A new titanosaur sauropod from the Late Cretaceous of Brazil.
A new titanosaur dinosaur, Brasilotitan nemophagus gen. et sp. nov., is described from the Adamantina Formation (Turonian-Santonian, Bauru Basin). The specimen consists of a dentary, cervical and sacral vertebrae, one ungual and remains of the pelvic region, that were collected near Presidente Prudente city, Sdo Paulo State. It shows a mandible with an 'L' shaped morphology, with the symphyseal region of the dentary slightly twisted medially, a feature never recorded before in a titanosaur. Brasilotitan nemophagus can be further separated from other members of this clade by: (1) the dorsal portion of the dentary symphyseal contact is broader anteroposteriorly than the ventral part; (2) the ventral portion of the cervical centrum is arched dorsally; (3) the presence of an anteriorly directed accessory prezygapophyseal articulation surface on the cervical vertebrae; (4) the intraprezygapophyseal laminae of the cervical vertebrae are 'V' shaped in dorsal view; and other features. Although the phylogenetic position of Brasilotitan nemophagus is difficult to establish, the new species is neither a basal nor a derived member of the Titanosauria and, based on the lower jaw morphology, appears to be closely related to Antarctosaurus wichmannianus and Bonitasaura salgadoi. This discovery enriches the titanosaur diversity of Brazil and further provides new anatomical information on the lower jaws of those herbivorous dinosaurs.


Dietary patterns and hypertension among Chinese adults: a nationally representative cross-sectional study.
Several healthful dietary patterns appear to be effective at lowering blood pressure and preventing hypertension. However, the relationship between dietary patterns and hypertension among a representative Chinese population sample is unclear. A nationally representative sample of 23 671 participants aged 18-59 years were recruited by the 2002 China National Nutrition and Health Survey. All participants had their blood pressure measured with standardized mercury sphygmomanometers. Hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. We conducted factor analysis using dietary information from a validated food frequency questionnaire to derive dietary patterns. Information of participants on physical activities, education level, annual household income, smoking status and family history of hypertension was collected by interviewer-administrated questionnaires. Three major dietary patterns, defined as 'Western', 'traditional northern', and 'traditional southern', were identified. Participants with the highest quartile for the score of the Western pattern had significantly higher blood pressure comparing with counterparts in the lowest quartile. In contrast, participants in the top quartile for the score of the traditional southern pattern presented significantly lower blood pressure comparing with counterparts in the lowest quartile. In multivariate analyses the traditional northern pattern score was associated with an odds ratio (OR) of 1.30 (95% confidence interval (CI) 1.11-1.53, P for trend = 0.0001) comparing with the lowest quartile. The OR for the top quartile of score for the traditional southern pattern was 0.73 (95% CI, 0.59-0.89, P for trend = 0.0040) compared with the lowest quartile of traditional southern pattern score. However, the significant association between the traditional northern pattern and prevalence of hypertension disappeared after further adjusting for body mass index (BMI) (P for trend = 0.3), whereas the association between the traditional southern pattern and prevalence of hypertension persisted after further adjusting for BMI (P for trend = 0.01). We observed a positive relationship between the traditional northern pattern and hypertension that was mediated through differences in BMI. In addition, the traditional southern pattern was significantly associated with lower odds of presenting with hypertension.


Use of an Industrial Tungsten Carbide Drill in the Treatment of a Complex Fracture in a Patient with Severe Osteopetrosis: A Case Report.
The treatment of fractures in osteopetrosis can be complicated and difficult. We describe the use of an industrial grade tungsten carbide drill bit in the treatment of one of these complex fractures. An industrial grade tungsten carbide drill bit was used to fashion a medullary canal in the surgical treatment of a left peri-implant fracture of the neck of femur in a patient with osteopetrosis. The patient was successfully treated with a hemiarthroplasty with good functional outcomes. A tungsten carbide drill bit serves as an effective and safe option in the treatment of osteopetrotic femoral neck fractures.


Diabetic and Elder Patients Experience Superior Cardiovascular Benefits After Gastric Bypass Induced Weight Loss.
Background/Objetives: Obesity and obesity related co-morbidities are well-recognized risks for cardiovascular (CV) disease and mortality. Weight loss improves CV risk factors and the efficacy of bariatric surgery in decreasing CV mortality is now well-established. Our aim was to assess CV risk progression and occurrence of CV events in a cohort of patients that underwent Roux-en-Y gastric bypass (RYGB) for obesity treatment in a single academic public center. Subjects and Methods: Ten year CV risk was estimated using the Framingham Equation at baseline and 2 years after RYGB surgery in our patients cohort (n = 260). In the subgroup with a follow-up time longer than 4 years after surgery (n = 185; mean 5.4 ± 0.1 years), CV risk adjusted for the time length after RYGB was similarly estimated and the occurrence of CV events for outcome adjudication was monitored during the same time period by reviewing the hospital patients' record, the electronic national health system patient register and our center outpatient clinic records. Results: Ten year CV risk was significantly reduced 2 years after surgery when compared to baseline, with reductions of 1.65 ± 0.25% in the risk of CV disease. Patients with prior type 2 diabetes and aged 50 years or older experienced a significantly superior CV risk reduction, with diabetic patients experiencing a reduction of their 10-year CV disease risk of 3.58 ± 1.11% vs. a reduction of 1.31 ± 0.20% in non-diabetic patients and with the 10-year risk of CV disease dropping 3.41 ± 0.75% in patients older than 50 vs. a reduction of 0.99 ± 0.18 in patients up to 50 years. For the subgroup of patients with a longer follow-up time, baseline CV risk estimation predicted the occurrence of 6.08 ± 0.56 cardiovascular disease (CVD) events, 3.87 ± 0.39 coronary heart disease (CHD) events, 1.49 ± 0.22 myocardial infarctions (MI), 0.71 ± 0.09 strokes, 0. 28 ± 0.05 deaths from CHD and 0.35 ± 0.05 deaths from CVD. No CV events were adjudicated in this subgroup during follow-up. Conclusions: RYGB significantly improves CV risk and prevents the occurrence of CV events. For similar weight loss, diabetic and elder patients experience a superior CV risk improvement and may have additional CV benefits after bariatric surgery.


Glucagon and the circulation.
Glucagon is a vasodilator substance that reduces blood pressure via a decreased vascular resistance in the splanchnic and hepatic vasculature. Species differences in the response of various vascular beds to glucagon have been documented. In the kidney, glucagon in relatively large doses increased renal plasma flow, glomerular filtration, and electrolyte excretion. It has been shown that intraarterial injection of glucagon into the renal artery can produce an increase in electrolyte excretion on the side that received an injection with minimal or no changes in glomerular filtration. This indicated a direct tubular effect of this polypeptide. This effect may be related to the increased glomerular filtration observed in poorly controlled diabetics where insulin concentrations are low and glucagon concentrations are high. The tubular effects of glucagon are probably mediated via cAMP and prostaglandin formation in renal tubular cells, especially the ascending limbs of Henle and collecting ducts. Glucagon increases the RNA concentration in glomerular tissue, and this effect is probably independent of cAMP. The latter effect of glucagon has been related to the glomerular enlargement and membrane thickening observed in poorly controlled insulin-dependent diabetics. Starvation natriuresis has been related to increased concentrations of glucagon in blood. The likely mechanism is that glucagon increased the renal excretion of organic acids, possibly by inhibiting the renal tubular reabsorption of these acids. Little is known concerning the effects of glucagon on the cAMP content of vascular smooth muscle. Indirect evidence suggests that such effects may be mediated via the production of cAMP. If this can be established, it would be likely that the glucagon-induced vasodilation is due to a cAMP-dependent phosphorylation of the myosin light chain kinase. This kinase shows reduced sensitivity to the Ca++ calmodulin complex when it is phosphorylated by the cAMP-dependent kinase and thus may produce relaxation of smooth muscle. In cardiac muscle, glucagon produced positive inotropic and chronotropic effects. These effects show species differences and in some species activate only the auricle with minimal effects of ventricular muscle. The effects of glucagon in general resemble those of a beta-adrenergic agent; however, glucagon seems to be nonarrhythmogenic in a variety of cardiac preparations and its effects are not blocked by propranolol. In some of these experimental conditions the chronotropic effects of glucagon play an important role in the antiarrhythmogenic effects, although direct cardiac membrane effects have been postulated. Several factors can modify the


Peptide receptor radionuclide therapy using radiolabeled somatostatin analogs: focus on future developments.
Peptide receptor radionuclide therapy (PRRT) has been shown to be an effective treatment for neuroendocrine tumors (NETs) if curative surgery is not an option. A majority of NETs abundantly express somatostatin receptors. Consequently, following administration of somatostatin (SST) analogs labeled with γ-emitting radionuclides, these tumors can be imaged for diagnosis, staging or follow-up purposes. Furthermore, when β-emitting radionuclides are used, radiolabeled peptides (radiopeptides) can also be used for the treatment for NET patients. Even though excellent results have been achieved with PRRT, complete responses are still rare, which means that there is room for improvement. In this review, we highlight some of the directions currently under investigation in pilot clinical studies or in preclinical development to achieve this goal. Although randomized clinical trials are still lacking, early studies have shown that tumor response might be improved by application of other radionuclides, such as α-emitters or radionuclide combinations, or by adjustment of radiopeptide administration routes. Individualized dosimetry and better insight into tumor and normal organ radiation doses may allow adjustment of the amount of administered activity per cycle or the number of treatment cycles, resulting in more personalized treatment schedules. Other options include the application of novel (radiolabeled) SST analogs with improved tumor uptake and radionuclide retention time, or a combination of PRRT with other systemic therapies, such as chemotherapy or treatment with radio sensitizers. Though promising directions appear to bring improvements of PRRT within reach, additional research (including randomized clinical trials) is needed to achieve such improvements.


Estimating and exploring the proportions of inter- and intrastate cattle shipments in the United States.
Mathematical models are key tools for the development of surveillance, preparedness and response plans for the potential events of emerging and introduced foreign animal diseases. Creating these types of plans requires data; when data are incomplete, mathematical models can help fill in missing information, provided they are informed by the data that are available. In the United States, the most complete national-scale data available on cattle shipments are based on Interstate Certificates of Veterinary Inspection, which track the shipment of cattle between states; data on intrastate cattle shipments are lacking. Here we develop four new datasets on intrastate cattle shipments in the U.S., including an expert elicitation survey covering 19 states and territories and three state-level brand inspection data sets. The expert elicitation survey provides estimates on the proportion of shipments that travel interstate over multiple regions of the U.S. These survey data also identify differences in shipment patterns between regions, cattle commodity types, and sectors of the cattle industry. These survey data cover more states than any other source of intrastate data; however, one limitation of these data is the small number of participating experts in many of the states, only seven of the 19 responding states and territories had a group size of three or larger. The brand data sets include origin and destination information for both intra- and interstate shipments. These data, therefore, also provide detailed information on the proportion of interstate shipments in three Western states, including the temporal and geographic variation in shipments. Because the survey and brand data overlap in the Western U.S., they can be compared. We find that in the Western U.S. the expert estimates of the overall proportion of cattle shipments matched the brand data well. However, the experts estimated that there would be larger differences in beef and dairy shipments than the brand data show. This suggests the cattle industries in the West may be sending similar proportions of commodity specific cattle shipments over state lines. We additionally used the expert survey data to explore how differences in the proportion of interstate shipments can change predictions about cattle shipment patterns using the example of model-guided suggestions for targeted surveillance in Texas. Together these four data sets are the most extensive and geographically comprehensive information to date on intrastate cattle shipments. Additionally, our analyses on predicted shipment patterns suggest that assumptions about intrastate shipments could have consequences for targeted surveillance.


Flagellin/TLR5 signaling potentiates airway serous secretion from swine tracheal submucosal glands.
Airway serous secretion is essential for the maintenance of mucociliary transport in airway mucosa, which is responsible for the upregulation of mucosal immunity. Although there are many articles concerning the importance of Toll-like receptors (TLRs) in airway immune systems, the direct relationship between TLRs and airway serous secretion has not been well investigated. Here, we focused on whether TLR5 ligand flagellin, which is one of the components of Pseudomonas aeruginosa, is involved in the upregulation of airway serous secretion. Freshly isolated swine tracheal submucosal gland cells were prepared, and the standard patch-clamp technique was applied for measurements of the whole cell ionic responses of these cells. Flagellin showed potentiating effects on these oscillatory currents induced by physiologically relevant low doses of acetylcholine (ACh) in a dose-dependent manner. These potentiating effects were TLR5 dependent but TLR4 independent. Both nitric oxide (NO) synthase inhibitors and cGMP-dependent protein kinase (cGK) inhibitors abolished these flagellin-induced potentiating effects. Furthermore, TLR5 was abundantly expressed on tracheal submucosal glands. Flagellin/TLR5 signaling further accelerated the intracellular NO synthesis induced by ACh. These findings suggest that TLR5 takes part in the airway mucosal defense systems as a unique endogenous potentiator of airway serous secretions and that NO/cGMP/cGK signaling is involved in this rapid potentiation by TLR5 signaling.


Recombination and phenotype evolution dynamics of Helicobacter pylori in colonized hosts.
The ample genetic diversity and variability of Helicobater pylori, and therefore its phenotypic evolution, relate not only to frequent mutation and selection but also to intra-specific recombination. Webb and Blaser applied a mathematical model to distinguish the role of selection and mutation for Lewis antigen phenotype evolution during long-term gastric colonization in infected animal hosts (mice and gerbils). To investigate the role of recombination in Lewis antigen phenotype evolution, we have developed a prior population dynamic by adding recombination term to the model. We simulate and interpret the new model simulation's results with a comparative analysis of biological aspects. The main conclusions are as follows: (i) the models and consequently the hosts with higher recombination rate require a longer time for stabilization; and (ii) recombination and mutation have opposite effects on the size of H. pylori populations with phenotypes in the range of the most-fit ones (i.e. those that have a selective advantage) due to natural selection, although both can increase phenotypic diversity.


Simple detection of germline microsatellite instability for diagnosis of constitutional mismatch repair cancer syndrome.
Heterozygous mutations in DNA mismatch repair (MMR) genes result in predisposition to colorectal cancer (hereditary nonpolyposis colorectal cancer or Lynch syndrome). Patients with biallelic mutations in these genes, however, present earlier, with constitutional mismatch repair deficiency cancer syndrome (CMMRD), which is characterized by a spectrum of rare childhood malignancies and café-au-lait skin patches. The hallmark of MMR deficiency, microsatellite instability (MSI), is readily detectable in tumor DNA in Lynch syndrome, but is also present in constitutional DNA of CMMRD patients. However, detection of constitutional or germline MSI (gMSI) has hitherto relied on technically difficult assays that are not routinely applicable for clinical diagnosis. Consequently, we have developed a simple high-throughput screening methodology to detect gMSI in CMMRD patients based on the presence of stutter peaks flanking a dinucleotide repeat allele when amplified from patient blood DNA samples. Using the three different microsatellite markers, the gMSI ratio was determined in a cohort of normal individuals and 10 CMMRD patients, with biallelic germline mutations in PMS2 (seven patients), MSH2 (one patient), or MSH6 (two patients). Subjects with either PMS2 or MSH2 mutations were easily identified; however, this measure was not altered in patients with CMMRD due to MSH6 mutation.


[Effect of tryptophan on gluconeogenesis in the perfused liver of irradiated rats].
The liver isolated at different times after exposure to 7 Gy radiation responded in a different way to the effect of tryptophan (0.75 g/l) used as a gluconeogenesis inhibitor. While 24 h after irradiation the addition of tryptophan inhibited gluconeogenesis from circulating exogenous amino acids, in 3 days, on the contrary, gluconeogenesis in the liver of donors was enhanced. It is suggested that these effects of tryptophan are associated with different functional status of the liver during the postirradiation observation period.


Developmental and growth temperature regulation of two different microsomal omega-6 desaturase genes in soybeans.
The polyunsaturated fatty acid content is one of the major factors influencing the quality of vegetable oils. Edible oils rich in monounsaturated fatty acid provide improved oil stability, flavor, and nutrition for human and animal consumption. In plants, the microsomal omega-6 desaturase-catalyzed pathway is the primary route of production of polyunsaturated lipids. We report the isolation of two different cDNA sequences, FAD2-1 and FAD2-2, encoding microsomal omega-6 desaturase in soybeans and the characterization of their developmental and temperature regulation. The FAD2-1 gene is strongly expressed in developing seeds, whereas the FAD2-2 gene is constitutively expressed in both vegetative tissues and developing seeds. Thus, the FAD2-2 gene-encoded omega-6 desaturase appears to be responsible for production of polyunsaturated fatty acids within membrane lipids in both vegetative tissues and developing seeds. The seed-specifically expressed FAD2-1 gene is likely to play a major role in controlling conversion of oleic acid to linoleic acid within storage lipids during seed development. In both soybean seed and leaf tissues, linoleic acid and linolenic acid levels gradually increase as temperature decreases. However, the levels of transcripts for FAD2-1, FAD2-2, and the plastidial omega-6 desaturase gene (FAD 6) do not increase at low temperature. These results suggest that the elevated polyunsaturated fatty acid levels in developing soybean seeds grown at low temperature are not due to the enhanced expression of omega-6 desaturase genes.


Shiga Toxin-Producing Escherichia coli in Feces of Finisher Pigs: Isolation, Identification, and Public Health Implications of Major and Minor Serogroups†.
Shiga toxin-producing Escherichia coli (STEC) are major foodborne human pathogens that cause mild to hemorrhagic colitis, which could lead to complications of hemolytic uremic syndrome. Seven serogroups, O26, O45, O103, O111, O121, O145, and O157, account for the majority of the STEC illnesses in the United States. Shiga toxins 1 and 2, encoded by stx1 and stx2, respectively, and intimin, encoded by eae gene, are major virulence factors. Cattle are a major reservoir of STEC, but swine also harbor them in the hindgut and shed STEC in the feces. Our objectives were to use a culture method to isolate and identify major and minor serogroups of STEC in finisher pig feces. Shiga toxin genes were subtyped to assess public health implications of STEC. Fecal samples (n = 598) from finisher pigs, collected from 10 pig flows, were enriched in E. coli broth and tested for stx1, stx2, and eae by a multiplex PCR (mPCR) assay. Samples positive for stx1 or stx2 gene were subjected to culture methods, with or without immunomagnetic separation and plating on selective or nonselective media, for isolation and identification of stx-positive isolates. The culture method yielded a total of 178 isolates belonging to 23 serogroups. The three predominant serogroups were O8, O86, and O121. The 178 STEC strains included 26 strains with stx1a and 152 strains with stx2e subtypes. Strains with stx1a, particularly in association with eae (O26 and O103), have the potential to cause severe human infections. All stx2-positive isolates carried the subtype stx2e, a subtype that causes edema disease in swine, but is rarely involved in human infections. Several strains were also positive for genes that encode for enterotoxins, which are involved in neonatal and postweaning diarrhea in swine. In conclusion, our study showed that healthy finisher pigs harbored and shed several serogroups of E. coli carrying virulence genes involved in neonatal diarrhea, postweaning diarrhea, and edema disease, but prevalence of STEC of public health importance was low.


The role of new antibiotics in intra-abdominal infections in the era of multi-resistant bacteria.
Complicated intra-abdominal infections (cIAI) are a substantial cause of morbidity at intensive care units. cIAI are frequently caused by multidrug-resistant strains of Enterobacteriaceae and Pseudomonas aeruginosa. In 592 cIAI patients from the First Department of Surgery, General University Hospital in Prague, we found an alarming increase in resistance of Escherichia coli to amoxicillin/clavulanic acid, piperacillin/tazobactam and third-generation cephalosporins in 2014-2017 (from 28.7% in 2014 to 37.5% in 2017, from 25% to 32% and from 2.3% to 5.6%, respectively). Ceftolozane/tazobactam and ceftazidime/avibactam are novel cephalosporins available for the treatment of cIAI. Ceftolozane/tazobactam is highly active against multidrug-resistant strains of P. aeruginosa, including carbapenem-resistant isolates. The new non-b-lactam b-lactamase inhibitor avibactam plus ceftazidime is active against carbapenemases-producing strains of Enterobacteriaceae. Both antibiotics are included in the new WSES guidelines for the management of cIAI.


Effects of Microplastics in Soil Ecosystems: Above and Below Ground.
Environmental contamination by microplastics is now considered an emerging threat to biodiversity and ecosystem functioning. Soil ecosystems, particularly agricultural land, have been recognized as a major sink of microplastics, but the impacts of microplastics on soil ecosystems (e.g., above and below ground) remain largely unknown. In this study, different types of microplastics [biodegradable polylactic acid (PLA)], conventional high-density polyethylene (HDPE), and microplastic clothing fibers were added to soil containing the endogeic Aporrectodea rosea (rosy-tipped earthworm) and planted with Lolium perenne (perennial ryegrass) to assess the biophysical soil response in a mesocosm experiment. When exposed to fibers or PLA microplastics, fewer seeds germinated. There was also a reduction in shoot height with PLA. The biomass of A. rosea exposed to HDPE was significantly reduced compared to control samples. Furthermore, with HDPE present there was a decrease in soil pH. The size distribution of water-stable soil aggregates was altered when microplastics were present, suggesting potential alterations of soil stability. This study provides evidence that microplastics manufactured of HDPE and PLA, and synthetic fibers can affect the development of L. perenne, health of A. rosea and basic, but crucial soil properties, with potential further impacts on soil ecosystem functioning.


Single-shot quantitative aberration and scattering length measurements in mouse brain tissues using an extended-source Shack-Hartmann wavefront sensor.
Deep fluorescence imaging in mammalian brain tissues remains challenging due to scattering and optical aberration-induced loss in signal and resolution. Correction of aberrations using adaptive optics (AO) requires their reliable measurement in the tissues. Here, we show that an extended-source Shack-Hartmann wavefront sensor (ESSH) allows quantitative aberration measurements through fixed brain slices with a thickness up to four times their scattering length. We demonstrate in particular that this wavefront measurement method based on image correlation is more robust to scattering compared to the standard centroid-based approach. Finally, we obtain a measurement of the tissue scattering length taking advantage of the geometry of a Shack-Hartmann sensor.


Functional roles for granzymes in murine epidermal gamma(delta) T-cell-mediated killing of tumor targets.
Granzymes, a family of serine proteases contained in cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells, play a critical role in killing tumor targets by triggering rapid breakdown of DNA and subsequent apoptosis. We have reported previously that dendritic epidermal T cells, which are skin-specific members of the tissue-type gamma(delta) T-cell family in mice, are capable of killing selected tumor cell lines. Here we report that short-term cultured dendritic epidermal T-cell lines contain significant N-alpha-benzyloxycarbonyl-L-Lys-thiobenzyl esterase activity, produce granzyme A protein, and express constitutively mRNA for granzymes A and B. Messenger RNA expression for granzyme B was also confirmed in freshly procured Thy-1+ epidermal cells (i.e., dendritic epidermal T cells). Finally, preincubation of dendritic epidermal T cell lines with a granzyme inhibitor, dichloroisocoumarin, but not with a cysteine protease inhibitor, E-64, abrogated completely their capacity to trigger DNA breakdown in YAC-1 target cells. These results reinforce the concept that dendritic epidermal T cells represent skin-resident killer cells that share several functional properties with conventional killer leukocytes, thereby playing a local immunosurveillance role against tumor development.


Postural control and fear of falling in persons with low-level paraplegia.
Falls are prevalent reasons for spinal cord injury (SCI). Postinjury fear of falling (FOF) can affect rehabilitation potential. We quantified FOF in 15 men with paraplegia (ambulatory with bilateral knee-ankle-foot orthoses [KAFOs] and elbow crutches) in correlation with their postural control at the center for long-term SCI rehabilitation of a tertiary-care teaching hospital. Our outcome measures comprised the American Spinal Injury Association Impairment Scale, the Modified Falls Efficacy Scale (MFES), postural sway measurements in the anteroposterior and mediolateral directions; and walking speed, cadence, and endurance. We assessed FOF with the MFES followed by measuring postural sway with a force platform. We measured gait parameters by asking the participant to ambulate on an indoor pathway. The mean postural sway was 314.13 +/- 184.05 mm (mean +/- standard deviation) in the anteroposterior direction and 222.16 +/- 112.34 mm in the mediolateral direction. The MFES score was 41.29 +/- 12.77, which showed a statistically significant negative correlation with postural control. The self-perception of confidence as measured by MFES might not really represent the actual postural stability in individuals with low-level paraplegia. FOF can adversely affect the postural control of individuals with low-level paraplegia. Clinicians should consider FOF as an influential factor in postural control during rehabilitation.


Cardiovascular disease risk factors among women veterans at VA medical facilities.
Hypertension, hyperlipidemia, diabetes, and obesity in middle adulthood each elevate the long-term risk of cardiovascular disease (CVD). The prevalence of these conditions among women veterans is incompletely described. To describe the prevalence of CVD risk factors among women veterans in middle adulthood. Serial cross-sectional studies of data from the Diabetes Epidemiologic Cohorts (DEpiC), a national, longitudinal data set including information on all patients in the Veterans Health Administration (VA). Women veterans (n = 255,891) and men veterans (n = 2,271,605) aged 35-64 receiving VA care in fiscal year (FY) 2010. Prevalence of CVD risk factors in FY2010 by age and, for those aged 45-54 years, by race, region, period of military service, priority status, and mental illness or substance abuse; prevalence by year from 2000 to 2010 in women veterans receiving VA care in both 2000 and 2010 who were free of the factor in 2000. Hypertension, hyperlipidemia, and diabetes were common among women and men, although more so among men. Hypertension was present in 13 % of women aged 35-44 years, 28 % of women aged 45-54, and 42 % of women aged 55-64. Hyperlipidemia prevalence was similar. Diabetes affected 4 % of women aged 35-44, and increased more than four-fold in prevalence to 18 % by age 55-64. The prevalence of obesity increased from 14 % to 18 % with age among women and was similarly prevalent in men. The relative rate of having two or more CVD risk factors in women compared to men increased progressively with age, from 0.55 (35-44 years) to 0.71 (45-54) to 0.73 (55-64). Most of the women with a factor present in 2010 were first diagnosed with the condition in the 10 years between 2000 and 2010. CVD risk factors are common among women veterans aged 35-64. Future research should investigate which interventions would most effectively reduce risk in this population.


Lipid-based systems as a promising approach for enhancing the bioavailability of poorly water-soluble drugs.
Low oral bioavailability as a consequence of low water solubility of drugs is a growing challenge to the development of new pharmaceutical products. One of the most popular approaches of oral bioavailability and solubility enhancement is the utilization of lipid-based drug delivery systems. Their use in product development is growing due to the versatility of pharmaceutical lipid excipients and drug formulations, and their compatibility with liquid, semi-solid, and solid dosage forms. Lipid formulations, such as self-emulsifying (SEDDS), self-microemulsifying SMEDDS) and self- -nanoemulsifying drug delivery systems (SNEDDS) were explored in many studies as an efficient approach for improving the bioavailability and dissolution rate of poorly water-soluble drugs. One of the greatest advantages of incorporating poorly soluble drugs into such formulations is their spontaneous emulsification and formation of an emulsion, microemulsion or nanoemulsion in aqueous media. This review article focuses on the following topics. First, it presents a classification overview of lipid-based drug delivery systems and mechanisms involved in improving the solubility and bioavailability of poorly water-soluble drugs. Second, the article reviews components of lipid-based drug delivery systems for oral use with their characteristics. Third, it brings a detailed description of SEDDS, SMEDDS and SNEDDS, which are very often misused in literature, with special emphasis on the comparison between microemulsions and nanoemulsions.


Effects of aspirin and acetaminophen in gastrointestinal hemorrhage. Results from the Boston Collaborative Drug Surveillance Program.
All patients observed in this analysis of the Boston Collaborative Drug Surveillance Program data had no known disease predisposing them to gastrointestinal (GI) bleeding. Major GI bleeding occurred in hospitalized patients recently exposed to ethacrynic acid (5/111; 4.5%), heparin sodium (7/575; 1.2%), corticosteroids (7/1,484; 0.5%), aspirin (6/2,081; 0.3%), and warfarin sodium (1/423; 0.2%); combinations of two or more of these drugs also resulted in substantial incidences of bleeding. The rates for minor GI bleeding in hospitalized patients varied from 8.3% for heparin to 1.6% for aspirin. In outpatients admitted because of serious GI bleeding, 14/88 (16%) had a history of heavy, regular aspirin use compared with 1,015/14,813 (6.9%) control subjects admitted for other reasons (relative risk, 2.1). No association between light regular use of aspirin and GI bleeding was noted. No association between the use of acetaminophen and GI bleeding was noted in any of the patients studied.


Tracking transmission of apicomplexan symbionts in diverse Caribbean corals.
Symbionts in each generation are transmitted to new host individuals either vertically (parent to offspring), horizontally (from exogenous sources), or a combination of both. Scleractinian corals make an excellent study system for understanding patterns of symbiont transmission since they harbor diverse symbionts and possess distinct reproductive modes of either internal brooding or external broadcast spawning that generally correlate with vertical or horizontal transmission, respectively. Here, we focused on the under-recognized, but apparently widespread, coral-associated apicomplexans (Protista: Alveolata) to determine if symbiont transmission depends on host reproductive mode. Specifically, a PCR-based assay was utilized towards identifying whether planula larvae and reproductive adults from brooding and broadcast spawning scleractinian coral species in Florida and Belize harbored apicomplexan DNA. Nearly all (85.5%; n = 85/89) examined planulae of five brooding species (Porites astreoides, Agaricia tenuifolia, Agaricia agaricites, Favia fragum, Mycetophyllia ferox) and adults of P. astreoides were positive for apicomplexan DNA. In contrast, no (n = 0/10) apicomplexan DNA was detected from planulae of four broadcast spawning species (Acropora cervicornis, Acropora palmata, Pseudodiploria strigosa, and Orbicella faveolata) and rarely in gametes (8.9%; n = 5/56) of these species sampled from the same geographical range as the brooding species. In contrast, tissue samples from nearly all (92.0%; n = 81/88) adults of the broadcast spawning species A. cervicornis, A. palmata and O. faveolata harbored apicomplexan DNA, including colonies whose gametes and planulae tested negative for these symbionts. Taken together, these data suggest apicomplexans are transmitted vertically in these brooding scleractinian coral species while the broadcast spawning scleractinian species examined here acquire these symbionts horizontally. Notably, these transmission patterns are consistent with those of other scleractinian coral symbionts. While this study furthers knowledge regarding these symbionts, numerous questions remain to be addressed, particularly in regard to the specific interaction(s) between these apicomplexans and their hosts.


Health implications of new age technologies for adolescents: a review of the research.
Within the past 20 years, there have been profound advances in personal technology. Although adolescents have embraced the Internet, video games and smart phones, with their extraordinary potential for education, entertainment and connecting with peers, respectively, there is a 'dark side' to these new age technologies. This article identifies many of the adverse physical, psychological, developmental and emotional consequences of our new age technologies. As Internet access has become easier, faster and more ubiquitous, there is increased evidence of its potential for direct and indirect harm to teens. Sexually explicit material is now indiscriminately available to youth, and studies have linked pornography with a number of negative health effects. Internet addiction is a problem even among teenagers who do not view pornography online. The rise of the Internet and social media sites now makes it easier for a student to bully a peer, and adolescents represent the majority of cyberbullying victims These technologies not only carry increased morbidity but also mortality, with increased suicides due to cyberbullying and motor vehicle deaths due to texting while driving. Paediatricians play a critical role in educating adolescents and their parents about the risks associated with new age technologies.


Intraventricular mass lesions at magnetic resonance imaging: iconographic essay - part 1.
The present essay is illustrated with magnetic resonance images obtained at the authors' institution over the past 15 years and discusses the main imaging findings of intraventricular tumor-like lesions (ependymoma, pilocytic astrocytoma, central neurocytoma, ganglioglioma, choroid plexus papilloma, primitive neuroectodermal tumors, meningioma, epidermoid tumor). Such lesions represent a subgroup of intracranial lesions with unique characteristics and some image patterns that may facilitate the differential diagnosis.


Are diversification rates and chromosome evolution in the temperate grasses (Pooideae) associated with major environmental changes in the Oligocene-Miocene?
The Pooideae are a highly diverse C3 grass subfamily that includes some of the most economically important crops, nested within the highly speciose core-pooid clade. Here, we build and explore the phylogeny of the Pooideae within a temporal framework, assessing its patterns of diversification and its chromosomal evolutionary changes in the light of past environmental transformations. We sequenced five plastid DNA loci, two coding (ndhF, matk) and three non-coding (trnH-psbA, trnT-L and trnL-F), in 163 Poaceae taxa, including representatives for all subfamilies of the grasses and all but four ingroup Pooideae tribes. Parsimony and Bayesian phylogenetic analyses were conducted and divergence times were inferred in BEAST using a relaxed molecular clock. Diversification rates were assessed using the MEDUSA approach, and chromosome evolution was analyzed using the chromEvol software. Diversification of the Pooideae started in the Late-Eocene and was especially intense during the Oligocene-Miocene. The background diversification rate increased significantly at the time of the origin of the Poodae + Triticodae clade. This shift in diversification occurred in a context of falling temperatures that potentially increased ecological opportunities for grasses adapted to open areas around the world. The base haploid chromosome number n = 7 has remained stable throughout the phylogenetic history of the core pooids and we found no link between chromosome transitions and major diversification events in the Pooideae.


Prior Sexually Transmitted Infection and Human Immunodeficiency Virus Risk Perception in a Diverse At-Risk Population of Men Who Have Sex with Men and Transgender Individuals.
Prior sexually transmitted infections (STIs) are associated with higher rates of subsequent human immunodeficiency virus (HIV) infection, but the influence of prior STIs on perceived vulnerability to HIV remains unclear. We aimed to assess this relationship, hypothesizing that a prior STI diagnosis is associated with higher self-assessed vulnerability to HIV. We performed a cross-sectional study of men and transgender individuals who have sex with men screening for HIV prevention trials in Philadelphia. An unadjusted regression analysis found no significant association between prior STI and HIV risk perception (p = 0.71) or HIV anxiety (p = 0.32). Multivariate logistic regression models that controlled for predetermined potential cofounders known to impact HIV risk-such as condom use, preexposure prophylaxis use, and demographics-also failed to show statistically significant associations between prior STI and HIV risk perception (p = 0.87) or HIV anxiety (p = 0.10). Furthermore, there was no effect modification by HIV preventive behaviors on the relationship between prior STI and HIV vulnerability. These data suggest that a gap exists between how clinicians may attribute individual HIV risk and how individuals view their own vulnerability at a given moment in time. Future research should focus on the dynamic relationship between perceived HIV vulnerability, STI diagnosis, and adoption of preventive behavior to determine better, individualized targets for HIV prevention interventions.


Mantle uplifted block in the Western Indian ocean.
An anomalous topographic high located close to the intersection of the Owen Fracture Zone with the Mid-Indian Ridge exposes exclusively ultramafic rocks for a thickness of more than 2 kilometers. The rocks, consisting of partly serpentinized spinel lherzolites, with minor harzburgites and dunites, display protogranular to porphyroclastic fabrics, but no cumulate textures. The chemistry of olivine, ortho-and clinopyroxene, and spinel crystals suggests that the rocks originated at a depth of at least 25 kilometers in the oceanic lithosphere and were partially reequilibrated and recrystallized during subsequent upwelling. Thus, field, textural, and mineral chemistry data indicate the presence of an uplifted block of upper mantle. The considerable vertical uplift can be explained by a two-stage process: mantle upwelling in the axial zone of plate accretion, followed by vertical tectonic uplift along the fracture zone. The rate of uplift in the fracture zone was of the order of 1 millimeter per year.


The representation of peripheral nerve inputs in the S-I hindpaw cortex of rats raised with incompletely innervated hindpaws.
The hindpaws of 1-d-old rats were partially denervated by transection and ligation of the sciatic nerve. Following growth to adulthood, the topographical organization of the hindpaw representation in primary somatosensory (S-I) cortex was studied with neurophysiological mapping techniques and compared to the organization of previously studied normal adult rats and adult rats that had sciatic transection. The goals were (1) to determine how the topographical organization of the hindpaw representation is affected when development occurs with an incomplete set of peripheral inputs, and (2) to identify possible differences in the capacity of neonatal and adult CNSs to adjust to loss of inputs. The rat hindpaw is relatively immature on the day of birth. Neonatal transection and ligation of the sciatic nerve stunted gross development of the hindpaw and resulted in a permanent loss of low-threshold mechanoreceptor inputs from hindpaw zones normally innervated by the sciatic nerve. A comparison of the cortical representations of neonatally denervated and normal rats indicated that early loss of sciatic inputs caused several changes in the topographical organization of the hindpaw cortex, including (1) a loss of the representation of hindpaw skin areas innervated by the sciatic nerve, (2) a limited infringement of cutaneous inputs from the hindquarter into the cortical zone deprived of sciatic hindpaw inputs, (3) increased variability in the topographical relationships of the hindpaw and hindquarter representations, and (4) a decrease in the size of the cortical area responsive to cutaneous inputs. A comparison of the cortical representations of neonatal and adult denervates indicated that the general cortical reaction to sciatic injury at both ages was similar: Neurons in some parts of the deprived hindpaw cortex were activated by cutaneous inputs from uninjured nerves, whereas neurons in other parts of this cortex were unresponsive to cutaneous stimulation. The topographical organization and size of projection zones of uninjured peripheral inputs were different, however, after denervation in neonatal and adult rats. From these findings we suggest that (1) development of a normal, topographically organized hindpaw representation requires integration of hindpaw inputs in a spatially specific manner, (2) more than one pattern of cortical adjustment occurs after sciatic injury, and age is an important determinant of the pattern that is established.(ABSTRACT TRUNCATED AT 400 WORDS)


Racial differences in the cause-specific prevalence of blindness in east Baltimore.
Bilateral blindness unrelated to simple refractive error is twice as prevalent among blacks as among whites, although the difference narrows among the elderly. The reasons for this race- and age-related pattern are uncertain. A randomly selected, stratified, multistage cluster sample of 2395 blacks and 2913 whites 40 years of age and older in East Baltimore underwent detailed ophthalmic examinations by a single team. We identified 64 subjects who were blind in both eyes. The leading causes of blindness were unoperated senile cataract (accounting for blindness in 27 of the total of 128 eyes), primary open-angle glaucoma (17 eyes), and age-related macular degeneration (16 eyes). Together, these three disorders accounted for 47 percent of all blindness in this sample. Unoperated cataract accounted for 27 percent of all blindness among blacks, among whom it was four times more common than among whites; whites were almost 50 percent more likely than blacks to have undergone cataract extraction before the age of 80 (P less than 0.002). Primary open-angle glaucoma accounted for 19 percent of all blindness among blacks; it was six times as frequent among blacks as among whites and began 10 years earlier, on average. By contrast, age-related macular degeneration resulting in blindness was limited to whites, among whom it was the leading cause of blindness (prevalence, 2.7 per 1000; 95 percent confidence interval, 1.2 to 5.4); it affected 3 percent of all white subjects 80 years of age or older. The pattern of blindness in urban Baltimore appears to be different among blacks and whites. Whites are far more likely to have age-related macular degeneration, and blacks to have primary open-angle glaucoma. The high rate of unoperated cataracts among younger blacks and among elderly subjects of both races suggests that health services are underused. Half of all blindness in this urban population is probably preventable or reversible.


Analysis of the regulation of gene expression during Bacillus subtilis sporulation by manipulation of the copy number of spo-lacZ fusions.
The control of expression of the Bacillus subtilis spoIIA locus was analyzed by titrating gene expression against gene copy number. A plasmid integrated into the B. subtilis chromosome and carrying the spoIIA control region fused to Escherichia coli lacZ was forced to form tandem repeats by the selection of clones that grow on high levels of chloramphenicol, the antibiotic against which the plasmid determines resistance. DNA from the clones was digested with BglII, which did not cut in the reiterated region, and the size of the fragment was determined by orthogonal-field-alternation gel electrophoresis to determine the copy number. Most clones had fairly homogeneous copy numbers. Gene expression was monitored by beta-galactosidase activity. The results indicate that spoIIA was under positive control by a moiety present at about five copies per chromosome. Spore formation was not affected by amplification, so spoIIA-lacZ reiteration did not sequester a molecule required elsewhere for sporulation.


[Incidence of anaplastic tumor in structure of other histologic forms of the thyroid gland cancer].
The degrees of invasiveness, proliferative activity, morphofunctional activity of nuclei in the thyroidal gland tumors were studied, while analyzing material, obtained in 1343 patients, suffering thyroidal gland cancer (THGC) and operated on in 2000-2013 yrs. Morphological point quantity of malignancy (as a criterion of the tumor progression grade) and mitotic activity in cellular population were determined in various kinds of THGC. Undifferentiated (anaplastic carcinoma) type of THGC is the most malignant one. There were determined a spindle-like, giant-cell and squamous-cell forms of undifferentiated THGC. The presence of sites of differentiated cancer in 33% of histological preparations witnesses the interrelationship with the earlier existed pathological process.


Smoking history-taking skills: a simple guide to teach medical students.
Many doctors rate themselves as ineffective smoking cessation counsellors. It is logical to initiate training efforts with medical students. We incorporated smoking history-taking in the physical diagnosis course at the University of North Carolina at Chapel Hill using a simple method to teach smoking history-taking skills and to assess its effectiveness as an educational intervention. The principal intervention was the distribution of a one-sheet Smoking-History Taking and Counseling Guide, adapted from the American Lung Association's Freedom From Smoking for You and Your Family self-help manual. The second intervention was a single prompt for 50% of the course preceptors. Students' smoking history-taking skills were evaluated in the Objective Structured Clinical Examination (OSCE) at the end of the course. Students who received the guide did significantly better on the OSCE, even after controlling for having discussed taking a smoking history with their preceptors. A simple guide combined with a one-time prompting of preceptors has a positive effect on the acquisition of smoking history-taking skills by the medical students. This strategy may also be useful for teaching and evaluating smoking-cessation counselling skills, for which good smoking history-taking is a necessary basis.


The importance of nursing homes in the spread of methicillin-resistant Staphylococcus aureus (MRSA) among hospitals.
Hospital infection control strategies and programs may not consider control of methicillin-resistant Staphylococcus aureus (MRSA) in nursing homes in a county. Using our Regional Healthcare Ecosystem Analyst, we augmented our existing agent-based model of all hospitals in Orange County (OC), California, by adding all nursing homes and then simulated MRSA outbreaks in various health care facilities. The addition of nursing homes substantially changed MRSA transmission dynamics throughout the county. The presence of nursing homes substantially potentiated the effects of hospital outbreaks on other hospitals, leading to an average 46.2% (range, 3.3%-156.1%) relative increase above and beyond the impact when only hospitals are included for an outbreak in OC's largest hospital. An outbreak in the largest hospital affected all other hospitals (average 2.1% relative prevalence increase) and the majority (~90%) of nursing homes (average 3.2% relative increase) after 6 months. An outbreak in the largest nursing home had effects on multiple OC hospitals, increasing MRSA prevalence in directly connected hospitals by an average 0.3% and in hospitals not directly connected through patient transfers by an average 0.1% after 6 months. A nursing home outbreak also had some effect on MRSA prevalence in other nursing homes. Nursing homes, even those not connected by direct patient transfers, may be a vital component of a hospital's infection control strategy. To achieve effective control, a hospital may want to better understand how regional nursing homes and hospitals are connected through both direct and indirect (with intervening stays at home) patient sharing.


Clinical dilemma of positive histologic chorioamnionitis in term newborn.
Although histologic chorioamnionitis (HCA) is known to be associated with poor outcomes in preterm infants, its clinical significance among term infants is not clearly known. To investigate the utility of HCA in determining early onset clinical sepsis (EOCS) among term newborns. The incidence of HCA and EOCS in term infants born during 2008-2009 was evaluated in a single center retrospective study (n = 3417). The predictive value of HCA for determining EOCS in term infants admitted to the neonatal intensive care unit (NICU) for suspected sepsis (n = 388) was quantified. Outcome of otherwise healthy term infants in the nursery with HCA was also investigated. Overall, 11% of term infants with HCA also had EOCS. HCA was associated with increased risk for EOCS (OR 2.6, 95% confidence interval 1.6-4.2, P < 0.001) among term infants admitted to the NICU for suspected sepsis. No cases of EOCS were found among otherwise well-appearing infants in the nursery with HCA. Multiple logistic regression analysis indicated that addition of HCA does not increase the power of a model combining C-reactive protein (CRP) and immature to total neutrophil ratio in determining EOCS. Although HCA in term infants is associated with EOCS, it did not improve the ability of CRP and immature to total neutrophil ratio to predict EOCS. Routine placental examination may not contribute to the diagnosis of EOCS in term infants.


Signal Integration by ABA in the Blue Light-Induced Acidification of Leaf Pavement Cells in Pea (Pisum sativum L. var. Argenteum).
Leaf pavement cell expansion in light depends on apoplastic acidification by a plasma membrane proton-pumping ATPase, modifying cell wall extensibility and providing the driving force for uptake of osmotically active solutes generating turgor. This paper shows that the plant hormone ABA inhibits light-induced leaf disk growth as well as the blue light-induced pavement cell growth in pea (Pisum sativum L.). In the phytochrome chromophore-deficient mutant pcd2, the effect of ABA on the blue light-induced apoplastic acidification response, which exhibits a high fluence phase via phytochrome and a low fluence phase via an unknown blue light receptor, is still present, indicating an interaction of ABA with the blue light receptor pathway. Furthermore, it is shown that ABA inhibits the blue light-induced apoplastic acidification reversibly. These results indicate that the effect of ABA on apoplastic acidification can provide a mechanism for short term, reversible adjustment of leaf growth rate to environmental change.


Drosophila PPY, a novel male specific protein serine/threonine phosphatase localised in somatic cells of the testis.
Drosophila protein phosphatase Y (PPY) displays 64% amino acid identity to protein serine/threonine phosphatase 1 (PP1) and 39% to protein phosphatase 2A (PP2A). Here we show by expression of cDNA in bacteria, that PPY is a protein serine phosphatase and that its biochemical properties are distinct from PP1 in both substrate specificity and regulation by the thermostable inhibitory proteins inhibitor 1 and inhibitor 2. We also demonstrate that PPY is a novel testis specific protein phosphatase by analysis of both mRNA and protein distribution. More precise immunolocalisation within the testis, using affinity purified anti-PPY protein and anti-PPY peptide antibodies, shows that PPY is present in somatic cyst cells, which encase the germ cells. The predominant location of PPY is in the nuclei of both head and tail cyst cells throughout the length of the testis except for the apical tip. The distribution of PPY, coupled with its unique biochemical properties, suggests that PPY may be required to prevent cyst cell division, increase transcription for provision of nutrients to the germ cells and/or provide a signal for spermatocyte differentiation.


Hemoperitoneum in horses: 67 cases (1989-2004).
To evaluate clinical findings, underlying causes, and short-term outcome associated with hemoperitoneum in horses. Retrospective case series. 67 horses with hemoperitoneum. Medical records of horses with hemo-peritoneum (excluding postoperative abdominal hemorrhage) from 1989 through 2004 were analyzed. Information obtained included history, signalment, physical examination findings, diagnostic test results, and short-term outcome. Breed distribution was 28 Thoroughbreds, 13 Arabians, 10 Quarter Horses, 5 Warmbloods, 3 Appaloosas, and 1 each of 8 other breeds. There were 40 mares, 23 geldings, and 4 stallions. Median age was 12 years (range, 1 month to 40 years). Signs of abdominal discomfort were the primary complaint in 79% of horses. Clinical findings included shock (60%) and pale mucous membranes (60%). Median heart rate was 76 beats/min (range, 30 to 216 beats/min), median respiratory rate was 30 breaths/min (range, 8 to 92 breaths/min), median Hct was 31% (range, 10.5% to 73.0%), and total protein concentration was 5.8 g/dL (range, 3.3 to 8.7 g/dL). Cause of hemoperitoneum was attributed to trauma (25.4%), neoplasia (17.9%), uterine artery rupture (13.4%), mesenteric injury (11.9%), disseminated intravascular coagulopathy (6.0%), other causes (3.0%), and idiopathic causes (22.4%). Fifty-one percent of horses survived to hospital discharge, 37% were euthanized, and 12% died. Poor short-term outcome was significantly associated with high respiratory rate and certain underlying causes. Hemoperitoneum is an infrequent but important cause of abdominal discomfort in horses. Predominant underlying causes were trauma, neoplasia, and idiopathic causes. Identification of underlying cause is important because of its association with outcome.


Fal1p is an essential DEAD-box protein involved in 40S-ribosomal-subunit biogenesis in Saccharomyces cerevisiae.
A previously uncharacterized Saccharomyces cerevisiae gene, FAL1, was found by sequence comparison as a homolog of the eukaryotic translation initiation factor 4A (eIF4A). Fal1p has 55% identity and 73% similarity on the amino acid level to yeast eIF4A, the prototype of ATP-dependent RNA helicases of the DEAD-box protein family. Although clearly grouped in the eIF4A subfamily, the essential Fal1p displays a different subcellular function and localization. An HA epitope-tagged Fal1p is localized predominantly in the nucleolus. Polysome analyses in a temperature-sensitive fal1-1 mutant and a Fal1p-depleted strain reveal a decrease in the number of 40S ribosomal subunits. Furthermore, these strains are hypersensitive to the aminoglycoside antibiotics paromomycin and neomycin. Pulse-chase labeling of pre-rRNA and steady-state-level analysis of pre-rRNAs and mature rRNAs by Northern hybridization and primer extension in the Fal1p-depleted strain show that Fal1p is required for pre-rRNA processing at sites A0, A1, and A2. Consequently, depletion of Fal1p leads to decreased 18S rRNA levels and to an overall deficit in 40S ribosomal subunits. Together, these results implicate Fal1p in the 18S rRNA maturation pathway rather than in translation initiation.


Amplified x-ray emission from core-ionized diatomic molecules.
We predict high-gain x-ray lasing in molecular nitrogen by ultrafast core ionization with an x-ray free-electron laser source. To estimate the spectral and temporal output of this molecular x-ray laser, we solve generalized Maxwell-Bloch equations, keeping track of the electronic and nuclear degrees of freedom. The spectrum of the amplified x-ray emission shows a strong dependence on the gain-length product. Whereas the emission at small gain length is similar to the relatively broad x-ray fluorescence band, the spectrum is determined by a single frequency in the linear gain region. The vibrational wave packet dynamics during the x-ray emission process is examined. By preparation of the initial vibrational quantum state, the x-ray emission frequency can be tuned within the fluorescence band. The present scheme is applicable to other homo- and heteronuclear diatomic systems, thereby extending the spectral range of coherent x-ray radiation sources based on amplification on bound transitions.


Same task, different strategies: how brain networks can be influenced by memory strategy.
Previous functional neuroimaging studies demonstrated that different neural networks underlie different types of cognitive processing by engaging participants in particular tasks, such as verbal or spatial working memory (WM) tasks. However, we report here that even when a WM task is defined as verbal or spatial, different types of memory strategies may be used to complete it, with concomitant variations in brain activity. We developed a questionnaire to characterize the type of strategy used by individual members in a group of 28 young healthy participants (18-25 years) during a spatial WM task. A cluster analysis was performed to differentiate groups. We acquired functional magnetoencephalography and structural diffusion tensor imaging measures to characterize the brain networks associated with the use of different strategies. We found two types of strategies were used during the spatial WM task, a visuospatial and a verbal strategy, and brain regions and time courses of activation differed between participants who used each. Task performance also varied by type of strategy used with verbal strategies showing an advantage. In addition, performance on neuropsychological tests (indices from Wechsler Adult Intelligence Scale-IV, Rey Complex Figure Test) correlated significantly with fractional anisotropy measures for the visuospatial strategy group in white matter tracts implicated in other WM and attention studies. We conclude that differences in memory strategy can have a pronounced effect on the locations and timing of brain activation and that these differences need further investigation as a possible confounding factor for studies using group averaging as a means for summarizing results.


microRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells.
ATG7 is a key autophagy-promoting gene that plays a critical role in the regulation of cell death and survival of various cell types. We report here that microRNAs (miRNAs), a class of endogenous 22-24 nucleotide noncoding RNA molecules able to affect stability and translation of mRNA, may represent a novel mechanism for regulating ATG7 expression and therefore autophagy. We demonstrated that ATG7 is a potential target for miR-17, and this miRNA could negatively regulate ATG7 expression, resulting in a modulation of the autophagic status in T98G glioblastoma cells. Treatment of these tumor cells with the miR-17 mimic decreased, and with the antagomir increased, the expression of ATG7 protein. Dual luciferase reporter assay confirmed that a specific miR-17 binding sequence in the 3'-UTR of ATG7 contributed to the modulation of the expression of the gene by miR-17. Interestingly, our results showed that anti-miR-17 administration activated autophagy through autophagosome formation, as resulted by LC3B and ATG7 protein expression increase, and by the analysis of GFP-LC3 positive autophagosome vesicles in living cells. Furthermore, the autophagy activation by anti-miR-17 resulted in a decrease of the threshold resistance at temozolomide doses in T98G cells, while miR-17 modulation in U373-MG glioblastoma cells resulted in a sensitization to low ionizing radiation doses. Our study of the role of miR-17 in regulating ATG7 expression and autophagy reveals a novel function for this miRNA sequence in a critical cellular event with significant impacts in cancer development, progression and treatment.


Chin fasciculations in Madras motor neuron disease: a new clinical feature.
The characteristic features of Madras motor neuron disease (MMND) are onset in the young in the first two decades, sporadic occurrence, facial and bulbar paralysis, sensorineural hearing impairment, asymmetrical weakness of limbs and pyramidal signs with a slow progression. The majority of the cases reported are from South India. MMND variant has the additional features of optic atrophy and cerebellar signs. We are reporting a 48 year old female of MMND who had persistent fasciculations of chin, with electromyographic features of fasciculations and fibrillations in mentalis muscle. Chin fasciculations, a rare clinical feature, is now described for the first time in Madras motor neuron disease adding a new feature to the clinical constellation of symptoms.


Withdrawing treatment at the direct or indirect request of patients or in their best interests: HNEAHS v A; Brightwater CG v Rossiter; and Australian Capital Territory v JT.
In Hunter and New England Area Health Service v A [2009] NSWSC 761; Brightwater Care Group (Inc) v Rossiter [2009] WASC 229; and Australian Capital Territory v JT [2009] ACTSC 105 Australian courts have recently considered the circumstances in which technically futile treatment may be withdrawn from patients at their direct or indirect request or purportedly in their best interests. The cases provide many valuable lessons about how norms of ethics, law and international human rights shape the regulatory framework of this area of health care in Australia.


Azo Reductase Activated Magnetic Resonance Tuning Probe with "Switch-On" Property for Specific and Sensitive Tumor Imaging in Vivo.
Cancer remains a threat to human health. However, if tumors can be detected in the early stage, then the effectiveness of cancer treatment could be significantly improved. Therefore, it is worthwhile to develop more sensitive and accurate cancer diagnostic methods. Herein, we demonstrated an azo reductase (AzoR)-activated magnetic resonance tuning (MRET) probe with a "switch-on" property for specific and sensitive tumor imaging in vivo. Specifically, Gd-labeled DNA1 (DNA1-Gd) and cyclodextrin-coated magnetic nanoparticles (MNP-CD) were employed as enhancer and quencher of MRET, respectively, while DNA2, an azobenzene (Azo) group-modified aptamer (AS1411), served as a linker between enhancer and quencher to construct the MRET probe of MNP@DNA(1-2)-Gd. In tumor tissues with high-level AzoR, the T1-weighted magnetic resonance signal of the MRET probe could be restored by intelligently regulating the switch from "OFF" to "ON" after activation with AzoR, thus accurately indicating the location of the tumor accurately. Moreover, the tumor with a 4 times smaller size than that of the normal tumor model could be imaged based on the proposed MRET probe. The as-proposed MRET-based magnetic resonance imaging strategy not only achieves tumor imaging accurately but also shows promise for early diagnosis of tumors, which might improve patients' survival rates and provide an opportunity for image-guided biomedical applications in the future.


Tissue distribution and excretion of copper-67 intraperitoneally administered to rats fed fructose or starch.
It has been suggested that impaired gut absorption of copper is the cause of the exacerbated copper deficiency signs in rats fed fructose when compared to rats fed starch. The present study was designed to examine how rats fed fructose or starch diets, either copper-deficient or supplemented, distributed and excreted 67Cu when the isotope was administered i.p. Intraperitoneal administration was chosen in an effort to circumvent primary gut absorption as a factor in the metabolism of 67Cu. After 7 wk of dietary treatment, rats received an i.p. injection of 67Cu and were placed in metabolic cages for 4 d. Regardless of dietary carbohydrate, copper-deficient rats retained similar levels of radioactivity in various tissues and excreted similar amounts of 67Cu in feces and urine. This similarity in copper metabolism in copper-deficient rats fed either fructose or starch when the gut was circumvented for isotope administration suggests that the gut could be responsible, at least in part, for the exacerbated signs associated with the copper deficiency in rats fed fructose. The possibility is discussed that alterations in metabolism may increase the requirement for copper when fructose is the main dietary carbohydrate.


3D Echocardiography - A Useful Method for Cardiovascular Risk Assessment in End-Stage Renal Disease Patients.
Patients with chronic kidney disease (CKD) have an increased risk of premature mortality, mainly due to cardiovascular causes. The association between hemodialysis and accelerated atherosclerosis has long been described. The ankle-brachial index (ABI) is a surrogate marker of atherosclerosis and recent studies indicate its utility as a predictor of future cardiovascular disease and all-cause mortality. The clinical implications of ABI cut-points are not well defined in patients with CKD. Echocardiography is the most widely used imaging method for cardiac evaluation. Structural and functional myocardial abnormalities are common in patients with CKD due to pressure and volume overload as well as non-hemodynamic factors associated with CKD. Our study aimed to identify markers of subclinical cardiovascular risk assessed using ABI and 2D and 3D echocardiographic parameters evaluating left ventricular (LV) structure and function in patients with end-stage renal disease (ESRD) (patients undergoing dialysis), patients after kidney transplantation and non-ESRD patients (control). In ESRD, particularly in hemodialysis patients, changes in cardiac structure, rather than function, seems to be more pronounced. 3D echocardiography appears to be more sensitive than 2D echocardiography in the assessment of myocardial structure and function in CKD patients. Particularly 3D derived end-diastolic volume and 3D derived LV mass indexed for body surface appears to deteriorate in dialyzed and transplanted patients. In 2D echocardiography, myocardial mass represented by left ventricular mass/body surface area index (LVMI) appears to be a more sensitive marker of cardiac structural changes, compared to relative wall thickness (RWT), left ventricle and diastolic diameter index (LVEDDI) and left atrial volume index (LAVI). We observed a generally favorable impact of kidney transplantation on cardiac structure and function; however, the differences were non-significant. The improvement seems to be more pronounced in cardiac function parameters, peak early diastolic velocity/average peak early diastolic velocity of mitral valve annulus (E/e´), 3D left ventricle ejection fraction (LV EF) and global longitudinal strain (GLS). We conclude that ABI is not an appropriate screening test to determine the cardiovascular risk in patients with ESRD.


Correlation of Treatment of Peptic Ulcer Bleeding by Argon Plasma Coagulation (APC) via Contact Heat Probe Method (heater probe) with Epinephrine Injection.
BACKGROUND This clinical investigation aimed to compare the efficacy of treatment of peptic ulcer hemorrhage by argon plasma coagulation (APC) via contact heat probe method (heater probe) along with epinephrine injection. METHODS 100 patients who underwent endoscopic treatment, were randomly divided into two groups consisting of 50 patients each. In the first group, an intervention was performed using foot pedal and 2.3 mm and 3.2 mm argon probes placed in a 2 to 8 mm distance of delivery place leading to plasma coagulation, sufficient necrosis and hemostasis. In the second group, wound press contact probe was used for wound healing with 15 watts of heat for about 25 degrees, causing coagulation and hemostasis. To evaluate and compare the ulcer treatment in both groups, the patient progress results were monitored for a period of one month from the day of discharge. Statistical analyses of data were performed using SPSS software version 22 along with Chi-square test and T-test. RESULTS No significant difference observed in two groups in term of age, sex and clinical symptoms, but patients treated with APC method had higher hemoglobin levels (p < 0.001). The duration of intervention and abdominal bloating in APC group was significantly higher with two cases of re-admission. In HP group, 3 cases (6.3%) had treatment failure and an average transfused blood was significantly higher in the HP group (p < 0.001). CONCLUSION Endoscopy treatment duration was significantly lower in patients treated with the HP method due to separate washing route. HP method seems to be more appropriate for treatment of cases with abdominal bloating, distal gastric lesion and HP bulbs.


Possible cellular mechanism for cerebral vasospasm after experimental subarachnoid hemorrhage in the dog.
This study was undertaken to examine some of the cellular ionic mechanisms responsible for the cerebral vasospasm that occurs as a consequence of subarachnoid hemorrhage (SAH). After cisternal injection of autologous blood we documented spasm of the basilar artery upon angiography from 4 to 7 d postictus in six dogs. When these basilar arteries were isolated we observed marked membrane depolarization and enhanced electrical spike activity compared with controls. The slope of the membrane potential vs log [K]0 curve was significantly reduced in arteries exposed to SAH. Further analysis supported the concept that such altered muscle cell properties resulted from reduction in resting K+ conductance (gk). Exposure of arteries in vitro to nicorandil (10(-9)-10(-7)M) (a drug which acts by increasing gk) hyperpolarized the muscle cells and increased internal diameter. Infusion of nicorandil (3-5 micrograms/kg per min) to intact, anesthetized animals reversed, by 50%, the reduction in basilar artery diameter after experimental SAH.


Analysis of iron-containing compounds in different compartments of the rat liver after iron loading.
The livers of iron-loaded rats were fractionated and a cytosolic fraction, a lysosomal fraction, a siderosomal fraction and haemosiderin were obtained. All iron-containing compounds from these fractions were isolated and their morphology, Fe/P ratios, iron core diameter and peptide content were compared. The cytosolic fraction contained ferritin (CF) and a slower sedimenting, light ferritin (CLF). The lysosomal fraction also contained ferritin (LF) and a slower sedimenting light ferritin (LLF). The siderosomal fraction contained ferritin (SF), a faster sedimenting non-ferritin iron compound (SIC) and haemosiderin (HS). SIC and HS did not resemble ferritin as much as the other products did, but were found to be water-insoluble aggregates. The Fe/P ratios of CF and CLF were lower than the Fe/P ratios of LF and LLF and these in turn had lower Fe/P ratios than SF, SIC and HS. The iron core diameter of the cytosolic ferritin was increased after lysosomal uptake. The iron core diameters of the siderosomal products were smaller. CLF, CF, LF, LLF and SF contained one kind of subunit of approximately 20.5 kDa. SIC and HS contained other peptides in addition to the 20.5-kDa subunit. The results indicate that storage of ferritin molecules is not limited to the cytosolic compartment, but is also the case in the lysosomes. Extensive degradation of the ferritin molecule seems to be confined to the siderosomes.


Characterization of an adenosine deaminase-deficient human histiocytic lymphoma cell line (DHL-9) and selection of mutants deficient in adenosir kinase and deoxycytidine kinase.
The association of adenosine deaminase (ADA) deficiency with immunodeficiency disease has emphasized the importance of this purine metabolic enzyme for human lymphocyte growth and function. This report describes the natural occurrence of ADA deficiency in a human histiocytic lymphoma cell line, DHL-9. The minimal ADA activity in DHL-9 extracts, 0.028 nmol/min/mg protein, was less than 50% of the activity in two B-lymphoblastoid cell lines from ADA-deficient patients and was resistant to the potent ADA inhibitor deoxycoformycin. A sensitive radioimmunoassay failed to detect immunoreactive ADA in DHL-9 cells. Moreover, in DHL-9 cells, deoxycoformycin did not augment either the growth-inhibitory effects of adenosine and deoxyadenosine or the accumulation of deoxyadenosine triphosphate from deoxyadenosine. When compared to six other human hematopoietic cell lines, DHL-9 had 5.6-fold-higher levels of adenosylhomocysteinase. Chromosome 20, which bears the structural gene for ADA and adenosylhomocysteinase, was diploid and had a normal Giemsa banding pattern. The parental DHL-9 cell line was used for the selection and cloning of secondary mutants deficient in deoxycytidine kinase and adenosine kinase.


Hysteresis in the voltage dependence of HCN channels: conversion between two modes affects pacemaker properties.
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels are important for rhythmic activity in the brain and in the heart. In this study, using ionic and gating current measurements, we show that cloned spHCN channels undergo a hysteresis in their voltage dependence during normal gating. For example, both the gating charge versus voltage curve, Q(V), and the conductance versus voltage curve, G(V), are shifted by about +60 mV when measured from a hyperpolarized holding potential compared with a depolarized holding potential. In addition, the kinetics of the tail current and the activation current change in parallel to the voltage shifts of the Q(V) and G(V) curves. Mammalian HCN1 channels display similar effects in their ionic currents, suggesting that the mammalian HCN channels also undergo voltage hysteresis. We propose a model in which HCN channels transit between two modes. The voltage dependence in the two modes is shifted relative to each other, and the occupancy of the two modes depends on the previous activation of the channel. The shifts in the voltage dependence are fast (tau approximately 100 ms) and are not accompanied by any apparent inactivation. In HCN1 channels, the shift in voltage dependence is slower in a 100 mM K extracellular solution compared with a 1 mM K solution. Based on these findings, we suggest that molecular conformations similar to slow (C-type) inactivation of K channels underlie voltage hysteresis in HCN channels. The voltage hysteresis results in HCN channels displaying different voltage dependences during different phases in the pacemaker cycle. Computer simulations suggest that voltage hysteresis in HCN channels decreases the risk of arrhythmia in pacemaker cells.


Physiologically based clearance/extraction models for compounds metabolized in the nose: an example with methyl methacrylate.
Airstream clearance (with units of volume/time) is the volumetric flow from which chemical would have to be completely removed to account for the net loss in the nose. Extraction is the proportion of airflow from which the chemical is completely removed. Over the past several years we have developed physiologically based clearance-extraction (PBCE) models for the nose to assess the physiological, biochemical, and anatomical factors that control airstream clearance. A generic clearance equation was derived for single airway/tissue compartments that had a separate air region and either one, two, or three underlying tissue regions. For all of these structures, airstream clearance (Cl(sys)) has a common form-Equation (1)-related to tissue clearance (Cltot), gas-phase diffusional clearance (PAgas), airflow (Q), and the mucus air partition coefficient (Hmuc:a). Clsys = CltotHm:aPAgasQ/CltotHm:a(Q + PAgas) + PAgasQ. A physiologically based clearance-extraction (PBCE) model for the whole nose combined three separate nasal tissue regions, each with a four-compartment tissue stack (air, mucus, epithelial tissue, and submucosal region). A steady-state solution of the PBCE model successfully described literature results on the steady-state extraction of methyl methacrylate (MMA) and several other metabolized vapors. Model-derived tissue dosimetry estimates, that is, the amount of MMA metabolized in the target epithelial compartment of the olfactory region, for rats and humans provide dosimetric adjustment factors (DAFs) required in calculating a human reference concentration (RfC) from rodent studies. Depending on the assignment of esterase activities to sustentacular and submucosal regions, the DAFs from the PBCE model varied between 1.6 and 8.0, compared to the default value of 0.145. From the experience with MMA, a minimal data set could be defined for building the PBCE model. It consists of mucus:air and blood:air partition coefficients, metabolic constants for enzymatic hydrolysis in nasal tissues from rat and human tissues, immunohistochemistry of the distribution of these activities in rats and human olfactory tissues, and extraction studies in anesthetized rats to assess the total nasal metabolism of the test compound.


From sequencer to supercomputer: an automatic pipeline for managing and processing next generation sequencing data.
Next Generation Sequencing is highly resource intensive. NGS Tasks related to data processing, management and analysis require high-end computing servers or even clusters. Additionally, processing NGS experiments requires suitable storage space and significant manual interaction. At The Ohio State University's Biomedical Informatics Shared Resource, we designed and implemented a scalable architecture to address the challenges associated with the resource intensive nature of NGS secondary analysis built around Illumina Genome Analyzer II sequencers and Illumina's Gerald data processing pipeline. The software infrastructure includes a distributed computing platform consisting of a LIMS called QUEST (http://bisr.osumc.edu), an Automation Server, a computer cluster for processing NGS pipelines, and a network attached storage device expandable up to 40TB. The system has been architected to scale to multiple sequencers without requiring additional computing or labor resources. This platform provides demonstrates how to manage and automate NGS experiments in an institutional or core facility setting.


Immunohistochemical characterization of chicken pituitary cells containing the vasotocin VT2 receptor.
Research in mammals has demonstrated a variety of regulatory effects of vasopressin and oxytocin on endocrine functions of the anterior pituitary gland. Less evidence is available regarding the hypophysiotropic action of arginine vasotocin (AVT) comprising vasopressic and oxytocic activities in birds. Some hypophysiotropic effects of AVT may result from its interactions with brain circuits controlling pituitary functions, whereas others are caused by its direct affect on pituitary cells. Use of an antiserum to the vasotocin receptor VT2 (VT2R) has revealed numerous immunoreactive cells in the anterior pituitary gland of the chicken. The objective of the present study has been to identify endocrine phenotypes of chicken pituitary cells containing VT2R by means of immunohistochemical labeling. VT2R immunoreactivity has been found in all cells immunoreactive for adrenocorticotropin and alpha-melanotropin. Approximately 10% of labeled lactotropes are also immunoreactive for VT2R and lie around the anatomical boundary dividing the cephalic and caudal lobes. In both corticotropes/melanotropes and lactotropes, immunoreactive VT2R is present in a narrow layer outlining cell bodies. Immunoreactive VT2R is not found in gonadotropes, thyrotropes, or somatotropes. These results provide evidence for the important role of VT2Rs in mediating effects of AVT on endocrine secretion from corticotropes and, partially, from lactotropes.


Gemst: a taylor-made combination that reverts neuroanatomical changes in stroke.
In a single transient middle cerebral artery occlusion model of stroke and using immunohistochemical techniques, the effects of a new therapeutic approach named Gemst (a member of the Poly-L-Lysine innovative therapies) have been studied in the rat brain. The expression of inflammatory (CD45, CD11b), oxidative (NO-tryptophan, NO2-tyrosine) and indoleamine 2, 3-dioxygenase pathway (kynurenic acid, 3-hydroxy anthranilic acid) markers has been evaluated in early and late phases of stroke. For this purpose, we have developed eight highly specific monoclonal antibodies directed against some of these markers. In the early phase (3 and 5 days of the stroke, we observed no effect of Gemst treatment (7.5 mg/day, subcutaneously for 3, 5 days). In the late phase (21 days) of stroke and exclusively in the ipsilateral side of non-treated animals an overexpression of kynurenic acid, 3-hydroxy anthranilic acid, CD45, CD11b, GFAP and ionized calcium-binding adapter molecule 1 (IBA-1) was found. In treated animals, the overexpression of the four former markers was completely abolished whereas the overexpression of the two latter ones was decreased down to normal levels. Gemst reversed the pathological conditions of stroke to normal situations. Gemst exerts a multifunctional action: down-regulates the indoleamine 2, 3-dioxygenase pathway and abolishes brain infiltration, microglial activation and gliosis. Moreover, Gemst has no effect on the expression of doublecortin, a protein involved in neuronal migration. Gemst could be a new drug for the treatment of stroke since it reverses the pathological findings of stroke and normalizes brain tissue conditions following the ischemic insult.


[Structural characteristics of dental cementum of skeletal remains of the first Catholic cemetery in Berlin (St. Hedwig's Cemetery, Central Berlin; 1777-1834)].
Analysis of the incremental lines of human tooth cementum permits the chronological age-at-death diagnosis in skeletal finds. In addition, certain life history parameters, especially times of higher physiological calcium demand, should also manifest themselves in the cementum in the form of hypomineralized incremental lines. It has been shown previously that counting the incremental lines leads to a chronological age-at-death diagnosis more precise than the morphological age-at-death assessment, particularly in less well preserved skeletal finds. Both aspects were subject of this investigation of an underprivileged early modern human population.


Increased serum level of Nup88 protein is associated with the development of colorectal cancer.
Nucleoporin88 (Nup88) has been shown to be overexpressed in a wide variety of malignancies including colorectal cancer (CRC). However, no study about serum Nup88 in human CRC was reported. Therefore, in this study, we investigated the level of serum Nup88 protein and its relationships with clinicopathological variables in CRC. The serum concentration of Nup88 protein was determined by a quantitative sandwich enzyme-linked immunosorbent assay (ELISA) in 118 pre-operative serum samples, 66 post-operative and 96 healthy controls. Among the patients, the levels of CEA (n = 91) and CA19-9 (n = 87) in the pre-operative serum were measured, and DNA sequencing was performed in 12 CRCs and 2 samples from non-cancerous colon tissue. In the same patients, the level of pre-operative serum Nup88 was significantly higher than that of post-operative Nup88 (P = 0.021). Furthermore, the level of pre-operative Nup88 was positively related to the depth of tumor invasion (P = 0.002) and advanced stage (P = 0.001). The level of pre-operative Nup88 in the left colon tended to be higher than that in the right colon and the rectum (P = 0.063). DNA sequencing results showed that there were two single nucleotide polymorphisms, distributed in exon 6 (NM_002532.3:c.1044G>A (ACG-ACA, Thr → Thr) and exon 10 (NM_002532.3:c.1389A>T, CCA-CCT, Pro → Pro). Serum Nup88 might be a candidate for a new biomarker implicated in the development and aggressiveness of CRCs.


Treatment of recurrent genotype 1 hepatitis C post-liver transplantation: single center experience with telaprevir-based triple therapy.
Recurrent HCV infection post-liver transplantation (post-LT) is still a major challenge in the treatment of hepatitis C virus (HCV) infection. In this retrospective analysis we gathered data about treatment response and safety of all 14 post-LT patients who were treated between 2011 and 2013 at our centre with a telaprevir (TVR)-based triple therapy. Seven out of 14 patients completed the full treatment course of 48 weeks. Five patients achieved a SVR 24, while 3 additional HCV RNA-negative patients are still in follow-up (end of treatment, SVR 12 and 22). Four patients discontinued treatment prematurely due to side effects. A virological non-response at TW 4 was seen in 1 patient. Virological breakthrough was observed in 2 patients at TW 16 and 28, respectively; 1 patient displayed a virological relapse after the end of treatment (EOT). Patients with a complicated course post-LT accumulated most of the severe side effects, largely infections. One patient with cholestatic hepatitis died 11 weeks after discontinuation of treatment due to progressive graft failure. In conclusion, TVR-based triple therapy in post-LT patients reveals an acceptable antiviral efficacy. Unfortunately, severe side effects are frequent and often require therapeutic interventions. Therefore, with the approval of less straining DAA like sofosbuvir in sight, TVR-based triple therapy in post-LT patients should be, if possible avoided.


Evidence for a lethal endotoxemia as the fundamental feature of irreversibility in three types of traumatic shock.
The data here reported (Table I) show that a toxin is present in the blood of animals with two types of irreversible hypovolemic shock. These data also show that although blood volume therapy does not correct the hypovolemia because of continuing loss of plasma at the site of injury, the major factor in the progressive decline and death is the endotoxemia rather than the hypovolemia. This is also true of severe and prolonged hemorrhagic shock that is irreversible to transfusion. The data also show that even when there is bacterial activity at the site of injury, the pool of endotoxin in the intestine is the chief source of the circulating endotoxin. In all three types of shock, the endotoxemia develops because persisting hypovolemic shock renders the RE system unable to destroy the endotoxin. The demonstration of an endotoxemia as the cause of irreversibility and death in three types of traumatic shock caused by three different agents suggests that a single pathophysiological mechanism accounts for the phenomenon of irreversibility in all types of traumatic shock.


Activity of peptidase in tobacco-leaf tissue in relation to senescence.
1. Peptidase extracted with buffer at pH5.2 from small samples of tobacco-leaf tissue was assayed by measuring the alpha-amino nitrogen liberated from gelatin at 40 degrees in 1hr. The rate of hydrolysis was constant during the digestion. 2. The inclusion of sodium thioglycollate (60mm) in the extracting medium increased the activity of the peptidase. 3. As the major products of hydrolysis were peptides, the enzyme is an endopeptidase. 4. The decrease in protein observed in leaves with increasing physiological age and with time after harvest is correlated with increase in specific activity of peptidase in extracts from the leaves.


Simplified approach for calculating moments of action for linear reaction-diffusion equations.
The mean action time is the mean of a probability density function that can be interpreted as a critical time, which is a finite estimate of the time taken for the transient solution of a reaction-diffusion equation to effectively reach steady state. For high-variance distributions, the mean action time underapproximates the critical time since it neglects to account for the spread about the mean. We can improve our estimate of the critical time by calculating the higher moments of the probability density function, called the moments of action, which provide additional information regarding the spread about the mean. Existing methods for calculating the nth moment of action require the solution of n nonhomogeneous boundary value problems which can be difficult and tedious to solve exactly. Here we present a simplified approach using Laplace transforms which allows us to calculate the nth moment of action without solving this family of boundary value problems and also without solving for the transient solution of the underlying reaction-diffusion problem. We demonstrate the generality of our method by calculating exact expressions for the moments of action for three problems from the biophysics literature. While the first problem we consider can be solved using existing methods, the second problem, which is readily solved using our approach, is intractable using previous techniques. The third problem illustrates how the Laplace transform approach can be used to study coupled linear reaction-diffusion equations.


The pore-forming toxin listeriolysin O is degraded by neutrophil metalloproteinase-8 and fails to mediate Listeria monocytogenes intracellular survival in neutrophils.
The pore-forming toxin listeriolysin O (LLO) is a major virulence factor secreted by the facultative intracellular pathogen Listeria monocytogenes. This toxin facilitates L. monocytogenes intracellular survival in macrophages and diverse nonphagocytic cells by disrupting the internalization vesicle, releasing the bacterium into its replicative niche, the cytosol. Neutrophils are innate immune cells that play an important role in the control of infections, yet it was unknown if LLO could confer a survival advantage to L. monocytogenes in neutrophils. We report that LLO can enhance the phagocytic efficiency of human neutrophils and is unable to protect L. monocytogenes from intracellular killing. To explain the absence of L. monocytogenes survival in neutrophils, we hypothesized that neutrophil degranulation leads to the release of LLO-neutralizing molecules in the forming phagosome. In support of this, L. monocytogenes is a potent inducer of neutrophil degranulation, since its virulence factors, such as LLO, facilitate granule exocytosis. Within the first few minutes of interaction with L. monocytogenes, granules can fuse with the plasma membrane at the bacterial interaction site before closure of the phagosome. Furthermore, granule products directly degrade LLO, irreversibly inhibiting its activity. The matrix metalloproteinase-8, stored in secondary granules, was identified as an endoprotease that degrades LLO, and blocking neutrophil proteases increased L. monocytogenes intracellular survival. In conclusion, we propose that LLO degradation by matrix metalloproteinase-8 during phagocytosis protects neutrophil membranes from perforation and contributes to maintaining L. monocytogenes in a bactericidal phagosome from which it cannot escape.


Breast cancer prognostic classification in the molecular era: the role of histological grade.
Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers.


The sex-specific effects of diet quality versus quantity on morphology in Drosophila melanogaster.
Variation in the quality and quantity of nutrition is a major contributor to phenotypic variation in animal populations. Although we know much of how dietary restriction impacts phenotype, and of the molecular-genetic and physiological mechanisms that underlie this response, we know much less of the effects of dietary imbalance. Specifically, although dietary imbalance and restriction both reduce overall body size, it is unclear whether both have the same effect on the size of individual traits. Here, we use the fruit fly Drosophila melanogaster to explore the effect of dietary food versus protein-to-carbohydrate ratio on body proportion and trait size. Our results indicate that body proportion and trait size respond differently to changes in diet quantity (food concentration) versus diet quality (protein-to-carbohydrate ratio), and that these effects are sex specific. While these differences suggest that Drosophila use at least partially distinct developmental mechanisms to respond to diet quality versus quantity, further analysis indicates that the responses can be largely explained by the independent and contrasting effects of protein and carbohydrate concentration on trait size. Our data highlight the importance of considering macronutrient composition when elucidating the effect of nutrition on trait size, at the levels of both morphology and developmental physiology.