of, thallium salts.


Evaluation of Hypoglycemic Therapy Through Physical Exercise in n5STZ-Induced Diabetes Rats.
Diabetes mellitus is a syndrome with multiple etiologies involving insulin, in which there is a lack of production and/or loss of sensitivity to this hormone resulting in insulin resistance. Treatment and control of this disease requires changes in diet, use of medication, and lifestyle, such as physical activity. These modifications may compromise quality-of-life if there is no proper guidance for the treatment or alert to possible complications caused by the disease. This study aimed to evaluate biochemical and hematological parameters, and to assess brain derived neurotrophic factor levels in diabetic Wistar rats submitted to chronic physical exercise. The results demonstrated an increase in plasma concentration of brain-derived neurotrophic factor (BDNF) in association with hyperglycemia reduction in diabetic animals. The results obtained suggest that there is a regulation of glucose homeostasis between peripheral tissues and the central nervous system. Exercise-induced BDNF also improved levels of glycemia, body weight, and dyslipidemia. In hematological evaluation, BDNF increase was positively correlated with an improvement in leukocyte parameters. Electrophoresis analyses demonstrated a reduction in levels of pro-inflammatory proteins, lipoprotein fractions, and albumin preservation in diabetic animals trained with elevated concentration of plasma BDNF. In conclusion, this study demonstrated that chronic exercise was able to elevate BDNF levels in plasma, which resulted directly in positive hypoglycemic activity in diabetic animals and a reduction of the metabolic syndrome associated with diabetes mellitus.


Hydrogen Sulfide (H2S) Removal via MOFs.
The removal of the environmentally toxic and corrosive hydrogen sulfide (H2S) from gas streams with varying overall pressure and H2S concentration is a long-standing challenge faced by the oil and gas industries. The present work focuses on H2S capture using a relatively new type of material, namely metal-organic frameworks (MOFs), in an effort to shed light on their potential as adsorbents in the field of gas storage and separation. MOFs hold great promise as they make possible the design of structures from organic and inorganic units, but also as they have provided an answer to a long-term challenging objective, i.e., how to design extended structures of materials. Moreover, in designing MOFs, one may functionalize the organic units and thus, in essence, create pores with different functionalities, and also to expand the pores in order to increase pore openings. The work presented herein provides a detailed discussion, by thoroughly combining the existing literature on new developments in MOFs for H2S removal, and tries to provide insight into new areas for further research.


CGAP: a new comprehensive platform for the comparative analysis of chloroplast genomes.
Chloroplast is an essential organelle in plants which contains independent genome. Chloroplast genomes have been widely used for plant phylogenetic inference recently. The number of complete chloroplast genomes increases rapidly with the development of various genome sequencing projects. However, no comprehensive platform or tool has been developed for the comparative and phylogenetic analysis of chloroplast genomes. Thus, we constructed a comprehensive platform for the comparative and phylogenetic analysis of complete chloroplast genomes which was named as chloroplast genome analysis platform (CGAP). CGAP is an interactive web-based platform which was designed for the comparative analysis of complete chloroplast genomes. CGAP integrated genome collection, visualization, content comparison, phylogeny analysis and annotation functions together. CGAP implemented four web servers including creating complete and regional genome maps of high quality, comparing genome features, constructing phylogenetic trees using complete genome sequences, and annotating draft chloroplast genomes submitted by users. Both CGAP and source code are available at http://www.herbbol.org:8000/chloroplast. CGAP will facilitate the collection, visualization, comparison and annotation of complete chloroplast genomes. Users can customize the comparative and phylogenetic analysis using their own unpublished chloroplast genomes.


Serum matrix metalloproteinase-9 levels in acute coronary syndrome patients with and without hyperglycemia.
to determine the difference in serum matrix metalloproteinase-9 (MMP-9) levels among acute coronary syndrome patients with and without hyperglycemia. this study was a cross-sectional study on patients with acute coronary syndrome admitted to ICCU of Dr.Sardjito Hospital Yogyakarta Indonesia. Measurements of blood glucose level were performed on hospital admission, while measurement of MMP-9 level was performed upon arrival at the ICCU. Hyperglycemia was defined as a random blood glucose level of >140 mg/dL. Student's t test was performed to analyze the difference of MMP-9 level between subjects with and without hyperglycemia. of 72 enrolled subjects, there were 34 subjects with hyperglycemia and 38 subjects without hyperglycemia. The mean blood glucose level was significantly different in subjects with hyperglycemia as compared to those without hyperglycemia (204.4±92.16 vs. 108.93±19.1 mg/dL, p=0.0001). The mean MMP-9 level in subjects with hyperglycemia was significantly higher than those without hyperglycemia (1574±573.61 vs. 1370±573.66 ng/mL, p=0.025). The prevalence ratio of high MMP-9 level among subjects with hyperglycemia was 2.88 (95% CI: 1.16-7.14), p=0.004. serum MMP-9 level in patients suffering from acute coronary syndrome with hyperglycemia was significantly higher than those without hyperglycemia.


Assessing adhesion, biofilm formation and motility of Acidovorax citrulli using microfluidic flow chambers.
Acidovorax citrulli is the causal agent of bacterial fruit blotch of cucurbits. We have shown previously that type IV pili (TFP) are required for wild-type levels of virulence of A. citrulli on melon and that this pathogen can colonize and move thorough the xylem vessels of host seedlings. Here, comparative studies between wild-type and TFP mutant strains using microfluidic flow chambers demonstrated that TFP play a critical role in both the surface attachment and the biofilm formation of A. citrulli under a medium flow. Additionally, TFP null mutants were unable to perform twitching movement against the direction of medium flow. Assays using a flagellin mutant showed that, in contrast to TFP, polar flagella do not contribute to the adhesion and biofilm formation of A. citrulli under tested conditions. Also, flagellum-mediated swimming motility of wild-type strains was not observed under medium flow. These results imply that TFP may play an important role in colonization and spread in the xylem vessels under sap flow conditions, while polar flagella could be more important for spread during periods of time when xylem flow is minimal.


The diverse functions of osteoglycin: a deceitful dwarf, or a master regulator of disease?
Small leucine-rich proteoglycans are emerging as important regulatory proteins within the extracellular matrix, where they exert both structural and nonstructural functions and hence are modulators of numerous biological processes, such as inflammation, fibrosis, and cell proliferation. One proteoglycan in particular, osteoglycin (OGN), also known as mimecan, shows great structural and functional diversity in normal physiology and in disease states, therefore making it a very interesting candidate for the development of novel therapeutic strategies. Unfortunately, the literature on OGN is confusing, as it has different names, and different transcript and protein variants have been identified. This review will give a clear overview of the different structures and functions of OGN that have been identified to date, portray its central role in pathophysiology, and highlight the importance of posttranslational processing, such as glycosylation, for the diversity of its functions.-Deckx, S., Heymans, S., Papageorgiou, A.-P. The diverse functions of osteoglycin: a deceitful dwarf, or a master regulator of disease?


Decoupling of size and shape fluctuations in heteropolymeric sequences reconciles discrepancies in SAXS vs. FRET measurements.
Unfolded states of proteins and native states of intrinsically disordered proteins (IDPs) populate heterogeneous conformational ensembles in solution. The average sizes of these heterogeneous systems, quantified by the radius of gyration (RG ), can be measured by small-angle X-ray scattering (SAXS). Another parameter, the mean dye-to-dye distance (RE ) for proteins with fluorescently labeled termini, can be estimated using single-molecule Förster resonance energy transfer (smFRET). A number of studies have reported inconsistencies in inferences drawn from the two sets of measurements for the dimensions of unfolded proteins and IDPs in the absence of chemical denaturants. These differences are typically attributed to the influence of fluorescent labels used in smFRET and to the impact of high concentrations and averaging features of SAXS. By measuring the dimensions of a collection of labeled and unlabeled polypeptides using smFRET and SAXS, we directly assessed the contributions of dyes to the experimental values RG and RE For chemically denatured proteins we obtain mutual consistency in our inferences based on RG and RE , whereas for IDPs under native conditions, we find substantial deviations. Using computations, we show that discrepant inferences are neither due to methodological shortcomings of specific measurements nor due to artifacts of dyes. Instead, our analysis suggests that chemical heterogeneity in heteropolymeric systems leads to a decoupling between RE and RG that is amplified in the absence of denaturants. Therefore, joint assessments of RG and RE combined with measurements of polymer shapes should provide a consistent and complete picture of the underlying ensembles.


Increasing frequency of penicillin-resistant pneumococci: epidemiological aspects and case-control study.
At the Hadassah University Hospital, Mt. Scopus, Jerusalem, the frequency of patients with relatively penicillin-resistant pneumococci (RPRP) isolates has increased from 0.9 to 10.8% during the years 1979-82. Infants and children were particularly involved. Significantly more RPRP isolates were found in those less than 14 years old than in those who were older (P less than 0.005). The determination of susceptibility or relative resistance to penicillin was based on the disk sensitivity method, which remained unchanged throughout the study period. The minimal inhibitory concentration (MIC) to penicillin G was also determined for 20 RPRP isolates and was found to be in the range of relative resistance to penicillin (0.25 to 0.50 micrograms/ml) in all 20 isolates. A case-control study of 16 index patients examined antibiotic usage during the 60 days preceding pneumococcal isolation. Total antibiotic usage was high in both groups (18.8 vs. 8.8 days, P = 0.2); beta-lactam antibiotic usage was significantly higher in the RPRP group than in the control group (13.3 vs. 4.2 days, 0.01 less than P less than 0.02). General prescribing practices, even in nonisolated areas where there is no need for public health programs to dispense prophylactic antibiotics, may produce sufficiently high antibiotic exposures to aid the emergence of RPRP strains.


Variations in the Anterolateral Thigh Flap's Vascular Anatomy in African Americans.
Variations in anterolateral thigh (ALT) arterial anatomy are well documented. Ethnicity is a known risk factor for vascular variation in several organ systems, but its impact on ALT anatomy has not been studied. Anecdotally, we observed frequent ALT arterial variation in African American (AA) patients. We thus hypothesized that AA patients have higher rates of anomalous branching. A total of 277 computed tomography angiograms (513 lower extremities) captured between May 1, 2013 and May 31, 2015 at a tertiary academic medical center were retrospectively analyzed to determine ALT arterial branching. Patient records were examined to ascertain demographics. Data were analyzed using descriptive statistics and multinomial logistic regression. Males comprised 84.5%. Ethnic distribution was 55.2% AA and 36.5% Caucasian. The descending branch of the lateral circumflex femoral artery (dLCFA) originated from non-LCFA arteries (deep femoral, common femoral, or superficial femoral arteries) in 18.9% of Caucasian versus 9.1% of AA (odds ratio [OR]: 2.28; 95% confidence interval [CI]: 1.33-3.93, p < 0.01). An oblique branch was identified in 41.1% of Caucasian versus 51.9% of AA (OR: 1.56; 95% CI: 1.08-2.24, p = 0.02). Ethnicity was the only driving factor of dLCFA and oblique branch of the LCFA (oLCFA) anatomy (Wald chi-square: 14 and 11, p = 0.03 and 0.02, respectively). Ethnicity significantly affects ALT arterial anatomy. AA are more likely to have classical dLCFA branching with a fourth oLCFA branch. A flap with an unrecognized oLCFA-dominant supply places patients at a higher risk for flap failure and loss. We recommend preoperative imaging before undertaking an ALT flap reconstruction.


Cross-link-governed dynamics of biopolymer networks.
Recent experiments show that networks of stiff biopolymers cross-linked by transient linker proteins exhibit complex stress relaxation, enabling network flow at long times. We present a model for the dynamics controlled by cross-links in such networks. We show that a single microscopic time scale for cross-linker unbinding leads to a broad spectrum of macroscopic relaxation times and a shear modulus G ∼ ω(1/2) for low frequencies ω. This model quantitatively describes the measured rheology of actin networks cross-linked with α-actinin-4 over more than four decades in frequency.


First description of NDM-1-, KPC-2-, VIM-2- and IMP-4-producing Klebsiella pneumoniae strains in a single Chinese teaching hospital.
A total of 180 non-duplicate carbapenem-resistant Klebsiella pneumoniae isolates were recovered from patients hospitalized between December 2010 and January 2012 at a Chinese hospital. Eight KPC-2, four NDM-1, one VIM-2, and five KPC-2 plus IMP-4 producers were identified and all were multidrug resistant due to the presence of other resistance determinants, including extended-spectrum β-lactamases (CTX-M-15, SHV-12), 16S rRNA methylases (armA, rmtB) and plasmid-mediated quinolone-resistance determinants (qnrA, B, S, aac(6')-Ib-cr). Nine K. pneumoniae clones (Kpn-A1/ST395, Kpn-A3/ST11, Kpn-A2/ST134, Kpn-B/ST263, Kpn-C/ST37, Kpn-D/ST39, Kpn-E/ST1151, Kpn-F/ST890, Kpn-G/ST1153) were identified. bla KPC-2 was located on transferable ~65 kb IncL/M (ST395, ST11, ST134, ST39) and ~100 kb IncA/C (ST37, ST1153, ST890) plasmids, respectively. On the other hand, bla NDM-1 was associated with a ~70 kb IncA/C plasmid (ST263). However, non-typable plasmids of ~40 kb containing bla VIM-2 were detected in the ST1151 clone. This work reports the first co-occurrence of four diverse types of carbapenemase of K. pneumoniae clones from a single hospital in China. IncA/C, IncL/M, and other successful plasmids may be important for the dissemination of carbapenemases, producing a complex epidemiological picture.


[Formation of a urinary reservoir from a small intestinal graft in children with exstrophy of the urinary bladder].
The authors suggest a new approach to the treatment of patients with exstrophy of the urinary bladder-the formation of an urinary reservoir from a detubulerized intestinal graft after II Kocks' method. This method, as well as its analogues, is mainly used in adults after radical cystectomy. Improved surgical techniques have been suggested on the basis of experimental works which allow the age features and the peculiarities of the functional condition of the formed reservoir to be taken into account. Analysis of the results of clinical use of the suggested method showed it to be effective in solving the problem of rehabilitation of patients with exstrophy of the urinary bladder, which allows it to be recommended as the operation of choice in the management of this developmental anomaly.


Development and Validation of a Probe Word List to Assess Speech Motor Skills in Children.
Purpose The aim of the study was to develop and validate a probe word list and scoring system to assess speech motor skills in preschool and school-age children with motor speech disorders. Method This article describes the development of a probe word list and scoring system using a modified word complexity measure and principles based on the hierarchical development of speech motor control known as the Motor Speech Hierarchy (MSH). The probe word list development accounted for factors related to word (i.e., motoric) complexity, linguistic variables, and content familiarity. The probe word list and scoring system was administered to 48 preschool and school-age children with moderate-to-severe speech motor delay at clinical centers in Ontario, Canada, and then evaluated for reliability and validity. Results One-way analyses of variance revealed that the motor complexity of the probe words increased significantly for each MSH stage, while no significant differences in the linguistic complexity were found for neighborhood density, mean biphone frequency, or log word frequency. The probe word list and scoring system yielded high reliability on measures of internal consistency and intrarater reliability. Interrater reliability indicated moderate agreement across the MSH stages, with the exception of MSH Stage V, which yielded substantial agreement. The probe word list and scoring system demonstrated high content, construct (unidimensionality, convergent validity, and discriminant validity), and criterion-related (concurrent and predictive) validity. Conclusions The probe word list and scoring system described in the current study provide a standardized method that speech-language pathologists can use in the assessment of speech motor control. It can support clinicians in identifying speech motor difficulties in preschool and school-age children, set appropriate goals, and potentially measure changes in these goals across time and/or after intervention.


Evidence for Improving Outcome Through Extent of Resection.
Surgical resection plays a central role in the management of gliomas however many tumors are within areas resulting in sensorimotor and cognitive consequences. This article reviews the evidence in support of extent of resection to improve survival, symptom management, and time to malignant transformation in low-grade gliomas. The authors summarize the evolving literature regarding the role of maximal safe resection in light of WHO subclassification of low-grade gliomas. Long lasting neurological deficits following glioma resection may hinder both survival and quality of life. New insights into glioma related central nervous system plasticity impact both surgical planning and timing of interventions.


The RNA-dependent-RNA polymerase, an emerging antiviral drug target for the Hendra virus.
Australia is facing a major national medical challenge with the emergence of the Hendra virus (HeV) as a medically and economically important pathogen of humans and animals. Clinical symptoms of human HeV infection can include fever, hypotension, dizziness, encephalitis, respiratory haemorrhage and edema. The window of opportunity for successful patient treatment remains unknown, but is likely to be very narrow. Currently, very few effective therapeutic options are available for the case management of severe HeV infections or the rapid silencing of local outbreaks. This underscores the need for more activity in the drug discovery arena to develop much needed therapeutics that specifically targets this deadly disease. The structural analysis of HeV is very much in its infancy, which leaves many gaps in our understanding of the biology of HeV and makes structure-guided drug design difficult. Structural studies of the viral RNAdependent- RNA polymerase (RdRp), which is the heart of the viral replication machinery, will set the stage for rational drug design and fill a major gap in our understanding of the HeV replication machinery. This review examines the current knowledge based on the multi-domain architecture of the Hendra RdRp and highlights which essential domain functions represent tangible targets for drug development against this deadly disease.


[Correction of fatty acid metabolism in stomach surgery patients by the infusion of a fatty emulsion].
The method of gas-liquid chromatography was used for studying the content of high molecular weight fatty acids in blood serum of 48 patients after operations on the stomach. It was established that in the early postoperative period the level of high molecular weight fatty acids including essential ones was considerably lower which deteriorated the course of the postoperative period and caused complications. The inclusion of fat emulsions in the programme of parenteral feeding in the early postoperative period is an effective measure of correction of the disturbed fatty acid metabolism resulting in the improvement of immediate results of the operation and less amount of postoperative complications.


The Aging Metabolome-Biomarkers to Hub Metabolites.
Aging biology is intimately associated with dysregulated metabolism, which is one of the hallmarks of aging. Aging-related pathways such as mTOR and AMPK, which are major targets of anti-aging interventions including rapamcyin, metformin, and exercise, either directly regulate or intersect with metabolic pathways. In this review, numerous candidate bio-markers of aging that have emerged using metabolomics are outlined. Metabolomics studies also reveal that not all metabolites are created equally. A set of core "hub" metabolites are emerging as central mediators of aging. The hub metabolites reviewed here are nicotinamide adenine dinucleotide, reduced nicotinamide dinucleotide phosphate, α-ketoglutarate, and β-hydroxybutyrate. These "hub" metabolites have signaling and epigenetic roles along with their canonical roles as co-factors or intermediates of carbon metabolism. Together these hub metabolites suggest a central role of the TCA cycle in signaling and metabolic dysregulation associated with aging.


Pharmaceutical VIP: prospects and problems.
Recently, multiple receptors for vasoactive intestinal peptide (VIP) have been molecularly cloned and our understanding of VIP chemistry and mechanisms of action has been broadened. The following review outlines the physiological effects of the hormone from growth regulation, reproduction, bronchodilation, vasodilation and immune interactions to neurotrophism. VIP-based drug design and non-invasive innovative delivery modes are discussed with emphasis on tumor diagnosis and treatment, impotence treatment and neuroprotection.


Electroconvulsive therapy for obsessive compulsive symptoms in a patient with schizophrenia: a brief report.
Comorbid obsessive-compulsive disorder (OCD) is common among patients with schizophrenia. The role of electroconvulsive therapy (ECT) in the treatment of OCD in schizophrenia is unclear. Herein, we present a 45-year-old man who was diagnosed with schizophrenia along with OCD and received ECT due to relapse of psychosis owing to refractive schizophrenia. Together with psychotic symptoms, obvious symptoms of OCD were observed prior to treatment, including obsessive thoughts, difficulty in starting activities, and repetitive and ritualistic behavior. After 12 sessions of ECT, symptoms of schizophrenia and OCD both improved significantly (Positive and Negative Syndrome Scale [PANSS] score decreased from 95 points to 58 points, and Yale - Brown Obsessive-Compulsive Scale [Y-BOCS] score decreased from 29 points to 11 points). Mild aggravation of OCD symptoms was noted 3 months after ECT treatment (Y-BOCS score increased from 11 points to 17 points) without obvious relapse of psychotic symptoms (PANSS score changed from 58 points to 62 points). In conclusion, ECT could be considered as an alternative therapy for patients with schizophrenia and OCD with limited response to pharmacological treatment.


The Use of Dexmedetomidine in the Emergency Department: A Cohort Study.
Management of sedation, analgesia, and anxiolysis are cornerstone therapies in the emergency department (ED). Dexmedetomidine (DEX), a central alpha-2 agonist, is increasingly being used, and intensive care unit (ICU) data demonstrate improved outcomes in patients with respiratory failure. However, there is a lack of ED-based data. We therefore sought to: 1) characterize ED DEX use; 2) describe the incidence of adverse events; and 3) explore factors associated with adverse events among patients receiving DEX in the ED. This was a single-center, retrospective, cohort study of consecutive ED patients administered DEX (January 1, 2017-July 1, 2019) at an academic, tertiary care ED with an annual census of ~90,000 patient visits. All included patients (n= 103) were analyzed for characterization of DEX use in the ED. The primary outcome was a composite of adverse events, bradycardia and hypotension. Secondary clinical outcomes included ventilator-, ICU-, and hospital-free days, and hospital mortality. To examine for variables associated with adverse events, we used a multivariable logistic regression model. We report on 103 patients. Dexmedetomidine was most commonly given for acute respiratory failure, including sedation for mechanical ventilation (28.9%) and facilitation of non-invasive ventilation (17.4%). Fifty-four (52.4%) patients experienced the composite adverse event, with hypotension occurring in 41 patients (39.8%) and bradycardia occurring in 18 patients (17.5%). Dexmedetomidine was stopped secondary to an adverse event in eight patients (7.8%). Duration of DEX use in the ED was associated with an increase adverse event risk (adjusted odds ratio, 1.004; 95% confidence interval, 1.001, 1.008). Dexmedetomidine is most commonly administered in the ED for patients with acute respiratory failure. Adverse events are relatively common, yet DEX is discontinued comparatively infrequently due to adverse events. Our results suggest that DEX could be a viable option for analgesia, anxiolysis, and sedation in ED patients.


USP10 modulates the SKP2/Bcr-Abl axis via stabilizing SKP2 in chronic myeloid leukemia.
Constitutive activation of tyrosine kinase Bcr-Abl is the leading cause of the development and progression of chronic myeloid leukemia (CML). Currently, the application of tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl is the primary therapy for CML patients. However, acquired resistance to TKIs that develops overtime in the long-term administration renders TKIs ineffective to patients with advanced CML. Therefore, increasing studies focus on the amplified expression or activation of Bcr-Abl which is proposed to contribute to the advanced phase. Here, we show that S-phase kinase-associated protein 2 (SKP2) acts as a co-regulator of Bcr-Abl by mediating its K63-linked ubiquitination and activation. Further investigations show that USP10 as a novel deubiquitinase of SKP2 amplifies the activation of Bcr-Abl via mediating deubiquitination and stabilization of SKP2 in CML cells. Moreover, inhibition of USP10 significantly suppresses the proliferation of both imatinib-sensitive and imatinib-resistant CML cells, which likely depends on SKP2 status. This findings are confirmed in primary CML cells because these cells are over-expressed with USP10 and SKP2 and are sensitive to a USP10 inhibitor. Taken together, the present study not only provides a novel insight into the amplified activation of Bcr-Abl in CML, but also demonstrates that targeting the USP10/SKP2/Bcr-Abl axis is a potential strategy to overcome imatinib resistance in CML patients.


Conformational relaxation following reduction of the photoactive bacteriopheophytin in reaction centers from Blastochloris viridis. Influence of mutations at position M208.
The photochemically trapped bacteriopheophytin (BPh) b radical anion in the active branch (Phi(A)(&z.rad;-)) of reaction centers (RCs) from Blastochloris (formerly called Rhodopseudomonas) viridis is characterized by 1H-ENDOR as well as optical absorption spectroscopy. The two site-directed mutants YF(M208) and YL(M208), in which tyrosine at position M208 is replaced by phenylalanine and leucine, respectively, are investigated and compared with the wild type. The residue at M208 is in close proximity to the primary electron donor, P, the monomeric bacteriochlorophyll (BChl), B(A), and the BPh, Phi(A), that are involved in the transmembrane electron transfer to the quinone, Q(A), in the RC. The analysis of the ENDOR spectra of Phi(A)(&z.rad;-) at 160 K indicates that two distinct states of Phi(A)(&z.rad;-) are present in the wild type and the mutant YF(M208). Based on a comparison with Phi(A)(&z.rad;-) in RCs of Rhodobacter sphaeroides the two states are interpreted as torsional isomers of the 3-acetyl group of Phi(A). Only one Phi(A)(&z.rad;-) state occurs in the mutant YL(M208). This effect of the leucine residue at position M208 is explained by steric hindrance that locks the acetyl group in one specific position. On the basis of these results, an interpretation of the optical absorption difference spectrum of the state Phi(A)(&z.rad;-)Q(A)(&z.rad;-) is attempted. This state can be accumulated at 100 K and undergoes an irreversible change between 100 and 200 K [Tiede et al., Biochim. Biophys. Acta 892 (1987) 294-302]. The corresponding absorbance changes in the BChl Q(x) and Q(y) regions observed in the wild type also occur in the YF(M208) mutant but not in YL(M208). The observed changes in the wild type and YF(M208) are assigned to RCs in which the 3-acetyl group of Phi(A) changes its orientation. It is concluded that this distinct structural relaxation of Phi(A) can significantly affect the optical properties of B(A) and contribute to the light-induced absorption difference spectra.


Histamine synthesis by intact mast cells from canine fundic mucosa and liver.
The synthesis and degradation of histamine by dog fundic mucosa was studied by using cells dispersed by enzymatic digestion and separated sequentially by velocity sedimentation in an elutriator rotor, and by density gradient. Histidine decarboxylase activity was found in appreciable amounts in fractions highly enriched in mast cells when these cells were studied intact, whereas only trace activity was detected in homogenates of these mucosal mast cells or of whole mucosa. Unlike the rat gastric mucosal histamine cell, dihydroxyphenylalanine decarboxylase activity was not present in the canine fundic mast cell. Serotonin, which is found in the rat peritoneal mast cell, was not detectable in the canine mast cell. The histamine-degrading enzyme, histamine methyltransferase, was also present in gastric mucosal cells, but not diamine oxidase. This methyltransferase activity was primarily associated with parietal cells and was not found in the mast cell-enriched functions. For comparison, fractions containing 60%-80% mast cells were enriched by elutriation from enzyme-dispersed cells of canine liver. As with the gastric mast cells, histidine decarboxylase activity was found in intact cell, but it was lost upon cell disruption.


Indication and management of allogeneic haematopoietic stem-cell transplantation in myelofibrosis: updated recommendations by the EBMT/ELN International Working Group.
New options for medical therapy and risk scoring systems containing molecular data are leading to increased complexity in the management of patients with myelofibrosis. To inform patients' optimal care, we updated the 2015 guidelines on indications for and management of allogeneic haematopoietic stem-cell transplantation (HSCT) with the support of the European Society for Blood and Marrow Transplantation (EBMT) and European LeukemiaNet (ELN). New recommendations were produced using a consensus-building methodology after a comprehensive review of articles released from January, 2015 to December, 2022. Seven domains and 18 key questions were selected through a series of questionnaires using a Delphi process. Key recommendations in this update include: patients with primary myelofibrosis and an intermediate-2 or high-risk Dynamic International Prognostic Scoring System score, or a high-risk Mutation-Enhanced International Prognostic Score Systems (MIPSS70 or MIPSS70-plus) score, or a low-risk or intermediate-risk Myelofibrosis Transplant Scoring System score should be considered candidates for allogeneic HSCT. All patients who are candidates for allogeneic HSCT with splenomegaly greater than 5 cm below the left costal margin or splenomegaly-related symptoms should receive a spleen-directed treatment, ideally with a JAK-inhibitor; HLA-matched sibling donors remain the preferred donor source to date. Reduced intensity conditioning and myeloablative conditioning are both valid options for patients with myelofibrosis. Regular post-transplantation driver mutation monitoring is recommended to detect and treat early relapse with donor lymphocyte infusion. In a disease where evidence-based guidance is scarce, these recommendations might help clinicians and patients in shared decision making.


Longitudinal study of retinal degeneration in a rat using spectral domain optical coherence tomography.
Rodent models of retinal degenerative diseases are used by vision scientists to develop therapies and to understand mechanisms of disease progression. Measurement of changes to the thickness of the various retinal layers provides an objective metric to evaluate the performance of the therapy. Because invasive histology is terminal and provides only a single data point, non-invasive imaging modalities are required to better study progression, and to reduce the number of animals used in research. Optical Coherence Tomography (OCT) has emerged as a dominant imaging modality for human ophthalmic imaging, but has only recently gained significant attention for rodent retinal imaging. OCT provides cross section images of retina with micron-scale resolution which permits measurement of the retinal layer thickness. However, in order to be useful to vision scientists, a significant fraction of the retinal surface needs to be measured. In addition, because the retinal thickness normally varies as a function of distance from optic nerve head, it is critical to sample all regions of the retina in a systematic fashion. We present a longitudinal study of OCT to measure retinal degeneration in rats which have undergone optic nerve axotomy, a well characterized form of rapid retinal degeneration. Volumetric images of the retina acquired with OCT in a time course study were segmented in 2D using a semi-automatic segmentation algorithm. Then, using a 3D algorithm, thickness measurements were quantified across the surface of the retina for all volume segmentations. The resulting maps of the changes to retinal thickness over time represent the progression of degeneration across the surface of the retina during injury. The computational tools complement OCT retinal volumetric acquisition, resulting in a powerful tool for vision scientists working with rodents.


Neonatal Hypoxic-Ischemic Encephalopathy Spectrum: Severity-Stratified Analysis of Neuroimaging Modalities and Association with Neurodevelopmental Outcomes.
To compare hypoxic-ischemic injury on early cranial ultrasonography (cUS) and post-rewarming brain magnetic resonance imaging (MRI) in newborn infants with hypoxic-ischemic encephalopathy (HIE) and to correlate that neuroimaging with neurodevelopmental outcomes. This was a retrospective cohort study of infants with mild, moderate, and severe HIE treated with therapeutic hypothermia and evaluated with early cUS and post-rewarming MRI. Validated scoring systems were used to compare the severity of brain injury on cUS and MRI. Neurodevelopmental outcomes were assessed at 18 months of age. Among the 149 included infants, abnormal white matter (WM) and deep gray matter (DGM) hyperechogenicity on cUS in the first 48 hours after birth were more common in the severe HIE group than the mild HIE group (81% vs. 39% and 50% vs. 0%, respectively; p <0.001). In infants with a normal cUS, 95% had normal or mildly abnormal brain MRIs. In infants with severely abnormal cUS, none had normal and 83% had severely abnormal brain MRIs. Total abnormality scores on cUS were higher in neonates with near-total brain injury on MRI than in neonates with normal MRI or WM-predominant injury pattern (adjusted p <0.001 for both). In the multivariable model, a severely abnormal MRI was the only independent risk factor for adverse outcomes (odds ratio: 19.9, 95% confidence interval: 4.0 to 98.1; p <0.001). The present study shows the complementary utility of cUS in the first 48 hours after birth as a predictive tool for the presence of hypoxic-ischemic injury on brain MRI.


[Obesity and malnutrition in children: profile of a low-income community]
OBJECTIVE: To establish the nutritional diagnosis of children living in a low-income community through anthropometric evaluation, detecting insufficient nutrition (low weight-for-age, wasting and stunting) and excessive nutrition (overweight and obesity). METHODS: A community-based survey identified children below 11 years living in a low-income community. Their weight and height (or lengths) were measured. The National Center for Health Statistics growth curve was used as reference. The cut-off points used were: low-weight-for-age z score of < -2 (weight-for-age), wasting (weight-for-height) and stunting (height-for-age); respective overweight and obesity z scores of +1 to +2 and of > +2, according to weight-for-height. RESULTS: Prevalence rates were 3.8% for low weight for age, and 24% for low-weight-for-age risk factors; 1.2% for wasting, and 21.6% for wasting risk factors; 5% for stunting, and 14.3% for stunting risk factors; 10.1% for overweight, and 4.6% for obesity. CONCLUSIONS: Main nutritional issues were present in children from that community, with simultaneous occurrence of chronic malnutrition and obesity.


Non-stationary and interactive effects of climate and competition on pink salmon productivity.
Pacific salmon (Oncorhynchus spp.) are exposed to increased environmental change and multiple human stressors. To anticipate future impacts of global change and to improve sustainable resource management, it is critical to understand how wild salmon populations respond to stressors associated with human-caused changes such as climate warming and ocean acidification, as well as competition in the ocean, which is intensified by the large-scale production and release of hatchery reared salmon. Pink salmon (O. gorbuscha) are a keystone species in the North Pacific Ocean and support highly valuable commercial fisheries. We investigated the joint effects of changes in ocean conditions and salmon abundances on the productivity of wild pink salmon. Our analysis focused on Prince William Sound in Alaska, because the region accounts for ~50% of the global production of hatchery pink salmon with local hatcheries releasing 600-700 million pink salmon fry annually. Using 60 years of data on wild pink salmon abundances, hatchery releases, and ecological conditions in the ocean, we find evidence that hatchery pink salmon releases negatively affect wild pink salmon productivity, likely through competition between wild and hatchery juveniles in nearshore marine habitats. We find no evidence for effects of ocean acidification on pink salmon productivity. However, a change in the leading mode of North Pacific climate in 1988-1989 weakened the temperature-productivity relationship and altered the strength of intraspecific density dependence. Therefore, our results suggest non-stationary (i.e., time varying) and interactive effects of ocean climate and competition on pink salmon productivity. Our findings further highlight the need for salmon management to consider potential adverse effects of large-scale hatchery production within the context of ocean change.


Appearance of T-wave inversions without raised serum enzyme activity in suspected acute myocardial infarction: clinical outcome in relation to subendocardial infarction.
In 67 patients with a clinical history of suspected acute myocardial infarction (MI) who developed T-wave inversions in standard ECG and had normal serum aspartate aminotransferase activity (possible MI) the clinical outcome was compared with that in patients fulfilling criteria for subendocardial infarction. Patients with possible MI had a lower mortality (p = 0.02) and also a lower reinfarction rate (p = 0.14) during the first 2 years as compared with those with subendocardial MI. Although patients with subendocardial MI had more problems with chest pain in the acute phase, angina pectoris occurred more frequently in patients with possible MI during a longer follow-up period. Congestive heart failure occurred more frequently in patients with subendocardial MI during initial hospitalization, whereas treatment for heart failure appeared similar in the two groups during a longer follow-up time. We conclude that the clinical course in patients with possible MI, here defined as chest pain and appearance of T-wave inversions without elevation of serum enzyme activity, seems to differ from that in patients with subendocardial MI, particularly regarding long-term survival and incidence of angina pectoris.


Work motivation theory and research at the dawn of the twenty-first century.
In the first Annual Review of Psychology chapter since 1977 devoted exclusively to work motivation, we examine progress made in theory and research on needs, traits, values, cognition, and affect as well as three bodies of literature dealing with the context of motivation: national culture, job design, and models of person-environment fit. We focus primarily on work reported between 1993 and 2003, concluding that goal-setting, social cognitive, and organizational justice theories are the three most important approaches to work motivation to appear in the last 30 years. We reach 10 generally positive conclusions regarding predicting, understanding, and influencing work motivation in the new millennium.


Glutaminase and poly(ADP-ribose) polymerase inhibitors suppress pyrimidine synthesis and VHL-deficient renal cancers.
Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate (αKG). Glutamine can also generate aspartate, the carbon source for pyrimidine biosynthesis, and glutathione for redox balance. Here we have shown that VHL-/- RCC cells rely on RC-derived aspartate to maintain de novo pyrimidine biosynthesis. Glutaminase 1 (GLS1) inhibitors depleted pyrimidines and increased ROS in VHL-/- cells but not in VHL+/+ cells, which utilized glucose oxidation for glutamate and aspartate production. GLS1 inhibitor-induced nucleoside depletion and ROS enhancement led to DNA replication stress and activation of an intra-S phase checkpoint, and suppressed the growth of VHL-/- RCC cells. These effects were rescued by administration of glutamate, αKG, or nucleobases with N-acetylcysteine. Further, we observed that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib synergizes with GLS1 inhibitors to suppress the growth of VHL-/- cells in vitro and in vivo. This work describes a mechanism that explains the sensitivity of RCC tumor growth to GLS1 inhibitors and supports the development of therapeutic strategies for targeting VHL-deficient RCC.


[Type 2 Diabetes and Dietary Patterns 1961 to 2009: Some Social Determinants in Mexico].
In order to analyze whether the increase in mortality from diabetes in Mexico is related to changes in eating patterns over the period 1961 to 2009, and if they in turn could be explained in the Mexican socioeconomic context, we conducted an ecological study with information from the Food Balance Sheets FAO. A cluster analysis was performed to shape eating patterns (three) and some socioeconomic variables were analyzed. It was observed that the energy derived from cereals and legumes (beans) was significantly reduced, and simultaneously, energy from sugars, animal foods, and vegetable fats had a significant increase. Various socioeconomic conditions may have favored changes in diet and increased mortality from diabetes. These conditions are: trade liberalization, low growth, rising inequality and informal work, declining agriculture, falling real wages in relation to the value of what is called the "basic food and non-food baskets", increasing prices of healthy food,low cost of processed foods and beverages, and the lack of control in the food market.


Pharmacoepigenomics: an interplay of epigenetic modulation of drug response and modulation of the epigenome by drugs.
Epigenetic modulation captures the lack of correlation between the genotype and the phenotype. It also provides an interface between environment and the genotype leading to functional plasticity of the genome. While drug response can be modulated by the epigenome, the therapeutic intervention by drugs can also be considered as an environmental cue for epigenetic alterations. The effect of genetic polymorphism has accrued considerable interest and population polymorphism leading to variation in drug response is being studied extensively. The available data on the epigenetic marking of the whole genome in different contexts implies that no biological pathway or process in the mammalian system is free of epigenetic influence and thus, drug metabolism would not be an exception. In the light of the fact that the epigenome is not only variable between individuals, but that it also varies between different tissues of the same individual and with the age of the individual, it is still a long journey to transit from the correlation to causal relationship between drug response and the epigenomic variations. The present review is focused on recent developments in the area and a brief discussion of the future prospects and challenges.


Transcriptomic profiles of muscle, heart, and spleen in reaction to circadian heat stress in Ethiopian highland and lowland male chicken.
Temperature stress impacts both welfare and productivity of livestock. Global warming is expected to increase the impact, especially in tropical areas. We investigated the biological mechanisms regulated by temperature stress due to the circadian temperature cycle in temperature adapted and non-adapted chicken under tropical conditions. We studied transcriptome profiles of heart, breast muscle, and spleen tissues of Ethiopian lowland chicken adapted to high circadian temperatures and non-adapted Ethiopian highland chicken under lowland conditions at three points during the day: morning, noon, and evening. Functional annotations and network analyses of genes differentially expressed among the time points of the day indicate major differences in the reactions of the tissues to increasing and decreasing temperatures, and also the two chickens lines differ. However, epigenetic changes of chromatin methylation and histone (de)acetylation seemed to be central regulatory mechanisms in all tissues in both chicken lines. Finally, all tissues showed differentially expressed genes between morning and evening times indicating biological mechanisms that need to change during the night to reach morning levels again the next day.


Amyloid beta and impairment in multiple memory systems in older transgenic APP TgCRND8 mice.
The relationship between amyloid beta and cognitive dysfunction in mouse models of Alzheimer's disease has been evaluated predominantly with the spatial reference memory version of the water maze task. However, as Alzheimer's disease encompasses decline in multiple memory systems, it is important to also utilize non-spatial tasks to fully characterize the role of amyloid on behaviour in animal models. We used the TgCRND8 mouse model of Alzheimer's disease to evaluate the effect of amyloid on spatial reference memory, as well as on the non-spatial task of acquisition of conditioned taste aversion, and on the procedural task of swimming to a visible platform. We demonstrate that 8- to 12-month-old TgCRND8 mice are significantly impaired in all three tasks, and that the levels of soluble amyloid beta are significantly correlated with impairment in spatial reference memory, but not with impairment in conditioned taste aversion or swimming to a visible platform. Insoluble fractions of amyloid, which correspond closely to amyloid plaque burden in the brain, are not associated with any behavioural measure. Our study extends the characterization of the model to stages of advanced amyloid pathology and demonstrates that older TgCRND8 mice are impaired in multiple memory systems, including procedural tasks, which are spared at younger ages. The lack of association between amyloid plaques and memory decline supports clinical findings in Alzheimer's patients.


Clinical analysis and prognostic study of ossified ligamentum flavum of the thoracic spine.
A variety of factors may affect surgery-related outcome in patients with ossification of the ligamentum flavum (OLF) of the thoracic spine. The aim of this study was to determine these factors on the basis of preoperative clinical and radiological findings. The authors treated 31 cases of symptomatic thoracic OLF between 1988 and 1999. The following factors were retrospectively studied: patient age, sex, morbidity level, initial symptoms, chief complaint, duration of symptoms, patellar reflex, Achilles reflex, computerized tomography (CT) finding, presence of intramedullary change determined by magnetic resonance imaging, coexistent spinal lesions, preoperative grade, and postoperative grade. A decompressive laminectomy was performed in all cases. In 29 patients (94%) improved symptoms were demonstrated postoperatively. In terms of functional prognosis, the preoperative duration of symptoms was significantly shorter in the group of patients with excellent outcomes than in those with fair outcomes (p < 0.05). No significant difference was observed in the correlation between other factors. To evaluate the degree of preoperative thoracic stenosis and the severity/extent of OLF-induced spinal compression, we used an original OLF CT scoring system. A score of excellent on the CT scale tended to indicate an excellent prognosis (p < 0.01). Thoracic OLF frequently develops in the lower-thoracic spine in middle-aged men, and it is complicated by various spinal lesions in many cases. Early diagnosis and treatment are important for understanding the clinical symptoms and imaging diagnosis because the present findings suggest that a delay in diagnosis and treatment correlates with the functional prognosis postoperatively.


Recurrent pancreatic pseudocyst diagnosed 9 years after initial surgical drainage.
A pancreatic pseudocyst is defined as a collection of pancreatic juice enclosed by a wall of fibrous or granulation tissue which is not lined by epithelium. Acute pseudocysts occur in acute pancreatitis but can be found after an acute exacerbation of chronic pancreatitis. Chronic pancreatic pseudocysts are typically found in chronic pancreatitis but may develop after an occurrence of acute pancreatitis as well. Most acute fluid collections and pseudocysts will show spontaneous resolution while the remaining may persist with or without symptoms, or progress to produce complications. Treatment is indicated for persistent, symptomatic pseudocysts and, in the case of complications. There is no clear consensus regarding the optimal clinical or radiologic follow-up after treatment. Detection of late recurrence is not common, and the possibility of a cystic neoplasm must be ruled out. We report the case of a 67-year-old female patient who was referred to our institution as the result of a pancreatic pseudocyst. The patient had presented a pancreatic pseudocyst 9 years earlier which had been surgically treated by a cystogastrostomy. No additional acute pancreatic episodes occurred. The diagnostic and treatment approach of this unusual late recurrent pancreatic pseudocyst is herein described. The unusual late presentation of a recurrent pancreatic pseudocyst requires clinical, laboratory and radiological evaluation. In the present case, the clinical background, amylase fluid levels and tomographic findings were highly suggestive of a pancreatic pseudocyst.


Identification and characterization of novel lysine-independent apolipoprotein(a)-binding sites in fibrin(ogen) alphaC-domains.
Accumulation of lipoprotein(a) (Lp(a)) in atherosclerotic plaques is mediated through interaction of fibrin-(ogen) deposits with the apolipoprotein(a) (apo(a)) moiety of Lp(a). It was suggested that because apo(a) competes with plasminogen for binding to fibrin, causing inhibition of fibrinolysis, it could also promote atherothrombosis. Because the fibrin(ogen) alphaC-domains bind plasminogen and tissue-type plasminogen activator with high affinity in a Lys-dependent manner, we hypothesized that they could also bind apo(a). To test this hypothesis, we studied the interaction between the recombinant apo(a) A10 isoform and the recombinant alphaC-fragment (Aalpha-(221-610)) corresponding to the alphaC-domain by enzyme-linked immunosorbent assay and surface plasmon resonance. Both methods revealed a high affinity interaction (Kd = 19-21 nm) between the immobilized alphaC-fragment and apo(a), indicating that the former contains an apo(a)-binding site. This affinity was comparable to that of apo(a) for fibrin. At the same time, no interaction was observed between soluble fibrinogen and immobilized apo(a), suggesting that, in the former, this and other apo(a)-binding sites are cryptic. Further experiments with truncated recombinant variants of the alphaC-fragment allowed localization of the apo(a)-binding site to the Aalpha-(392-610) region. The presence of epsilon-aminocaproic acid only slightly inhibited binding of apo(a) to the alphaC-fragment, indicating the Lys-independent nature of their interaction. In agreement, the influence of plasminogen or tissue-type plasminogen activator on binding of apo(a) to the alphaC-fragment was minimal. These results indicate that the alphaC-domains contain novel high affinity apo(a)-binding sites that may provide a Lys-independent mechanism for bringing Lp(a) to places of fibrin deposition such as injured vessels or atherosclerotic lesions.


Changing attitudes about the employability of the deaf and hard of hearing.
Hearing students viewed a videotape featuring positive deaf and hard of hearing role models in a variety of employment settings. Attitudes about the employability of these individuals were measured in a pretest posttest control group design. Attitudes after viewing the role model videotape were significantly more positive than those reported prior to viewing the videotape. Respondents were able to generalize their positive attitudes beyond the limited number of occupations featured in the tape to other occupations. Further, the attitude change was of an enduring nature, with posttest two results indicating no significant attitude change from posttest one attitudes. The findings of the present study indicate that video-tape can be an effective means of introducing positive deaf and hard of hearing role models in both educational and employment settings.


Cardioselectivity of alpha-tocopherol analogues, with free radical scavenger activity, in the rat.
MDL74270 (6-acetyloxy-3,4-dihydro-N,N,N,2,5,7, 8-heptamethyl-2H-1-benzopyran-2-ethanaminium, 4-methylbenzenesulfonate) is a quaternary amine analogue of alpha-tocopherol with free radical scavenger properties. Rats were injected iv with [14C]MDL74270 (0.91 mg/kg), and whole blood and heart tissue were sampled. Five min after drug, the heart tissue/blood ratio (T/B) of radioactivity was 3.5, whereas at 1 hr it was 20.1 and remained at this value up to at least 6 hr. After iv administration the t 1/2 of radioactivity in blood was 6.3 hr, but po blood levels could not be quantified. The 0- to 96-hr urinary elimination of radioactivity was 39.9 +/- 5.7% of the dose after iv and only 1.2 +/- 0.4% after po administration, conversely, 44.7 +/- 5.2% was excreted in feces after iv and 79.1 +/- 17.4% after po administration. These results confirmed poor oral absorption of the compound. Tissue distribution of [14C]MDL74270 was compared with that of its tertiary amine analogue [14C]MDL74366 in rat heart, skeletal muscle, brain, and whole blood, after iv administration (1 mg/kg). The heart T/B was above 20, 1-6 hr after [14C]MDL74270, whereas it was less than 2 after [14C]MDL74366. Over the 1- to 6-hr time interval, skeletal muscle T/B varied from 1.8 to 5 compared with 1.5 to 0.6 for [14C] MDL74366. Brain T/B was higher after the tertiary amine compound. Results showed marked cardioselectivity of radioactivity after [14C] MDL74270. Differential centrifugation of heart homogenates showed that radioactivity was equally distributed between the major subcellular fractions studied.(ABSTRACT TRUNCATED AT 250 WORDS)


Parental favoritism in a wild bird population.
In most taxa with altricial young, offspring solicit food from their parents using a combination of visual and acoustic stimuli, but exactly what these young are communicating, and how selection shapes parental responses, remains unresolved. Theory posits that parents' interpretation and response to begging should vary with the likelihood of a return on their investment. We tested this in a wild population of prothonotary warblers (Protonotaria citrea), predicting that parents bias food non-randomly toward certain individuals within their broods depending on both the size and number of offspring. We observed parent-offspring interactions and detected strong dependence between brood size and nestling size in shaping parental responses to begging. Larger siblings were less likely to solicit food during feeding events than their smaller siblings, but they received a disproportionate share from parents in nests containing fewer-than-average young, whereas the smaller-than-average nestlings were disproportionately fed in broods containing a greater-than-average number of young. These findings suggest that parents respond to begging signals according to multiple social cues, favoring the stronger siblings with greater survival prospects when few copies of their genes are present, but overtly favoring runts to ensure whole-brood survival when capable of fledging more young. Future experimental studies may shed light on the contributions of parental decision-making and memory, how young nestlings learn in parent-offspring communication systems, and the adaptive significance of these behaviors.


Zinc status of women with low bone mineral density who receive calcium supplements.
We evaluated whether a daily high-dose calcium supplement perturbs the zinc status in 23 postmenopausal women (mean age: 63 yr) with low bone mineral density. Plasma and erythrocyte zinc concentrations, plasma bone-specific alkaline phosphatase (BSAP) and 5'-nucleotidase activities, and urinary zinc and calcium excretion were determined first at the end of 4 wk of daily oral calcium (1200 mg) and were measured again at the end of the subsequent 4 wk of daily cosupplementation with calcium (1200 mg) and zinc (30 mg). Mean plasma and erythrocyte zinc concentrations after 4 wk of calcium alone were not significantly different from concentrations after cosupplementation of calcium and zinc. Mean plasma BSAP activities before cosupplementation with zinc was significantly higher than that after zinc (p < 0.02), whereas plasma 5'-nucleotidase activities were not affected by zinc supplementation. Urinary zinc excretion slightly, but significantly, increased after the supplementation of zinc (p < 0.05), whereas calcium excretion remained similar. Our data indicate that a 4-wk zinc supplementation did not significantly improve zinc status. Although limited by the small sample size and short study duration, our data suggest that a daily calcium dose of 1200 mg had no effect on the zinc status of our subjects.


Hospital Characteristics by Proportion of Patients from Disadvantaged Neighborhoods.
Neighborhood disadvantage reflects historic and ongoing systemic injustices. Without addressing these upstream social determinants of health, hospitals may face different risk profiles for important quality metrics. Our objective was to assess differences in hospital characteristics where the proportion of patients residing in severely disadvantaged neighborhoods was high vs low. Using Medicare fee-for-service claims between January 1, 2014 and November 30, 2014 (5,807,499 hospital stays), we calculated Area Disadvantage Share (ADS), the proportion of each hospital's discharges to severely disadvantaged neighborhoods, for 4,528 hospitals. We examined hospital characteristics by distribution of ADS and by risk-adjusted 30-day readmission. Hospitals in the highest decile cared for a higher proportion of Black patients, were more often located in rural areas, and had higher patient risk of 30-day readmission compared to all other deciles. Hospitals face unequal burdens of neighborhood disadvantage, a factor distinct from other social determinants such as rurality.


Differential CD28 and inducible costimulatory molecule signaling requirements for protective CD4+ T-cell-mediated immunity against genital tract Chlamydia trachomatis infection.
Th1 cells and gamma interferon (IFN-gamma) production play critical roles in protective immunity against genital tract infections by Chlamydia trachomatis. Here we show that inducible costimulatory molecule (ICOS)(-/-) mice develop greatly augmented host resistance against chlamydial infection. Protection following a primary infection was characterized by strong Th1 immunity with enhanced CD4(+) T-cell-mediated IFN-gamma production in the genital tract and high expression of T-bet in the draining para-aortic lymph node. This Th1 dominance was associated with low expression of interleukin 10 (IL-10) mRNA in the uteruses of protected ICOS(-/-) mice. By contrast, CD28(-/-) mice were severely impaired in their adaptive immune response, demonstrating a lack of CD4(+) T cells and IFN-gamma in the genital tract, with a substantial delay in bacterial elimination compared to that seen in wild-type (WT) mice. Upon reinfection, WT mice exhibited a transient local infection with evidence of regulatory T-cell (Treg)/Foxp3 mRNA and a more balanced Th1 and Th2 response in the genital tract than ICOS(-/-) mice, whereas 90% of the latter mice developed sterile immunity, poor expression of local Treg/Foxp3 mRNA, and macroscopic signs of enhanced local immunopathology. Therefore, different requirements for CD28 signaling and ICOS signaling clearly apply to host protection against a genital tract infection by C. trachomatis. Whereas, CD28 signaling is critical, ICOS appears to be dispensable and can have a dampening effect on Th1 development by driving Th2 immunity and anti-inflammation through IL-10 production and promotion of the Foxp3(+) Treg populations in the genital tract. Both the CD28-deficient and the ICOS-deficient mice demonstrated poor specific antibody production, supporting the fact that antibodies are not needed for protection against genital tract chlamydial infections.


Space-frequency localized image compression.
Subband and wavelet-based image compression can be viewed as frequency oriented techniques because each subimage in the decomposition is essentially a band-pass version of the original image. The authors suggest a space-frequency partition scheme to fully exploit the excellent localization properties of wavelets in both the spatial and frequency domains. Due to the relatively large number of blocks in this partition compared with traditional subband coders, the rate required for communicating the quantizer configurations must be taken into account. An iterative bit allocation algorithm is suggested that minimizes the mean square error given the overall rate for specifying the quantization configuration and for quantizing the wavelet coefficients. Images encoded using scalar quantization under this scheme show improvements in PSNR versus rate over traditional subband and wavelet-based methods.


Regenerative therapy and cancer: in vitro and in vivo studies of the interaction between adipose-derived stem cells and breast cancer cells from clinical isolates.
Adipose-derived stem cells (ASCs) have been proposed to stabilize autologous fat grafts for regenerative therapy, but their safety is unknown in the setting of reconstructive surgery after mastectomy. Both bone marrow mesenchymal stem cells (MSCs) and ASC have been shown to enhance tumorigenesis of established breast cancer cell lines, but primary patient material has not been tested. Here, we ask whether ASC promote the in vitro growth and in vivo tumorigenesis of metastatic breast cancer clinical isolates. Metastatic pleural effusion (MPE) cells were used for coculture experiments. ASC enhanced the proliferation of MPE cells in vitro (5.1-fold). For xenograft experiments (100 sorted cells/injection site), nonhematopoietic MPE cells were sorted into resting and active populations: CD90+ resting (low scatter, 2.1%≥2N DNA), CD90+ active (high scatter, 10.6%≥2N DNA), and CD90-. Resting CD90+ MPE cells were tumorigenic in 4/40 sites but growth was not augmented by ASC. Active CD90+ MPE cells were tumorigenic (17/40 sites) only when coinjected with ASC (p=0.0005, χ2 test). The multilineage potentiality and MSC-like immunophenotype of ASC were confirmed by flow cytometry, differentiation cultures, and immunostaining. The secretome profile of ASC resembled that reported for MSC, but included adipose-associated adipsin and the hormone leptin, shown to promote breast cancer growth. Our data indicate that ASC enhance the growth of active, but not resting tumor cells. Thus, reconstructive therapy utilizing ASC-augmented whole fat should be postponed until there is no evidence of active disease.


To Wnt or Lose: The Missing Non-Coding Linc in Colorectal Cancer.
Colorectal cancer (CRC) is the third most frequent cancer and one of the leading causes for cancer-related mortality. Aberrant activation of the Wnt signaling is an essential initiating factor in colon carcinogenesis, and a driving force of CRC progression. Recently, long non-coding RNAs (lncRNAs) have emerged as significant players in CRC pathogenesis through diversified mechanisms. Although both Wnt signaling and lncRNAs represent interesting research areas for CRC, an effort of directly connecting these two areas is lacking. To fill in the knowledge gap, we focus on the reported findings of lncRNAs that regulate Wnt signaling or essential Wnt signaling targets. These include several newly discovered lncRNAs originated from the amplified cancer-associated chromosome 8q24 region that surrounds the essential Wnt target MYC gene, lncRNAs reported to be involved in CRC stem cells, and several individual lncRNAs connected to Wnt signaling through other mechanisms. This review will provide essential information that assists in understanding the missing link of lncRNAs to the classical Wnt signaling in CRC.


[Changes in the intragastric vessels after a chemical burn].
The functional and morphological studies have proved that some considerable vascular changes occur in the injured stomach wall within the first hours after a superficial chemical burn. The most gross injuries in the arterial, venous and capillary network of the mucous occur 24 hours after the contamination with a corrosion substance. Regenerative processes in the vascular system together with functional improvement start after 3 days. Normalization of the circulation in the injured stomach wall comes about after 14 days.


Knowledge of journal impact factors among nursing faculty: a cross-sectional study.
The research assessed nursing faculty awareness and knowledge of the journal impact factor (JIF) and its impact on their publication choices. A qualitative cross-sectional questionnaire was developed using Fluid Survey and distributed electronically to nursing faculty and instructors at three post-secondary institutions in Saskatchewan. Data were collected on place and status of employment, knowledge and awareness of JIFs, and criteria used to choose journals for publication. A total of forty-four nursing faculty and instructors completed the questionnaire. The authors found that faculty lack awareness or complete understanding of JIFs and that JIFs are not the most important or only criterion used when they choose a journal for publication. There are various reasons for choosing a journal for publication. It is important for librarians to understand faculty views of JIFs and their criteria for choosing journals for publication, so that librarians are better equipped to guide researchers in considering their academic goals, needs, and personal values.


Opinions of Portuguese Veterinarians on Telemedicine-A Policy Delphi Study.
Telemedicine has only received limited attention by veterinary professional regulatory bodies, particularly in Europe. In Portugal, telemedicine is currently outside what is considered acceptable practice by the regulator, the Portuguese Veterinary Order (Ordem dos Médicos Veterinários). As part of a wider research aimed at gathering evidence for developing a new veterinary Code of Professional Conduct, this study describes the use of the Policy Delphi technique to gather the views and perceptions of a purposeful sample of 41 Portuguese veterinarians regarding telemedicine. Four main issues were addressed using mixed research methods: teleconsultation, teleconsulting, teleadvice, and the regulator's role. Responses highlight participants' perception of both the relevance of medical digital technologies in improving healthcare and their limitations. Overall opinion was that, although restrictions to remote veterinary practice should be reduced, improved guidance and regulation are warranted. Eighty percent of participants considered that limits to the use of veterinary telemedicine should be imposed and two thirds considered that a remote consultation must always be preceded by a face-to-face consultation. While most respondents thought that vet-to-vet teleconsulting using social media (namely Facebook) should not be banned, 83% recognized that it should be regulated by ethical standards. Participants' concerns with telemedicine had mostly to do with reputational risk for the veterinary profession, while overlooking privacy or confidentiality issues. A consultative group should be established to ensure that telemedicine providers comply with professional requirements. It is expected that these results will support policy-making by the Portuguese Veterinary Order and by veterinary regulators at other jurisdictions.


Kinetic equation of linear fractional stable motion and applications to modeling the scaling of intermittent bursts.
Lévy flights and fractional Brownian motion have become exemplars of the heavy-tailed jumps and long-ranged memory widely seen in physics. Natural time series frequently combine both effects, and linear fractional stable motion (lfsm) is a model process of this type, combining alpha-stable jumps with a memory kernel. In contrast complex physical spatiotemporal diffusion processes where both the above effects compete have for many years been modeled using the fully fractional kinetic equation for the continuous-time random walk (CTRW), with power laws in the probability density functions of both jump size and waiting time. We derive the analogous kinetic equation for lfsm and show that it has a diffusion coefficient with a power law in time rather than having a fractional time derivative like the CTRW. We discuss some preliminary results on the scaling of burst "sizes" and "durations" in lfsm time series, with applications to modeling existing observations in space physics and elsewhere.


Characterization and cholesterol management in patients with cardiovascular events and/or type 2 diabetes in the Netherlands.
To describe clinical characteristics and cholesterol management of patients with cardiovascular events (CVEs) and/or type 2 diabetes mellitus (T2DM) with high low-density lipoprotein cholesterol (LDL-C) > 1.8 mmol/L in the Netherlands. From the PHARMO Database Network a cross-sectional cohort was constructed. The descriptive study included patients on lipid modifying therapy (LMT) in 2009, classified as high cardiovascular risk based on a history of T2DM or CVE, with 2010 LDL-C levels above 1.8 mmol/L (2011 European Society of Cardiology [ESC] target). Sub-cohorts were created: T2DM + CVE from the T2DM cohort and multiple CVE from the CVE only cohort. Clinical characteristics and drug treatment were determined at the time of the last LDL-C measurement in 2010. Of 10,864 very high risk patients, 66% had T2DM, 37% of whom also had CVE. In the CVE only cohort (34%), 18% had multiple events. More regular check-ups skewed inclusion towards diabetes patients. T2DM vs. CVE cohort characteristics were: 53% vs. 63% male, 42% vs. 27% obese, 19% vs. 24% current smoker, 54% vs. 51% systolic blood pressure <140 mmHg, with similar proportions in the sub-cohorts. Proportions reaching the Dutch guideline LDL-C target of <2.5 mmol/L were 56% (T2DM), 57% (T2DM + CVE), 48% (CVE only) and 53% (multiple CVE only). Frequencies of high intensity dose statin (simvastatin ≥80 mg, atorvastatin ≥40 mg or rosuvastatin ≥20 mg) were 6% (T2DM), 9% (T2DM + CVE, CVE only) and 14% (multiple CVE only); 1-2% received additional ezetimibe and 3-5% received non-statin LMT only, including ezetimibe. Despite LMT, >40% of the patients above ESC target also failed to reach the less stringent Dutch target, even in the higher risk groups. Therefore, management of hypercholesterolemia after CVE or T2DM should be optimized to improve cardiovascular outcomes. There is substantial room for improving other cardiovascular risk factors.


[Safety and immunogenecity of a vaccine of polyssacharide Vi from Salmonella typhi in Cuban youths].
A randomized, controlled and double-blind study was conducted in young adults aged 18-20 aimed at evaluating the reactogenecity and immunogenecity of vaz-TyVi, a vaccine of polyssacharide Vi from Salmonella typhi. They were distributed into 3 groups: immunized with a dose of Vax-TyVi (Finlay Institute), TYPHIM Vi (Pasteur-Mérieux) or vax-TET (tetanic toxoid). Serum samples were taken before and 21 days after immunization. The immunogenecity was evaluated in 323 volunteers by an indirect ELISA. The seroconversion of those receiving vax-TyVi was 81.97% and 65.05 % for TYPHIM Vi. The postvaccine mean geometric titers were 7.41 U/mL (5.92-9.27 U/mL) and 5.41 U/mL (4.35-6.72 U/mL), respectively. The seroconversion with vax-TET was 0%. The reactogenecity of both polysaccharide vaccines was low. It was concluded that the immunogenecity of vax-TyVi was not lower than that of TYPHIM Vi and that its reactogenecity was similar.


The Anaphase-Promoting Complex (APC) ubiquitin ligase regulates GABA transmission at the C. elegans neuromuscular junction.
Regulation of both excitatory and inhibitory synaptic transmission is critical for proper nervous system function. Aberrant synaptic signaling, including altered excitatory to inhibitory balance, is observed in numerous neurological diseases. The ubiquitin enzyme system controls the abundance of many synaptic proteins and thus plays a key role in regulating synaptic transmission. The Anaphase-Promoting Complex (APC) is a multi-subunit ubiquitin ligase that was originally discovered as a key regulator of protein turnover during the cell cycle. More recently, the APC has been shown to function in postmitotic neurons, where it regulates diverse processes such as synapse development and synaptic transmission at glutamatergic synapses. Here we report that the APC regulates synaptic GABA signaling by acting in motor neurons to control the balance of excitatory (acetylcholine) to inhibitory (GABA) transmission at the Caenorhabditis elegans neuromuscular junction (NMJ). Loss-of-function mutants in multiple APC subunits have increased muscle excitation at the NMJ; this phenotype is rescued by expression of the missing subunit in GABA neurons. Quantitative imaging and electrophysiological analyses indicate that APC mutants have decreased GABA release but normal cholinergic transmission. Consistent with this, APC mutants exhibit convulsions in a seizure assay sensitive to reductions in GABA signaling. Previous studies in other systems showed that the APC can negatively regulate the levels of the active zone protein SYD-2 Liprin-α. Similarly, we found that SYD-2 accumulates in APC mutants at GABAergic presynaptic sites. Finally, we found that the APC subunit EMB-27 CDC16 can localize to presynapses in GABA neurons. Together, our data suggest a model in which the APC acts at GABAergic presynapses to promote GABA release and inhibit muscle excitation. These findings are the first evidence that the APC regulates transmission at inhibitory synapses and have implications for understanding nervous system pathologies, such as epilepsy, that are characterized by misregulated GABA signaling.


Di-(2-ethylhexyl)phthalate and deep venous thrombosis in children: a clinical and experimental analysis.
Five children with catheter-related deep venous thrombosis were encountered in our PICU. Three types of polyvinyl chloride tubing for the administration of intravenous solutions were in use (Terumo, Codan, and Perfusend). All were di-(2-ethylhexyl)phthalate plasticized. We suspected problems with the Codan tubing. Different types of tubing at different time intervals in vitro were investigated. Tubing segments were assessed on structural alterations by surface electron microscopy. High-performance liquid chromatography-diode array detection and liquid chromatography-mass spectrometry-diode array detection were performed to identify and to quantify di-(2-ethylhexyl)phthalate. The hospital's minimal clinical data set (coded with the International Classification of Diseases, Ninth Revision, Clinical Modification) was investigated on catheter-related deep venous thrombosis between 2000 and 2004. Surface electron microscopy demonstrated that the Codan tubing's inner surface was severely altered, showing large particles (34.5 +/- 6.1 microm). High-performance liquid chromatography documented that all Codan samples showed a peak at the di-(2-ethylhexyl)phthalate retention time. The analysis of the minimal clinical data set for total catheter-related deep venous thrombosis showed an unusual high incidence in 2001 (52) compared with the expected 36 per year. Such occurrence of catheter-related deep venous thrombosis led to the assumption that disintegration of intravenous tubing resulted in intravenous administration of debris. Our data suggested that the particles derived from the tubing are of such size that they might induce catheter-related deep venous thrombosis. The absence of catheter-related deep venous thrombosis caused by the introduction of submicron inline filters outlines the important pathophysiological role of di-(2-ethylhexyl)phthalate-plasticized particles in the onset of catheter-related deep venous thrombosis. Our data indicate that a considerable number of patients might have been exposed to di-(2-ethylhexyl)phthalate, and a major concern is whether this jeopardized the health of the patients at that time.


[The polymorphism of genes of synthesis and metabolism of estrogens and the risk of breast cancer].
The genetic polymorphism of enzymes of synthesis and metabolism of estrogens can input into predisposition to breast cancer. The purpose of actual study was to analyze the associations of polymorphic loci CYP17/B1rs10556836, CYP1A 1rs1048943, CYP1A2rs762551, CYP19A1rs2470152 and CYP17A1rs743572 with risk of development of breast cancer in Russian residents of the Western-Siberian region of Russia. The rates of alleles and genotypes of the given loci were determined in sampling of women suffering with breast cancer (n = 670 females) and in control group (480 females without oncological diseases). The sub-groups of patients with breast cancer in pre-menopause--and post-menopause were analyzed separately. The border-line association of locus CYP17A1rs743572 is demonstrated with increasing of risk of breast cancer during pre-menopause (allele C: p = 0.04). Among the rest of polymorphic loci no association was detected.


In Situ Measurement of the Plane-Strain Modulus of the Solid Electrolyte Interphase on Lithium-Metal Anodes in Ionic Liquid Electrolytes.
We present an experimental approach for in situ measurement of elastic modulus of the solid electrolyte interphase (SEI), which is formed from reactions between a lithium thin-film [on a polydimethylsiloxane (PDMS) substrate] and a room-temperature ionic liquid (RTIL) electrolyte. The SEI forms under a state of compressive stress, which causes buckling of the sample surface. In situ atomic force microscopy is used to measure the dominant wavelength of the wrinkled surface topography. A mechanics analysis of strain-induced elastic buckling instability of a stiff thin film on a soft substrate is used to determine the plane strain modulus of the SEI from the measured wavelength. The measurements are performed for three RTIL electrolytes: 1-butyl 1-methylpiperidinium bis(trifluoromethylsulfonyl)imide (P14 TFSI) without any lithium salt, 1.0 M lithium bis(trifluoromethylsulfonyl)imide (Li TFSI) in P14 TFSI, and 1.0 M lithium bis(fluorosulfonyl)imide (Li FSI) in P14 TFSI to investigate the influence of lithium salts on the plane strain modulus of the SEI. The measurements yield plane-strain moduli of approximately 1.3 GPa for no-salt P14 TFSI and approximately 1.6 GPa for 1.0 M Li TFSI in P14 TFSI and 1.0 M Li FSI in P14 TFSI. The experimental technique presented here eliminates some of the uncertainties associated with traditional SEI mechanical characterization approaches and offers a platform to engineer an SEI with desired mechanical properties by approaches that include altering the electrolyte composition.


Trauma during pregnancy. A review of 79 cases.
Few studies provide data on pregnant trauma patients that can be used to direct management decisions. Therefore, this retrospective study of 79 pregnant patients who were injured and admitted to a trauma center during a 9-year period was conducted to obtain such information. Maternal mortality for these pregnant patients was 10%, which was not different from that for nonpregnant females. Overall, rate of fetal loss was 34%. Rates of fetal loss were not different in patients with and without evidence of shock and/or hypoxia or in restrained and unrestrained automobile occupants. Diagnostic peritoneal lavage proved to be 95% accurate and safe. Based on these findings, we concluded the following: pregnancy does not increase maternal mortality from trauma. Blood pressure, pulse rate, and PO2 are unreliable indicators of adequate maternal resuscitation and fetal well-being. Assumption of maternal and fetal stability based solely on these usually standard criteria is unwise. Use of seat belts during pregnancy is advisable in the absence of evidence that restraints increase the rate of fetal loss.


Z2 topological edge state in honeycomb lattice of coupled resonant optical waveguides with a flat band.
Two-dimensional (2D) coupled resonant optical waveguide (CROW), exhibiting topological edge states, provides an efficient platform for designing integrated topological photonic devices. In this paper, we propose an experimentally feasible design of 2D honeycomb CROW photonic structure. The characteristic optical system possesses two-fold and three-fold Dirac points at different positions in the Brillouin zone. The effective gauge fields implemented by the intrinsic pseudo-spin-orbit interaction open up topologically nontrivial bandgaps through the Dirac points. Spatial lattice geometries allow destructive wave interference, leading to a dispersionless, near-flat energy band in the vicinity of the three-fold Dirac point in the telecommunication frequency regime. This nontrivial structure with a near-flat band yields topologically protected edge states. These characteristics underpin the fundamental importance as well as the potential applications in various optical devices. Based on the honeycomb CROW lattice, we design the shape-independent topological cavity and the beam splitter, which demonstrate the relevance for a wide range of photonic applications.