Effects of nucleotide supplementation in milk replacer on small intestinal absorptive capacity in dairy calves.
Milk replacer was supplemented with nucleotides and fed to dairy calves from birth through weaning to examine the potential for enhancing recovery of small intestinal function after enteric infection. Three treatments of 23 calves each were fed milk replacer (10% body weight/d) supplemented with no nucleotides (C), purified nucleotides (N), or nucleotides from an extract of Saccharomyces cerevisiae (S). Average daily gain, health scores, fecal dry matter, and fecal bacteria were monitored, and blood was analyzed for packed cell volume, glucose, blood urea nitrogen (BUN), and creatinine. Calves were monitored twice daily for fecal score, and 48 h after increased fecal fluidity was recorded, intestinal function was evaluated by measuring absorption of orally administered xylose (0.5 g/kg of body weight). Packed cell volume of blood was greater for treatment N for wk 2 and 5 compared with other treatment groups. Four calves per treatment were killed, and intestinal tissue was evaluated for morphology, enzyme activities, and nucleoside transporter mRNA expression. Treatment S calves had increased abundance of nucleoside transporter mRNA, numerically longer villi, and lower alkaline phosphatase than other groups. Growth measurements and plasma concentrations of glucose, BUN, creatinine, and IgG were not different between treatments; however, BUN-to-creatinine ratio was higher for treatment N, possibly indicating decreased kidney function. There were also no treatment effects on fecal dry matter and fecal bacteria population. However, N-treated calves had the highest detrimental and lowest beneficial bacteria overall, indicating an unfavorable intestinal environment. Supplementation of purified nucleotides did not improve intestinal morphology or function and resulted in higher fecal water loss and calf dehydration. Supplementation of nucleotides derived from yeast tended to increase calf intestinal function, provide a more beneficial intestinal environment, and improve intestinal morphology.


Evaluation of the Medical Academic Community of Bosnia and Herzegovina Based on Scopus Parameters.
The academic community of Bosnia and Herzegovina (B&H) is represented by four Academies, which include eminent personalities in the field of medical sciences (Academy of Sciences and Arts of Bosnia and Herzegovina, Department for Medical Sciences (ANUBiH), Academy of Sciences and Arts of the Republika Srpska (ANURS), Croatian Academy of Sciences and Arts in BiH (HAZU B&H), and the Academy of Medical Sciences of Bosnia and Herzegovina (AMNuBiH)). To present scientometric analysis of members of the medical sphere of the ANUBiH, ANURS, HAZU B&H and AMNuBiH, to evaluate members and their scientific rating. The work has an analytical character and presents analysis of the data obtained from the Scopus database. Results are shown through number of cases, percentage, arithmetic mean, standard deviation, median and interquartile range, with Spearman's rank correlation coefficient. The analysis showed a significant correlation between the Academy and the country of origin of the academician. In AMNuBiH and ANUBiH are mainly represented academics originating from Bosnia and Herzegovina, while ANURS, 71.4% of the members, are academics with background from Serbia. There is no significant correlation between the observed parameters (Scopus parameters-number of papers, H index, number of citations) according to memberschip in Academies. By analyzing the correlation between the country of residence, the number of papers, H index and the number of citations, it has been shown that the correlation is significant between the state and the number of papers, but not the other two observed parameters. Criteria for admission to main academic communities are highly questionable, as this analysis showed. Progress in the academic hierarchy must be more stringent, and the criteria must be set to the highest possible level, as this is the only path which leads to progress.


A questionnaire assessment of nutrition knowledge--validity and reliability issues.
This study describes an evaluation of validity and reliability measures in a questionnaire designed to assess knowledge of applied nutrition in children participating in an after-school care dietary intervention programme being undertaken in an area of high social disadvantage. Three domains were assessed: Knowledge of Applied Nutrition (KN), Knowledge of Food Preparation (KP) and Perceived Confidence in Cooking Skills (PC). Four pilot studies were undertaken to determine item reliability, test-retest reliability, discrimination and difficulty indices, and content, cognitive and face validity. Primary schools in Dundee, Scotland and Newcastle upon Tyne, England. Ninety-eight children aged 11 years. The final instrument comprised 36 questions (18 KN items, 9 KP items and 9 PC items) presented on four sides of paper, which could be self-completed in less than 15 minutes. Question formatting included open and closed structures (KP) and multiple choice (KN and PC) items. All knowledge questions could be answered correctly by 5 to 95% of the target population, with discrimination scores ranging from 0.06 to 0.83. Retest reliability scores were significant (KN 0.458, KP 0.577, PC 0.381, ) and internal reliability (Cronbach's alpha) of each component was also significant. The test meets basic psychometric criteria for reliability and validity and forms a suitable instrument for measuring changes associated with intervention work aimed at improving food and dietary knowledge.


Critical thinking dispositions among newly graduated nurses.
The aim of the study was to describe critical thinking dispositions among newly graduated nurses in Norway, and to study whether background data had any impact on critical thinking dispositions. Competence in critical thinking is one of the expectations of nursing education. Critical thinkers are described as well-informed, inquisitive, open-minded and orderly in complex matters. Critical thinking competence has thus been designated as an outcome for judging the quality of nursing education programmes and for the development of clinical judgement. The ability to think critically is also described as reducing the research-practice gap and fostering evidence-based nursing. A cross-sectional descriptive study was performed. The data were collected between October 2006 and April 2007 using the California Critical Thinking Disposition Inventory. The response rate was 33% (n = 618). Pearson's chi-square tests were used to analyse the data. Nearly 80% of the respondents reported a positive disposition towards critical thinking. The highest mean score was on the Inquisitiveness subscale and the lowest on the Truth-seeking subscale. A statistically significant higher proportion of nurses with high critical thinking scores were found among those older than 30 years, those with university education prior to nursing education, and those working in community health care. Nurse leaders and nurse teachers should encourage and nurture critical thinking among newly graduated nurses and nursing students. The low Truth-seeking scores found may be a result of traditional teaching strategies in nursing education and might indicate a need for more student-active learning models.


Longitudinal proton relaxation rates in rabbit tissues after intravenous injection of free and chelated Mn2+.
The factors that determine the field-dependent increase in 1/T1 of tissue water protons were investigated for MnCl2 and Mn2+ (PDTA) (1,3-propylenediamine-N,N',N'',N'''-tetraacetic acid) introduced intravenously into rabbits. Mn2+ was used in preference to other paramagnetic ions in part because of the distinct NMRD profiles (magnetic field dependence of 1/T1) of free Mn2+ ions, their small chelate complexes, and their macromolecular conjugates, and in part because the relatively low toxicity of Mn2+ is favorable for animal studies. Tissue content of Mn2+ was determined in all samples by inductively coupled plasma analyses the state of Mn2+ in excised tissues was determined from the form of the 1/T1 NMRD profile of water protons; and distribution of contrast agent within tissue and access of water on a T1 time scale were determined by double-exponential analyses of proton relaxation behavior in intact doped tissue, as well as by the change of single-exponential relaxation rates and proton signal intensity upon gentle disruption of the tissue. MnCl2 is found in all tissues, except fat and skeletal muscle, but liver is most avid at low dose, and Mn2+ accumulates in spleen after high doses. Chelation targets Mn2+ to liver and kidney, saturating the liver chemically at relatively low dose. We suggest that pronounced increase in tissue relaxivity results from irrotationally bound Mn2+, ostensibly associated with the polar head groups of cell membranes. Compartmentalization of contrast agent and restricted diffusion of tissue water influences the maximum relaxation rates attainable, so that there is an optimal dose of these contrast agents which is rather low.


The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study.
The REG2 Anticoagulation System consists of pegnivacogin, a subcutaneously administered aptamer factor IXa inhibitor, and its intravenous active control agent, anivamersen. Its effect on thrombin generation is unknown. A prospectively designed thrombin generation study was conducted within the phase 1 ascending dose study of REG2 to assess the effect of REG2 on thrombin generation kinetics. A total of 32 healthy volunteers were recruited into four cohorts of ascending dose pegnivacogin for the phase 1 study. In this pre-specified substudy, blood samples were drawn in the presence or absence of corn trypsin inhibitor at specified times within each dosing cohort. Thrombin generation was initiated with tissue factor and thrombin generation kinetics were measured using the Calibrated Automated Thrombogram (CAT). REG2 attenuated thrombin generation in a dose-dependent manner. All parameters of the CAT assay, except for lag time, showed a dose and concentration-dependent response to pegnivacogin [time to peak thrombin generation (PTm), endogenous thrombin potential, peak thrombin generation, and velocity index (VIx)]. Reversal of the effect of pegnivacogin with anivamersen demonstrated restoration of thrombin generation without rebound effect. This first-in-human study of the effect of the REG2 Anticoagulation System on thrombin generation demonstrates concentration-dependent suppression of thrombin generation that is reversible without rebound effect, as measured by the CAT assay.


[Safety of long-term replacement hormonal therapy in patients with erectile dysfunction and androgen deficiency].
Safety of testosterone undecanoate in relation to initiation of cancer and prostatic adenoma (PA) in patients with androgenic deficiency and erectile dysfunction (ED) was studied for 12 months in 49 patients aged 57 to 73 years treated with intramuscular testosteron injections. The size of the prostate in patients with adenoma was 46.34 +/- 21.12 cm3 while in adenoma-free patients--19.11 +/- 6.57 sm3. Diabetes mellitus of type 2 (DM-2) was diagnosed in 46.9% patients. All the patients had documented hypogonadism and ED. Tests for PSA and transrectal ultrasound investigation was made in all the patients. 12 month testosterone therapy produced normalization of a mean level of testosterone in both groups, index of erectile function increased. In one patient PSA rose higher than normal value. None of the patients developed obstruction of the urinary tract. Body mass index, lipid spectrum and carbohydrate metabolism also improved. Thus, long-term therapy with testosterone undecanoate has no effect on PSA level, does not induce urinary obstruction with enlarged prostate. The presence of DM-2 is not a contraindication for androgen therapy in adenoma patients. By reducing body mass index, total cholesterol, triglycerides and LDLP, testosterone therapy lowers the risk of prostatic cancer.


Metabolism, Transport and Drug-Drug Interactions of Silymarin.
Silymarin, the extract of milk thistle, and its major active flavonolignan silybin, are common products widely used in the phytotherapy of liver diseases. They also have promising effects in protecting the pancreas, kidney, myocardium, and the central nervous system. However, inconsistent results are noted in the different clinical studies due to the low bioavailability of silymarin. Extensive studies were conducted to explore the metabolism and transport of silymarin/silybin as well as the impact of its consumption on the pharmacokinetics of other clinical drugs. Here, we aimed to summarize and highlight the current knowledge of the metabolism and transport of silymarin. It was concluded that the major efflux transporters of silybin are multidrug resistance-associated protein (MRP2) and breast cancer resistance protein (BCRP) based on results from the transporter-overexpressing cell lines and MRP2-deficient (TR-) rats. Nevertheless, compounds that inhibit the efflux transporters MRP2 and BCRP can enhance the absorption and activity of silybin. Although silymarin does inhibit certain drug-metabolizing enzymes and drug transporters, such effects are unlikely to manifest in clinical settings. Overall, silymarin is a safe and well-tolerated phytomedicine.


No prognostic significance of chronic infection with Chlamydia pneumoniae in acute coronary syndromes: insights from the Global Utilization of Strategies to Open Occluded Arteries IV Acute Coronary Syndromes trial.
Although relationships between chronic Chlamydia pneumoniae (Cpn) infection and the risk of coronary events in stable coronary artery disease patients have been reported, a similar link in acute coronary syndrome (ACS) patients has not been consistently observed. In a nested case-control substudy of the Global Utilization of Strategies to Open Occluded Arteries IV Acute Coronary Syndromes trial, 295 cases (30-day death/myocardial infarction [MI]) were matched by age, sex, baseline creatine kinase-myocardial kinase, and smoking status with 295 control subjects. To test the hypothesis on 1-year mortality, another subset (n = 276) was drawn from the 590-patient cohort; 138 patients who died at 1 year plus the matching controls who survived at 1 year. We measured Cpn IgG and IgA antibody titers in baseline serum with microimmunofluorescence. Conditional logistic regression was used to quantify the prognostic relevance seropositivity (IgG > or = 1:32; IgA > or = 1:16) and elevated titer levels. The prevalence of Cpn IgG and IgA was similar between cases and controls (30-day death/MI: IgG, 80% vs 85%, P = .126; IgA, 45% vs 37%, P = .079), and were not statistically significant predictors of 30-day death/MI after baseline adjustment. Likewise, the 1-year death cohort had comparable proportions of Cpn IgG and IgA among cases and controls (86% vs 91% [P = .265] and 49% vs 43% [P = .334], respectively), and did not add prognostic value. These findings are in concert with study results suggesting that chronic Cpn infection is not associated with 30-day death/MI or 1-year mortality in non-ST elevation ACS.


Complement and complement-like activity in lower vertebrates and invertebrates.
A purified cobra venom factor with C-inhibiting activity also promotes lysis of erythrocytes in fresh mammalian serum. Lysis-inducing activity of purified cobra venom factor was found in sera of lower vertebrates including the cyclostome hagfish and in invertebrates. Lysis-inducing activity was most effective with frog serum. Frog serum was found to be more hemolytic for E(s) in the presence of CVF than when cells were sensitized with hemolysin. The hemolysis induced by CVF with frog serum, as in the higher vertebrates, was inhibited when sera were pretreated with known C inhibitors including heat, chelators, endotoxin, immune complexes, and CVF itself. Complexes formed with CVF and either frog serum or invertebrate hemolymph promoted lysis of indicator cells in the presence of frog serum in EDTA. This lysis was most marked when the starfish-CVF complex was used and was C-dependent. Conversely, complex formed with frog serum and CVF promoted lysis of E in the presence of invertebrate hemolymph (Limulus) in EDTA. Hence, serum components were to some degree at least interchangeable between vertebrate sera and invertebrate hemolymph. Lysis-inducing activity of purified CVF occurs in a wide range of species, has revealed activities resembling those of terminal C-components in lower vertebrates and invertebrates, and provides one means for study of C and C-like activities in primitive species.


Assessment of function and quality of life in a phase II multi-institutional clinical trial of fractionated simultaneous in-field boost radiotherapy for patients with 1-3 metastases.
We examined functional outcomes and quality of life of whole brain radiotherapy (WBRT) with integrated fractionated stereotactic radiotherapy boost (FSRT) for brain metastases treatment. Eighty seven people with 1-3 brain metastases (54/87 lung primary, 42/87 single brain metastases) were enrolled on this Phase II trial of WBRT (30 Gy/10) + simultaneous FSRT, (60 Gy/10). Median overall follow-up and survival was 5.4 months, 6 month actuarial intra-lesional control was 78 %; only 1 patient exhibited grade 4 toxicity (worsened seizures); most treatment related toxicity was grade 1 or 2; 2/87 patients demonstrated asymptomatic radiation necrosis on follow-up imaging. Mean (Min-Max) baseline KPS, Mini Mental Status Exam (MMSE) and FACT-BR quality of life were 83 (70-100), 28 (21-30) and 143 (98-153). Lower baseline MMSE (but not KPS or FACT-Br) was associated with worse survival after adjusting for age, number of metastases, primary and extra-cranial disease status. Crude rates of deterioration (>10 points decrease from baseline for KPS and FACT-Br, MMSE fall to <27) ranged from 26 to 38 % for KPS, 32-59 % for FACT-Br and 0-16 % for MMSE depending on the time-point assessed with higher rates generally noted at earlier time points (≤6 months post-treatment). Using a linear mixed models analysis, significant declines from baseline were noted for KPS and FACT-Br (largest effects at 6 weeks to 3 months) with no significant change in MMSE. The effects on function and quality of life of this integrated treatment of WBRT + simultaneous FSRT were similar to other published series combining WBRT + radiosurgery.


How does IQ affect onset of smoking and cessation of smoking--linking the Swedish 1969 conscription cohort to the Swedish survey of living conditions.
To examine the association between intelligence quotient (IQ) measured at ages 18 to 20 and onset of smoking, and the association between IQ and smoking cessation. Data on IQ, smoking, mental health, and social background among 49,321 Swedish men born 1949 to 51, collected at conscription for military service in 1969, were used. The association between IQ and smoking cessation was investigated among those 694 members of the full cohort also interviewed in the Swedish Level of Living Conditions study 1981 to 2002. Lower IQ measured at ages 18 to 20 was weakly associated with increased prevalence of smoking, independently of indicators of mental illness and social misbehavior measured in late adolescence. By contrast, smoking cessation later in life among those who smoked at ages 18 to 20 was not associated with IQ. Among smokers, lower IQ was significantly associated with a lower level of smoking after adjusting for other factors. Low IQ was associated with an increased prevalence of smoking in adolescence. However, the main part of this association disappeared after adjustment for measures of mental health and social function in early life. IQ was not associated with likelihood of quitting smoking.


Schizophrenia polygenic risk score in psychosis proneness.
Schizophrenia (SZ) is a complex disorder with a highly polygenic inheritance. It can be conceived as the extreme expression of a continuum of traits that are present in the general population often broadly referred to as schizotypy. However, it is still poorly understood how these traits overlap genetically with the disorder. We investigated whether polygenic risk for SZ is associated with these disorder-related phenotypes (schizotypy, psychotic-like experiences, and subclinical psychopathology) in a sample of 253 non-clinically identified participants. Polygenic risk scores (PRSs) were constructed based on the latest SZ genome-wide association study using the PRS-CS method. Their association with self-report and interview measures of SZ-related traits was tested. No association with either schizotypy or psychotic-like experiences was found. However, we identified a significant association with the Motor Change subscale of the Comprehensive Assessment of At-Risk Mental States (CAARMS) interview. Our results indicate that the genetic overlap of SZ with schizotypy and psychotic-like experiences is less robust than previously hypothesized. The relationship between high PRS for SZ and motor abnormalities could reflect neurodevelopmental processes associated with psychosis proneness and SZ.


Understanding cross-national differences in depression prevalence.
BACKGROUND. Previous epidemiological studies indicate large cross-national differences in prevalence of depression. At 15 centres in 14 countries. 25,916 primary care patients were screened for common mental disorders. A stratified random sample of 5,447 primary care patients completed a baseline diagnostic assessment and 3,197 completed a 12-month follow-up assessment. Psychiatric symptoms and diagnoses were assessed using the Composite International Diagnostic Interview (CIDI). Interviewer-rated disability was assessed using the Social Disability Schedule (SDS). Prevalence of current major depression varied 15-fold across centres. When centres were divided into three groups according to prevalence rates, the symptom pattern or latent structure of depressive illness was generally similar at low-, medium-, and high-prevalence centres. Depression was universally associated with disability, but this association varied significantly (t = 3.51, P = 0.0005) across centres. At higher-prevalence centres, depression was associated with lower levels of impairment. At 1 year follow-up, higher prevalence centres had both significantly higher rates of depression onset (t = 3.11, P = 0.002) and higher rates of persistence among those depressed at baseline (t = 2 49, P = 0.013). Large cross-national variations in depression prevalence cannot be attributed to 'category fallacy' (cross-national differences in the nature or validity of depressive disorder). Use of identical measures and diagnostic criteria may actually identify different levels of depression severity in different countries or cultures. Cross-national differences in the onset and outcome of depression may reflect either true prevalence differences or differences in diagnostic threshold.


Poor outcome of patients with resectable breast cancer receiving adjuvant high-dose sequential chemotherapy following preoperative treatment.
The prognosis of resectable high risk breast cancer (BC) patients (N+ > 10) is poor with a five-year disease-free survival (DFS) after standard adjuvant ADM/CMF chemotherapy (CT) of about 40%. An improvement in survival has been reported when high-dose chemotherapy with autologous stem cell support is given. It has been recently suggested that nodal status and the degree of pathological remission following preoperative CT administered in patients harbouring tumors larger than 3 cm represent the most important prognostic factors for DFS. Since no data are available regarding the impact of primary CT in the high dose CT adjuvant setting, we retrospectively evaluated the efficacy of administering megadoses of cytotoxic drugs with stem cell support in the subgroup of patients showing poor response to preoperative CT., Fourteen women with high risk BC, N+ > 10 and tumor size > 3 cm following antracyclin-based primary CT, received high dose sequential chemotherapy (HDS). The median number of positive axillary nodes at surgery was 18 and tumor size was greater than 5 cm in 6 patients. HDS chemotherapy consisted of cyclophosphamide (7 gr/m2), methotrexate (8 gr/m2) plus vincristin (2 mg), 2 courses of carboplatin (360 mg/m2), and Thiotepa (600 mg/m2) plus L-PAM (160 mg/m2) as final myeloablative regimen requiring stem cell support. At a minimum follow up of 12 months (median 18 months, range 12-40) 5 patients remained disease free (36%) and 9 (64%) have relapsed (7 within the first 10 months). Our retrospective analysis suggests that BC patients showing poor response to primary CT might fail to achieve the benefits expected from high dose intensification.


p38 Map kinase regulates vascular smooth muscle cell collagen synthesis by angiotensin II in SHR but not in WKY.
Vascular remodeling in hypertension is associated with cell growth and increased deposition of extracellular matrix components, particularly collagen. Mechanisms underlying these processes are unclear, but MAP kinases, particularly ERK1/2 and p38 MAP kinase, may be important. We studied the role of ERK1/2 and p38 MAP kinase in vascular smooth muscle cell (VSMC) collagen synthesis and growth mediated by angiotensin (Ang) II in spontaneously hypertensive rats (SHR). Cultured mesenteric VSMC from Wistar-Kyoto rats and SHR were used. Phosphorylation of ERK1/2 and p38 MAP kinase were assessed by Western blots with phosphospecific antibodies. Ang II-stimulated DNA and collagen synthesis were determined by measuring incorporation of (3)H-thymidine and (3)H-proline, respectively. mRNA expression of procollagen I and III was determined by reverse transcription-polymerase chain reaction. Ang II increased ERK1/2 and p38 MAP kinase phosphorylation. Responses were augmented in SHR. Effects were inhibited by irbesartan, a selective AT(1) antagonist, but not by PD123319, a selective AT(2) blocker. Ang II stimulated (3)H-thymidine and (3)H-proline incorporation. These actions were enhanced 2- to 3-fold in SHR. PD98059, selective inhibitor of the ERK1/2 pathway, attenuated Ang II-induced growth and collagen effects and normalized responses in SHR. SB212190, a selective p38 MAP kinase inhibitor, did not alter Ang II-elicited DNA synthesis but reduced collagen production and mRNA expression of procollagen I and III in SHR. These data demonstrate that (1) Ang II-mediated activation of p38 and ERK1/2 is increased in SHR, (2) augmented growth responses are generated by ERK1/2-dependent, p38 MAP kinase-independent pathways, and (3) p38 MAP kinase influences Ang II-induced collagen production in SHR but not in Wistar-Kyoto rats. These results indicate differential roles of ERK1/2 and p38 MAP kinase in AT(1)-stimulated VSMC growth and collagen production, which may contribute to vascular remodeling in hypertension.


Three-Dimensional Nitrogen-Doped Carbonaceous Networks Anchored with Cobalt as Separator Modification Layers for Low-Polarization and Long-Lifespan Aluminum-Sulfur Batteries.
Aluminum-sulfur (Al-S) batteries have attracted extensive interest due to their high theoretical energy density, inherent safety, and low cost. However, severe polarization and poor cycling performance significantly limit the development of Al-S batteries. Herein, three-dimensional (3D) nitrogen-doped carbonaceous networks anchored with cobalt (Co@CMel-ZIF) is proposed as a separator modification layer to mitigate these issues, prepared via carbonizations of a mixture of ZIF-7, melamine, and CoCl2. It exhibits a 3D network structure with a moderate surface area and high average pore diameter, which is demonstrated to be effective in adsorbing the aluminum polysulfides and hindering the mobility of polysulfides across the separator for enhanced cyclic stability of Al-S batteries. Meanwhile, Co@CMel-ZIF are characterized by abundant catalytic pyridinic-N and Co-Nx active sites that effectively eliminate the barrier of sulfides' conversion and thereby facilitate the polarization reduction. As a result, Al-S cells based on the separator modified with Co@CMel-ZIF exhibit a low voltage polarization of 0.47 V under the current density of 50 mA g-1 at 20 °C and a high discharge specific capacity of 503 mAh g-1 after 150 cycles. In contrast, the cell employing a bare separator exhibits a polarization of 1.01 V and a discharge capacity of 300 mAh g-1 after 70 cycles under the same conditions. This work demonstrates that modifying the separators is a promising strategy to mitigate the high polarization and poor cyclability of Al-S batteries.


Associations of the Ratios of n-3 to n-6 Dietary Fatty Acids With Longitudinal Changes in Depressive Symptoms Among US Women.
In the present study, we examined longitudinal changes in self-reported depressive symptoms (and related domains) in relation to baseline intakes of n-3 fatty acids (absolute and relative to n-6 fatty acids). Sex-specific associations were evaluated in a prospective cohort of adults (n = 2,053) from Baltimore, Maryland, who were 30-64 years of age at baseline and were followed for a mean of 4.65 (standard deviation, 0.93) years (2004-2013). Using mean intakes of n-3 and n-6 fatty acids reported on two 24-hour dietary recalls, we estimated the ratios of n-3 to n-6 fatty acids for both highly unsaturated fatty acids (≥20 carbon atoms) (HUFAs) and polyunsaturated fatty acids (≥18 carbon atoms) (PUFAs). Outcomes included total and domain-specific scores on the 20-item Center for Epidemiologic Studies-Depression scale. Based on mixed-effects regression models, among women, both higher n-3 HUFA:n-6 PUFA and n-3 PUFA:n-6 PUFA ratios were associated with a slower rate of increase in total Center for Epidemiologic Studies-Depression scores over time. Higher n-3 HUFA:n-6 HUFA ratios were associated with slower increases in somatic complaints in men, whereas among women, higher n-3 HUFA:n-6 PUFA and n-3 PUFA:n-6 PUFA ratios were both linked to putative longitudinal improvement in positive affect over time. Among US adults, n-3:n-6 dietary fatty acid ratio was associated with longitudinal changes in depressive symptoms, with a higher ratio linked to a slower increase in depressive symptoms over time, particularly among women.


[Immunological shifts in trauma].
The level of immunoglobulins, complement and properdin, data of leukograms were studied in 40 patients with closed fractures of bones with noncomplicated and complicated (by a purulent infection) course of the posttraumatic period. The authors have established variants of changes of these parameters, their correlation with the adaptation reactions of the organism and severity of the trauma.


Role of selective alpha 1 blockers in the therapy of hypertension.
As millions more patients with mild hypertension are being brought into active drug therapy, the need for effective medications that are safe for long-term use has increased. This is, in part, as a result of the adverse effect on coronary heart disease mortality observed in two of the major therapeutic trials, the Oslo Study and the Multiple Risk Factor Intervention Trial. In both of these, the diuretic-first, stepped-care approach was used. Administration of diuretics is frequently associated with such biochemical abnormalities as hypokalemia, hypercholesterolemia, and hyperglycemia. Thus, the wisdom of the routine use of a diuretic as the first choice of therapy is being questioned. Alternative drugs for initial therapy include beta blockers and selective alpha 1 blockers. With beta blockers, there is a tendency for serum triglycerides to increase and high-density lipoprotein cholesterol to decline, as well as a tendency for an undesirable reduction in cardiac output and an increase in peripheral resistance. Selective alpha 1 blockers, because they lower blood pressure in a hemodynamically more favorable manner and have a tendency to improve the lipid profile, are becoming increasingly attractive as initial therapy for mild hypertension and also as part of the combination needed for more severe disease. The favorable results noted with the new selective alpha 1 blocker terazosin strongly support its addition to the list of preferred drugs for initial therapy.


Number of viable CD34(+) cells reinfused predicts engraftment in autologous hematopoietic stem cell transplantation.
Reduced CD34(+) cell viability due to cryopreservation has unknown effects on subsequent hematopoietic engraftment in autologous transplantation. Thirty-six consecutive autologous peripheral stem cell collections were analyzed for absolute viable CD34(+) cell numbers at the time of stem cell collection and prior to re-infusion. Viable CD34(+) cells were enumerated using single platform flow cytometry and the molecular exclusion dye 7-amino actinomycin D. The median number of viable CD34(+) cells was 3.6 x 10(6)/kg at the time of harvest and 2.0 x 10(6)/kg after thawing. When viable CD34(+)cells enumerated after thawing were <2.0, 2.0-5.0, or >5.0 x 10(6)/kg, the median time to platelet engraftment was 17, 12 and 10 days, respectively (P < 0.05 for comparison of the group with <2.0 x 10(6)/kg and the other two groups), and the median time to neutrophil engraftment was 13, 14 and 12 days, respectively (P = NS). A minimum of 2.0 x 10(6) CD34(+) cells/kg was harvested in 33 of 36 patients (92%) but only 19 of 36 (52%) patients met this threshold at the time of reinfusion. The reduced numbers of viable CD34(+) cells measured prior to re-infusion is associated with time to platelet engraftment and may be useful in monitoring stem cell loss during processing and identifying patients at risk of graft failure.


Clinical experience with long-term cromolyn sodium administration in 53 asthmatic children.
Cromolyn sodium was administered by inhalation four times a day to 53 severely asthmatic children for periods ranging from 10 to 43 months. The patients were seen at follow-up vists at least once a month through the entire study period. At the cut-off point of the study cromolyn sodium had been effective in controlling asthma by reducing the level of asthma symptoms, such as coughing, wheezing, sleep disturbance and sputum output. In addition there was a reduction in the patients' requirements for concomitant anti-asthma medications (including corticosteroids) and the number of hospitalizations and school absences.


A change in the management of intractable obstetrical hemorrhage over 15 years in a tertiary care center.
Peripartum hysterectomy was the gold standard to save a woman with persistent obstetrical bleeding, but compromised the menstrual and reproductive functions. Bilateral internal iliac artery ligation (BIAL) is a potentially effective, fertility preserving means of controlling pelvic hemorrhage, but with surgical and anesthetic risks and low success. Angiographic embolization has the potential to arrest severe pelvic hemorrhage without removing the uterus and without hazarding general anesthesia in a hemodynamically unstable patient. The aim of this study is to discuss change in the management of intractable obstetrical hemorrhage from removing to conserving the uterus over 15 years. A retrospective analysis of 122 cases of intractable obstetrical hemorrhage over a period of 15 years (January 1997 to December 2011) was done. We started uterine artery embolization (UAE) in 2007 for obstetrical hemorrhage. The patients were analyzed for maternal characteristics, indications, treatment modality, maternal morbidity, and mortality. Descriptive. We analyzed 12,055 deliveries, (6029 cesarean sections; 6026 vaginal deliveries). One hundred and twenty-two cases of intractable obstetrical hemorrhage were managed with obstetrical hysterectomies in 63, UAE in 53 cases and BIAL in six cases. During the period between 1997 and 2006 intractable obstetrical hemorrhage was managed by hysterectomy/internal iliac artery ligation. The last 5 years of the study period had 80 patients with intractable obstetrical hemorrhage, 53 patients underwent arterial embolization and 35 had a hysterectomy and two had internal artery ligation. There was no mortality and significantly less morbidity in embolization group in our study. Embolization should be tried in patients with intractable obstetrical hemorrhage before proceeding for surgical intervention.


Teicoplanin as an anti-methicillin resistant Staphylococcus aureus agent in infections of severely poisoned intensive care unit patients/ Tehran- Iran.
Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is related to high morbidity and mortality. Glycopeptide antibiotic is the choice of treatment in MRSA infections. Teicoplanin is a semi synthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Our objective is the evaluation of efficacy and safety of Teicoplanin in MRSA infections among severely poisoned intensive care unit (ICU) patients. During a 6 months period, in a prospective cross sectional study 54 eligible patients from 80 clinically suspicious with MRSA infections were recruited. The efficacy and safety of Teicoplanin was evaluated 5 times. The clinical findings, laboratory data, and bacteriologic responses were defined as cure, improvement and failure. The mean age of the patients was 36.3 years (range, 20-72, SD = 13.3). 75.9% were male. Suicidal attempts were recorded in 63%. The most common poisoning was TCAs, BZDs, tramadol and opium. 94.4% were unconscious and under mechanical ventilation. Tracheal cultures were positive in 98.1% by VAP diagnosis. Length of stay in the ICU was between 4-54 days. Total clinical effectiveness was 90.4%, and failure 9.6%. Mortality rate of the patient, was 9/54 (16.6 %) which 3 of them were for lack of a clinical response. On the fourth visit, the adverse effects included: rash (11.10%), anemia (36.17%), nephrotoxicity (17.02%) and thrombocytopenia < 150000 (100%). Other side effects such as: leucopenia, severe thrombocytopenia (< 50000), pancytopenia and red man syndrome were not detected. Teicoplanin is suggestible for MRSA infections among severely poisoned patients according to its efficacy, safety, half life and tolerance.


A chicken embryo protein related to the mammalian DEAD box protein p68 is tightly associated with the highly purified protein-RNA complex of 5-MeC-DNA glycosylase.
We have shown previously that DNA demethylation by chick embryo 5-methylcytosine (5-MeC)-DNA glycosylase needs both protein and RNA. Amino acid sequences of nine peptides derived from a highly purified 5-MeC-DNA glycosylase complex were identified by Nanoelectrospray ionisation mass spectrometry to be identical to the mammalian nuclear DEAD box protein p68 RNA helicase. Antibodies directed against human p68 helicase cross-reacted with the purified 5-MeC-DNA glycosylase complex and immunoprecipitated the glycosylase activity. A 2690 bp cDNA coding for the chicken homologue of mammalian p68 was isolated and sequenced. Its derived amino acid sequence is almost identical to the human p68 DEAD box protein up to amino acid position 473 (from a total of 595). This sequence contains all the essential conserved motifs from the DEAD box proteins which are the ATPase, RNA unwinding and RNA binding motifs. The rest of the 122 amino acids in the C-terminal region rather diverge from the human p68 RNA helicase sequence. The recombinant chicken DEAD box protein expressed in Escherichia coli cross-reacts with the same p68 antibodies as the purified chicken embryo 5-MeC-DNA glycosylase complex. The recombinant protein has an RNA-dependent ATPase and an ATP-dependent helicase activity. However, in the presence or absence of RNA the recombinant protein had no 5-MeC-DNA glycosylase activity. In situ hybridisation of 5 day-old chicken embryos with antisense probes of the chicken DEAD box protein shows a high abundance of its transcripts in differentiating embryonic tissues.


TNFRSF25 agonistic antibody and galectin-9 combination therapy controls herpes simplex virus-induced immunoinflammatory lesions.
Ocular infection with herpes simplex virus 1 (HSV-1) results in a chronic immunoinflamammtory reaction in the cornea, which is primarily orchestrated by CD4(+) T cells. Hence, targeting proinflammatory CD4(+) T cells or increasing the representation of cells that regulate their function is a relevant therapeutic strategy. In this report, we demonstrate that effective therapeutic control can be achieved using a combination of approaches under circumstances where monotherapy is ineffective. We use a convenient and highly effective monoclonal antibody (MAb) approach with MAbT25 to expand cells that express the tumor necrosis factor receptor superfamily member 25 (TNFRSF25). In naïve animals, these are predominantly cells that are Foxp3-positive regulatory T cells. MAbT25 treatment before or at the time of initial HSV infection was an effective means of reducing the severity of subsequent stromal keratitis lesions. However, MAbT25 treatment was not effective if given 6 days after infection since it expanded proinflammatory effector T cells, which also express TNFRSF25. Therefore, the MAbT25 procedure was combined with galectin-9 (Gal-9), an approach that compromises the activity of T cells involved in tissue damage. The combination therapy provided highly effective lesion control over that achieved by treatment with one of them. The beneficial outcome of the combination therapy was attributed to the expansion of the regulatory T cell population that additionally expressed activation markers such as CD103 needed to access inflammatory sites. Additionally, there was a marked reduction of CD4(+) gamma interferon-producing effector T cells responsible for orchestrating the tissue damage. The approach that we describe has potential application to control a wide range of inflammatory diseases, in addition to stromal keratitis, an important cause of human blindness.


Melatonin signaling dysfunction in adolescent idiopathic scoliosis.
In vitro assays were performed with bone-forming cells isolated from 41 patients with adolescent idiopathic scoliosis and 17 control patients exhibiting another type of scoliosis or none. To determine whether a dysfunction of the melatonin-signaling pathway in tissues targeted by this hormone is involved in adolescent idiopathic scoliosis. Pinealectomy in chicken has led to the formation of a scoliotic deformity, thereby suggesting that a melatonin deficiency may be at the source of adolescent idiopathic scoliosis. However, the relevance of melatonin in the etiopathogenesis of that condition is controversial because most studies have reported no significant change in circulating levels of melatonin in patients with adolescent idiopathic scoliosis. Primary osteoblast cultures prepared from bone specimens obtained intraoperatively during spine surgeries were used to test the ability of melatonin and Gpp(NH)p, a GTP analogue, to block cAMP accumulation induced by forskolin. In parallel, melatonin receptor and Gi protein functions were evaluated by immunohistochemistry and by coimmunoprecipitation experiments. The cAMP assays demonstrated that melatonin signaling was impaired in osteoblasts isolated from adolescent idiopathic scoliosis patients to different degrees allowing their classification in 3 distinct groups based on their responsiveness to melatonin or Gpp(NH)p. Melatonin signaling is clearly impaired in osteoblasts of all patients with adolescent idiopathic scoliosis tested. Classification of patients with adolescent idiopathic scoliosis in 3 groups based on functional in vitro assays suggests the presence of distinct mutations interfering with the melatonin signal transduction. Posttranslational modifications affecting Gi protein function, such as serine residues phosphorylation, should be considered as one possible mechanism in the etiopathogenesis of AIS.


Systemic spread and propagation of a plant-pathogenic virus in European honeybees, Apis mellifera.
Emerging and reemerging diseases that result from pathogen host shifts are a threat to the health of humans and their domesticates. RNA viruses have extremely high mutation rates and thus represent a significant source of these infectious diseases. In the present study, we showed that a plant-pathogenic RNA virus, tobacco ringspot virus (TRSV), could replicate and produce virions in honeybees, Apis mellifera, resulting in infections that were found throughout the entire body. Additionally, we showed that TRSV-infected individuals were continually present in some monitored colonies. While intracellular life cycle, species-level genetic variation, and pathogenesis of the virus in honeybee hosts remain to be determined, the increasing prevalence of TRSV in conjunction with other bee viruses from spring toward winter in infected colonies was associated with gradual decline of host populations and winter colony collapse, suggesting the negative impact of the virus on colony survival. Furthermore, we showed that TRSV was also found in ectoparasitic Varroa mites that feed on bee hemolymph, but in those instances the virus was restricted to the gastric cecum of Varroa mites, suggesting that Varroa mites may facilitate the spread of TRSV in bees but do not experience systemic invasion. Finally, our phylogenetic analysis revealed that TRSV isolates from bees, bee pollen, and Varroa mites clustered together, forming a monophyletic clade. The tree topology indicated that the TRSVs from arthropod hosts shared a common ancestor with those from plant hosts and subsequently evolved as a distinct lineage after transkingdom host alteration. This study represents a unique example of viruses with host ranges spanning both the plant and animal kingdoms. Pathogen host shifts represent a major source of new infectious diseases. Here we provide evidence that a pollen-borne plant virus, tobacco ringspot virus (TRSV), also replicates in honeybees and that the virus systemically invades and replicates in different body parts. In addition, the virus was detected inside the body of parasitic Varroa mites, which consume bee hemolymph, suggesting that Varroa mites may play a role in facilitating the spread of the virus in bee colonies. This study represents the first evidence that honeybees exposed to virus-contaminated pollen could also be infected and raises awareness of potential risks of new viral disease emergence due to host shift events. About 5% of known plant viruses are pollen transmitted, and these are potential sources of future host-jumping viruses. The findings from this study showcase the need for increased surveillance for potential host-jumping events as an integrated part of insect pollinator management programs.


Increased sensitivity of nontumorigenic fibroblasts expressing ras or myc oncogenes to malignant transformation induced by 5-aza-2'-deoxycytidine.
The hypomethylating chemotherapeutic drug 5-aza-2'-deoxycytidine (5AzadC) has been shown to induce cell differentiation in some systems, while promoting neoplastic transformation in others. Using both in vitro and in vivo models, we have explored the relationship between oncogene expression and the susceptibility of cells to malignant transformation by 5AzadC. The study involved several nontumorigenic subclones of NIH3T3 fibroblasts, including cells transfected with deregulated c-myc, as well as phenotypic revertants expressing v-Ki-ras or long terminal repeat-activated c-Ha-ras. Transient 5AzadC treatment of the oncogene-bearing cell lines was associated with a rapid and efficient neoplastic transformation. In some cases, over 50% of the cell population exhibited loss of contact inhibition of growth within 1 week of treatment. The transformants were capable of forming s.c. tumors and experimental lung metastases in recipient nude mice. In contrast, 5AzadC failed to induce malignant properties in control 3T3 cultures transfected with the bacterial neor gene; rather, treatment of these cells was associated with differentiation into adipocytes and myotubes. The differential response to 5AzadC was also observed in vivo, in mice first inoculated s.c. with the premalignant cells and then treated with 5AzadC 24 h later. In agreement with the in vitro model, tumor development in mice correlated with the presence of cells with activated ras or myc oncogenes. Cytidine analogs that do not inhibit DNA methylation (i.e., 6-azacytidine and 1-beta-D-arabinofuranosyl cytosine) had no effect on cell phenotype. The results indicate that exposure of cells to 5AzadC can lead to tumor progression both in vitro and in vivo and suggest that preexisting alterations in oncogene expression may facilitate the evolution of cancerous growth induced by hypomethylating agents.


Rethinking liquid biopsy: Microfluidic assays for mobile tumor cells in human body fluids.
Traditionally, liquid biopsy is a blood test involving the harvesting of tumor materials from peripheral blood. Tumor cells from non-blood body fluids have always been clinically available in cytological examinations but limited for use in differential diagnosis due to the low sensitivity of conventional cytopathology. With the recent significant progress in microfluidic and downstream molecular technologies, liquid biopsies have now evolved to include harvesting tumor cells and DNA fragments in all kinds of non-blood body fluids. This expansion into general body fluids presages the notion that liquid biopsy could soon be used in competition, as well as, in complementarity with tissue biopsy. Preliminary research of fluid-harvested tumor materials to spot early-stage tumors, monitor disease progression for metastasis and recurrence, and detect chemoresistance have been reported. To reflect the propagation of tumor cells in non-blood body fluids, we introduced the term Mobile Tumor Cells (MTCs), in lieu of the widely accepted term of circulating tumor cells (CTCs) resident in the bloodstream. Our review starts with a discussion on the clinical significance of MTCs, followed by a presentation of microfluidic techniques for MTC capture and various strategies for their identification. Hopefully, the phenotypic and genomic data acquired from harvested MTCs can be used to guide and improve cancer treatment decisions.


A Novel Gain-of-Function KCND3 Variant Associated with Brugada Syndrome.
Brugada syndrome (BrS) is a known cause of sudden cardiac death (SCD) characterized by abnormal electrocardiograms and fatal arrhythmias. The variants in KCND3 encoding the KV4.3 potassium-channel (the α-subunit of the Ito) have seldom been reported in BrS. This study aimed to identify novel KCND3 variants associated with BrS and elucidate BrS pathogenesis. High-depth targeted sequencing was performed and the electrophysiological properties of the variants were detected by whole-cell patch-clamp methods in a cultured-cell expressing system. The transcriptional levels of KV4.3 in different genotypes were studied by real-time PCR. Western blot was used to assess channel protein expression. A novel KCND3heterozygous variant, c.1292G>A (Arg431His, R431H), was found in the proband. Whole-cell patch-clamp results revealed a gain-of-function phenotype in the variant, with peak Ito current density increased and faster recovery from inactivation. The expression of mutant Kv4.3 membrane protein increased and the cytoplasmic protein decreased, demonstrating that the membrane/cytoplasm ratio was significantly different. In conclusion, a novel KCND3 heterozygous variant was associated with BrS. The increased Ito current explained the critical role of KCND3 in the pathogenesis of BrS. Genetic screening for KCND3 could be useful for understanding the pathogenesis of BrS and providing effective risk stratification in the clinic.


Determinants of phencyclidine potency on the nicotinic acetylcholine receptors from muscle and electric organ.
1. Phencyclidine (PCP) is an inhibitor of the nicotinic acetylcholine receptor (AChR) with characteristics of an open-channel blocker. The location of PCP binding site on the AChR molecule is unknown. 2. PCP inhibits the AChR from electric organ with a higher potency than muscle AChR. To find the molecular basis of this difference, we expressed the two native and six hybrid receptors, and two receptors containing mutated mouse gamma subunits in Xenopus laevis oocytes. The inhibition of ACh-induced current in these receptors by PCP was studied using whole-cell voltage-clamp. All hybrid receptors generated robust ACh-induced currents, while incomplete receptors (gamma-less or delta-less) did not. 3. PCP potency was higher on hybrids containing Torpedo beta and gamma subunits regardless of the alpha and delta subunit origin. A mouse gamma subunit containing the asparagine 6' to the serine mutation in the M2 segment conferred a high sensitivity to PCP. 4. These results support the conclusion that the amino acid residues at the position 6' of the M2 segments contribute to the PCP potency difference between Torpedo and mouse receptors. 5. Another noncompetitive inhibitor of the AChR, the cembranoid eupalmerin acetate (EUAC), also inhibited the electric organ receptor with a somewhat higher potency than muscle AChR. However, the IC50 values for EUAC inhibition of hybrid receptors did not follow the pattern observed for PCP. Therefore, these two inhibitors interact differently with the AChR molecule.


Development of a novel triamcinolone acetonide-loaded spray solution for the treatment of stomatitis.
To develop a novel triamcinolone acetonide (TAA)-loaded spray for the treatment of stomatitis, several spray solutions were prepared using various amounts of TAA, Eudragit L100 (Eudragit L) and PEG 400, and 100 ml ethanol. Their viscosity and spraying potential were investigated, with the result that the spraying threshold was 9.5 cP. The effect of PEG 400 on the properties of films formed after spraying was assessed. Its anti-inflammatory effect in mice was evaluated and compared to a commercial product. As the PEG 400 concentration increased, the film elongation and washability by the saliva solution increased, and tensile strength decreased. PEG 400 had little effect on mucoadhesive force and drug release. The TAA-loaded spray solution containing TAA, Eudragit L, PEG 400 and ethanol at the ratio of 1:6:3:100 (w/w/w/v) was easy to spray onto stomatitis lesions in the mouth via a spraying vessel incorporating a long straw. After spraying, the TAA-loaded spray formed a film with suitable elongation, tensile strength and washability that attached onto the mucosal membrane and released the drug. Moreover, it had excellent anti-inflammatory properties, similar to those of the commercial product. Thus, this novel TAA-loaded spray solution was easy to administer, had good film properties and excellent anti-inflammatory efficacy, and is therefore a potential candidate for the treatment of stomatitis.


The use of reference strand-mediated conformational analysis for the study of cheetah (Acinonyx jubatus) feline leucocyte antigen class II DRB polymorphisms.
There is now considerable evidence to suggest the cheetah (Acinonyx jubatus) has limited genetic diversity. However, the extent of this and its significance to the fitness of the cheetah population, both in the wild and captivity, is the subject of some debate. This reflects the difficulty associated with establishing a direct link between low variability at biologically significant loci and deleterious aspects of phenotype in this, and other, species. Attempts to study one such region, the feline leucocyte antigen (FLA), are hampered by a general reliance on cloning and sequencing which is expensive, labour-intensive, subject to PCR artefact and always likely to underestimate true variability. In this study we have applied reference strand-mediated conformational analysis (RSCA) to determine the FLA-DRB phenotypes of 25 cheetahs. This technique was rapid, repeatable and less prone to polymerase chain reaction (PCR)-induced sequence artefacts associated with cloning. Individual cheetahs were shown to have up to three FLA-DRB genes. A total of five alleles were identified (DRB*ha14-17 and DRB*gd01) distributed among four genotypes. Fifteen cheetahs were DRB*ha14/ha15/ha16/ha17, three were DRB*ha15/ha16/ha17, six were DRB*ha14/ha16/ha17 and one was DRB*ha14/ha15/ha16/ha17/gd01. Sequence analysis of DRB*gd01 suggested it was a recombinant of DRB*ha16 and DRB*ha17. Generation of new alleles is difficult to document, and the clear demonstration of such an event is unusual. This study confirms further the limited genetic variability of the cheetah at a biologically significant region. RSCA will facilitate large-scale studies that will be needed to correlate genetic diversity at such loci with population fitness in the cheetah and other species.


Phylogenetic network analysis of SARS-CoV-2 genomes.
In a phylogenetic network analysis of 160 complete human severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) genomes, we find three central variants distinguished by amino acid changes, which we have named A, B, and C, with A being the ancestral type according to the bat outgroup coronavirus. The A and C types are found in significant proportions outside East Asia, that is, in Europeans and Americans. In contrast, the B type is the most common type in East Asia, and its ancestral genome appears not to have spread outside East Asia without first mutating into derived B types, pointing to founder effects or immunological or environmental resistance against this type outside Asia. The network faithfully traces routes of infections for documented coronavirus disease 2019 (COVID-19) cases, indicating that phylogenetic networks can likewise be successfully used to help trace undocumented COVID-19 infection sources, which can then be quarantined to prevent recurrent spread of the disease worldwide.


Urological injuries during obstetric and gynaecological surgical procedures.
Urological injuries during obstetric and gynaecological operations carried out between Jan. '88 to Dec. '88, at a hospital involved in resident teaching programmes were analysed retrospectively. Each case was reviewed for predisposing factors, location and type of injury, time and method of recognition and management. Fifteen injuries were documented in 892 gynaecological procedures and 296 obstetric procedures. Twelve injuries occurred during gynaecological operations whereas 3 occurred during obstetric operations. Thirteen were bladder injuries and two were ureteric injuries. Infiltrating carcinoma of cervix, pelvic adhesions, adhesions because of previous operations and distorted anatomy, were the important risk factors.


[Hemodynamics and its regulation in acute occlusion of the terminal aorta].
The results of 129 experiments have shown that acute occlusion produces during the ischemic period serious shifts in haemodynamics, caused by disorders in the regulatory systems. Changes supervening in the first 6 hours are reversible, further increase in occlusion time leads to marked cardiovascular disorders.


In Vivo Measurement of Tau Depositions in Anti-IgLON5 Disease Using [18F]PI-2620 PET.
Anti-IgLON5 disease is a recently discovered neurologic disorder combining autoimmunity and neurodegeneration. Core manifestations include sleep disorders, bulbar symptoms, gait abnormalities, and cognitive dysfunction, but other presentations have been reported. Hallmarks are autoantibodies targeting the neuronal surface protein IgLON5, a strong human leukocyte antigen system Class II association, and brainstem and hypothalamus-dominant tau deposits. The purpose of this cohort study was to visualize tau deposition in vivo with the second-generation tau-PET tracer. A cohort of 4 patients with anti-IgLON5 disease underwent a dynamic PET scan with [18F]PI-2620. One patient received a follow-up scan. Z-deviation maps and a 2-sample t test in comparison with healthy controls (n = 10) were performed. Antibody titers, neurofilament light chain, and disease duration were correlated with brainstem binding potentials. Patients demonstrated increased [18F]PI2620 tau binding potentials in the pons, dorsal medulla, and cerebellum. The longitudinal scan after 28 months showed an increase of tracer uptake in the medulla despite immunotherapy. Higher antibody titers and neurofilament light chain correlated with higher tracer retention. The results indicate that tau depositions in anti-IgLON5 disease can be visualized with [18F]PI-2620 and might correlate with the extent of disease. For validation, a larger longitudinal study is necessary.


Emerging role of Alemtuzumab in renal and renal-pancreas transplantation.
Alemtuzumab is a humanized anti-CD52 monoclonal antibody that is increasingly used in solid organ transplantation. The novel mechanism by which alemtuzumab works was used to provide an understanding of its clinical efficacy and adverse effects. Human studies of alemtuzumab in adult renal and pancreas transplantation were reviewed. These studies looked at the role of alemtuzumab as a tolerogenic and induction agent as well as its role in the treatment of acute rejection. Overall, alemtuzumab induction resulted in patient and graft outcomes comparable to other induction strategies but studies failed to show development of true tolerance. Economic benefit is a major attraction for alemtuzumab use. Future studies will further identify the optimal use of alemtuzumab.


Ultrasonographic characteristics of lipiduria in clinically normal cats.
Echoes are frequently seen in the urinary bladder of cats during abdominal ultrasound. These have been attributed to hematuria, pyuria, crystalluria, and lipid. However, sonographic findings have not been previously correlated with urinalysis. We prospectively evaluated 40 clinically normal cats via ultrasound, serum chemistry, and urinalysis. Thin layer chromatography was performed on the urine to determine the amount (mg) of lipid subfractions including diacylglycerol, triglyceride, phospholipid, free fatty acid, cholesterol, and cholesterol ester. Ninety percent (36/40) of the cats in our population had sonographic echoes suspended in the urinary bladder, with most having a subjective score of mild echoes (n = 20). None of the sonographic echoes were gravity dependent or caused distal acoustic shadowing, reverberation, or twinkle artifact. Of the cats with sonographic echoes in the urine, 66% (24/36) had no significant findings on urinalysis other than the presence of lipid. The total amount of subjective sonographic echoes was not significantly related to the total amount of fat measured on thin layer chromatography or the number of lipid droplets seen on urinalysis. An increased amount of urine diacylglycerol was significantly associated with clumping of echoes (P = 0.02) and the amount of lipid droplets seen on urinalysis (P = 0.04). An association between increased amounts of urine diacylglycerol and the amount of echoes seen on ultrasound approached significance (P = 0.05). Findings from this study support previously published theories that sonographic echoes within the urinary bladder of clinically normal cats may be due to urine lipid.


Reduced Short-Latency Afferent Inhibition in Prefrontal but not Motor Cortex and Its Association With Executive Function in Schizophrenia: A Combined TMS-EEG Study.
Cholinergic dysfunction is increasingly assumed to be involved in the pathophysiology of schizophrenia. Short-latency afferent inhibition (SAI) is a transcranial magnetic stimulation (TMS) paradigm that has been shown to assay central cholinergic activity from the motor cortex (M1). Recently, we established a method to index SAI from the dorsolateral prefrontal cortex (DLPFC), an area implicated in the pathophysiology of schizophrenia. We investigated SAI in M1 and DLPFC in schizophrenia. We hypothesized that modulation of N100 on TMS-evoked potentials (TEPs) from the DLPFC would be attenuated in patients with schizophrenia compared to healthy controls. SAI was examined in 12 patients, whose age was matched to controls, using TMS combined with electroencephalography (EEG). SAI was recorded with TMS applied to left M1 (M1-SAI) and DLPFC (DLPFC-SAI). For group comparison, we used the SAI data of healthy participants in our previous study. In patients, N100 TEP was significantly attenuated with DLPFC-SAI, whereas P180 TEP was significantly increased with M1-SAI. Between patients and controls, there were significant differences in modulation of P180 TEP by M1-SAI (t22 = -2.748, P = .012; patients > controls) and N100 TEP by DLPFC-SAI (t22 = 5.456, P < .0001; patients < controls). Further, modulation of N100 TEP by DLPFC-SAI significantly correlated with executive function (r = -.740, P = .006, N = 12). Our findings suggest that DLPFC-SAI but not M1-SAI were reduced in patients with schizophrenia and this was linked to deficits in cognition. This may reflect prefrontal cholinergic deficits and represent a biomarker for cholinergic and executive dysfunction in patients with schizophrenia.


Risk factors for herpes simplex virus epithelial keratitis recurring during treatment of stromal keratitis or iridocyclitis. Herpetic Eye Disease Study Group.
Possible risk factors were evaluated for herpes simplex virus (HSV) epithelial keratitis in patients with stromal keratouveitis. The study population included 260 patients who had active stromal keratitis and/or iridocyclitis without epithelial disease and who were enrolled in one of three clinical trials of the Herpetic Eye Disease Study. Study treatment involved a 10 week course of topical placebo, topical prednisolone phosphate, or topical prednisolone phosphate with oral acyclovir. All groups received topical trifluridine four times daily for 3 weeks then twice daily for another 7 weeks. Patients were examined for HSV epithelial keratitis for 16 weeks. Dendritic or geographic epithelial keratitis occurred in 12 (4.6%) study patients. Adverse effects attributable to trifluridine prophylaxis were acute allergic blepharoconjunctivitis in 10 (3.8%) study patients and corneal epithelial erosions in 11 (4.2%) study patients. No significant difference in the occurrence of HSV epithelial keratitis was found among the study treatment groups: one (2.0%) of 49 topical placebo treated patients, nine (6.5%) of 138 patients treated with topical corticosteroids without acyclovir, and two (2.7%) of 73 patients treated with topical corticosteroids and oral acyclovir. Univariate exponential models suggested that patients with a history of previous HSV epithelial keratitis and non-white patients were more likely to develop HSV epithelial keratitis during treatment of stromal keratouveitis. Individuals with prior HSV epithelial keratitis and certain ethnic groups may have a higher rate of recurrent epithelial keratitis during the acute treatment of HSV stromal keratouveitis.


Association of Exposure to Police Violence With Prevalence of Mental Health Symptoms Among Urban Residents in the United States.
Police violence is reportedly widespread in the United States and may pose a significant risk to public mental health. To examine the association between 12-month exposure to police violence and concurrent mental health symptoms independent of trauma history, crime involvement, and other forms of interpersonal violence exposure. This cross-sectional, general population survey study of 1221 eligible adults was conducted in Baltimore, Maryland, and New York City, New York, from October through December 2017. Participants were identified through Qualtrics panels, an internet-based survey administration service using quota sampling. Past 12-month exposure to police violence, assessed using the Police Practices Inventory. Subtypes of violence exposure were coded according to the World Health Organization domains of violence (ie, physical, sexual, psychological, and neglectful). Current Kessler Screening Scale for Psychological Distress (K6) score, past 12-month psychotic experiences (World Health Organization Composite International Diagnostic Interview), and past 12-month suicidal ideation and attempts. Of 1221 eligible participants, there were 1000 respondents (81.9% participation rate). The sample matched the adult population of included cities on race/ethnicity (non-Hispanic white, 339 [33.9%]; non-Hispanic black/African American, 390 [39.0%]; Hispanic/Latino, 178 [17.8%]; other, 93 [9.3%]), age (mean [SD], 39.8 [15.2] years), and gender (women, 600 [60.0%]; men, 394 [39.4%]; transgender, 6 [0.6%]) within 10% above or beyond 2010 census distributions. Twelve-month prevalence of police violence was 3.2% for sexual violence, 7.5% for physical violence without a weapon, 4.6% for physical violence with a weapon, 13.2% for psychological violence, and 14.9% for neglect. Police violence exposures were higher among men, people of color, and those identified as homosexual or transgender. Respondents reported suicidal ideation (9.1%), suicide attempts (3.1%), and psychotic experiences (20.6%). The mean (SD) K6 score was 5.8 (6.1). All mental health outcomes were associated with police violence exposure in adjusted logistic regression analyses. Physical violence with a weapon and sexual violence were associated with greater odds of psychotic experiences (odds ratio [95% CI]: 4.34 [2.05-9.18] for physical violence with a weapon; 6.61 [2.52-17.36] for sexual violence), suicide attempts (odds ratio [95% CI]: 7.30 [2.94-18.14] for physical violence with a weapon; 6.63 [2.64-16.64] for sexual violence), and suicidal ideation (odds ratio [95% CI]: 2.72 [1.30-5.68] for physical violence with a weapon; 3.76 [1.72-8.20] for sexual violence). Police violence was commonly reported, especially among racial/ethnic and sexual minorities. Associations between violence and mental health outcomes did not appear to be explained by confounding factors and appeared to be especially pronounced for assaultive forms of violence.


Ferroelastic n-heptylammonium dihydrogenarsenate.
n-Heptylammonium dihydrogenarsenate, (C(7)H(18)N)[As(O)(2)(OH)(2)] (C7ADA), is ferroelastic at room temperature and isostructural with n-heptylammonium dihydrogenphosphate (C7ADP). In contrast to the other known n-alkylammonium dihydrogenphosphates (CnADP) and dihydrogenarsenates (CnADA), two independent anions in the present structure are substantially disordered ( approximately 88 and approximately 12%, respectively). There are strong hydrogen bonds between the dihydrogenarsenates themselves, and moderate hydrogen bonds between the dihydrogenarsenates and the n-alkylammonium groups. The hydrogen-bond distances correspond well to those observed in the dihydrogenphosphates. There are two H atoms in the structure which are involved in asymmetric hydrogen bonds between respective oxygen pairs. These H atoms jump from the donor to the acceptor O atoms during ferroelastic switching.


[Heredity and immunology in Sjogren's syndrome].
Over the next 3-5 years, the rapid progress in genomic research will enable the discovery of many genes associated with the more common diseases. An example of such a common disease is the rheumatic disorder Sjögren's syndrome, an autoimmune disease. A more precise genetic explanation of the mechanism leading to Sjögren's syndrome remains to be given. One way of investigating the disease related genes in such complex polygenic diseases is to perform linkage studies in families with two or more affected. Another possibility is to conduct association studies on trios (parents and affected child), case control studies, or other experimental designs. In association studies one is testing if an allele is significantly elevated among patients compared to controls, while in linkage analyses one finds subchromosomal regions that are significantly more often inherited by patients than by healthy family members. The most well defined genetic association in Sjögren's syndrome is currently related to different HLA alleles and their association with anti-Ro/SSA and anti-La/SSB autoantibodies. Additional genetic studies focusing on non-HLA regions are under way. Increased genetic knowledge would allow optimisation of the diagnostic criteria as well as development of new and more effective treatment for Sjögren's syndrome, which causes substantial suffering for a large group of patients.


Evaluation of biochemical effects of Casuarina equisetifolia extract on gentamicin-induced nephrotoxicity and oxidative stress in rats. Phytochemical analysis.
Nephrotoxicity is defined as renal dysfunction that arises as result of exposure to external agents such as drugs and environmental chemicals. The present work was undertaken to carry out the phytochemical study and nephroprotective activity of methanolic extract of Casuarina equisetifolia leaves in gentamicin-induced nephrotoxicity in Wistar rats. Flavonoids and phenolic acids were identified and quantified using high performance liquid chromatography. Subcutaneous injection of rats with gentamicin (80 mg/kg body weight/day) for six consecutive days induced marked acute renal toxicity, manifested by a significant increase in serum urea, creatinine and uric acid levels, along with a significant depletion of serum potassium level, compared to normal controls. Also oxidative stress was noticed in renal tissue as evidenced by a significant decrease in glutathione level, superoxide dismutase, glutathione-S-transferase activities, also a significant increase in malondialdehyde and nitric oxide levels when compared to control group. Administration of plant extract at a dose of 300 mg/kg once daily for 4 weeks restored normal renal functions and attenuated oxidative stress. In conclusion, Casuarina equisetifolia leaves extract ameliorates gentamicin-induced nephrotoxicity and oxidative damage by scavenging oxygen free radicals, decreasing lipid peroxidation and improving intracellular antioxidant defense, thus extract may be used as nephroprotective agent.


Normothermic ex vivo lung perfusion: Does the indication impact organ utilization and patient outcomes after transplantation?
Ex vivo lung perfusion (EVLP) is being increasingly applied as a method to evaluate and treat donor lungs for transplantation. However, with the previous limited worldwide experience, no studies have been able to evaluate the impact of indication for EVLP on organ utilization rates and recipient outcomes after lung transplantation (LTx). We examined these outcomes in a large-cohort, single-center series of clinical EVLP cases. All EVLP procedures performed at our institution between October 2008 and December 2017 were examined. The EVLPs were divided into 4 groups based on the indication for the procedure: group 1, high-risk brain death donors (HR-BDD); group 2, standard-risk donation after cardiac death (S-DCD); group 3, high-risk donation after cardiac death (HR-DCD); and group 4, logistics (LOGISTICS, the need for prolongation of preservation time or organ retrieval by a different transplantation team). During the study period, a total of 1106 lung transplants were performed in our institution. In this period, 372 EVLPs were performed, 255 (69%) of which were accepted for transplantation, resulting in 262 transplants. Utilization rates were 70% (140 of 198) for group 1, 82% (40 of 49) for group 2, 63% (69 of 109) for group 3, and 81% (13 of 16) for group 4 (P = .42, Fisher's exact test). Recipient age (P = .27) and medical diagnosis (P = .31) were not different across the 4 groups. Kaplan-Meier survival by EVLP indication group demonstrated no differences. Thirty-day mortality was 2.1% in group 1, 5% in group 2, 2.9% in group 3, and 0% in group 4 (P = .87, Fisher's exact test). The median days of mechanical ventilation, intensive care unit stay, and hospital stay were 2, 4, and 21 in group 1; 2, 3, and 21 in group 2; 3, 5, and 28 in group 3; and 2, 4, and 17 in group 4 (P = .29, .17, and .09, respectively, Kruskal-Wallis rank-sum test). Clinical implementation of EVLP has allowed our program to expand the annual lung transplantation activity by 70% in this time period. It has improved confidence in the utilization of DCD lungs and BDD lungs, with an average 70% utilization of post-EVLP treated donor lungs with excellent outcomes, while addressing significant challenges in donor lung assessment and the logistics of "real-life" clinical lung transplantation.


Universal linguistic hierarchies are not innately wired. Evidence from multiple adjectives.
Linguists and psychologists have explained the remarkable similarities in the orderings of linguistic elements across languages by suggesting that our inborn ability for language makes available certain innately wired primitives. Different types of adjectives, adverbs, and other elements in the functional spine are considered to occupy fixed positions via innate hierarchies that determine orderings such as A>B>C, banning other permutations (*B>C>A). The goal of this research is to tap into the nature and rigidity of such hierarchies by comparing what happens when people process orderings that either comply with them or violate them. N = 170 neurotypical, adult speakers completed a timed forced choice task that featured stimuli showing a combination of two adjectives and a Spelke-object (e.g., 'I bought a square black table'). Two types of responses were collected: (i) acceptability judgments on a 3-point Likert scale that featured the options 'correct', 'neither correct nor wrong', and 'wrong' and (ii) reaction times. The task featured three conditions: 1. size adjective > nationality adjective, 2. color adjective > shape adjective, 3. subjective comment adjective > material adjective. Each condition had two orders. In the congruent order, the adjective pair was ordered in agreement with what is traditionally accepted as dictated by the universal hierarchy. In the incongruent order, the ordering was reversed, thus the hierarchy was violated. In the first experiment, the results of n = 140 monolinguals showed that across conditions, both congruent and incongruent orders were generally accepted as correct. For 2/3 conditions, the difference in acceptability ratings between congruent and incongruent orders did not reach statistical significance. Using time as a window to processing, reaction times showed that incongruent orders do not take longer to process than congruent ones, as should be the case if the former were treated as being licensed under some type of special condition (e.g., contrastive focus) that reverses the unmarked order and legitimizes the violation of the hierarchy. In the second experiment, the results of n = 30 bidialectals, tested in both language varieties, corroborated the findings of the first experiment. Our findings do not provide evidence for an innate hierarchy for adjective ordering that imposes one rigid, unmarked order. We discuss the importance of notions such as subjectivity and inherentness, and show that for some conditions, not only is there no evidence for a hard constraint that bans incongruent orders, but even simple preferences of congruent orders over incongruent ones are hard to discern. Capturing the bigger picture, given that both the hierarchies and their legit permutations have been described as innate, our results reduce the amount of primitives that are cast as innate, eventually offering a deflationist approach to human linguistic cognition.


Emery-Dreifuss Muscular Dystrophy 1 is associated with high risk of malignant ventricular arrhythmias and end-stage heart failure.
Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterise the cardiac complications of EMD variants. Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidence in male and female variant-carriers was determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared to consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers (mean [SD] ages 33.4 [13.3] and 43.3 [16.8] years, respectively). Nine (23.6%) males developed MVA and five (13.2%) developed ESHF during a median [IQR] follow-up of 65.0 [24.3, 109.5] months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median [IQR] age of 58.6 [53.2, 60.4] years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank p = 0.49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank p = 0.09). Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.


Interview with Lisa Shipley. Interviewed by Lisa Parks.
Lisa Shipley is Vice President of Pharmacokinetics, Pharmacodynamics and Drug Metabolism at Merck Research Laboratories. She is responsible for preclinical and clinical ADME activities and molecular biomarker assay development activities at all Merck research sites and support of all programs from discovery through to post-product launch. Prior to joining Merck in 2008, Shipley spent over 20 years at Eli Lilly and Company in roles of increasing responsibility, including the positions of executive director at Lean Six Sigma and vice president of Drug Disposition, PK/PD and Trial Simulations. Shipley obtained her undergraduate degree from McDaniel College and her doctoral degree in Pharmacology and Toxicology from the University of Maryland at Baltimore. This interview was conducted by Lisa Parks, Assistant Commissioning Editor of Bioanalysis.


Exploring the tuberculosis medication program in Indonesia as perceived by patients and their families: A qualitative study.
Tuberculosis (TB) remains a significant public health challenge in Indonesia, with the country experiencing one of the highest numbers of lost cases in TB management. Therefore, there is a need to identify the underlying reasons for this problem. This study aimed to explore the experiences of TB-diagnosed patients and their families during the time of diagnosis and while undergoing the TB medication program. This study employed a qualitative descriptive-interpretive approach. The study was conducted in government community health centers (CHC) from May 2022 to July 2022. A total of 22 participants, consisting of 12 TB-diagnosed patients and ten family members, were included in the study. Data were collected through focus group discussions and analyzed thematically. Five themes were developed: (1) Delay in tuberculosis diagnosis, (2) Delay in starting TB treatment, (3) High willingness of patients and their families to recover, (4) Understanding that TB is an infectious disease, and (5) Factors affecting patient recovery. The study findings might contribute to the National TB elimination program. It is recommended that all health workers practicing in the community should be involved in the TB program to improve its management. Collaboration between multiple sectors in the community can also provide an advantage in solving TB problems by increasing new case detection. Additionally, it is suggested that all nurses working with TB patients establish rapport with health cadres and patients' families to enhance medication adherence in patients.


1,3-Diaxially substituted trans-decalins: potential nonsteroidal human progesterone receptor inhibitors.
On the basis of molecular modeling and QSAR analysis of the known human progesterone receptor (hPR) inhibitor Mifepristone (RU-486) and other hPR ligands, a new class of potential nonsteroidal hPR inhibitors was designed. The parent racemic compound 1 was synthesized through an efficient 13-step synthetic pathway. The key constructive steps are a stereoselective epoxide ring opening and the reductive Heck cyclization to form the main framework of (+/-)-1. The current established flexible synthetic route allows for further chemical diversification.


The human Rad51 K133A mutant is functional for DNA double-strand break repair in human cells.
The human Rad51 protein requires ATP for the catalysis of DNA strand exchange, as do all Rad51 and RecA-like recombinases. However, understanding the specific mechanistic requirements for ATP binding and hydrolysis has been complicated by the fact that ATP appears to have distinctly different effects on the functional properties of human Rad51 versus yeast Rad51 and bacterial RecA. Here we use RNAi methods to test the function of two ATP binding site mutants, K133R and K133A, in human cells. Unexpectedly, we find that the K133A mutant is functional for repair of DNA double-strand breaks when endogenous Rad51 is depleted. We also find that the K133A protein maintains wild-type-like DNA binding activity and interactions with Brca2 and Xrcc3, properties that undoubtedly promote its DNA repair capability in the cell-based assay used here. Although a Lys to Ala substitution in the Walker A motif is commonly assumed to prevent ATP binding, we show that the K133A protein binds ATP, but with an affinity approximately 100-fold lower than that of wild-type Rad51. Our data suggest that ATP binding and release without hydrolysis by the K133A protein act as a mechanistic surrogate in a catalytic process that applies to all RecA-like recombinases. ATP binding promotes assembly and stabilization of a catalytically active nucleoprotein filament, while ATP hydrolysis promotes filament disassembly and release from DNA.


A Roadmap for Global Acceleration of Genomics Integration Across Nursing.
The changes needed to accelerate integration of genomics across nursing are complex, with significant challenges faced globally. Common themes lend themselves to a coordinated and collaborative strategic approach to sustained change. We aim to synthesize the outputs of a research program to present a roadmap for nursing leadership to guide integration of genomics across practice. Mixed methods involving a purposive sample of global nursing leaders and nursing organizations in a sustained, highly interactive program. Experts in nursing, health care and healthcare services, policy, and leadership were recruited. Online surveys preceded a 3-day residential meeting utilizing participatory methods and techniques to gain consensus on the essential elements of a roadmap to promote genomics integration. Twenty-three leaders representing 19 countries and seven organizations participated overall. Data on the scope and status of nursing, genomics health care, and resources have been synthesized. Participants identified 117 facilitators to genomics integration across diverse sources. Barriers and priorities identified were mapped to the constructs of the Consolidated Framework for Implementation Research. The roadmap is underpinned by a maturity matrix created by participants to guide and benchmark progress in genomics integration. Nurse leaders seeking to accelerate change can access practical guidance with the roadmap, underpinned by support through the Global Genomics Nursing Alliance and its strategic priorities. Genomics is shaping the future of healthcare, but change is needed for integration across nursing. This practical roadmap, adaptable to local health systems and clinical and educational contexts, is relevant to nurse leaders aiming to accelerate change.


gsGator: an integrated web platform for cross-species gene set analysis.
Gene set analysis (GSA) is useful in deducing biological significance of gene lists using a priori defined gene sets such as gene ontology (GO) or pathways. Phenotypic annotation is sparse for human genes, but is far more abundant for other model organisms such as mouse, fly, and worm. Often, GSA needs to be done highly interactively by combining or modifying gene lists or inspecting gene-gene interactions in a molecular network. We developed gsGator, a web-based platform for functional interpretation of gene sets with useful features such as cross-species GSA, simultaneous analysis of multiple gene sets, and a fully integrated network viewer for visualizing both GSA results and molecular networks. An extensive set of gene annotation information is amassed including GO & pathways, genomic annotations, protein-protein interaction, transcription factor-target (TF-target), miRNA targeting, and phenotype information for various model organisms. By combining the functionalities of Set Creator, Set Operator and Network Navigator, user can perform highly flexible and interactive GSA by creating a new gene list by any combination of existing gene sets (intersection, union and difference) or expanding genes interactively along the molecular networks such as protein-protein interaction and TF-target. We also demonstrate the utility of our interactive and cross-species GSA implemented in gsGator by several usage examples for interpreting genome-wide association study (GWAS) results. gsGator is freely available at http://gsGator.ewha.ac.kr. Interactive and cross-species GSA in gsGator greatly extends the scope and utility of GSA, leading to novel insights via conserved functional gene modules across different species.


Outcomes Following Cytoreductive Surgery and Hyperthermic Intraoperative Thoraco-Abdominal Chemotherapy with Diaphragm Resection for Peritoneal Carcinomatosis: A Retrospective Cohort Study.
We aimed to evaluate the safety and efficacy of hyperthermic intraoperative thoraco-abdominal chemotherapy (HITAC) and cytoreductive surgery (CRS) for peritoneal carcinomatosis (PC) patients who underwent diaphragm resection. PC patients who underwent CRS with diaphragm resection were selected from a prospectively established database and were divided into hyperthermic intraperitoneal chemotherapy (HIPEC) and HITAC groups. The clinicopathological characteristics, treatment-related variables, perioperative adverse events (AEs), and survival outcomes were compared between the two groups. Of 1168 CRS + HIPEC/HITACs, 102 patients were enrolled-61 HITAC patients and 41 HIPEC patients. In the HITAC and HIPEC groups, the incidence of grade III-V AEs was 29.5% versus 34.1% (p = 0.621). The pleural progression rates were 13.2 versus 18.9% (p = 0.462) and the median overall survival (OS) was 50.5 versus 52.7 months (p = 0.958). Median time to progression (TTP) in thoracic disease was not reached. There was no significant difference in perioperative AEs, TTP, and OS for total patients and the completeness of cytoreduction (CC) score subgroups (p > 0.05). Age ≥ 60 years (hazard ratio [HR] 4.162, p = 0.026) was an independent risk factor influencing pleural progression, and primary malignant peritoneal mesothelioma (MPM; HR 2.749, p = 0.016) and the presence of two or more serious AEs (SAEs; HR 7.294, p = 0.001) were independent risk factors influencing OS. HITAC can be performed in carefully selected PC patients who underwent diaphragm resection, with no worsening of the safety profile and a possible benefit for pleural progression. In those patients, age ≥ 60 years is associated with a shorter TTP of thoracic disease, while primary MPM and two or more perioperative SAEs are associated with worse OS.


Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na(+) channel alpha subunit.
Mutations of amino acid residues in the inner two-thirds of the S6 segment in domain III of the rat brain type IIA Na(+) channel (G1460A to I1473A) caused periodic positive and negative shifts in the voltage dependence of activation, consistent with an alpha-helix having one face on which mutations to alanine oppose activation. Mutations in the outer one-third of the IIIS6 segment all favored activation. Mutations in the inner half of IIIS6 had strong effects on the voltage dependence of inactivation from closed states without effect on open-state inactivation. Only three mutations had strong effects on block by local anesthetics and anticonvulsants. Mutations L1465A and I1469A decreased affinity of inactivated Na(+) channels up to 8-fold for the anticonvulsant lamotrigine and its congeners 227c89, 4030w92, and 619c89 as well as for the local anesthetic etidocaine. N1466A decreased affinity of inactivated Na(+) channels for the anticonvulsant 4030w92 and etidocaine by 3- and 8-fold, respectively, but had no effect on affinity of the other tested compounds. Leu-1465, Asn-1466, and Ile-1469 are located on one side of the IIIS6 helix, and mutation of each caused a positive shift in the voltage dependence of activation. Evidently, these amino acid residues face the lumen of the pore, contribute to formation of the high-affinity receptor site for pore-blocking drugs, and are involved in voltage-dependent activation and coupling to closed-state inactivation.


The effect of surface coating of femoral prostheses implanted without cement: a 2- to 4-year follow-up study.
A randomized, concurrently controlled, prospective, single-blinded, multicenter study was done to evaluate the effect of proximal surface coating of a femoral prosthesis on clinical and radiographic results of cementless total hip arthroplasty (THA). The Profile femoral prosthesis (DePuy, Warsaw, IN), an anatomic titanium alloy stem, was used in one of three configurations: (1) smooth, (2) porous coated, or (3) hydroxyapatite (HA) coated. Ninety-one cases were enrolled in the study, with seven cases lost to follow-up and 79 cases available for clinical review with 24- to 48-month follow-up. The study shows that HA-coated stems performed as well, if not better than, porous-coated or smooth stems. Results show HA-costed stems with statistically superior total Harris hip scores (microHA = 96.0) than smooth stems (microS = 85.1) (Student's t-test, P = 0.004). This was primarily due to differences between the functional score of the two groups (microHA - 31.6; microS = 27.9, P = 0.003). Porous-coated stems were intermediate in performance (microPC = 89.8), with hip scores that were statistically indistinguishable from both smooth and HA-coated stems. Our data support the hypothesis that clinical differences exist and are attributable to the type of surface coating used for the cementless femoral components in THA.


Some aspects of quantitative bacteriology in burn wounds.
There is clinical evidence that it is important to follow the concentrations of bacteria in burn wounds. This can be done either by quantitative cultures from wound biopsies or from quantitative swab samples or by microscopy. Monitoring by culture is probably better because it gives evidence of the different types of bacteria involved and their antimicrobial sensitivities in advance.


Sodium accumulation is associated with disability and a progressive course in multiple sclerosis.
Neuroaxonal loss is a major substrate of irreversible disability in multiple sclerosis, however, its cause is not understood. In multiple sclerosis there may be intracellular sodium accumulation due to neuroaxonal metabolic dysfunction, and increased extracellular sodium due to expansion of the extracellular space secondary to neuroaxonal loss. Sodium magnetic resonance imaging measures total sodium concentration in the brain, and could investigate this neuroaxonal dysfunction and loss in vivo. Sodium magnetic resonance imaging has been examined in small cohorts with relapsing-remitting multiple sclerosis, but has not been investigated in patients with a progressive course and high levels of disability. We performed sodium magnetic resonance imaging in 27 healthy control subjects, 27 patients with relapsing-remitting, 23 with secondary-progressive and 20 with primary-progressive multiple sclerosis. Cortical sodium concentrations were significantly higher in all subgroups of multiple sclerosis compared with controls, and deep grey and normal appearing white matter sodium concentrations were higher in primary and secondary-progressive multiple sclerosis. Sodium concentrations were higher in secondary-progressive compared with relapsing-remitting multiple sclerosis in cortical grey matter (41.3 ± 4.2 mM versus 38.5 ± 2.8 mM, P = 0.008), normal appearing white matter (36.1 ± 3.5 mM versus 33.6 ± 2.5 mM, P = 0.018) and deep grey matter (38.1 ± 3.1 mM versus 35.7 ± 2.4 mM, P = 0.02). Higher sodium concentrations were seen in T₁ isointense (44.6 ± 7.2 mM) and T1 hypointense lesions (46.8 ± 8.3 mM) compared with normal appearing white matter (34.9 ± 3.3 mM, P < 0.001 for both comparisons). Higher sodium concentration was observed in T₁ hypointense lesions in secondary-progressive (49.0 ± 7.0 mM) and primary-progressive (49.3 ± 8.0 mM) compared with relapsing-remitting multiple sclerosis (43.0 ± 8.5 mM, P = 0.029 for both comparisons). Independent association was seen of deep grey matter sodium concentration with expanded disability status score (coefficient = 0.24, P = 0.003) and timed 25 ft walk speed (coefficient = -0.24, P = 0.01), and of T1 lesion sodium concentration with the z-scores of the nine hole peg test (coefficient = -0.12, P < 0.001) and paced auditory serial addition test (coefficient = -0.081, P < 0.001). Sodium concentration is increased within lesions, normal appearing white matter and cortical and deep grey matter in multiple sclerosis, with higher concentrations seen in secondary-progressive multiple sclerosis and in patients with greater disability. Increased total sodium concentration is likely to reflect neuroaxonal pathophysiology leading to clinical progression and increased disability.


How electronic health records can unmask the hidden value of PAs.
The Fee for Value (FFV) Task Force, a subgroup of the American Academy of PAs' Research and Strategic Initiatives Commission, has examined tools and mechanisms aimed at better clarifying the volume and value of PA work and how that work contributes to improving access to high-quality care. Establishing the value of PAs has been a challenging task for many healthcare providers. Often, PA value has been defined by their clinical productivity, without any clear direction as to what constitutes value versus productivity. The objective of this article is to unmask the value of PAs through the role of electronic health records and highlight PAs' ability to produce services that are value-oriented and quantifiably productive.