Crystal structures of human and murine deoxyribonucleotidases: insights into recognition of substrates and nucleotide analogues.
Cytosolic 5'(3')-deoxyribonucleotidase (cdN) and mitochondrial 5'(3')-deoxyribonucleotidase (mdN) catalyze the dephosphorylation of deoxyribonucleoside monophosphates and regulate dTTP formation in cytosol and mitochondria, protecting DNA replication from imbalanced precursor pools. They can also interfere with the phosphorylation-dependent activation of nucleoside analogues used in anticancer and antiviral treatment. To understand the relatively narrow substrate specificity of these two enzymes and their ability to use nucleotide analogues as substrates, we determined the crystal structures of human cdN in complex with deoxyuridine, murine cdN in complex with dUMP and dGMP, and human mdN in complex with the nucleotide analogues AZTMP and BVdUMP. Our results show that the active site residues Leu45 and Tyr65 in cdN form a more favorable binding surface for purine nucleotides than the corresponding Trp75 and Trp76 in mdN, explaining why cdN has higher activity for purine nucleotides than does mdN. The molecular interactions of mdN with AZTMP and BVdUMP indicate why these nucleotide analogues are poorer substrates as compared with the physiological substrate, and they provide a structural rationale for the design of drugs that are less prone to inactivation by the deoxyribonucleotidases. We suggest that introduction of substituents in the 3'-position may result in nucleoside analogues with increased resistance to dephosphorylation.


Zeta (zeta), a growth-related opioid receptor in developing rat cerebellum: identification and characterization.
Endogenous opioids and opioid receptors (i.e. endogenous opioid systems) are expressed during neural ontogeny, and play a role in the development of the nervous system. Using [3H][Met5]-enkephalin, a potent ligand involved in neural growth, particularly cell proliferation, specific and saturable binding was detected in homogenates of 6-day-old rat cerebellum; the data were consistent with a single binding site. Scatchard analysis yielded a binding affinity (Kd) of 2.2 nM and a binding capacity (Bmax) of 22.3 fmol/mg protein. Binding was linear with protein concentration, dependent on time, temperature, and pH, and was sensitive to Na+, Mg2+, and guanyl nucleotides. Optimal binding required protease inhibitors, and pretreatment of the homogenates with trypsin markedly reduced binding, suggesting that the binding site was proteinaceous in character. The [Met5]-enkephalin binding site was an integral membrane protein located in the nuclear fraction. Competition experiments indicated that [Met5] enkephalin was the most potent displacer of [3H][Met5]-enkephalin, and that binding was stereospecific. In the adult rat cerebellum, non-opioid receptor binding of [3H][Met5]-enkephalin was recorded, mu and kappa receptors were also found in the developing rat cerebellum, while mu, delta, and kappa receptors were recorded in adult cerebellar tissue. The function, pharmacological and biochemical characteristics, subcellular distribution, and temporal expression of the [Met5]-enkephalin binding site suggest the presence of a unique opioid receptor, termed zeta (zeta), in the developing nervous system.


Gene expression in the digestive tissues of ruminants and their relationships with feeding and digestive processes.
The gastrointestinal tract (GIT) has multiple functions including digestion, nutrient absorption, secretion of hormones and excretion of wastes. In the ruminant animal, development of this organ system is more complex than that of the monogastric animal due to the necessity to establish a fully functional and differentiated rumen, in which a diverse microbial population of bacteria, fungi and protozoa support fermentation and digestion of dietary fiber. Central to the goal of animal scientists to enhance nutrient uptake and production efficiency of ruminants is the need for a comprehensive understanding of GIT development, as well as conditions that alter the digestion process. The relatively recent availability of genome sequence information has permitted physiological investigations related to the process of digestion for many agriculturally important species at the gene transcript level. For instance, numerous studies have evaluated the expression of ruminant GIT genes to gain insight into mechanisms involved in normal function, physiology and development, such as nutrient uptake and transport across the epithelial cell barrier throughout the alimentary canal, maintenance of rumen pH, and regulation of GIT motility and cell proliferation. Further, multiple studies have examined the effects of dietary modification, including feeding of supplemental fat, starch and protein, or a forage- v. concentrate-based diet on expression of critical gene pathways in the gut. In addition, the expression of genes in the GIT in response to disease, such as infection with gastrointestinal parasites, has been investigated. This review will summarize some of the recent scientific literature related to the gene expression in the GIT of ruminants, primarily cattle, sheep and goats, as it pertains to normal physiology, and dietary, developmental, and disease effects to provide an overview of critical proteins participating in the overall digestive processes, and their physiological functions. Recent findings from our laboratory will be highlighted also related to expression of the glucagon-like peptide two-hormone pathway in the GIT of dairy cattle during in various stages of the development and lactation, alterations in gene pathways associated with the rumen development and differentiation in the weaning calf, and genes of the GIT responding to Ostertagia, a common nematode infection of the cattle. Finally, prospective areas of investigation will be highlighted.


Respiratory effects of non-tobacco cigarettes: a longitudinal study in general population.
Data from four consecutive surveys of Tucson longitudinal study of airways obstructive disease were used to examine the relation of respiratory symptoms and pulmonary function to non-tobacco cigarette smoking. The surveys were conducted over a six-year period and provided data on 1802 subjects 15-60 years of age, with a total of 5659 individual questionnaires. Estimated odds ratio (OR) of current non-tobacco smoking for chronic cough was 1.73, for chronic phlegm: 1.53, and for wheeze: 2.01 (p less than 0.05). These estimates were adjusted for age, tobacco smoking and occurrence of the symptom in preceding survey. The increased risk of the symptoms was related to the habit continued for several years, and there was no immediate remission of the symptoms after quitting smoking. A significant (p less than 0.05) reduction in pulmonary function (FEV1, Vmax50 and their ratios with FVC) was found a year or more after current non-tobacco smoking was reported. Although the average consumption of non-tobacco cigarettes, believed to be marijuana smoking, was less than one per day, significant effects were still detectable in both pulmonary function and respiratory symptoms.


Education Research: Electronic patient portal enrollment and no-show rates within a neurology resident clinic.
To identify factors that affect appointment adherence and investigate the association of electronic patient portal (ePP) enrollment and patient adherence rates to appointments in the Neurology Resident Clinic (NRC). Patients scheduled for an appointment during the months of October 2015, February 2016, and June 2016 in the NRC were included. ePP enrollment, date of clinic appointment, method of referral to the clinic, and key demographic criteria were collected. χ2 tests were performed to assess the association of appointment status (i.e., no-show, showed, and canceled) with demographic, comorbidity, and visit information. Patients with ePP enrollment had significantly lower rates of no-show (19% vs 27%) and higher rates of showed (59% vs 48%) compared to patients without ePP enrollment. Younger patients (18-49) had the highest rates of no-show (28%), while older patients (65+) had the lowest rates of no-show (17%). Caucasian patients had significantly lower rates of no-show compared to non-Caucasian patients (14% vs 24%). Non-English-speaking patients had high rates of no-show (34%). Patients with a physician referral had significantly lower rates of no-show (20% vs 28%) and higher rates of showed (61% vs 44%) compared to patients with a self-referral. Our study indicates that ePP enrollment, age, race, and physician referral might be associated with reduced no-show rates in the NRC.


Improving rice eating and cooking quality by enhancing endogenous expression of a nitrogen-dependent floral regulator.
Improving rice eating and cooking quality (ECQ) is one of the primary tasks in rice production to meet the rising demands of consumers. However, improving grain ECQ without compromising yield faces a great challenge under varied nitrogen (N) supplies. Here, we report the approach to upgrade rice ECQ by native promoter-controlled high expression of a key N-dependent floral and circadian clock regulator Nhd1. The amplification of endogenous Nhd1 abundance alters rice heading date but does not affect the entire length of growth duration, N use efficiency and grain yield under both low and sufficient N conditions. Enhanced expression of Nhd1 reduces amylose content, pasting temperature and protein content while increasing gel consistence in grains. Metabolome and transcriptome analyses revealed that increased expression of Nhd1 mainly regulates the metabolism of carbohydrates and amino acids in the grain filling stage. Moreover, expression level of Nhd1 shows a positive relationship with grain ECQ in some local main cultivars. Thus, intensifying endogenous abundance of Nhd1 is a promising strategy to upgrade grain ECQ in rice production.


Time-dependent interactions between iboga agents and cocaine.
The purpose of this study was to clarify the effects of iboga agents on cocaine-induced hyperactivity. Both inhibition and enhancement of cocaine-induced activity by ibogaine have been reported. In the present study, rats were treated with either ibogaine (40 mg/kg, i.p.), noribogaine (40 mg/kg, i.p.), 18-methoxycoronaridine (40 mg/kg, i.p.), or saline, 1 or 19 h prior to the administration of cocaine (20 mg/kg, i.p.) or saline. Motor activity was monitored thereafter for 3 h. All three iboga agents had acute inhibitory effects and delayed potentiating effects on cocaine-induced hyperactivity. These time-dependent effects, which could not be attributed to the motor activity induced by the iboga agents alone, account for divergent results reported in the literature.


Novel in situ activity assays for the quantitative molecular analysis of neurodegenerative processes in the retina.
The mechanisms of neuronal cell death are still only poorly understood, which has hindered the advancement of therapies for many currently untreatable neurodegenerative diseases. This calls for the development of new methods which reveal critical molecular mechanisms of the celldeath machinery with both high sensitivity and cellular resolution. Using animal models for hereditary neurodegeneration in the retina, we have developed or adapted different biochemical assays to determine the enzymatic activities of calpain, poly-ADP-ribose-polymerase (PARP), and histone deacetylase (HDAC) directly and in situ. Additionally, the enzymatic activity of cGMP-dependent protein kinase (PKG) was assessed indirectly using in situ immunohistological techniques to detect PKG-activity-dependent products. Combining these assays with in situ cell death markers revealed close temporospatial correlations, suggesting causal connections between the PKG, HDAC, PARP and calpain activities and neuronal cell death. Using different pharmacological and genetic manipulations, causality could indeed be demonstrated. Surprisingly, the often dramatic rises in metabolic activities didnot match by corresponding increases in expression, highlighting the importance of analyses of protein activities at the cellular level. The above mentioned studies identified a number of metabolic processes previously unknownto be involved in inherited retinal degeneration. Comparing different animal retinal degeneration models uncovered striking similarities in enzymatic activities, suggesting a generality of the destructive pathways. Taken together, these findings provided a number of novel targets for neuroprotection and as such opened up new perspectives for the therapy of hereditary neurodegeneration in the retina and possibly other parts of the central nervous system.


Reintroduction of the 2G12 epitope in an HIV-1 clade C gp120.
Many clade C isolates of HIV-1 do not react with monoclonal antibody (MAb) 2G12, a broad-ranging human neutralizing MAb that recognizes high mannose carbohydrate groups attached to glycoprotein gp120. We reintroduced a partial and complete 2G12 epitope into a clade C background, HIV-1(CN54), and examined the antibody reactivity of the resulting recombinant molecules. Two glycosylation sites recovered 2G12 binding completely, but some binding was evident after the reintroduction of a single glycosylation site at Asn295.


Increased expression of insulin-like growth factor I receptor in malignant cells expressing aberrant p53: functional impact.
We investigated the functional impact of p53 on insulin-like growth factor I receptor (IGF-IR) expression in malignant cells. Using the BL-41tsp53-2 cell line, a transfectant carrying temperature-sensitive (ts) p53 and endogenous mutant p53 (codon 248), we demonstrated a drastic down-regulation of plasma membrane-bound IGF-IRs on induction of wild-type p53. However, a similar response was obtained by treatment of BL-41tsp53-2 cells expressing mutant ts p53 with a p53 antisense oligonucleotide. Thus, even if the negative effect of wild-type p53 predominates under a competitive condition, these data indicate that mutant p53 may be important for up-regulation of IGF-IR. To further elucidate this issue, three melanoma cell lines (BE, SK-MEL-5, and SK-MEL-28) that overexpressed p53 were investigated. The BE cell line has a "hot spot" mutation (codon 248) and expresses only codon 248-mutant p53. SK-MEL-28 has a point mutation at codon 145. SK-MEL-5 cells did not exhibit any p53 mutations, but the absence of p21Waf1 expression suggested functionally aberrant p53. Our data suggest that interaction with Mdm-2 may underlie p53 inactivation in these cells. Using p53 antisense oligonucleotides, we demonstrated a substantial down-regulation of cell surface expression of IGF-IR proteins in all melanoma cell lines after 24 h. This was paralleled by decreased tyrosine phosphorylation of IGF-IR and growth arrest, and, subsequently, massive cell death was observed (this was also seen in BL-41tsp53-2 cells with mutant conformation of ts p53). Taken together, our results suggest that up-regulation of IGF-IR as a result of expression of aberrant p53 may be important for the growth and survival of malignant cells.


[Baseline Incidence of HPV-Associated Invasive and in Situ Cancers in Germany Prior to Potential Vaccination Effects].
Vaccines against human papillomaviruses are covered by statutory health insurances in Germany since March 2007. A reduction of cervical and other HPV-associated cancers is expected. Incidence rates of HPV-associated cancers preceding the introduction of vaccines are unknown. These, however, are important for assessing the effects of HPV vaccines. The aim of the present study was to bridge this knowledge gap. Based on cancer registry data from seven federal states, average yearly incidence rates for cervical, anogenital, oropharyngeal cancers and cancers of the oral cavity were calculated for the period 2003 to 2007. Additionally, estimated numbers of cases give an overview on the total burden of disease caused by HPV-associated cancers in Germany. Incidence trends from 2003 to 2013 are also presented. In Germany, 11,686 cases of invasive HPV-associated cancers occurred yearly before the introduction of HPV vaccines. The most common sites are cervical cancers for women (4,387 cases) and oropharyngeal cancers for men (2,770 cases) with age-standardized incidence rates of 8.8 and 5.9 cases per 100,000 persons, respectively. The age-standardized incidence rate for in situ cervical cancers amounts to 23.5 cases per 100 000 women. Incidence trends show significant increases of invasive vulvar, penile and anorectal cancers. This work presents robust incidence data of HPV-associated cancers in Germany prior to the introduction of the HPV vaccine. Effects of HPV vaccines on the incidence of HPV-associated cancers can be estimated for Germany earliest in 2019.


Mechanism for the antitumor and anticachectic effects of n-3 fatty acids.
Dietary intake of the n-6 fatty acid (FA) linoleic acid (LA) has a strong growth-promoting effect on many rodent tumors and human tumor xenografts grown in immunodeficient rodents. n-3 FAs such as alpha-linolenic and eicosapentaenoic acids (EPAs), which differ from LA and arachidonic acid, respectively, by only a single double bond in the n-3 position, are recognized cancer chemopreventive and anticachectic agents. Understanding how this seemingly small structural difference leads to such remarkable functional differences has been a challenge. In a previous study, we showed that LA uptake, [3H]thymidine incorporation into DNA, and total DNA content were decreased in tissue-isolated hepatoma 7288CTC perfused in situ with arterial blood containing alpha-linolenic acid, EPA, or docosahexaenoic acids. The Ki for the inhibition of LA uptake and [3H]thymidine incorporation by alpha-linolenic acid was 0.18 and 0.25 mM, respectively. Here we show that the addition of alpha-linolenic acid or EPA to arterial blood inhibits tumor FA uptake, including LA, and the subsequent conversion of LA to the mitogen 13-hydroxyoctadecadienoic acid (13-HODE) in vivo and during perfusion in situ. [3H]Thymidine incorporation during perfusion in situ was also inhibited. Addition of 13-HODE to the arterial blood reversed the inhibition of [3H]thymidine incorporation but had no effect on FA uptake. These two n-3 FAs also inhibited FA transport in inguinal fat pads in vivo and during perfusion in situ in fed (FA uptake) and fasted (FA release) rats. The effects of EPA and talinolenic acid on transport of saturated, monounsaturated, and n-6 polyunsaturated FAs in hepatoma 7288CTC and inguinal fat pads during perfusion in situ were reversed by the addition of forskolin (1 microM), pertussis toxin (0.5 microg/ml), or 8-bromo-cyclic AMP (10 microM) to the arterial blood. We conclude that the antitumor and anticachectic effects of n-3 FAs on hepatoma 7288CTC and inguinal fat pads in vivo result from an inhibition of FA transport. These inhibitions are mediated by a putative n-3 FA receptor via a Gi protein-coupled signal transduction pathway that decreases intracellular cyclic AMP. A specific decrease in LA uptake and its conversion to the mitogen 13-HODE causes the tumor growth inhibition.


Identification of Sociodemographic, Clinical, and Genetic Factors to Aid Alaska Native and American Indian People to Successfully Quit Smoking.
Alaska Native and American Indian (ANAI) people have a smoking prevalence of 23%. Nicotine metabolite ratio (NMR) and genetic testing may enable tailored selection of tobacco cessation medication. The purpose of this study was to evaluate the relative contributions of NMR, cessation medication, demographics, and tobacco use history to cessation. Participants were recruited into an observational cohort study consisting of a baseline visit prior to their quit date and 6 week follow-up. Demographic and tobacco use surveys and blood, urine, and breath samples were collected at each visit. Electronic health records were queried for cessation medications. NMR was categorized into slow or normal nicotine metabolism phenotypes (<0.31 and ≥0.31 respectively). The main outcome was cessation at 6 weeks. Analyses consisted of descriptive statistics, medication/phenotype concordance, and estimates of relative risk of quitting. We enrolled 151 ANAI adults who smoked cigarettes daily. Two-thirds had normal nicotine metabolism phenotype. Retrospective medication/phenotype concordance was 39%. The overall quit rate was 25%. No demographic factors or tobacco use history were associated with quit success. Varenicline and bupropion increased the likelihood of quitting (RR=2.93 [1.42, 6.03] and RR=2.52 [1.12, 5.64] respectively) compared to nicotine replacement therapy. Non-optimal medication/phenotype concordance decreased likelihood of quit success (RR=0.44 [0.22, 0.91]) compared to optimal concordance. This exploratory study found associations between quit success and tobacco cessation medication as well as medication/phenotype concordance. Additional research is needed to assess use of NMR for treatment selection among ANAI people. These results broadly support additional community-engaged research to improve medication/phenotype concordance in tribal health settings. Such interventional research holds promise to improve expectations, quit success, and health outcomes amongst individuals attempting to quit smoking.


Generation and Starch Characterization of Non-Transgenic BEI and BEIIb Double Mutant Rice (Oryza sativa) with Ultra-High Level of Resistant Starch.
Cereals high in resistant starch (RS) are gaining popularity, as their intake is thought to help manage diabetes and prediabetes. Number of patients suffering from diabetes is also increasing in Asian countries where people consume rice as a staple food, hence generation of practically growable high RS rice line has been anticipated. It is known that suppression of starch branching enzyme (BE) IIb increases RS content in cereals. To further increase RS content and for more practical use, we generated a non-transgenic be1 be2b double mutant rice (Oryza sativa) line, which completely lacked both proteins, by crossing a be1 mutant with a be2b mutant. The be1 be2b mutant showed a decrease in intermediate amylopectin chains and an increase in long amylopectin chains compared with be2b. The amylose content of be1 be2b mutant (51.7%) was the highest among all pre-existing non-transgenic rice lines. To understand the effects of chewing cooked rice and cooking rice flour on RS content, RS content of mashed and un-mashed cooked rice as well as raw and gelatinized rice flour were measured using be1 be2b and its parent mutant lines. The RS contents of mashed cooked rice and raw rice flour of be1 be2b mutant (28.4% and 35.1%, respectively) were 3-fold higher than those of be2b mutant. Gel-filtration analyses of starch treated with digestive enzymes showed that the RS in be1 be2b mutant was composed of the degradation products of amylose and long amylopectin chains. Seed weight of be1 be2b mutant was approximately 60% of the wild type and rather heavier than that of be2b mutant. The endosperm starch in be1 be2b double mutant rice were enriched with long amylopectin chains. This led to a great increase in RS content in cooked rice grains and rice flour in be1 be2b compared with be2b single mutant. be1 be2b generated in this study must serve as a good material for an ultra-high RS rice cultivar.


[Surveillance of nosocomial infections].
The field of hospital hygiene in Germany has undergone some changes in recent years. In addition to the traditional focus on hygiene, epidemiological activities in the field of nosocomial infections have become important for many hospitals. In order to measure these infections, a surveillance system has been established in Germany, which is known under the acronym KISS (Krankenhaus-Infektions-Surveillance-System, system for surveillance of hospital acquired infections). The system is based on the experiences and principles of the American NNIS-system (National Nosocomial Infections Surveillance), but takes into account the local circumstances and possibilities of participating hospitals in Germany. Meanwhile, hospitals can select among 6 KISS modules, which focus on the following topics or areas: intensive care units, neonatology intensive care unit, oncology, surgical patients, patients with venous or urinary catheters, as well as outpatients. KISS data may be used for quality management issues by individual hospitals and for benchmarking between hospitals. The time spent for surveillance in each hospital for one of the modules averages between two and three hours per week. The scientific literature on the subject of surveillance has convincingly shown that this kind of activity is cost-efficient. Cost-effectiveness is likely associated with surveillance activities within the KISS framework, as these activities will have a beneficial effect on nosocomial infection rates in participating hospitals.


On the importance of identifying, characterizing, and predicting fundamental phenomena towards microbial electrochemistry applications.
The development of microbial electrochemistry research toward technological applications has increased significantly in the past years, leading to many process configurations. This short review focuses on the need to identify and characterize the fundamental phenomena that control the performance of microbial electrochemical cells (MXCs). Specifically, it discusses the importance of recent efforts to discover and characterize novel microorganisms for MXC applications, as well as recent developments to understand transport limitations in MXCs. As we increase our understanding of how MXCs operate, it is imperative to continue modeling efforts in order to effectively predict their performance, design efficient MXC technologies, and implement them commercially. Thus, the success of MXC technologies largely depends on the path of identifying, understanding, and predicting fundamental phenomena that determine MXC performance.


Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression.
Drotrecogin alfa (activated) was approved for use in severe sepsis in 2001 on the basis of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, but controversies about its effectiveness remain. We aimed to assess effectiveness and safety of use of this drug in the past 10 years and compare them with the original PROWESS results. We searched PubMed, Embase, Ovid, Cochrane Library, Evidence-Based Medicine, and the American College of Physicians Journal Club databases for experimental and analytical studies of drotrecogin alfa (activated) in adults with severe sepsis until Jan 31, 2012. We calculated adjusted risk ratios for effectiveness and safety outcomes with random-effects models. We did a metaregression to assess the effect of severity of illness on the risk of death and the risk of bleeding associated with drotrecogin alfa (activated). We included nine controlled trials (41,401 patients) and 16 single-group studies (5822 patients) in effectiveness analyses and 20 studies (8245 patients) in safety analyses. Hospital mortality was reduced by 18% with drotrecogin alfa (activated) compared with controls (relative risk 0·822, 95% CI 0·779-0·867; p<0·0001; I(2)=40%). This mortality reduction was much the same as was noted in PROWESS (0·851, 0·740-0·979), but smaller than that of patients in PROWESS with high disease severity (0·708, 0·590-0·849). Propensity-adjusted studies also showed a significant mortality reduction with lower heterogeneity (0·844, 0·800-0·891; p<0·0001, I(2)=18%). These findings were not changed by the addition of PROWESS-SHOCK results. Metaregression showed greater benefits of drotrecogin alfa (activated) with increasing control mortality (p=0·01) and more severe disease (p=0·04). Hospital mortality for single-group studies of drotrecogin alfa (activated) was 41% (95% CI 35-48), and was higher than that noted in PROWESS at 31% (27-36; p<0·0001). The serious bleeding rate with drotrecogin alfa (activated) was 5·6% (4·5-6·9), which was higher than the 3·5% (2·5-5·0) noted in PROWESS (p=0·003), but similar to that reported in PROWESS high disease severity (p=0·073). Real-life use of drotrecrogin alfa (activated) was associated with significant reduction in hospital mortality and increased rates of bleeding in patients with severe sepsis. Our effectiveness findings were in line with the PROWESS trial but not with the PROWESS-SHOCK trial. None.


Clonal hematopoiesis of indeterminate potential: implications for the cardiologists.
Myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and myelofibrosis, are characterized by somatic gene mutations in bone marrow stem cells, which trigger an inflammatory response influencing the development of associated cardiovascular complications. In recent years, the same mutations were found in individuals with cardiovascular diseases even in the absence of hematological alterations. These genetic events allow the identification of a new entity called 'clonal hematopoiesis of indeterminate potential' (CHIP), as it was uncertain whether it could evolve toward hematological malignancies. CHIP is age-related and, remarkably, myocardial infarction, stroke, and heart failure were frequently reported in these individuals and attributed to systemic chronic inflammation driven by the genetic mutation. We reviewed the connection between clonal hematopoiesis, inflammation, and cardiovascular diseases, with a practical approach to improve clinical practice and highlight the current unmet needs in this area of knowledge.


Skeletal Muscle Ultrasonography in Nutrition and Functional Outcome Assessment of Critically Ill Children: Experience and Insights From Pediatric Disease and Adult Critical Care Studies [Formula: see text].
Evidence suggests that critically ill children develop muscle wasting, which could affect outcomes. Muscle ultrasound has been used to track muscle wasting and association with outcomes in critically ill adults but not children. This review aims to summarize methodological considerations of muscle ultrasound, structural findings, and possibilities for its application in the assessment of nutrition and functional outcomes in critically ill children. Medline, Embase, and CINAHL databases were searched up until April 2016. Articles describing skeletal muscle ultrasound in children and critically ill adults were analyzed qualitatively for details on techniques and findings. Thickness and cross-sectional area of various upper and lower body muscles have been studied to quantify muscle mass and detect muscle changes. The quadriceps femoris muscle is one of the most commonly measured muscles due to its relation to mobility and is sensitive to changes over time. However, the margin of error for quadriceps thickness is too wide to reliably detect muscle changes in critically ill children. Muscle size and its correlation with strength and function also have not yet been studied in critically ill children. Echogenicity, used to detect compromised muscle structure in neuromuscular disease, may be another property worth studying in critically ill children. Muscle ultrasound may be useful in detecting muscle wasting in critically ill children but has not been shown to be sufficiently reliable in this population. Further study of the reliability and correlation with functional outcomes and nutrition intake is required before muscle ultrasound is routinely employed in critically ill children.


Clustering of cardiovascular risk factors among obese urban schoolchildren in Sousse, Tunisia.
Against a background of increasing obesity among Tunisians, we conducted a transversal survey of 1569 children aged 13-19 years selected by multistage cluster sampling to evaluate the prevalence of obesity and clustering of cardiovascular risk factors among obese schoolchildren in the urban area of Sousse. Obese children were found to have higher blood pressure, higher triglyceride levels and lower high-density lipoprotein cholesterol levels than children of normal weight. In both genders, the mean height and weight across all age groups was significantly higher in urban than in rural children. Our study indicates that obesity and the adverse effects of being over the ideal body weight are no longer limited to industrialized countries.


An exploration of contextual dimensions impacting goals of care conversations in postgraduate medical education.
Postgraduate medical trainees are not well prepared difficult conversations about goals of care with patients and families in the acute care clinical setting. While contextual nuances within the workplace can impact communication, research to date has largely focused on individual communication skills. Our objective was to explore contextual factors that influence conversations between trainees and patients/families about goals of care in the acute care setting. We conducted an exploratory qualitative study involving five focus groups with Internal Medicine trainees (n = 20) and a series of interviews with clinical faculty (n = 11) within a single Canadian centre. Thematic framework analysis was applied to categorize the data and identify themes and subthemes. Challenges and factors enabling goals of care conversations emerged within individual, interpersonal and system dimensions. Challenges included inadequate preparation for these conversations, disconnection between trainees, faculty and patients, policies around documentation, the structure of postgraduate medical education, and resource limitations; these challenges led to missed opportunities, uncertainty and emotional distress. Enabling factors were awareness of the importance of goals of care conversations, support in these discussions, collaboration with colleagues, and educational initiatives enabling skill development; these factors have resulted in learning, appreciation, and an established foundation for future educational initiatives. Contextual factors impact how postgraduate medical trainees communicate with patients/families about goals of care. Attention to individual, interpersonal and system-related factors will be important in designing educational programs that help trainees develop the capacities needed for challenging conversations.


[Hydroxyproline concentration in the blood of patients with diabetes mellitus complicated by angiopathies].
The authors used oxyproline indices for the diagnosis of diabetic nephroangiopathies. Patients with diabetes mellitus of various severity (47 in all) were examined. Disturbance of oxyproline metabolism observed in these patients was particularly pronounced in development of nephroangiopathies; this can apparently be attributed to destruction of the basal membrane. The authors believe that it is difficult to assess the collagen metabolism in patients with diabetes mellitus by the urinary oxyproline content, since these patients display a disturbance of the glomerular function of the liver at various stages of the disease.


Importance of potent P2Y(12) receptor blockade in acute myocardial infarction: focus on prasugrel.
Prasugrel therapy is recommended in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). This article reviews the efficacy and safety profile of prasugrel, cost considerations, and its role in clinical practice based on published data. The authors searched PubMed and Ovid databases for English language clinical trial articles involving the use of prasugrel in human subjects and patients, published through June 2012. The keyword "prasugrel" was used. The review focuses on clinical trials, but other articles including Food and Drug Administration documents are also reviewed. Prasugrel has a more rapid and greater pharmacodynamic (PD) effect than clopidogrel. No significant drug - drug interactions have been reported. In a large-scale randomized clinical trial, prasugrel was associated with better protection against ischemic event occurrence compared to clopidogrel, but more bleeding in ACS patients undergoing PCI. Adverse outcomes outweighed the benefit of prasugrel in certain subgroups, including patients over the age of 75, those weighing less than 60 kg, and patients with a prior history of stroke or transient ischemic attack. In subsequent PD studies, prasugrel therapy showed suboptimal platelet inhibition in selected patients. In addition, "hyper-responsiveness" to prasugrel may increase the risk of serious bleeding in high-risk patients. More detailed studies are warranted to explore antiplatelet regimens tailored to optimally limit ischemic and bleeding event occurrences. A Phase-III TRILOGY trial (NCT00699998) will indicate the clinical efficacy and safety of prasugrel in patients with non-ST-segment elevation ACS, who are medically managed without coronary revascularization.


Descriptive Study on Sexuality for Women with Gynecological Cancer.
This study aimed to identify sexuality for women with gynecological cancer. A total of seven women with gynecological cancer agreed to participate in this study. The data were collected utilizing in-depth semi-structured interviews style. A descriptive study design was used in this study. The interviews were analyzed using inductive content analysis methodology. Three themes identified were: 'women with gynecological cancer who give up their sexual life due to misunderstanding and fear', 'women with gynecological cancer who control their body and mind for recovery', 'women with gynecological cancer resume their sexual life with their partner's will'. To improve sexual health and quality of life for women with gynecological cancer, we need to develop programs related to sexual health. An adjusted sexual health program will contribute to increased sexual health and quality of life for women with gynecological cancer.


Missed diagnosis of anterior urethral valve complicated with a foreign body: a cause for concern.
Anterior urethral valve (AUV) is a long known but rare anomaly, which is occasionally encountered in boys with obstructive uropathy. We present a case of AUV with a diverticulum which was misdiagnosed at other center as neurogenic bladder resulting in chronic renal failure. The case was further complicated by breakage of tip of the catheter used for clean intermittent catheterization (CIC) in the diverticulum presenting as a foreign body in the urethra. This article highlights the frequently missed diagnosis of AUV by most practitioners wrongly labeling it as neurogenic bladder, leading to improper management and renal failure in young boys.


The importance of myocardial perfusion in the pathogenesis of the cardiac pathology associated with +Gz exposure in miniature swine.
Minor cardiomyopathy has been associated with exposure of miniature swine to levels of high sustained +Gz which can be attained routinely in new USAF high-performance aircraft. One possible cause of these lesions is total or regional myocardial ischemia. To test this hypothesis, regional coronary blood flow was measured with the radiolabeled microsphere technique in chronically instrumented miniature swine during 60-s exposures to +3Gz, +5Gz, or +7Gz. Acceleration exposure resulted in detectable left ventricular subendocardial hemorrhage in 1 of 5 animals exposed to +3Gz, in 7 of 8 animals exposed to +5Gz and in all 8 animals exposed to +7Gz. All levels of +Gz stress caused 2-3 fold increases in coronary blood flow. The regional distribution of coronary blood flow during +Gz was similar to that under resting control conditions as long as aortic diastolic pressure was maintained. There was no clear evidence of total or regional myocardial ischemia during +Gz or of any relationship between regional coronary blood flow and the presence of subendocardial hemorrhage. It is concluded that myocardial ischemia is not a primary factor in the pathogenesis of the cardiac lesions associated with the exposure of miniature swine to +Gz stress.


Severe Paraproteinemic Demyelinating Neuropathy With Impaired Excitability of the Distal Segments of the Peripheral Nerves.
We report clinical and detailed nerve conduction findings in case of polyneuropathy associated with kappa light chains monoclonal gammopathy of undetermined significance with progression to lymphoproliferative disorder. A 55-year-old man had a predominantly distal, chronic (5 years duration), slowly progressive, symmetric, predominantly sensory impairment with sensory ataxia, and mild weakness. M protein was identified by serum protein electrophoresis. The kappa/lambda ratio of free light chains was significantly elevated to 11.96. The cerebrospinal fluid protein level was elevated at 3.5 g/L. This case study has revealed 2 unusual electrophysiological phenomena-a very unusual prolongation of distal motor latencies of compound muscle action potentials (CMAP) up to 86.5 ms and impaired excitability of the distal segments of the peripheral nerves. The distal CMAP areas were considerably lower compared with the proximal CMAP areas. Radiography of the skull revealed osteolytic lesions.


Network-based analysis reveals distinct association patterns in a semantic MEDLINE-based drug-disease-gene network.
A huge amount of associations among different biological entities (e.g., disease, drug, and gene) are scattered in millions of biomedical articles. Systematic analysis of such heterogeneous data can infer novel associations among different biological entities in the context of personalized medicine and translational research. Recently, network-based computational approaches have gained popularity in investigating such heterogeneous data, proposing novel therapeutic targets and deciphering disease mechanisms. However, little effort has been devoted to investigating associations among drugs, diseases, and genes in an integrative manner. We propose a novel network-based computational framework to identify statistically over-expressed subnetwork patterns, called network motifs, in an integrated disease-drug-gene network extracted from Semantic MEDLINE. The framework consists of two steps. The first step is to construct an association network by extracting pair-wise associations between diseases, drugs and genes in Semantic MEDLINE using a domain pattern driven strategy. A Resource Description Framework (RDF)-linked data approach is used to re-organize the data to increase the flexibility of data integration, the interoperability within domain ontologies, and the efficiency of data storage. Unique associations among drugs, diseases, and genes are extracted for downstream network-based analysis. The second step is to apply a network-based approach to mine the local network structure of this heterogeneous network. Significant network motifs are then identified as the backbone of the network. A simplified network based on those significant motifs is then constructed to facilitate discovery. We implemented our computational framework and identified five network motifs, each of which corresponds to specific biological meanings. Three case studies demonstrate that novel associations are derived from the network topology analysis of reconstructed networks of significant network motifs, further validated by expert knowledge and functional enrichment analyses. We have developed a novel network-based computational approach to investigate the heterogeneous drug-gene-disease network extracted from Semantic MEDLINE. We demonstrate the power of this approach by prioritizing candidate disease genes, inferring potential disease relationships, and proposing novel drug targets, within the context of the entire knowledge. The results indicate that such approach will facilitate the formulization of novel research hypotheses, which is critical for translational medicine research and personalized medicine.


Tyrosine sulfation as a protein post-translational modification.
Integration of inorganic sulfate into biological molecules plays an important role in biological systems and is directly involved in the instigation of diseases. Protein tyrosine sulfation (PTS) is a common post-translational modification that was first reported in the literature fifty years ago. However, the significance of PTS under physiological conditions and its link to diseases have just begun to be appreciated in recent years. PTS is catalyzed by tyrosylprotein sulfotransferase (TPST) through transfer of an activated sulfate from 3'-phosphoadenosine-5'-phosphosulfate to tyrosine in a variety of proteins and peptides. Currently, only a small fraction of sulfated proteins is known and the understanding of the biological sulfation mechanisms is still in progress. In this review, we give an introductory and selective brief review of PTS and then summarize the basic biochemical information including the activity and the preparation of TPST, methods for the determination of PTS, and kinetics and reaction mechanism of TPST. This information is fundamental for the further exploration of the function of PTS that induces protein-protein interactions and the subsequent biochemical and physiological reactions.


[Relief pictures of the posterior pole of the eye (author's transl)].
A method for transformation of photographic transparencies into three-dimensional relief pictures is presented. Black-and-white or color slides of fundi were scanned by a TV camera, the video signals digitized point by point into 256 gray levels and fed into an image processing computer. After passing low pass filter programs, the pictures were retransformed in an analog form to display them on the monitor of an analog processor in relief form. Free choice of the analog relief parameters allow to produce topographic reliefs, which give three-dimensional impression of the optic disk, the macula and of other contrast-containing structures. The method is peculiarly suitable for the control of optic disk atrophies in case of glaucoma and neuritis.


Cancer prevention studies in p53-deficient mice.
Future progress in mechanism-based cancer prevention research may be facilitated by animal models displaying specific genetic susceptibilities for cancer, such as mice deficient in 1 (+/-) or both (-/-) alleles of the p53 tumor suppressor gene. We observed in p53-/- mice that calorie restriction (CR) increased the latency of spontaneous tumor development (mostly lymphomas) by approximately 75%, decreased serum insulin-like growth factor-1 (IGF-1) and leptin levels, slowed thymocyte cell cycle traverse, and induced apoptosis in immature thymocytes. In p53+/- mice, CR and a 1 d/wk fast each delayed spontaneous tumor development (a mix of lymphomas, sarcomas, and epithelial tumors) and decreased serum IGF-1 and leptin levels, even when begun late in life. In p53+/-Wnt-1 transgenic mice, a mammary tumor model, the same interventions increased mammary tumor latency and reduced mean serum IGF-1 and leptin levels to <50% of those of control mice. We capitalized on the susceptibility of p53+/- mice to chronic, low-dose aromatic amine-induced bladder carcinogenesis to develop a useful model for evaluating bladder cancer prevention approaches. These examples clearly indicate that mice with specific (and humanlike) genetic susceptibilities for cancer are powerful models for testing interventions that may inhibit carcinogenesis in humans.


Family and racial factors associated with suicide and emotional distress among latino students.
Latino youth experience disproportionate rates of mental health problems including suicide and depression. Better understanding of underlying risk and protective factors on the part of school-based health professionals, teachers, and health care providers in their lives is warranted. The aims of this secondary analysis of 2004 Minnesota Student Survey data were to (1) describe the mental health status of a statewide sample of Latino 9th- and 12th-grade students; (2) explore relationships of family protective factors (communication, caring, and connection) with suicidal ideation, suicidal attempts, and emotional distress; and (3) highlight similarities and differences in family protective factors among subgroups of Latino students. Parallel analyses were completed for Latino-only and Latino-mixed students. Bivariate logistic regression models were used to examine associations between each family variable and each study outcome. Nearly 1 in 5 Latino high school students have had suicidal thoughts in the past year; past year suicide attempts ranged from 6% to 18.5% across grade and gender subgroups. Most concerning are ninth-grade Latino girls, a group in which 30-40% reported suicidal thoughts and 14-19% reported attempting suicide in the past year. An important study finding is the high rate of suicidal ideation, suicide attempts, and emotional distress among students who self-identified as being of mixed ethnicity. Study findings can be used to inform mental health promotion initiatives and culturally tailor interventions with Latino students.


Global gene expression analysis of rat colon cancers induced by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
Colon cancers develop after accumulation of multiple genetic and epigenetic alterations in colon epithelial cells. To shed light on global changes in gene expression of colon cancers and to gain further insight into the molecular mechanisms underlying colon carcinogenesis, we have conducted a comprehensive microarray analysis of mRNA using a rat colon cancer model with the food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Of 8749 genes or ESTs on a high density oligonucleotide microarray, 27 and 46 were over- and underexpressed, respectively, by > or =3-fold in colon cancers in common in two rat strains with distinct susceptibility to PhIP carcinogenesis. For example, genes involved in inflammation and matrix proteases and a cell cycle regulator gene, cyclin D2, were highly expressed in colon cancers. In contrast, genes encoding structural proteins, muscle-related proteins, matrix-composing and mucin-like proteins were underexpressed. Interestingly, a subset of genes whose expression is characteristic of Paneth cells, i.e. the defensins and matrilysin, were highly overexpressed in colon cancers. The presence of defensin 3 and defensin 5 transcripts in cancer cells could also be confirmed by in situ mRNA hybridization. Furthermore, Alcian blue/periodic acid Schiff base (AB-PAS) staining and immunohistochemical analysis with an anti-lysozyme antibody demonstrated Paneth cells in the cancer tissues. AB-PAS-positive cells were also observed in high grade dysplastic aberrant crypt foci, which are considered to be preneoplastic lesions of the colon. Our results suggest that Paneth cell differentiation in colon epithelial cells could be an early morphological change in cryptic cells during colon carcinogenesis.


Double-immunolabeling systems for phenotyping of immune cells harboring bovine viral diarrhea virus.
Optimal staining conditions were defined for simultaneous detection of bovine viral diarrhea virus (BVDV) and mononuclear leukocyte surface antigens in tissue sections and cytospins. Because of the extreme lability of the virus antigens and the variable stability of the epitopes on the cell differentiation antigens, cryopreservation had to be used. This method gives slightly sub-optimal preservation of morphology. However, the specificity and sensitivity of the immunolabeling ensured reliable identification of the double-labeled cells, i.e., the phenotypic identification of virus-infected cells within the immune system.


[Concern about the safety of erythropoietin in cancer patients].
Erythropoietin has been shown to shorten survival in cancer patients under certain circumstances. Possible mechanisms are an increase in thrombotic events, tumour progression, and induction of angiogenesis. The FDA advises its use in oncology only as a replacement for blood transfusions in patients receiving chemotherapy. In these patients, a rise in haemoglobin above 7.4 mmol/l should be avoided.


Laparoscopic Sleeve Gastrectomy under Awake Paravertebral Blockade Versus General Anesthesia: Comparison of Short-Term Outcomes.
This study aimed at comparing the pre-, intra-, and early postoperative outcomes, between patients who underwent PVB vs general anesthesia (GA) during LSG. Follow-up of weight loss at least 1 year postoperatively was also evaluated. A cohort study was conducted by selecting all patients who underwent LSG under PVB and GA at Makassed General Hospital between 2010 and 2016. Demographic, social, pre-op health status, body mass index (BMI), operative time, postoperative pain and pain medication consumption, postoperative complications and length of hospital stay, all were studied. Follow-up weight loss was collected up to 5 years postoperatively. Data entry, management, and descriptive and inferential statistics were performed using SPSS. A total of 210 participants were included in this study of which 48 constituted the PVB group and 162 patients composed the GA group. Both groups were similar in baseline demographic factors, with patients in PVB suffering from higher number and advanced stage of comorbidities than the GA group. Mean operative time was similar in between the two groups with 80 ± 20 min for PVB and 82 ± 18 min for GA group. Intraoperative complications were scarce among both study groups. GA group requested a second dose of analgesia earlier than PVB group. After at least 1 year postoperatively, the mean percentage of excess weight loss was 81.35 ± 15.5% and 77.89 ± 14.3% for the PVB and GA groups, respectively, P value 0.45. Outcomes of LSG under both types of anesthesia (PVB alone and GA alone) were found to be comparable. However, the need for analgesia was significantly less in the PVB group compared to GA group.


Scattering of a gaussian beam by an infinite cylinder with arbitrary location and arbitrary orientation: numerical results.
We present numerical results concerning the properties of the electromagnetic field scattered by an infinite circular cylinder illuminated by a circular Gaussian beam. The cylinder is arbitrarily located and arbitrarily oriented with respect to the illuminating Gaussian beam. Numerical evaluations are provided within the framework of a rigorous electromagnetic theory, the generalized Lorenz-Mie theory, for infinite cylinders. This theory provides new insights that could not be obtained from older formulations, i.e., geometrical optics and plane-wave scattering. In particular, some emphasis is laid on the waveguiding effect and on the rainbow phenomenon whose fine structure is hardly predictable by use of geometrical optics.


A review of high LET facilities, existing and projected, with emphasis on the radiobiologic aspects.
The introduction of high LET radiations into radiotherapy is an exciting development. Neutron facilities are already in clinical use in England and the United States, while machines to produce negative pi mesons and high energy heavy ions are in an advanced stage of development in Canada, the United States and Europe. The state of the art at each of these installations is reviewed. The therapeutic merits of various heavy particles are compared with conventional photon beams. Lowering the OER (oxygen enhancement ratio) and improvement in the depth dose pattern are the principal advantages sought. Neutrons result in a somewhat lower OER but offer depth-dose patterns that are barely the equal of x- and gamma-rays. Protons by contrast produce excellent dose distributions, but no reduction of OER. Negative pi mesons improve both depth dose pattern and OER to some extent. High energy heavy nuclei show the greatest promise as far as lowering the OER is concerned, but will probably not equal pions in depth dose pattern. More radiobiologic data are urgently needed for all of these new radiation modalities.


[Deficiencies in proteins C and S in a patient with idiopathic portal hypertension accompanied by portal vein thrombosis].
Portal vein thrombosis (PVT) is an uncommon cause of presinusoidal portal hypertension. Among various hepatoportal disorders, noncirrhotic portal hypertension conditions such as idiopathic portal hypertension (IPH) are considered to have a close relation with PVT. PVT is known to have several predisposing conditions, including infection, malignancies, and coagulation disorders. There is growing interest and recognition that deficiencies in proteins C and S are associated with a hypercoagulable state. These deficiencies are regarded as key factors of systemic hypercoagulability and recurrent venous thromboembolism. We report the case of a 19-year-old male diagnosed as IPH with PVT and combined deficiencies in proteins C and S.


Hyponatremia with Loss of High Signal Intensity in the Posterior Pituitary Lobe on T1-weighted Magnetic Resonance Imaging.
Herein, we report on an 82-year-old woman who presented with anorexia. The patient had hyponatremia with preserved urinary osmotic pressure. T1-weighted magnetic resonance imaging (MRI) showed a lack of high signal intensity (SI) in the posterior pituitary lobe. Based on the patient's high levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP), heart failure was suspected. The heart failure may have caused arginine vasopressin (AVP) secretion. The depletion of AVP secretory granules may therefore cause the posterior pituitary gland to disappear on T1-weighted MRI.


An evidence-based review of yoga as a complementary intervention for patients with cancer.
To conduct an evidence-based review of yoga as an intervention for patients with cancer. Specifically, this paper reviewed the impact of yoga on psychological adjustment among cancer patients. A systematic literature search was conducted between May 2007 and April 2008. Data from each identified study were extracted by two independent raters; studies were included if they assessed psychological functioning and focused on yoga as a main intervention. Using a quality rating scale (range = 9-45), the raters assessed the methodological quality of the studies, and CONSORT guidelines were used to assess randomized controlled trials (RCTs). Effect sizes were calculated when possible. In addition, each study was narratively reviewed with attention to outcome variables, the type of yoga intervention employed, and methodological strengths and limitations. Ten studies were included, including six RCTs. Across studies, the majority of participants were women, and breast cancer was the most common diagnosis. Methodological quality ranged greatly across studies (range = 15.5-42), with the average rating (M = 33.55) indicating adequate quality. Studies also varied in terms of cancer populations and yoga interventions sampled. This study provided a systematic evaluation of the yoga and cancer literature. Although some positive results were noted, variability across studies and methodological drawbacks limit the extent to which yoga can be deemed effective for managing cancer-related symptoms. However, further research in this area is certainly warranted. Future research should examine what components of yoga are most beneficial, and what types of patients receive the greatest benefit from yoga interventions.


[Use of lophenal in patients with malignant ovarian tumors].
The use of lophenal in complex treatment of 27 patients with malignant ovarian tumors has shown that the substance possesses a definite antitumor activity, manifested in gaining the clinical effect in 60.9% of patients with an average duration of remission lasting for 5.3 months. The toxic effect on hemopoiesis as well as the side effect of the substance were liquidated by pharmacological drugs. It is concluded that lophenal should be used along with other chemotherapeutic drugs for treatment of patients with malignant ovarian tumors.


Principles of differential diagnostic pacing maneuvers: serial versus parallel conduction.
In this article we will review differential diagnostic pacing maneuvers. It is not meant to be an exhaustive review of all such maneuvers. Rather, we offer some general analytic principles as they apply to electrophysiology (EP) and illustrate their use through several examples. Our hope is to provide a framework for thinking about electrogram data that acts more like a compass and map than like a specific set of directions. Amongst the most helpful pieces of advice that we can offer the EP trainee is to actively try to picture the waves of electricity spreading through the heart, passing beneath the recording electrodes and generating the electrograms you seek to interpret. Digest the fact that more than one propagation pattern can result in the same electrogram pattern and that differential diagnostic pacing is aimed at distinguishing between these possibilities. A fundamental tenet of differential diagnostic maneuvers of any kind (not simply pacing) is to choose a test that maximizes the difference between possible explanations. This perspective and a careful and meticulous cataloguing of what you can unambiguously conclude from the electrograms versus what remains to be determined via pacing offers the best approach to succeeding at EP. We will discuss pacing maneuvers in three contexts: differential diagnosis of narrow complex tachycardia, mapping of accessory pathways, and Para-Hisian pacing.


Average volume of alcohol consumed, drinking patterns, and metabolic syndrome in older Korean adults.
Controversial results have been reported on the relationship between alcohol intake and metabolic syndrome (MetS). We examined the association of average volume of alcohol consumed and drinking patterns with MetS and its components. This study was conducted as a baseline survey for the Dong-gu Study of adults aged 50 years or older. Drinking patterns were assessed using a structured interview, and average volume of alcohol consumed was calculated. MetS was defined according to the updated version of the National Cholesterol Education Program. Compared with individuals who never drank, the adjusted odds ratio (OR) for the prevalence of MetS was significantly higher in men who consumed 2.1 to 4.0 drinks/day (OR, 1.53; 95% CI, 1.17-2.00) and greater than 4.0 drinks/day (OR, 1.63; 95% CI, 1.23-2.14), whereas no significant association was observed in women. Significant dose-response relationships between average volume of alcohol consumed and all metabolic components were observed in men. A usual quantity of 5 to 6 drinks/drinking day (OR, 1.57; 95% CI, 1.19-2.09), 7 or more drinks/drinking day (OR, 1.88; 95% CI, 1.45-2.44), and binge drinking on at least 1 occasion/week (OR, 1.33; 95% CI, 1.01-1.76) were associated with a significantly higher OR for prevalence of MetS in men; however, none of these drinking patterns were associated with MetS in women. Unhealthy drinking patterns such as high usual quantity and binge drinking were significantly associated with MetS, suggesting that the effect of alcohol consumption on MetS should be considered in the context of drinking pattern, particularly in men.


Getting started as a physician executive.
In clinical practice, technical skills often outweigh interpersonal and leadership skills as success factors--you can be a great doctor and a so-so person. But the reverse seems to be true in the physician executive role; it is precisely the intangible leadership skills that contribute to and determine potential success. And they can be tough to master, especially when you focus on them for the first time, partway through an already-successful career. Practicing leadership is like practicing medicine. It's not just a matter of learning some new things--if it were only that, physicians are known to be excellent learners. Nor is it just a matter of determination or application--this is not a battle that sweat and effort alone can win. Most physicians will want to "try on" the executive role before making strategic moves in that direction. But be clear about what you want to get out of any project or activity before you jump in. If you're seeking a management degree, the best approach is to tie together developing your technical and interpersonal skills, as well as the formal credentials.


A longitudinal study of children of alcoholics: predicting young adult substance use disorders, anxiety, and depression.
This study tested the specificity of parent alcoholism effects on young adult alcohol and drug abuse/dependence, anxiety, and depression, and tested whether adolescent symptomatology and substance use mediated parent alcoholism effects. Participants were from a longitudinal study in which a target child was assessed in adolescence and young adulthood with structured interview measures (N = 454 families at Time 1). Results showed unique effects of parent alcoholism on young adult substance abuse/dependence diagnoses over and above the effects of other parental psychopathology. There was some evidence of parent alcoholism effects on young adult depression and of maternal alcoholism effects on young adult anxiety, although these were not found consistently across subsamples. Mediational models suggested that parent alcoholism effects could be partially (but not totally) explained by adolescent externalizing symptoms.


The relationship between doctors' and nurses' own weight status and their weight management practices: a systematic review.
It has been established that health professionals' smoking and physical activity influence their related health-promoting behaviours, but it is unclear whether health professionals' weight status also influences their related professional practices. A systematic review was conducted to understand the relationship between personal weight status and weight management practices. Nine eligible studies were identified from a search of the Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and Chinese databases. All included studies were cross-sectional surveys employing self-reported questionnaires. Weight management practice variables studied were classified under six practice indicators, developed from weight management guidelines. Syntheses of the findings from the selected studies suggest that: normal weight doctors and nurses were more likely than those who were overweight to use strategies to prevent obesity in-patients, and, also, provide overweight or obese patients with general advice to achieve weight loss. Doctors' and nurses' own weight status was not found to be significantly related to their referral and assessment of overweight or obese patients, and associations with their relevant knowledge/skills and specific treatment behaviours were inconsistent. Additionally, in female, primary care providers, relevant knowledge and training, self-efficacy and a clear professional identity emerged as positive predictors of weight management practices. This review's findings will need to be confirmed by prospective theoretically driven studies, which employ objective measures of weight status and weight management practices and involve multivariate analyses to identify the relative contribution of weight status to weight management.


Fallopian Tube Lesions in Women at High Risk for Ovarian Cancer: A Multicenter Study.
The prognosis of women diagnosed with invasive high-grade serous ovarian carcinoma (HGSC) is poor. More information about serous tubal intraepithelial carcinoma (STIC) and serous tubal intraepithelial lesions (STIL), putative precursor lesions of HGSC, could inform prevention efforts. We conducted a multicenter study to identify risk/protective factors associated with STIC/STILs and characterize p53 signatures in the fallopian tube. The fallopian tubes and ovaries of 479 high-risk women ≥30 years of age who underwent bilateral risk-reducing salpingo-oophorectomy were reviewed for invasive cancer/STICs/STILs. Epidemiologic data was available for 400 of these women. In 105 women, extensive sampling of the tubes for STICs/STILs/p53 signatures were undertaken. Descriptive statistics were used to compare groups with and without lesions. The combined prevalence of unique tubal lesions [invasive serous cancer (n = 6) /STICs (n = 14)/STILs (n = 5)] was 6.3% and this was split equally among BRCA1 (3.0%) and BRCA2 mutation carriers (3.3%). A diagnosis of invasive cancer was associated with older age but no risk/protective factor was significantly associated with STICs/STILs. Extensive sampling identified double the number of STICs/STILs (11.9%), many p53 signatures (27.0%), and multiple lesions in 50% of the cases. Women with p53 signatures in the fimbria were older than women with signatures in the remaining tube (P = 0.03). STICs/STILs may not share the protective factors that are associated with HGSC. It is plausible that these factors are only associated with STICs that progress to HGSC. Having multiple lesions in the fimbria may be an important predictor of disease progression. Cancer Prev Res; 11(11); 697-706. ©2018 AACR.


Percutaneous Coronary Intervention in an Octogenarian With Anomalous Origin Arising From Right Sinus: A Rare Case Report.
Anomalous coronary artery origins are not common in routine clinical practice. The incidence of coronary anomalies in patients undergoing coronary angiography is less than 1%. The greatest challenges faced in the management are delays in identification and difficulty engaging the anomalous coronary artery. Operator experience in promptly identifying the anomaly and selection of the appropriate catheter is critical for successful intervention. We are presenting a case of acute inferior and posterior wall myocardial infarction (MI) with an anomalous origin of the left circumflex artery from the right coronary sinus. Learning objective is that percutaneous coronary intervention (PCI) in an anomalous left circumflex can be technically difficult because selective cannulation of the vessel may not be easy. An anomalous left circumflex artery has a rare presentation of ST-elevation myocardial infarction (STEMI). Complicated STEMI with cardiogenic shock is not commonly seen in anomalous coronary artery origin from the right sinus. Percutaneous intervention in patients with STEMI with an anomalous left circumflex artery has a high risk and is technically challenging.


Influence of terbutaline on endotoxin-induced lung injury.
The effects of the beta-2-receptor agonist terbutaline on central hemodynamics, gas exchange, and platelet and leukocyte counts during 3 hr of endotoxin shock were studied. Ten sheep were anesthetized and ventilated without positive end-expiratory pressure (PEEP). After 1 hr of stabilization (t = -30), five animals (Group T) received intravenous (i.v.) infusion of terbutaline, 20 micrograms/kg/hr for 3.5 hr, whereas the other five received no drug treatment and served as controls (Group C). Thirty min later (t = 0) all animals received Escherichia coli endotoxin 10 micrograms/kg by i.v. infusion over 15 min. The terbutaline infusion increased the heart rate (HR) initially by 30% and the cardiac index (CI) by 50%, whereas mean arterial pressure (MAP), pulmonary artery pressure (PAP), and gas exchange remained unchanged. Terbutaline pretreatment did not prevent the pulmonary hypertension that characteristically occurs after endotoxin injection, nor did it decrease the initial fall in platelet count, leukocyte count, arterial oxygen tension (PaO2), or respiratory compliance (t = 30). However, during the permeability phase (after 120-180 min), there was a significant improvement in MAP, PAP, respiratory compliance, PaO2, and arterial pH in the animals treated with terbutaline as compared with the control animals. Also, the wet weight to dry weight ratio of the lungs from animals receiving terbutaline was significantly lower than in controls. It was concluded that terbutaline does not influence the hypertension phase during endotoxin shock, but it may decrease pulmonary microvascular leakage during the permeability phase.


Melatonin and Vitamin D Orchestrate Adipose Derived Stem Cell Fate by Modulating Epigenetic Regulatory Genes.
Melatonin, that regulates many physiological processes including circadian rhythms, is a molecule able to promote osteoblasts maturation in vitro and to prevent bone loss in vivo, while regulating also adipocytes metabolism. In this regard, we have previously shown that melatonin in combination with vitamin D, is able to counteract the appearance of an adipogenic phenotype in adipose derived stem cells (ADSCs), cultured in an adipogenic favoring condition. In the present study, we aimed at evaluating the specific phenotype elicited by melatonin and vitamin D based medium, considering also the involvement of epigenetic regulating genes. ADSCs were cultured in a specific adipogenic conditioned media, in the presence of melatonin alone or with vitamin D. The expression of specific osteogenic related genes was evaluated at different time points, together with the histone deacetylases epigenetic regulators, HDAC1 and Sirtuins (SIRT) 1 and 2. Our results show that melatonin and vitamin D are able to modulate ADSCs commitment towards osteogenic phenotype through the upregulation of HDAC1, SIRT 1 and 2, unfolding an epigenetic regulation in stem cell differentiation and opening novel strategies for future therapeutic balancing of stem cell fate toward adipogenic or osteogenic phenotype.


Atelectasis during anaesthesia and in the postoperative period.
Transverse sections of lung tissue were studied in patients by computerized tomography during anaesthesia and in the postoperative period. Eight patients were studied during intravenous (thiopentone) and six during inhalational (halothane) anaesthesia. The latter patients were studied during both spontaneous and mechanical ventilation. Five of the patients who underwent surgery for inguinal hernia and five patients in whom laparotomy was performed were studied 1 h and 24 h postoperatively. No patient showed any lung changes while awake preoperatively, and all patients developed dependent, crest-shaped lung densities within 5-10 min of anaesthesia. The densities comprised 3.4% of the lung volume in the caudal (basal) 5 cm of the lung tissue. No significant differences in the size and distribution of the densities were noted between spontaneous breathing and mechanical ventilation during anaesthesia, or between intravenous and inhalational anaesthesia. The densities remained in nine of ten patients 1 h postoperatively, and they remained in five of ten patients 24 h after anaesthesia. The densities are considered to be compression atelectases which may develop as a result of relaxation of the diaphragm. They may be important contributors to postoperative pulmonary complications.


Lessons from cognitive neuropsychology for cognitive science: a reply to Patterson and Plaut (2009).
A recent article in this journal (Patterson & Plaut, 2009) argued that cognitive neuropsychology has told us very little over the past 30 or 40 years about "how the brain accomplishes its cognitive business." This may well be true, but it is not important, because the principal aim of cognitive neuropsychology is not to learn about the brain. Its principal aim is instead to learn about the mind, that is, to elucidate the functional architecture of cognition. I show that this is so (a) via extensive quotations from leading figures in this field and (b) by analysis of the subject matter of articles in the leading journal in the field, Cognitive Neuropsychology. Recent reviews of the past 25 years of work in this field (Coltheart & Caramazza, 2006) have concluded that cognitive neuropsychology has told us much about the functional architecture of cognition in a variety of cognitive domains. Patterson and Plaut (2009) did not consider this aim of cognitive neuropsychology. Therefore, their conclusions that cognitive neuropsychology has not been successful, and that this is because the particular methods it uses are flawed, are not justified.


Ultrasound imaging for the rheumatologist XIV. Ultrasound imaging in connective tissue diseases.
Ultrasound (US) role is becoming more and more relevant in the assessment of rheumatic diseases but there are still some almost unexplored fields and, surely, one of these is represented by the great family of connective tissue diseases (CTD). In this review we provide an update of the available data regarding some applications of US in CTD. Besides an overview of the role of US in their musculoskeletal involvement, we will report data on the use of US in the evaluation of skin and lung in systemic sclerosis and of salivary glands in Sjögren's syndrome. US assessment of heart, kidney or vascular involvement in CTD will not be the subjects of this paper.


[Hypertension in D3 dopamine receptor deficient mice].
To investigate the mechanisms by which hypertension occurs in D(3) dopamine receptor null mice (D(3)-/-). Several parameters, including blood pressure, renal sodium excretion, D(3) receptor protein and mRNA expression, plasma renin activity, norepinephrine concentration and AT(1) receptor expression were checked in D(3)-/- mice and their littermate wild type mice (D(3)+/+). Moreover, the vasorelaxant effect of D(3) receptor stimulation was measured with ex-vivo mesenteric artery isolated from Wistar-Kyoto rats. Blood pressure was higher in D(3)-/- mice compared with that in D(3)+/+ mice, salt-loading had no effect on blood pressure in both groups, at the last period, sodium excretion was lower in D(3)-/- mice as compared with D(3)+/+ mice, renal renin activity and AT(1) receptor expression were higher in D(3) -/- [corrected] mice than in D(3) +/+ [corrected] mice. In contrast, no difference of renal norepinephrine was found in two groups. When using angiotensin II subtype-1 receptor antagonist, the systolic blood pressure declined for a longer duration in mutant mice than in wild-type mice. Vaso-relaxation was found in ex-vivo isolated mesenteric artery when D(3) receptor was stimulated. Elevation of blood pressure in D(3)-/- mice might be related with impaired renal sodium excretion and vaso-relaxation in resistance artery.


Identification of porcine transmissible gastroenteritis virus in house flies (Musca domestica Linneaus).
Transmissible gastroenteritis (TGE) virus was detected in house flies (Musca domestica Linneaus) by staining with specific fluorescent antibody. The flies were collected within a swine confinement facility in which TGE was enzootic. Laboratory-reared flies were infected experimentally with TGE virus and the virus was recovered from the insects for 72 hours after infection. The TGE virus was identified both by the fluorescent antibody technique and by isolation in cell culture. The nature of plaque formation in cell monolayers inoculated with the virus passaged through flies changed from a large plaque (4 mm or greater in diameter) to a small plaque (1 mm in diameter) over the period. Large plaques were observed early after infection and were attributed to TGE virus mechanically carried by the flies. Small plaques occurred 8 to 12 hours after infection and were considered to be produced by virus replicated in the dipterous cell.


Female sexual dysfunction post radical cystectomy and urinary diversion.
To evaluate the impact of radical cystectomy and urinary diversion on female sexual function. A Medline search was conducted according to the PRISMA statement for all English full-text articles published between 1980 and 2016 and assessing female sexual function post radical cystectomy and urinary diversion. Eligible studies were subjected to critical analysis and revision. The primary outcomes were the reporting methods for female sexual dysfunction (FSD), manifestations of FSD, and factors associated with FSD, postoperative recoverability of FSD, and awareness level regarding FSD. From the resulting 117 articles, 11 studies were finally included in our systematic review, with a total of 361 women. Loss of sexual desire and orgasm disorders were the most frequently reported (49% and 39%). Dyspareunia and vaginal lubrication disorders were reported in 25% and 9.5%, respectively. The incidence of sexual dysfunction was 10% in 30 patients receiving genital- or nerve-sparing cystectomy vs. 59% receiving conventional cystectomy. Although female sexual function is an important predictor of health-related quality of life post radical cystectomy and urinary diversion, the available literature is not enough to provide proper information for surgeons and patients.


Mass Balance of the Greenland Ice Sheet at High Elevations.
Comparison of ice discharge from higher elevation areas of the entire Greenland Ice Sheet with total snow accumulation gives estimates of ice thickening rates over the past few decades. On average, the region has been in balance, but with thickening of 21 centimeters per year in the southwest and thinning of 30 centimeters per year in the southeast. The north of the ice sheet shows less variability, with average thickening of 2 centimeters per year in the northeast and thinning of about 5 centimeters per year in the northwest. These results agree well with those from repeated altimeter surveys, except in the extreme south, where we find substantially higher rates of both thickening and thinning.


Mast cell stabilization decreases cardiomyocyte and LV function in dogs with isolated mitral regurgitation.
Mast cells are increased in isolated mitral regurgitation (MR) in the dog and may mediate extracellular matrix loss and left ventricular (LV) dilatation. We tested the hypothesis that mast cell stabilization would attenuate LV remodeling and improve function in the MR dog. MR was induced in adult dogs randomized to no treatment (MR, n = 5) or to the mast cell stabilizer, ketotifen (MR + MCS, n = 4) for 4 months. LV hemodynamics were obtained at baseline and after 4 months of MR and magnetic resonance imaging (MRI) was performed at sacrifice. MRI-derived, serial, short-axis LV end-diastolic (ED) and end-systolic (ES) volumes, LVED volume/mass ratio, and LV 3-dimensional radius/wall thickness were increased in MR and MR + MCS dogs compared with normal dogs (n = 6) (P < .05). Interstitial collagen was decreased by 30% in both MR and MR + MCS versus normal dogs (P < .05). LV contractility by LV maximum time-varying elastance was significantly depressed in MR and MR + MCS dogs. Furthermore, cardiomyocyte fractional shortening was decreased in MR versus normal dogs and further depressed in MR + MCS dogs (P < .05). In vitro administration of ketotifen to normal cardiomyocytes also significantly decreased fractional shortening and calcium transients. Chronic mast cell stabilization did not attenuate eccentric LV remodeling or collagen loss in MR. However, MCS therapy had a detrimental effect on LV function because of a direct negative inotropic effect on cardiomyocyte function.


Systemic effects of NaHCO3 in experimental lactic acidosis in dogs.
Lactic acidosis is characterized by metabolic acidosis due to accumulation of H+ ions from lactic acid with blood lactate of at least 5 mM. The standard treatment is intravenous NaHCO3, with resultant mortality in excess of 50%. Despite the high mortality, the metabolic and systemic effects of NaHCO3 used in the treatment of lactic acidosis have not been extensively studied. The present experiments in diabetic dogs were designed to address these questions. Dogs with phenformin-induced lactic acidosis (blood lactate above 5 mM, arterial pH below 7.20) were treated with equimolar amounts of either NaCl or NaHCO3 or received no therapy. Intravenous NaHCO3 resulted in a decline of cardiac output and intracellular pH (pHi) of liver and erythrocytes, whereas treatment with NaCl did not. With NaHCO3 but not with NaCl infusion gut lactate production increased almost stoichiometrically, with no change in arterial pH or bicarbonate but with a doubling of lactate. Bicarbonate also resulted in a decrease of hepatic portal vein blood flow. The mean survival time and percent mortality were similar in NaCl- vs. NAHCO3(-) treated animals. Although both groups lived longer than did animals receiving no therapy, the differences were not significant. Thus, treatment of experimental lactic acidosis with either NaCl or NaHCO3 or with no therapy results in no change of blood pH and bicarbonate and in a similar mortality. In terms of systemic effects, however, NaHCO3 results in significant decrements of liver and erythrocyte pHi, hepatic portal vein blood flow, and cardiac output and in significant increments of gut lactate production, whereas NaCl does not. The data suggest that the rationale for therapy of lactic acidosis with NaHCO3 should probably be reevaluated.


[Hypothermic temperature control after successful resuscitation of out-of-hospital cardiac arrest in adults : Statement from the resuscitation and postresuscitation treatment working groups of the German Society of Medical Intensive Care and Emergency Medicine (DGIIN) and the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI), the German Society for Interdisciplinary Emergency and Acute Medicine (DGINA) and the Austrian Association of Emergency Medicine (AAEM)].
In Germany per year approximately 60,000 and in Austria 5,000 adult patients suffer from out-of-hospital cardiac arrest. Only 10-15% of these patients survive without neurological damage. For decades hypothermic temperature control has been a central component of post-resuscitation treatment, but is controversial due to recently published studies.


Attentional diversion during adaptation affects the velocity as well as the duration of motion after-effects.
The effects of diverting attention on early motion processing in human vision were studied with a selective adaptation technique. The velocity of motion after-effects (MAEs) produced on a stationary test grating after prolonged exposure to drifting luminance-modulated gratings was measured by matching MAE velocity with that of another physically moving grating. Initial MAE velocities decreased and their rate of decay increased with the distance of the adapting and test gratings from the fixation point. When attention was diverted from the adapting grating, by having subjects process the intermittently changing digit which formed the fixation point, initial MAE velocities were reduced and rate of decay increased, with the largest effect of diversion being found for gratings near the fixation point. The effects of varying attention mimic those of varying adapting duration, rather than adapting contrast or velocity, and appear to reflect a genuine change in motion-processing mechanisms.


The United States of America and scientific research.
To gauge the current commitment to scientific research in the United States of America (US), we compared federal research funding (FRF) with the US gross domestic product (GDP) and industry research spending during the past six decades. In order to address the recent globalization of scientific research, we also focused on four key indicators of research activities: research and development (R&D) funding, total science and engineering doctoral degrees, patents, and scientific publications. We compared these indicators across three major population and economic regions: the US, the European Union (EU) and the People's Republic of China (China) over the past decade. We discovered a number of interesting trends with direct relevance for science policy. The level of US FRF has varied between 0.2% and 0.6% of the GDP during the last six decades. Since the 1960s, the US FRF contribution has fallen from twice that of industrial research funding to roughly equal. Also, in the last two decades, the portion of the US government R&D spending devoted to research has increased. Although well below the US and the EU in overall funding, the current growth rate for R&D funding in China greatly exceeds that of both. Finally, the EU currently produces more science and engineering doctoral graduates and scientific publications than the US in absolute terms, but not per capita. This study's aim is to facilitate a serious discussion of key questions by the research community and federal policy makers. In particular, our results raise two questions with respect to: a) the increasing globalization of science: "What role is the US playing now, and what role will it play in the future of international science?"; and b) the ability to produce beneficial innovations for society: "How will the US continue to foster its strengths?"


Magnetic resonance imaging in the diagnosis of lymphoma involving the brachial plexus in a cat.
An 11-year-old, neutered, female Domestic Long Hair cat had a 3-week history of left forelimb lameness. Conscious proprioception and postural reflexes were absent on the left thoracic limb. The cat had slightly reduced placing and hopping responses on the left pelvic limb, absent cutaneous trunci muscle reflex on the left side, and left triceps muscle atrophy. Magnetic resonance imaging revealed a 2 x 2 x 2 cm mass in the region of the left brachial plexus. The cat was treated by left forelimb amputation and hemilaminectomy. Histopathology of the brachial plexus revealed lymphoma.


Jarcho-Levin syndrome presenting as neural tube defect: report of four cases and pitfalls of diagnosis.
Jarcho-Levin syndrome (JLS) causes severe vertebral and thoracic deformity and has an autosomal-recessive mode of inheritance. Prenatal diagnosis may be difficult in some cases without the history of an affected baby. We present 4 cases of JLS with neural tube defects as the prominent finding. In 2 of them the deformity of the thorax was minimal and was not detected by ultrasonography. Rib anomalies were revealed with radiological and pathological examinations after the termination. The location of the vertebral defect may be the determinant factor for the severity of the thoracic deformity. The real recurrence risk could only be found out after postnatal examinations in cases with neural tube defects.


The joint neurotoxic action of inhaled methyl butyl ketone vapor and dermally applied O-ethyl O-4-nitrophenyl phenylphosphonothioate in hens: potentiating effect.
The neurotoxic action of inhaled technical grade methyl butyl ketone and dermally applied (O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN) was studied. Three groups of five hens each were treated 5 days/week for 90 days with a dermal dose of 1.0 mg/kg of EPN (85%) on the unprotected back of the neck. These groups were exposed simultaneously to 10, 50, or 100 ppm of technical methyl butyl ketone (MBK; methyl n-butyl ketone:methyl isobutyl ketone, 7:3) in inhalation chambers. A fourth group was treated only with the dose of EPN and a fifth group with only 100 ppm MBK. The control consisted of a group of five hens treated with a dose of 0.1 ml acetone. Treatment was followed by a 30-day observation period. Simultaneous exposure to EPN and MBK greatly enhanced the neurotoxicity produced when compared to the neurotoxicity produced by either chemical when applied alone. Continued exposure to EPN and MBK resulted in earlier onset and more severe signs of neurotoxicity than exposure to either individual compound. The severity and characteristics of histopathologic lesions in hens given the same daily dermal dose of EPN in combination with inhaled MBK depended on the MBK concentration. Histopathologic changes were more severe and prevalent in the 100 ppm MBK:1 mg/kg EPN group than in the others. In this group, Wallerian-type degeneration was seen along with paranodal axonal swellings. The morphology and distribution of these lesions were characteristic of those induced by MBK. In the 50 ppm MBK:1 mg/kg EPN group axonal swelling was evident but not clearly identifiable as paranodal. Hens treated with 10 ppm MBK:1 mg/kg EPN had minimal lesions with low incidence of axonal swellings. These were not as large as those seen in MBK neurotoxicity, but instead resembled the histopathologic lesions caused by EPN. The results indicate that the combined treatment gave a value for neurotoxicity coefficient which was two times the additive neurotoxic effect of each treatment alone. Pretreatment with three daily ip doses of 5 mmol/kg technical grade MBK or methyl n-butyl ketone (MnBK), equally increased chicken hepatic microsomal cytochrome P-450 content. Also, hepatic microsomes from MBK-treated hens metabolized [14C]EPN in vitro to [14C]EPN oxon to a much greater extent than those from control hens. These results suggest that MBK potentiates the neurotoxic effect of EPN, at least in part, by increasing the metabolic activation of EPN to the more neurotoxic metabolite EPN oxon.(ABSTRACT TRUNCATED AT 400 WORDS)


An update on Acanthamoeba keratitis: diagnosis, pathogenesis and treatment.
Free-living amoebae of the genus Acanthamoeba are causal agents of a severe sight-threatening infection of the cornea known as Acanthamoeba keratitis. Moreover, the number of reported cases worldwide is increasing year after year, mostly in contact lens wearers, although cases have also been reported in non-contact lens wearers. Interestingly, Acanthamoeba keratitis has remained significant, despite our advances in antimicrobial chemotherapy and supportive care. In part, this is due to an incomplete understanding of the pathogenesis and pathophysiology of the disease, diagnostic delays and problems associated with chemotherapeutic interventions. In view of the devastating nature of this disease, here we present our current understanding of Acanthamoeba keratitis and molecular mechanisms associated with the disease, as well as virulence traits of Acanthamoeba that may be potential targets for improved diagnosis, therapeutic interventions and/or for the development of preventative measures. Novel molecular approaches such as proteomics, RNAi and a consensus in the diagnostic approaches for a suspected case of Acanthamoeba keratitis are proposed and reviewed based on data which have been compiled after years of working on this amoebic organism using many different techniques and listening to many experts in this field at conferences, workshops and international meetings. Altogether, this review may serve as the milestone for developing an effective solution for the prevention, control and treatment of Acanthamoeba infections.


Isomorphism between ice and silica.
Both ice and silica crystallize into solid-state structures composed of tetrahedral building units that are joined together to form an infinite four-connected net. Mathematical considerations suggest that there is a vast number of such nets and thus potential crystal structures. It is therefore perhaps surprising to discover that, despite the differences in the nature of interatomic interactions in these materials, a fair number of commonly observed ice and silica phases are based on common nets. Here we use computer simulation to investigate the origin of this symmetry between the structures formed for ice and silica and to attempt to understand why it is not complete. We start from a comparison of the dense phases and then move to the relationship between the different open (zeolitic and clathratic) structures formed for both materials. We show that there is a remarkably strong correlation between the energetics of isomorphic silica and water ice structures and that this correlation arises because of the strong link between the total energy of a material and its local geometric features. Finally, we discuss a number of as yet unsynthesized low-energy structures which include a phase of ice based on quartz, a silica based on the structure of ice VI, and an ice clathrate that is isomorphic to the silicate structure nonasil.


Lung transplantation in sarcoidosis.
Lung transplantation (LT) is an appropriate therapeutic option for patients with severe, fibrocystic pulmonary sarcoidosis refractory to medical therapy. Survival rates following LT for sarcoidosis are generally comparable to other indications. Timing of transplantation for patients with sarcoidosis is challenging because mortality rates are high (27 to 53%) among sarcoid patients awaiting LT. Deciding when to refer patients for LT is difficult because models predicting mortality have not been validated. Importantly, algorithms or parameters predicting mortality in idiopathic pulmonary fibrosis and other interstitial pneumonias may not apply to sarcoidosis. Pulmonary function tests do not correlate well with mortality risk in patients with sarcoidosis. However, retrospective studies have shown that the presence of pulmonary arterial hypertension in sarcoidosis is an ominous sign and warrants referral for LT. This article reviews indications and contraindications to LT among patients with sarcoidosis, examines risk factors for mortality, and discusses optimal timing of referral for LT. Early referral of patients allows for timely evaluation of patients for possible listing. If the risks specific to transplantation in sarcoidosis are considered and carefully evaluated, outcomes are reasonable and match those of other diagnoses. Recurrent sarcoidosis in the lung allografts can occur but does not affect survival or risk for complications.


Kronos scRT: a uniform framework for single-cell replication timing analysis.
Mammalian genomes are replicated in a cell type-specific order and in coordination with transcription and chromatin organization. Currently, single-cell replication studies require individual processing of sorted cells, yielding a limited number (<100) of cells. Here, we develop Kronos scRT, a software for single-cell Replication Timing (scRT) analysis. Kronos scRT does not require a specific platform or cell sorting, which allows investigating large datasets obtained from asynchronous cells. By applying our tool to published data as well as droplet-based single-cell whole-genome sequencing data generated in this study, we exploit scRT from thousands of cells for different mouse and human cell lines. Our results demonstrate that although genomic regions are frequently replicated around their population average RT, replication can occur stochastically throughout S phase. Altogether, Kronos scRT allows fast and comprehensive investigations of the RT programme at the single-cell resolution for both homogeneous and heterogeneous cell populations.