Validity and reliability of the German version of the 9-item European Heart Failure Self-care Behaviour Scale.
The promotion of self-care in patients with heart failure (HF) is a promising strategy for maintaining health and preventing exacerbation of HF and a continuous need for healthcare services. To assess patient self-care, valid and reliable instruments are needed, but there is no psychometrically tested instrument for use in a German HF population. The aim of this study was to determine the validity and reliability of the German version of the 9-item European Heart Failure Self-care Behaviour Scale (G9-EHFScBS). Construct validity including factor analysis and discriminant validity, concurrent validity, test-retest reliability and internal consistency were analysed. The G9-EHFScBS was translated into German, and its validity and reliability were tested with 109 patients. The item-total correlation ranged from 0.09 to 0.63. Internal consistency was fair, with a Cronbach's alpha of 0.71 (95%CI: 0.63 to 0.77). Test-retest reliability using an intra-class correlation coefficient showed substantial agreement for the entire scale (ICC: 0.69; 95%CI: 0.56 to 0.79). The G9-EHFScBS was able to distinguish patients with and without extra HF education at a statistically significant level (t = 2.105; p = 0.04). A factor analysis did not show the theoretical assumed dimensions of the scale. The G9-EHFScBS is deemed a valid and reliable instrument to assess HF-specific self-care in a German HF population.


Molecular genotyping of methicillin-resistant Staphylococcus aureus via fluorophore-enhanced repetitive-sequence PCR.
Methicillin resistance in Staphylococcus aureus is a frequent cause of nosocomial and community-acquired infections. Accurate, rapid epidemiologic typing is crucial to the identification of the source and spread of infectious disease and could provide detailed information on the generation of methicillin-resistant S. aureus (MRSA) strains. The high degree of genetic relatedness of MRSA strains has precluded the use of more conventional methods of genetic fingerprinting. A rapid DNA fingerprinting method that exploits PCR amplification from a DNA repeat sequence in MRSA is described. The random chromosomal distribution of this repeat sequence provides an ideal target for detecting DNA fragment patterns specific to individual MRSA strains. Two PCR fingerprinting methods which use an oligonucleotide primer based on a repetitive sequence found in Mycoplasma pneumoniae are presented. The repetitive element sequence-based PCR (rep-PCR) and fluorophore-enhanced rep-PCR (FERP) can identify epidemic strains among background MRSA. The combination of oligonucleotide primers labeled with different fluorescent dyes allowed simultaneous FERP fingerprinting and mecA gene detection. Eight different fingerprint patterns were observed in MRSA strains collected from different sources. These techniques provide a rapid discriminatory means of molecular epidemiologic typing of MRSA involved in nosocomial infections.


Modeling ion sensing in molecular electronics.
We examine the ability of molecules to sense ions by measuring the change in molecular conductance in the presence of such charged species. The detection of protons (H(+)), alkali metal cations (M(+)), calcium ions (Ca(2+)), and hydronium ions (H3O(+)) is considered. Density functional theory (DFT) is used within the Keldysh non-equilibrium Green's function framework (NEGF) to model electron transport properties of quinolinedithiol (QDT, C9H7NS2), bridging Al electrodes. The geometry of the transport region is relaxed with DFT. The transport properties of the device are modeled with NEGF-DFT to determine if this device can distinguish among the M(+) + QDT species containing monovalent cations, where M(+) = H(+), Li(+), Na(+), or K(+). Because of the asymmetry of QDT in between the two electrodes, both positive and negative biases are considered. The electron transmission function and conductance properties are simulated for electrode biases in the range from -0.5 V to 0.5 V at increments of 0.1 V. Scattering state analysis is used to determine the molecular orbitals that are the main contributors to the peaks in the transmission function near the Fermi level of the electrodes, and current-voltage relationships are obtained. The results show that QDT can be used as a proton detector by measuring transport through it and can conceivably act as a pH sensor in solutions. In addition, QDT may be able to distinguish among different monovalent species. This work suggests an approach to design modern molecular electronic conductance sensors with high sensitivity and specificity using well-established quantum chemistry.


Prevalent vertebral deformities: relationship to bone mineral density and spinal osteophytosis in elderly men and women.
The aims of this study were to ascertain vertebral deformity prevalence in elderly men and women and to describe the association between bone mineral density (BMD) at the lumbar spine and femoral neck, severity of spinal degenerative disease and vertebral deformity prevalence. We performed standardized spinal radiographs in a random sample of 300 elderly men and women participating in the Dubbo Osteoporosis Epidemiology Study, a population-based study of fracture risk factors. Radiographs were read independently by masked observers for the prevalence of vertebral deformity and severity of osteophytosis. BMD was measured by dual-energy X-ray absorptiometry. The prevalence of vertebral deformities was critically dependent on the criterion used. The less strict criteria seemed to overestimate deformities at either end of the spine region analysed. However, irrespective of the criterion used, prevalence of deformity was higher in men than in women (25% vs 20% for the 3 SD criterion, 17% vs 12% for the 4 SD criterion and 27% vs 25% for the 25% criterion). Femoral neck BMD was more strongly associated with vertebral deformities than spinal BMD for the 25% criterion (OR/SD change in BMD 1.39 (p = 0.02) vs 1.20 (p = 0.19)), 3 SD criterion (OR/SD change in BMD 1.45 (p = 0.01) vs 1.10 (p = 0.34)) and 4 SD criterion (OR/SD change in BMD 1.98 (p = 0.0002) vs 1.68 (p = 0.008)). BMD was also more strongly associated with biconcave deformities than either wedge or crush deformities and more so in men than in women. Severity of spinal osteophytosis was not associated with vertebral deformity. In conclusion, femoral neck BMD is at least equivalent to the lumbar spine BMD in strength of association with prevalent vertebral fractures. Spinal osteophytosis falsely elevates BMD without a concomitant decrease in fracture risk, indicating that any interpretation of spinal BMD needs to be adjusted for osteophytosis. These findings support the use of femoral neck bone densitometry in older men and women. Moreover, these data indicate that current criteria for radiological assessment of vertebral deformity are sufficiently loose to include a substantial proportion of non-fractures in the elderly, with important implications for the design of clinical trials. However, irrespective of the criterion used, vertebral deformities in men are at least as common, if not more so, than in women, suggesting that vertebral osteoporotic fractures are overlooked in men.


Three Nontraditional Approaches to Improving the Capacity, Accessibility, and Quality of Mental Health Services: An Overview.
To provide evidence for wider use of peer workers and other nonprofessionals, the authors examined three approaches to mental health service provision-peer support worker (PSW) programs, task shifting, and mental health first-aid and community advocacy organizations-summarizing their effectiveness, identifying similarities and differences, and highlighting opportunities for integration. Relevant articles obtained from PubMed, MEDLINE, and Google Scholar searches are discussed. Studies indicate that PSWs can achieve outcomes equal to or better than those achieved by nonpeer mental health professionals. PSWs can be particularly effective in reducing hospital admissions and inpatient days and engaging severely ill patients. When certain care tasks are given to individuals with less training than professionals (task shifting), these staff members can provide psychoeducation, engage service users in treatment, and help them achieve symptom reduction and manage risk of relapse. Mental health first-aid and community organizations can reduce stigma, increase awareness of mental health issues, and encourage help seeking. Most PSW programs have reported implementation challenges, whereas such challenges are fewer in task-shifting programs and minimal in mental health first-aid. Despite challenges in scaling and integrating these approaches into larger systems, they hold promise for improving access to and quality of care. Research is needed on how these approaches can be combined to expand a community's capacity to provide care. Because of the serious shortage of mental health providers globally and the rising prevalence of mental illness, utilizing nontraditional providers may be the only solution in both low- and high-resource settings, at least in the short term.


The effects of various irrigating solutions on intra-radicular dentinal surface: An SEM analysis.
The action of irrigant solutions on intra- radicular dentinal surface were evaluated in an in vitro setting using a scanning electron microscope (SEM) and it was observed that sodium hypochlorite and MTAD produced the cleanest surface and that none of the irrigants were able to produce an ideal preparation of the dentinal surface when used individually. The primary objective of endodontic therapy is to achieve a clean, optimal environment in root canals to avoid unsuccessful treatment outcomes. The complexities of the root canal system necessitate the use of irrigating solutions which act on radicular dentin surface, modifying it. The action of irrigants can be beneficial, and yet at the same time, as they modify the surface structure of dentin, they can have an adverse impact on the properties of dentin. The present study was undertaken to assess the effect of various irrigants on the dentinal surface using an SEM. Forty-five roots were randomly divided into nine groups (n=5) and prepared by sectioning at the level of cemento-enamel junction (CEJ) and 10 mm from the CEJ and split longitudinally. The dentin surface was prepared and the cemental surfaces were coated with double layer of varnish. The irrigants tested were normal saline, de-ionized water, 17% ethylenediaminetetraacetic acid (EDTA), 5% sodium hypochlorite (NaOCl), 5% NaOCl with ultrasonic agitation, 3% hydrogen peroxide, 2% chlorhexidine (CHX), MTAD, and MTAD with ultrasonic agitation. The prepared samples were placed in the irrigant solution for 3 min, subsequently dehydrated, sputter coated, and observed under SEM. The images were subsequently analyzed for dentinal surface changes. 17% EDTA and MTAD produced the cleanest dentinal surface. Ultrasonic agitation enhanced the effect of irrigants. 5% NaOCl and 3% hydrogen peroxide were efficient at removal of organic debris, but were unable to remove the smear layer. De-ionized water, normal saline, and 2% chlorhexidine were not effective at removing the debris or the smear layer. None of the irrigants individually were able to achieve conditions of an ideal dentinal surface preparation.


Tissue invasive macrophage density is correlated with prognosis in cholangiocarcinoma.
Cholangiocarcinoma (CCA) is a high metastatic cancer with no effective treatment. Here, the pro-metastatic action of tissue macrophages in CCA is demonstrated and suggested as a prognostic marker and novel target for the therapeutic intervention of CCA. Fifty CCA tissues were immunohistochemically stained with a marker for reactive/infiltrating monocytes/macrophages (MAC387) and matrix metalloproteinase (MMP)-9. The antigenic densities in positively-stained cells along the leading edge of tumors were scored. Correlations between the densities of MAC387, MMP-9-positive cells, clinicopathological features and patient survival were investigated. High densities of MAC387-positive cells were detected in more than 60% of the CCA tissues. This was significantly associated with poor prognosis parameters (non-papillary and mass-forming type CCA). Overall survival was worst in patients with high-density MAC387-positive cells. Double immunofluorescent staining indicated that MAC387-positive cells co-expressed MMP-9. Immunohistochemical staining of MMP-9 in serial sections of CCA tissues indicated that MMP-9 was rarely expressed in CCA tumor cells, but highly expressed in MAC387-positive cells and polymorphonucleated infiltrating cells. Patients with high tissue expression levels of MAC387 in combination with MMP-9-expressing cells had the worst survival. These factors were found to be independent predictors of the post-resectional survival of CCA patients. Since CCA tumor cells rarely expressed MMP-9, it is likely that tissue macrophages are critical for degrading the extracellular matrix and for facilitating tumor metastasis. They may therefore serve as a prognostic marker for poor clinical outcome, and represent novel targets for the therapeutic intervention of CCA.


Ab initio study of poly(vinyl chloride) propagation kinetics: head-to-head versus head-to-tail additions.
The relative importance of head-to-head versus head-to-tail additions during the free-radical polymerization of vinyl chloride is determined by ab initio methods for different chain lengths of the polymer. First, a level of theory study is performed to determine cost-effective methods for the ab initio description of the propagation kinetics of vinyl chloride. The study includes the following DFT-based methods: B3LYP, B3PW91, BHandH, BHandHLYP, BLYP, BP86, MPW1K and MPW1PW91, in combination with double or triple zeta basis sets 6-31G(d) and 6-311G(d,p). Also, the more recently developed BMK and MPW1K functionals are included. The influence of diffuse functions is tested by comparison with the basis sets 6-31+G(d) and 6-311++G(3df,2p). The best-performing methods are B3LYP, B3PW91 and MPW1 K combined with the 6-31+G(d) basis set. The converged probability of head-to-head propagation (2 per 1000 monomer units) is put into relation with the experimental concentrations of defect structures. A comparison is made with the head-to-head (HH) content of fluorine-substituted polymers and poly(vinyl acetate). The ab initio calculations correctly predict the relative sequence of HH content among the various polymers.


Comparison of the effects of local and systemic dexamethasone on the rat traumatic sciatic nerve model.
The aim of the study was to evaluate the effect of peroperatively locally administered dexamethasone on nerve recovery after induced nerve crush injury. 4 groups of 8 animals were formed. The sciatic nerves of 32 rats were exposed at midthigh level and those of 24 rats were crushed for 30 seconds with a pair of jeweler's forceps. Sciatic functional index (SFI) measurements of all the animals included at days 7, 14, 21 and 28 was statistically significant (p < 0.05). Pinch tests that were done on the first 13 days gave negative results in all the groups. There was a difference between the test results of Group II and those of Group III and IV at days 14, 21 and 28. When the duration of the experiment was taken as a whole, no difference was observed between the test results of Group III and IV. Recovery in the group treated with local dexamethasone was more remarkable than that in the group treated with systemic dexamethasone in our study. As the difference was statistically significant, we recommend the perioperative use of local dexamethasone in procedures that might induce nerve injury.


A longitudinal study on dying in a Norwegian hospital.
A research project conducted at a Norwegian hospital in 1977 (n = 213 deaths) was repeated in 1987 and 1997 (n = 100 deaths each year). The purpose was to discover if and how terminal care had changed during these 20 years. Data sources included case records, nurses' reports and interviews with close relatives approximately 12 weeks after death. The average stay in hospital decreased by one-third from 1977 to 1997. Active life-prolonging treatment, as defined by use of antibiotics, resuscitation and parenteral fluids, was greatly reduced from 1977 to 1987, but there was an increase in the use of such treatment in 1997. Interestingly, palliative treatments--either broadly defined as the giving of analgesics in general, or more narrowly as the giving of opiates only--have increased steadily over the years and are now offered to most patients. However, the findings demonstrated that the next-of-kin were less well informed about the patient's impending death in 1997 than in 1977.


Chronic fenfluramine administration: some cerebral effects.
Human cerebral function was monitored electrophysiologically during sleep over a period of months before, during, and after the intake of fenfluramine, 40-120 mg/day. Effects included dose-related reduction of paradoxical sleep, increase of intra-sleep restlessness, and changes in E.E.G. slow-wave sleep. It is hypothesized that weight loss may be associated with increase of the last. Grinding of teeth (bruxism) also was noted.Long-term studies make it possible to demonstrate changing central effects with time, including tolerance phenomena. Withdrawal abnormalities are related to the time taken for the drug to be eliminated-in the present case reaching a maximum four days after withdrawal.


Human evolution out of Africa: the role of refugia and climate change.
Although an African origin of the modern human species is generally accepted, the evolutionary processes involved in the speciation, geographical spread, and eventual extinction of archaic humans outside of Africa are much debated. An additional complexity has been the recent evidence of limited interbreeding between modern humans and the Neandertals and Denisovans. Modern human migrations and interactions began during the buildup to the Last Glacial Maximum, starting about 100,000 years ago. By examining the history of other organisms through glacial cycles, valuable models for evolutionary biogeography can be formulated. According to one such model, the adoption of a new refugium by a subgroup of a species may lead to important evolutionary changes.


Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma.
Protein kinase C beta (PKCbeta) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKCbeta, enzastaurin, in patients with relapsed or refractory DLBCL. Enzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for > or= two cycles (one cycle = 28 days), objective response, and toxicity. Fifty-five patients (median age, 68 years) were enrolled. Patients had received a median number of two prior therapies (range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), and thrombocytopenia (n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22%; 95% CI, 13% to 46%) experienced FFP for two cycles, and eight patients remained free from progression for four cycles (15%; 95% CI, 6% to 27%). Four patients (7%; 95% CI, 2% to 18%), including three complete responders and one patient with stable disease, continue to experience FFP 20+ to 50+ months after study entry. Treatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.


Surface structure and properties of plant seed oil bodies.
Storage triacylglycerols (TAG) in plant seeds are present in small discrete intracellular organelles called oil bodies. An oil body has a matrix of TAG, which is surrounded by phospholipids (PL) and alkaline proteins, termed oleosins. Oil bodies isolated from mature maize (Zea mays) embryos maintained their discreteness, but coalesced after treatment with trypsin but not with phospholipase A2 or C. Phospholipase A2 or C exerted its activity on oil bodies only after the exposed portion of oleosins had been removed by trypsin. Attempts were made to reconstitute oil bodies from their constituents. TAG, either extracted from oil bodies or of a 1:2 molar mixture of triolein and trilinolein, in a dilute buffer were sonicated to produce droplets of sizes similar to those of oil bodies; these droplets were unstable and coalesced rapidly. Addition of oil body PL or dioleoyl phosphatidylcholine, with or without charged stearylamine/stearic acid, or oleosins, to the medium before sonication provided limited stabilization effects to the TAG droplets. High stability was achieved only when the TAG were sonicated with both oil body PL (or dioleoyl phosphatidylcholine) and oleosins of proportions similar to or higher than those in the native oil bodies. These stabilized droplets were similar to the isolated oil bodies in chemical properties, and can be considered as reconstituted oil bodies. Reconstituted oil bodies were also produced from TAG of a 1:2 molar mixture of triolein and trilinolein, dioleoyl phosphatidylcholine, and oleosins from rice (Oryza sativa), wheat (Triticum aestivum), rapeseed (Brassica napus), soybean (Glycine max), or jojoba (Simmondsia chinensis). It is concluded that both oleosins and PL are required to stabilize the oil bodies and that oleosins prevent oil bodies from coalescing by providing steric hindrance. A structural model of an oil body is presented. The current findings on seed oil bodies could be extended to the intracellular storage lipid particles present in diverse organisms.


Etiology, epidemiology and clinical characteristics of acute diarrhea in hospitalized children in rural Peru.
Diarrhea remains one of the main causes of morbidity and mortality in children under five years of age especially in low-income countries. In Peru, epidemiological reports about enteropathogens related to acute diarrhea are scarce in rural areas. The aim of this study was to describe the etiology, epidemiology, and clinical characteristics of the principal causes of acute infectious diarrhea in in a northern rural region of Peru. A prospective study was conducted from January 2011 to December 2012 to describe the main pathogens causing acute diarrhea using PCR assay. A total of 117 children diagnosed with acute diarrhea were included in the study. A single etiological agent was identified in 41.03% of samples, being rotavirus followed by norovirus and Shigella. Co-infections containing virus and bacteria were found in 22.22% of samples. Vomiting was most commonly found symptoms in 58.97% cases followed by fever (54.70%). Malnutrition was detected in 14.53% of the children. High prevalence of rotavirus, as well as adenovirus and norovirus, was observed in the present study. Shigella was the most common bacteria found in acute diarrhea in the area. The implementation of a better surveillance system is mandatory in order to identify the principal etiologies of gastroenteritis in the rural areas of Peru and to develop of better prevention strategies and reduce diarrhea-associated mortalities.


Electric field perturbations of spiral waves attached to millimeter-size obstacles.
Reentrant spiral waves can become pinned to small anatomical obstacles in the heart and lead to monomorphic ventricular tachycardia that can degenerate into polymorphic tachycardia and ventricular fibrillation. Electric field-induced secondary source stimulation can excite directly at the obstacle, and may provide a means to terminate the pinned wave or inhibit the transition to more complex arrhythmia. We used confluent monolayers of neonatal rat ventricular myocytes to investigate the use of low intensity electric field stimulation to perturb the spiral wave. A hole 2-4 mm in diameter was created in the center to pin the spiral wave. Monolayers were stained with voltage-sensitive dye di-4-ANEPPS and mapped at 253 sites. Spiral waves were initiated that attached to the hole (n = 10 monolayers). Electric field pulses 1-s in duration were delivered with increasing strength (0.5-5 V/cm) until the wave terminated after detaching from the hole. At subdetachment intensities, cycle length increased with field strength, was sustained for the duration of the pulse, and returned to its original value after termination of the pulse. Mechanistically, conduction velocity near the wave tip decreased with field strength in the region of depolarization at the obstacle. In summary, electric fields cause strength-dependent slowing or detachment of pinned spiral waves. Our results suggest a means to decelerate tachycardia that may help to prevent wave degeneration.


Determining parental origin of embryo aneuploidy: analysis of genetic error observed in 305 embryos derived from anonymous donor oocyte IVF cycles.
Since oocyte donors are typically young and believed to be a source of highly competent gametes, donor oocyte IVF is considered to be an effective treatment for diminished ovarian reserve. However, the aneuploidy rate for embryos originating from anonymously donated oocytes remains incompletely characterized. Here, comprehensive chromosomal screening results were reviewed from embryos obtained from anonymous donor-egg IVF cycles to determine both the aneuploidy rate and parental source of the genetic error. To measure this, preimplantation genetic screening (PGS) data on embryos were retrospectively collated with parental DNA obtained before IVF for chromosome-specific assessments. This approach permitted mitotic and meiotic copy errors to be differentiated for each chromosome among all embryos tested, thus providing information on the parental source of embryo aneuploidy (i.e., from the anonymous egg donor vs. sperm source). 305 embryos generated for 24 patients who began IVF treatment in 2013. For oocyte donors (n = 24), mean (±SD) age was 24.0 ± 2.7 years (range = 20-29). For embryos with full chromosomal reporting (n = 284), euploidy was present in only 133 (46.8%). Considering all embryo chromosomes, the average error rate was 18%. 133 of 151 observed embryo aneuploidies (88.1%) were attributable to an oocyte donor source. Among all aneuploid embryos (n = 151), chromosomal errors from both genetic parents (i.e., oocyte donor and sperm source) were present in 57%. The average correlation coefficient across all pairs of chromosomal abnormalities (r = 0.60) suggests that chromosomes tend to have multiple and simultaneous errors (complex aneuploidy) even when oocytes from young donors are used. These data show that even when young donors provide oocytes for IVF, the probability of embryo aneuploidy remains high. The oocyte donor appears to make an important contribution to embryo aneuploidy even when her age is <30 yrs. If these findings are confirmed with larger, prospective studies, the routine integration of PGS with donor oocyte IVF cycles to identify single euploid embryos for transfer should be considered.


Dietary salt produces abnormal renal vasoconstrictor responses to upright posture in borderline hypertensive subjects.
We studied the effect of high and low NaCl diets in normotensive and borderline hypertensive subjects to determine if a high NaCl diet produces abnormal renal vasoconstriction during the stress of upright posture in borderline hypertensive subjects. We studied 13 normotensive young men with diastolic blood pressures below 85 mm Hg and nine borderline hypertensive young men defined by diastolic blood pressures intermittently above 90 mm Hg. The subjects achieved comparable sodium balance during 6 days of low NaCl (10 mEq Na, 40 mEq Cl, 100 mEq K) and high NaCl (400 mEq Na, 400 mEq Cl, 100 mEq K) diets. In the normotensive subjects, standing for 30 minutes resulted in a tendency for diastolic blood pressure to fall during both diets. In contrast, during standing borderline hypertensive subjects showed no change in diastolic blood pressure during the low salt diet and a tendency for diastolic blood pressure to increase after the high salt diet. Standing reduced renal plasma flow in both groups during both diets. However, only during the high NaCl diet did the absolute decrease and percent decrease in renal plasma flow during standing differ significantly (p less than 0.05 and p less than 0.01, respectively) between the borderline hypertensive (-151 +/- 24 ml/min/1.73m2; -29 +/- 4%) and normotensive subjects (-79 +/- 17 ml/min/1.73m2; -15 +/- 3%). The resultant increase in the renal vascular resistance index with standing did not differ between the two groups during the low NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)


Case report: Concomitant MitraClip implantation for severe mitral regurgitation and plug closure of endocarditis induced fistula between aortic root and left atrium after transcatheter aortic valve implantation.
Infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI) occurs in up to 1.5% of patients within the first year. The development of an aorto-atrial fistula (AAF) is a rare but problematic complication of IE, which can be confirmed with transoesophageal echocardiography (TOE). We present an exceptional case of occluding an aorto-left atrial fistula only diagnosed with intraprocedural TOE during a subsequent procedure of MitraClip implantation. A 79-year-old symptomatic male patient with multiple comorbidities was referred due to severe mitral regurgitation (MR). He has had prior TAVI which was complicated with streptococcal IE for which he had received prolonged antibacterial therapy. Transthoracic echocardiography (TTE) revealed severe MR. The patient was accepted for a MitraClip procedure by the heart team. Intra-procedural TOE revealed also a significant continuous shunt through an AAF which was likely caused by the endocarditis. The strategy was therefore defined as to occlude the fistula with an Amplatzer Vascular Plug II 12 mm. The plug was released in the fistula leaving an insignificant residual shunt. After the transseptal puncture one MitraClip XTR was implanted, reducing the MR to mild. After the procedure, the patient's general clinical condition improved without signs of haemolysis. The pre-discharge TTE confirmed trace residual shunt, mild residual MR and mild paravalvular leakage. Our case illustrates a complex transcatheter structural heart intervention with improvised procedural strategies based on the intra-procedural TOE findings. We conclude that the pre-procedural TOE needs to be comprehensive rather than exclusive, particularly in the context of bioprosthesis-related endocarditis.


High prevalence of hepatitis B virus infection in B-cell non-Hodgkin's lymphoma.
In this hospital-based, multicenter case-control study we investigated the prevalence of hepatitis B virus (HBV)-related markers and HBV/hepatitis C virus (HCV) co-infection among B-cell non-Hodgkin's lymphoma (B-NHL) cases and controls. Four hundred newly diagnosed B-NHL cases and 392 controls from other departments of the same hospitals were studied. The prevalence of positivity for hepatitis B surface antigen (HBsAg) was 8.5% among B-NHL cases and 2.8% among controls (adjusted odds ratio, 3.67; 95% confidence interval, 1.75-7.66). HBV/HCV co-infection was found in four cases, but in no controls. The finding of a positive association between HBV infection and B-NHL raises the possibility that HBV may play an etiologic role in the induction of B-NHL.


Cosmetic preservatives as therapeutic corneal and scleral tissue cross-linking agents.
Previously, aliphatic β-nitroalcohols (BNAs) have been studied as a means to chemically induce tissue cross-linking (TXL) of cornea and sclera. There are a number of related and possibly more potent agents, known as formaldehyde releasers (FARs), that are in commercial use as preservatives in cosmetics and other personal care products. The present study was undertaken in order to screen such compounds for potential clinical utility as therapeutic TXL agents. A chemical registry of 62 FARs was created from a literature review and included characteristics relevant to TXL such as molecular weight, carcinogenicity/mutagenicity, toxicity, hydrophobicity, and commercial availability. From this registry, five compounds [diazolidinyl urea (DAU), imidazolidinyl urea (IMU), sodium hydroxymethylglycinate (SMG), DMDM hydantoin (DMDM), 5-Ethyl-3,7-dioxa-1-azabicyclo [3.3.0] octane (OCT)] were selected for efficacy screening using two independent systems, an ex vivo rabbit corneal cross-linking simulation setup and incubation of cut scleral tissue pieces. Treatments were conducted at pH 7.4 or 8.5 for 30 minutes. Efficacy was evaluated using thermal denaturation temperature (Tm), and cell toxicity was studied using the trypan blue exclusion method. Cross-linking effects in the five selected FARs were pH and concentration dependent. Overall, the Tm shifts were in agreement with both cornea and sclera. By comparison with BNAs previously reported upon, the FARs identified in this study were significantly more potent but with similar or better cytotoxicity. The FARs, a class of compounds well known to the cosmetic industry, may have utility as therapeutic TXL agents. The compounds studied thus far show promise and will be further tested.


SIRT1 reduces endothelial activation without affecting vascular function in ApoE-/- mice.
Excessive production of reactive oxygen species (ROS) contributes to progression of atherosclerosis, at least in part by causing endothelial dysfunction and inflammatory activation. The class III histone deacetylase SIRT1 has been implicated in extension of lifespan. In the vasculature,SIRT1 gain-of-function using SIRT1 overexpression or activation has been shown to improve endothelial function in mice and rats via stimulation of endothelial nitric oxide (NO) synthase (eNOS). However, the effects of SIRT1 loss-of-function on the endothelium in atherosclerosis remain to be characterized. Thus, we have investigated the endothelial effects of decreased endogenous SIRT1 in hypercholesterolemic ApoE-/- mice. We observed no difference in endothelial relaxation and eNOS (Ser1177) phosphorylation between 20-week old male atherosclerotic ApoE-/- SIRT1+/- and ApoE-/- SIRT1+/+ mice. However, SIRT1 prevented endothelial superoxide production, inhibited NF-kappaB signaling, and diminished expression of adhesion molecules. Treatment of young hypercholesterolemic ApoE-/- SIRT1+/- mice with lipopolysaccharide to boost NF-kappaB signaling led to a more pronounced endothelial expression of ICAM-1 and VCAM-1 as compared to ApoE-/- SIRT1+/+ mice. In conclusion, endogenous SIRT1 diminishes endothelial activation in ApoE-/- mice, but does not affect endothelium-dependent vasodilatation.


Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis.
To update the evidence for the safety of synthetic disease-modifying antirheumatic drugs (sDMARDs), glucocorticoids (GC) and biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism (EULAR) recommendations for the management of RA. Systematic literature review (SLR) of observational studies (including registries). Interventions were any bDMARD (anakinra, infliximab, etanercept, adalimumab, rituximab, abatacept, tocilizumab, golimumab or certolizumab pegol) or sDMARD (methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, gold/auranofin, azathioprine, chlorambucil, chloroquine, cyclosporin, cyclophosphamide, mycophenolate, minocycline, penicillamine, tacrolimus or tofacitinib) and a comparator was required. Information on GCs was collected from the included studies. All safety outcomes were included. Forty-nine observational studies addressing diverse safety outcomes of therapy with bDMARDs met eligibility criteria. Substantial heterogeneity precluded meta-analysis of any of the outcomes. Patients on tumour necrosis factor inhibitors (TNFi) compared to patients on conventional sDMARDs had a higher risk of serious infections (adjusted HR (aHR) 1.1-1.8), a higher risk of tuberculosis, and an increased risk of infection by herpes zoster cannot be excluded. Patients on TNFi did not have an increased risk for malignancies in general, lymphoma or non-melanoma skin cancer, but the risk of melanoma may be slightly increased (aHR 1.5). From the studies identified on conventional sDMARDs, no new safety signals were found. The findings from this SLR confirm the known safety pattern of sDMARDs and bDMARDs for the treatment of RA.


Recent advances in inferring viral diversity from high-throughput sequencing data.
Rapidly evolving RNA viruses prevail within a host as a collection of closely related variants, referred to as viral quasispecies. Advances in high-throughput sequencing (HTS) technologies have facilitated the assessment of the genetic diversity of such virus populations at an unprecedented level of detail. However, analysis of HTS data from virus populations is challenging due to short, error-prone reads. In order to account for uncertainties originating from these limitations, several computational and statistical methods have been developed for studying the genetic heterogeneity of virus population. Here, we review methods for the analysis of HTS reads, including approaches to local diversity estimation and global haplotype reconstruction. Challenges posed by aligning reads, as well as the impact of reference biases on diversity estimates are also discussed. In addition, we address some of the experimental approaches designed to improve the biological signal-to-noise ratio. In the future, computational methods for the analysis of heterogeneous virus populations are likely to continue being complemented by technological developments.


Screening for Cardiovascular Disease Risk With Resting or Exercise Electrocardiography: Evidence Report and Systematic Review for the US Preventive Services Task Force.
Cardiovascular disease (CVD) is the leading cause of death in the United States. To review the evidence on screening asymptomatic adults for CVD risk using electrocardiography (ECG) to inform the US Preventive Services Task Force. MEDLINE, Cochrane Library, and trial registries through May 2017; references; experts; literature surveillance through April 4, 2018. English-language randomized clinical trials (RCTs); prospective cohort studies reporting reclassification, calibration, or discrimination that compared risk assessment using ECG plus traditional risk factors vs traditional risk factors alone. For harms, additional study designs were eligible. Studies of persons with symptoms or a CVD diagnosis were excluded. Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings. Mortality, cardiovascular events, reclassification, calibration, discrimination, and harms. Sixteen studies were included (N = 77 140). Two RCTs (n = 1151) found no significant improvement for screening with exercise ECG (vs no screening) in adults aged 50 to 75 years with diabetes for the primary cardiovascular composite outcomes (hazard ratios, 1.00 [95% CI, 0.59-1.71] and 0.85 [95% CI, 0.39-1.84] for each study). No RCTs evaluated screening with resting ECG. Evidence from 5 cohort studies (n = 9582) showed that adding exercise ECG to traditional risk factors such as age, sex, current smoking, diabetes, total cholesterol level, and high-density lipoprotein cholesterol level produced small improvements in discrimination (absolute improvements in area under the curve [AUC] or C statistics, 0.02-0.03, reported by 3 studies); whether calibration or appropriate risk classification improves is uncertain. Evidence from 9 cohort studies (n = 66 407) showed that adding resting ECG to traditional risk factors produced small improvements in discrimination (absolute improvement in AUC or C statistics, 0.001-0.05) and appropriate risk classification for prediction of multiple cardiovascular outcomes, although evidence was limited by imprecision, quality, considerable heterogeneity, and inconsistent use of risk thresholds used for clinical decision making. Total net reclassification improvements ranged from 3.6% (2.7% event; 0.6% nonevent) to 30% (17% event; 19% nonevent) for studies using the Framingham Risk Score or Pooled Cohort Equations base models. Evidence on potential harms (eg, from subsequent angiography or revascularization) in asymptomatic persons was limited. RCTs of screening with exercise ECG found no improvement in health outcomes, despite focusing on higher-risk populations with diabetes. The addition of resting ECG to traditional risk factors accurately reclassified persons, but evidence for this finding had many limitations. The frequency of harms from screening is uncertain.


Comparison of multiparametric MRI-based and transrectal ultrasound-based preplans with intraoperative ultrasound-based planning for low dose rate interstitial prostate seed implantation.
Transrectal ultrasound images are routinely acquired for low dose rate (LDR) prostate brachytherapy dosimetric preplanning (pTRUS), although diagnostic multiparametric magnetic resonance imaging (mpMRI) may serve this purpose as well. We compared the predictive abilities of TRUS vs MRI relative to intraoperative TRUS (iTRUS) to assess the role of mpMRI in brachytherapy preplanning. Retrospective analysis was performed on 32 patients who underwent iTRUS-guided prostate LDR brachytherapy as either mono- or combination therapy. 56.3% had pTRUS-only volume studies and 43.7% had both 3T-mpMRI and pTRUS preplanning. MRI was used for preplanning and its image fusion with iTRUS was also used for intraoperative guidance of seed placement. Differences in gland volume, seed number, and activity and procedure time were examined, as well as the identification of lesions suspicious for tumor foci. Pearson correlation coefficient and Fisher's Z test were used to estimate associations between continuous measures. There was good correlation of planning volumes between iTRUS and either pTRUS or MRI (r = 0.89, r = 0.77), not impacted by the addition of hormonal therapy (P = 0.65, P = 0.33). Both consistently predicted intraoperative seed number (r = 0.87, r = 0.86). MRI/TRUS fusion did not significantly increase surgical or anesthesia time (P = 0.10, P = 0.46). mpMRI revealed suspicious focal lesions in 11 of 14 cases not visible on pTRUS, that when correlated with histopathology, were incorporated into the plan. Relative to pTRUS, MRI yielded reliable preplanning measures, supporting the role of MRI-only LDR treatment planning. mpMRI carries numerous diagnostic, staging and preplanning advantages that facilitate better patient selection and delivery of novel dose escalation and targeted therapy, with no additional surgical or anesthesia time. Prospective studies assessing its impact on treatment planning and delivery can serve to establish mpMRI as the standard of care in LDR prostate brachytherapy planning.


The efficacy of glycemic control with continuous glucose monitoring on atheroma progression: rationale and design of the Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus (OPTIMAL).
Patients with type 2 diabetes mellitus (T2DM) are high-risk subjects who more frequently have micro- and macrovascular diseases including coronary artery disease (CAD). Since impaired glycemic homeostasis directly influences the formation and propagation of atherosclerotic plaques, optimal management of glycemic status is required for the prevention of diabetic atherosclerosis. Continuous glucose monitoring (CGM) provides not only average glucose level but also the degree of glucose fluctuation and hypoglycemia. Given the association of glycemic variability with diabetic macrovascular diseases, CGM-based glycemic management could favorably modulate glycemic fluctuation, thereby potentially modifying atheroma burden in T2DM subjects. To test this hypothesis, the Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus (OPTIMAL) study has been designed (Japan Registry of Clinical Trials: jRCT1052180152, University Hospital Medical Information Network Clinical Trial Registry UMIN000036721). The OPTIMAL is a single-center, randomized trial to evaluate the efficacy of CGM-based glycemic control on atheroma progression in T2DM patients with CAD by using serial intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) imaging. A total of 90 eligible subjects will be randomized 1:1 into two groups to receive either CGM-based glycemic control or HbA1c-baded glycemic management. Coronary angiography and NIRS/IVUS imaging is repeated at the end of the assigned treatment period. The primary endpoint is the normalized absolute change in total atheroma volume (TAV) from baseline to 12 months. The secondary endpoints include (I) the absolute change in percent atheroma volume, (II) the percent change in lipid core burden index, (III) the change in coefficient variance measured by CGM, (IV) the change in atherogenic markers (high-density lipoprotein functionality, proprotein convertase subxilisin/kexin type 9 and fatty-acid binding proteins), and (V) the frequency of hypoglycemia. Safety will also be evaluated. The collaboration of CGM use with serial NIRS/IVUS imaging will enable to compare atheroma progression rate under CGM-based glycemic management and HbA1c-based approach.


The association between singing and/or playing a musical instrument and cognitive functions in older adults.
Cognitive decline happens to everyone when aging, but to some more than others. Studies with children, adults, and professional musicians suggest that making music could be associated with better cognitive functioning. In older adults however, this association is less well investigated, which is therefore the aim of this study. In this cross-sectional study data from 1101 participants aged 64 and older from the Longitudinal Aging Study Amsterdam were used. Multivariable linear regression analyses were performed to test the association between making music and cognitive functioning and time spent making music and cognitive functioning. ANCOVA analyses were performed to differentiate between participants who made no music, only sang, only played an instrument or both sang and played an instrument in terms of cognitive functioning. Making music was significantly positively associated with letter fluency, learning and attention/short-term memory. Time spent making music yielded no significant results. The ANCOVA analyses showed higher scores for participants who only played an instrument compared to participants who made no music on learning, working memory and processing speed. For processing speed the instrument only group also had a higher score than participants who only sang. Making music at least once every two weeks and especially playing a musical instrument, is associated with better attention, episodic memory and executive functions. The results suggest that making music might be a potential protective factor for cognitive decline; however, to support this notion a longitudinal study design is needed.


Involvement of Endogenous Opioid System in Swim Stress-Induced Pain Modulation During the Interphase of the Formalin Test.
Some evidence demonstrates endogenous inhibitory pathways of pain involved in the interphase (phase between early and later phase) of the formalin test. We previously showed that swimming stress modulates the pain-related behaviors during the interphase of the formalin test. In this study, we evaluated the role of the endogenous opioid system in modulating nociceptive responses of the formalin test. Swim stress was performed in different heights of water (5, 25, 50 cm) in a swimming tank. The mean nociceptive scores were measured during phase 1 (1-7 min), interphase (8-14 min), and phase 2 (15-90 min) of the formalin test. Opioid receptor antagonist, naloxone (3 mg/kg; IP) was injected immediately before swim stress. Swim stress attenuated nociceptive behaviors in the first phase and increased the duration of interphase in the formalin test in a water-height-dependent manner, compared to the control group. Naloxone significantly increased nociceptive behaviors in the first phase, interphase, and the second phase of the formalin test, compared to the control group. Stress could affect the nociceptive response. Swim stress in different heights of water could have different effects on the nociception in different phases of the formalin test. In addition, the involvement of the endogenous opioid system is further demonstrated in the swim stress-induced modulation of pain behaviors in phase 1, phase 2, as well as interphase of formalin test in rats.


Characteristics and adaptability of iron- and sulfur-oxidizing microorganisms used for the recovery of metals from minerals and their concentrates.
Microorganisms are used in large-scale heap or tank aeration processes for the commercial extraction of a variety of metals from their ores or concentrates. These include copper, cobalt, gold and, in the past, uranium. The metal solubilization processes are considered to be largely chemical with the microorganisms providing the chemicals and the space (exopolysaccharide layer) where the mineral dissolution reactions occur. Temperatures at which these processes are carried out can vary from ambient to 80 degrees C and the types of organisms present depends to a large extent on the process temperature used. Irrespective of the operation temperature, biomining microbes have several characteristics in common. One shared characteristic is their ability to produce the ferric iron and sulfuric acid required to degrade the mineral and facilitate metal recovery. Other characteristics are their ability to grow autotrophically, their acid-tolerance and their inherent metal resistance or ability to acquire metal resistance. Although the microorganisms that drive the process have the above properties in common, biomining microbes usually occur in consortia in which cross-feeding may occur such that a combination of microbes including some with heterotrophic tendencies may contribute to the efficiency of the process. The remarkable adaptability of these organisms is assisted by several of the processes being continuous-flow systems that enable the continual selection of microorganisms that are more efficient at mineral degradation. Adaptability is also assisted by the processes being open and non-sterile thereby permitting new organisms to enter. This openness allows for the possibility of new genes that improve cell fitness to be selected from the horizontal gene pool. Characteristics that biomining microorganisms have in common and examples of their remarkable adaptability are described.


Compact optical fiber curvature sensor based on concatenating two tapers.
A low-loss, compact, and highly sensitive optical fiber curvature sensor is presented. The device consists of two identical low-loss fused fiber tapers in tandem separated by a distance L. When the optical fiber is kept straight and fixed, no interference pattern appears in the transmitted spectrum. However, when the device is bent, the symmetry of the straight taper is lost and the first taper couples light into the cladding modes. In the second taper, a fraction of the total light guided by the cladding modes will be coupled back to the fundamental mode, producing an interference pattern in the transmitted spectrum. As the fiber device is bent, visibility of the interference fringes grows, reaching values close to 1. The dynamic range of the device can be tailored by the proper selection of taper diameter and separation between tapers. The effects of temperature and refractive index of the external medium on the response of the curvature sensor is also discussed.


Measurement of enzymatic activity and specificity of human and avian influenza neuraminidases from whole virus by glycoarray and MALDI-TOF mass spectrometry.
Influenza neuraminidases hydrolyze the ketosidic linkage between N-acetylneuraminic acid and its adjacent galactose residue in sialosides. This enzyme is a tetrameric protein that plays a critical role in the release of progeny virions. Several methods have been described for the determination of neuraminidase activity, usually based on colorimetric, fluorescent, or chemiluminescent detection. However, only a few of these tests allow discrimination of the sialyl-linkage specificity (i.e., α2-3- versus α2-6-linked sialyllactosides) of the neuraminidase. Herein we report a glycoarray-based assay and a MALDI-TOF study for assessing the activity and specificity of two influenza neuraminidases on whole viruses. The human A(H3N2) and avian A(H5N2) neuraminidase activities were investigated. The results from both approaches demonstrated that α2-3 sialyllactoside was a better substrate than α2-6 sialyllactoside for both viruses and that H5N2 virus had a lower hydrolytic activity than H3N2.


Clusterin interacts with Paclitaxel and confer Paclitaxel resistance in ovarian cancer.
Optimal debulking followed by chemotherapy is the standard treatment of managing late-stage ovarian cancer, but chemoresistance is still a major problem. In this study, we compared expression profiles of primary tumor tissue from five long-term (>8 years) and five short-term (<2 years) ovarian cancer survivors and identified clusterin as one of the genes that were significantly up-regulated in short-term survivors. We then evaluated the prognostic significance of clusterin and its possible correlation with chemoresistance in ovarian cancer by immunohistostaining of clusterin in 62 tumor samples from patients with stage III, high-grade serous ovarian cancer. After adjusting for debulking status and age, Cox regression analyses showed that high levels of clusterin expression correlate with poor survival (hazard ratio, 1.07; 95% confidence interval, 1.002-1.443; P = .04). We also investigated clusterin in paclitaxel resistance by modulating the endogenous clusterin expression in ovarian cancer cells and treating the cells with purified clusterin. Results indicate that high-clusterin-expressing ovarian cancer cells are more resistant to paclitaxel. Moreover, exposing ovarian cancer cells to exogenous clusterin increases cells' resistance to paclitaxel. Finally, using size exclusion chromatography and fluorescently labeled paclitaxel, we demonstrated that clusterin binds to paclitaxel. In summary, our findings suggest that high levels of clusterin expression increase paclitaxel resistance in ovarian cancer cells by physically binding to paclitaxel, which may prevent paclitaxel from interacting with microtubules to induce apoptosis. Thus, clusterin is a potential therapeutic target for enhancing chemoresponsiveness in patients with a high-level clusterin expression.


Reclassification of Xanthomonas campestris pv. citri (ex Hasse 1915) Dye 1978 forms A, B/C/D, and E as X. smithii subsp. citri (ex Hasse) sp. nov. nom. rev. comb. nov., X. fuscans subsp. aurantifolii (ex Gabriel 1989) sp. nov. nom. rev. comb. nov., and X. alfalfae subsp. citrumelo (ex Riker and Jones) Gabriel et al., 1989 sp. nov. nom. rev. comb. nov.; X. campestris pv malvacearum (ex smith 1901) Dye 1978 as X. smithii subsp. smithii nov. comb. nov. nom. nov.; X. campestris pv. alfalfae (ex Riker and Jones, 1935) dye 1978 as X. alfalfae subsp. alfalfae (ex Riker et al., 1935) sp. nov. nom. rev.; and "var. fuscans" of X. campestris pv. phaseoli (ex Smith, 1987) Dye 1978 as X. fuscans subsp. fuscans sp. nov.
Bacterial canker of citrus is a serious disease of citrus worldwide. Five forms of the disease have been described, cankers "A", "B", "C", "D", and "E". Although considerable genetic diversity has been described among the causal agents of the five forms of citrus canker and supports multiple taxons, the causal agents currently are classified as pathovars citri ("A"), aurantifolii ("B/C/D") and citrumelo ("E") of a single species, Xanthomonas campestris pv. citri (or X. axonopodis pv. citri). To determine the taxonomic relatedness among strains of X. campestris pv. citri, we conducted DNA-DNA relatedness assays, sequenced the 16S-23S intergenic spacer (ITS) regions, and performed amplified fragment length polymorphism (AFLP) analysis, using 44 strains representative of the five recognized forms of citrus canker. Under stringent DNA reassociation conditions (Tm - 15 degrees C), three distinct genotypes of citrus pathogens were revealed: taxon I included all "A" strains; taxon II contained all "B", "C", and "D" strains; and taxon III contained all "E" strains. The three citrus taxa showed less than 50% (mean) DNA-DNA relatedness to each other and less than 30% (mean) to X. campestris pv. campestris and X. axonopodis pv. axonopodis. Taxa I and II strains share over 70% DNA relatedness to X. campestris pv. malvacearum and X. campestris pv. phaseoli var. fuscans, respectively (at Tm - 15 degrees C). Taxon III strains share 70% relatedness to X. campestris pv. alfalfae. Previous and present phenotypic data support these DNA reassociation data. Taxon II strains grow more slowly on agar media than taxa I and III strains. Taxa I and III strains utilize maltose, and liquefy gelatin whereas taxon II strains do not. Taxon I strains hydrolyze pectate (pH 7.0) whereas Taxon II strains do not. Taxon III strains utilize raffinose whereas Taxon I strains do not. Each taxon can be differentiated by serology and pathogenicity. We propose taxa I, II, and III citrus strains be named, respectively, Xanthomonas smithii subsp. citri (ex Hasse, 1915) sp. nov. nom. rev. comb. nov., Xanthomonas fuscans subsp. aurantifolii (ex Gabriel et al., 1989) sp. nov. nom. rev. comb. nov., and Xanthomonas alfalfae subsp. citrumelo (ex Riker and Jones) Gabriel et al., 1989 nov. rev. comb. nov. Furthermore, based on the analysis of 40 strains of 19 other xanthomonads, we propose to reclassify X. campestris pv. malvacearum (ex Smith, 1901) Dye 1978 as X. smithii subsp. smithii sp. nov. comb. nov. nom. nov.; X. campestris pv. alfalfae (ex Riker and Jones) Dye 1978 as X. alfalfae subsp. alfalfae (ex Riker et al., 1935) sp. nov. nov. rev.; and "var. fuscans" (ex Burkholder 1930) of X. campestris pv. phaseoli (ex Smith, 1897) as X. fuscans subsp. fuscans sp. nov.


Stress-induced insulin resistance: recent developments.
Interest in stress-induced insulin resistance has increased during the past 5 years. Relevant clinical and mechanistic investigations during the past year will be reviewed. Recent trials of intensive insulin therapy in intensive care units have brought attention to a high incidence of hypoglycemic episodes with such treatment. The clinical relevance of such hypoglycemia has been shown to be minor, however. Furthermore, animal and in-vitro work further supports the finding that glucose control, rather than glycemia-independent effects of insulin, is the primary mechanism of action of intensive insulin therapy. In elective surgery, cohort studies show an association between intraoperative hyperglycemia and postoperative morbidity. Beneficial effects of preoperative oral carbohydrate treatment on immunocompetence and cardiac contractility have been demonstrated. Laparoscopic segmental colectomy was associated with considerably attenuated derangements in glucose metabolism compared with conventional, open surgery. Better methods of insulin dosing and administration and glucose monitoring are warranted to further minimize the risks of intensive insulin therapy. In elective surgery, perioperative measures such as preoperative oral carbohydrate treatment and laparoscopic techniques attenuate metabolic and other physiological derangements and such methods should be integrated into perioperative care protocols to minimize morbidity and enhance recovery.


Plasma Biomarkers to Detect Prevalent or Predict Progressive Tuberculosis Associated With Human Immunodeficiency Virus-1.
The risk of individuals infected with human immunodeficiency virus (HIV)-1 developing tuberculosis (TB) is high, while both prognostic and diagnostic tools remain insensitive. The potential for plasma biomarkers to predict which HIV-1-infected individuals are likely to progress to active disease is unknown. Thirteen analytes were measured from QuantiFERON Gold in-tube (QFT) plasma samples in 421 HIV-1-infected persons recruited within the screening and enrollment phases of a randomized, controlled trial of isoniazid preventive therapy. Blood for QFT was obtained pre-randomization. Individuals were classified into prevalent TB, incident TB, and control groups. Comparisons between groups, supervised learning methods, and weighted correlation network analyses were applied utilizing the unstimulated and background-corrected plasma analyte concentrations. Unstimulated samples showed higher analyte concentrations in the prevalent and incident TB groups compared to the control group. The largest differences were seen for C-X-C motif chemokine 10 (CXCL10), interleukin-2 (IL-2), IL-1α, transforming growth factor-α (TGF-α). A predictive model analysis using unstimulated analytes discriminated best between the control and prevalent TB groups (area under the curve [AUC] = 0.9), reasonably well between the incident and prevalent TB groups (AUC > 0.8), and poorly between the control and incident TB groups. Unstimulated IL-2 and IFN-γ were ranked at or near the top for all comparisons, except the comparison between the control vs incident TB groups. Models using background-adjusted values performed poorly. Single plasma biomarkers are unlikely to distinguish between disease states in HIV-1 co-infected individuals, and combinations of biomarkers are required. The ability to detect prevalent TB is potentially important, as no blood test hitherto has been suggested as having the utility to detect prevalent TB amongst HIV-1 co-infected persons.


Elements of Condom-Use Decision Making among South African Men Who Have Sex with Men.
South African men who have sex with men (MSM) are at increased risk for HIV infection, and male condoms are fundamental to HIV prevention programs. We explored condom use experiences through in-depth interviews with 34 South African MSM from Cape Town and Port Elizabeth. For data analysis, we generated a codebook and used the constant comparison method. Condom use reinforcing elements included use of alternative sexual strategies, having a high level of self-worth that was linked to protective behaviors, and use of ready-made condom negotiation scripts. Elements inhibiting condom use included perceiving substantial declines in sexual pleasure/performance, experiences of condom failure (possibly related to petroleum-based lubricant), and being in trusted relationships. Our findings suggest nuanced HIV prevention approaches such as bolstering condom negotiation skills based on successful tactics already in use. Further research is needed to address how to mitigate perceptions and experiences that condoms negatively impact sexual pleasure and performance.


Depth of cure and compressive strength of dental composites cured with blue light emitting diodes (LEDs).
The primary objective of this pilot study was to test the hypotheses that (i) depth of cure and (ii) compressive strength of dental composites cured with either a light emitting diode (LED) based light curing unit (LCU) or a conventional halogen LCU do not differ significantly. The second objective of this study was to characterise irradiance and the emitted light spectra for both LCUs to allow comparisons between the units. Dental composite (Spectrum TPH, shades A2 and A4) was cured for 40 s with either a commercial halogen LCU or a LED LCU, respectively. The LED LCU uses 27 blue LEDs as the light source. The composites' depth of cure was measured for 10 samples of 4 mm diameter and 8 mm depth for each shade with a penetrometer. The results were compared using a Student's t-test. Compressive strengths were determined after 6 and 72 h, for six samples of 4 mm diameter and 6 mm depth for each shade after being polymerised for 40 s from each end of the mould. Groups were compared using a three way ANOVA. The conventional halogen LCU cured composites significantly (p < 0.05) deeper (6.40 mm A2, 5.19 mm A4) than did the LED LCU (5.33 mm A2, 4.27 mm A4). Both units cured the composite deeper than required by both ISO 4049 and the manufacturer. A three way ANOVA showed that there were no significant differences in the compressive strengths of samples produced with either the LED LCU or the halogen LCU (p = 0.460). Significant differences in compressive strength of samples stored for 6 and 72 h (p = 0.0006) and of samples of different shades (p = 0.035) were found as confirmed by the three way ANOVA. The light spectra of both units differed strongly. While the halogen LCU showed a broad distribution of wavelengths with a power peak at 497 nm, the LED LCU emitted most of the generated light at 465 nm. The LED LCU produced a total irradiance of 350 mW cm-2 whereas the halogen LCU produced a total irradiance of 755 mW cm-2. The results showed that both units provided sufficient output to exceed minimum requirements in terms of composites' depth of cure according to ISO 4049 and the depth of cure and the composites' compressive strength stated by the manufacturer. Compressive strengths of dental composites cured under laboratory conditions with a LED LCU were statistically equivalent to those cured with a conventional halogen LCU. With its inherent advantages, such as a constant power output over the lifetime of the diodes, LED LCUs have great potential to achieve a clinically consistent quality of composite cure.


Signal transduction pathways involved in brain death-induced renal injury.
Kidneys derived from brain death organ donors show an inferior survival when compared to kidneys derived from living donors. Brain death is known to induce organ injury by evoking an inflammatory response in the donor. Neuronal injury triggers an inflammatory response in the brain, leading to endothelial dysfunction and the release of cytokines in the circulation. Serum levels of interleukin-6, -8, -10, and monocyte chemoattractant protein-1 (MCP-1) are increased after brain death. Binding with cytokine-receptors in kidneys stimulates activation of nuclear factor-kappa B (NF-kappaB), selectins, adhesion molecules and production of chemokines leading to cellular influx. Mitogen-activated protein kinases (MAP-kinases) mediate inflammatory responses and together with NF-kappaB they seem to play an important role in brain death induced renal injury. Altering the activation state of MAP-kinases could be a promising drug target for early intervention to reduce cerebral injury related donor kidney damage and improve outcome after transplantation.


Differential effects of 30- vs. 60-second static muscle stretching on vertical jump performance.
It has been proposed that pre-exercise static stretching may reduce muscle force and power. Recent systematic and meta-analytical reviews have proposed a threshold regarding the effect of short (<45 seconds) and moderate (≥60 seconds) stretching durations on subsequent performance in a multi-joint task (e.g., jump performance), although its effect on power output remains less clear. Furthermore, no single experimental study has explicitly compared the effect of short (e.g., 30 seconds) and moderate (60 seconds) durations of continuous static stretching on multi-joint performance. Therefore, the aim of the present study was determine the effect of acute short- and moderate-duration continuous stretching interventions on vertical jump performance and power output. Sixteen physically active men (21.0 ± 1.9 years; 1.7 ± 0.1 m; 78.4 ± 12.1 kg) volunteered for the study. After familiarization, subjects attended the laboratory for 3 testing sessions. In the nonstretching (NS) condition, subjects performed a countermovement jump (CMJ) test without a preceding stretching bout. In the other 2 conditions, subjects performed 30-second (30SS; 4 minutes) or 60-second (60SS; 8 minutes) static stretching bouts in calf muscles, hamstrings, gluteus maximus, and quadriceps, respectively, followed by the CMJ test. Results were compared by repeated-measures analysis of variance. In comparison with NS, 60SS resulted in a lower CMJ height (-3.4%, p ≤ 0.05) and average (-2.7%, p ≤ 0.05) and peak power output (-2.0%, p ≤ 0.05), but no difference was observed between 30SS and the other conditions (p > 0.05). These data suggest a dose-dependent effect of stretching on muscular performance, which is in accordance with previous studies. The present results suggest a threshold of continuous static stretching in which muscular power output in a multi-joint task may be impaired immediately following moderate-duration (60 seconds; 8 minutes) static stretching while short-duration (30 seconds; 4 minutes) stretching has a negligible influence.


Optimization of a widefield structured illumination microscope for non-destructive assessment and quantification of nuclear features in tumor margins of a primary mouse model of sarcoma.
Cancer is associated with specific cellular morphological changes, such as increased nuclear size and crowding from rapidly proliferating cells. In situ tissue imaging using fluorescent stains may be useful for intraoperative detection of residual cancer in surgical tumor margins. We developed a widefield fluorescence structured illumination microscope (SIM) system with a single-shot FOV of 2.1 × 1.6 mm (3.4 mm(2)) and sub-cellular resolution (4.4 µm). The objectives of this work were to measure the relationship between illumination pattern frequency and optical sectioning strength and signal-to-noise ratio in turbid (i.e. thick) samples for selection of the optimum frequency, and to determine feasibility for detecting residual cancer on tumor resection margins, using a genetically engineered primary mouse model of sarcoma. The SIM system was tested in tissue mimicking solid phantoms with various scattering levels to determine impact of both turbidity and illumination frequency on two SIM metrics, optical section thickness and modulation depth. To demonstrate preclinical feasibility, ex vivo 50 µm frozen sections and fresh intact thick tissue samples excised from a primary mouse model of sarcoma were stained with acridine orange, which stains cell nuclei, skeletal muscle, and collagenous stroma. The cell nuclei were segmented using a high-pass filter algorithm, which allowed quantification of nuclear density. The results showed that the optimal illumination frequency was 31.7 µm(-1) used in conjunction with a 4 × 0.1 NA objective (v=0.165). This yielded an optical section thickness of 128 µm and an 8.9 × contrast enhancement over uniform illumination. We successfully demonstrated the ability to resolve cell nuclei in situ achieved via SIM, which allowed segmentation of nuclei from heterogeneous tissues in the presence of considerable background fluorescence. Specifically, we demonstrate that optical sectioning of fresh intact thick tissues performed equivalently in regards to nuclear density quantification, to physical frozen sectioning and standard microscopy.


Traumatic Stress-Induced Increases in Anxiety-like Behavior and Alcohol Self-Administration Are Mediated by Central Amygdala CRF1 Neurons That Project to the Lateral Hypothalamus.
Avoidance stress coping, defined as persistent internal and/or external avoidance of stress-related stimuli, is a key feature of anxiety- and stress-related disorders, and contributes to increases in alcohol misuse after stress exposure. Previous work using a rat model of predator odor stress avoidance identified corticotropin-releasing factor (CRF) signaling via CRF Type 1 receptors (CRF1) in the CeA, as well as CeA projections to the lateral hypothalamus (LH) as key mediators of conditioned avoidance of stress-paired contexts and/or increased alcohol drinking after stress. Here, we report that CRF1-expressing CeA cells that project to the LH are preferentially activated in male and female rats that show persistent avoidance of predator odor stress-paired contexts (termed Avoider rats), and that chemogenetic inhibition of these cells rescues stress-induced increases in anxiety-like behavior and alcohol self-administration in male and female Avoider rats. Using slice electrophysiology, we found that prior predator odor stress exposure blunts inhibitory synaptic transmission and increases synaptic drive in CRF1 CeA-LH cells. In addition, we found that CRF bath application reduces synaptic drive in CRF1 CeA-LH cells in Non-Avoiders only. Collectively, these data show that CRF1 CeA-LH cells contribute to stress-induced increases in anxiety-like behavior and alcohol self-administration in male and female Avoider rats.SIGNIFICANCE STATEMENT Stress may lead to a variety of behavioral and physiological negative consequences, and better understanding of the neurobiological mechanisms that contribute to negative stress effects may lead to improved prevention and treatment strategies. This study, performed in laboratory rats, shows that animals that exhibit avoidance stress coping go on to develop heightened anxiety-like behavior and alcohol self-administration, and that these behaviors can be rescued by inhibiting the activity of a specific population of neurons in the central amygdala. This study also describes stress-induced physiological changes in these neurons that may contribute to their role in promoting increased anxiety and alcohol self-administration.


Native shrub reestablishment in exotic annual grasslands: do ecosystem processes recover?
The impacts of exotic plant species on ecosystem processes are well established, motivating numerous efforts to facilitate native-species recovery. Nonetheless, how the return of native species influences ecosystem processes and how these changes feed back to influence the recovery process are poorly understood. We examined these questions in exotic annual grasslands on Santa Cruz Island, California, USA, where the removal of nonnative herbivores has led to the recovery of the native shrubs Artemisia californica and Eriogonum arborescens. To examine the influence of shrub colonization on nutrient cycling, and the mechanisms by which these changes arise, we measured available nitrogen and phosphorus, and quantified nitrogen mineralization and litterfall rates under shrubs and grasses in the field and in experimental monoculture plots. Both native shrubs altered nitrogen cycling as they colonized the grassland, but they did so in opposite directions. Eriogonum depressed nitrogen pools and mineralization rates via large inputs of nitrogen-poor litter. In contrast Artemisia increased nitrogen and phosphorus pools and nitrogen mineralization rates. Last, to determine if shrub effects on soils favor shrubs or grasses, we conducted a nitrogen and phosphorus fertilization experiment in the field. Only the exotic grass was significantly limited by nitrogen. Thus the depressed nitrogen availability associated with Eriogonum colonization is more harmful to exotic grasses than to the native shrub. By contrast, the elevated nitrogen associated with recovering Artemisia favors grasses over the shrub, possibly hindering recovery of the native. Mechanistic studies of the ecosystem ,impacts of native-plant recovery are useful for managers wishing to predict which native species return ecosystem function, and whether such changes feed back to influence native recovery.


Functionalization of polyacrylamide for nanotrapping positively charged biomolecules.
Engineering new materials which are capable of trapping biomolecules in nanoscale quantities, is crucial in order to achieve earlier diagnostics in different diseases. This article demonstrates that using free radical copolymerization, polyacrylamide can be successfully functionalized with specific synthons for nanotrapping positively charged molecules, such as numerous proteins, through electrostatic interactions due to their negative charge. Specifically, two functional random copolymers, acrylamide/acrylic acid (1) and acrylamide/acrylic acid/N-(pyridin-4-yl-methyl)acrylamide (2), whose negative net charges differ in their water solutions, were synthetized and their ability to trap positively charged proteins was studied using myoglobin as a proof-of-concept example. In aqueous solutions, copolymer 1, whose net charge for a 100 chain fragment (Q pH 6/M) is -1.323 × 10-3, interacted with myoglobin forming a stable monodisperse nanosuspension. In contrast, copolymer 2, whose value of Q pH 6/M equals -0.361 × 10-3, was not able to form stable particles with myoglobin. Nevertheless, thin films of both copolymers were grown using a dewetting process, which exhibited nanoscale cavities capable of trapping different amounts of myoglobin, as demonstrated by bimodal AFM imaging. The simple procedures used to build protein traps make this engineering approach promising for the development of new materials for biomedical applications where trapping biomolecules is required.


The diagnostic accuracy for ARDS of global versus regional lung ultrasound scores - a post hoc analysis of an observational study in invasively ventilated ICU patients.
Semi-quantification of lung aeration by ultrasound helps to assess presence and extent of pulmonary pathologies, including the acute respiratory distress syndrome (ARDS). It is uncertain which lung regions add most to the diagnostic accuracy for ARDS of the frequently used global lung ultrasound (LUS) score. We aimed to compare the diagnostic accuracy of the global versus those of regional LUS scores in invasively ventilated intensive care unit patients. This was a post-hoc analysis of a single-center observational study in the mixed medical-surgical intensive care unit of a university-affiliated hospital in the Netherlands. Consecutive patients, aged ≥ 18 years, and are expected to receive invasive ventilation for > 24 h underwent a LUS examination within the first 2 days of ventilation. The Berlin Definition was used to diagnose ARDS, and to classify ARDS severity. From the 12-region LUS examinations, the global score (minimum 0 to maximum 36) and 3 regional scores (the 'anterior,' 'lateral,' and 'posterior' score, minimum 0 to maximum 12) were computed. The area under the receiver operating characteristic (AUROC) curve was calculated and the best cutoff for ARDS discrimination was determined for all scores. The study enrolled 152 patients; 35 patients had ARDS. The global score was higher in patients with ARDS compared to patients without ARDS (median 19 [15-23] vs. 5 [3-9]; P < 0.001). The posterior score was the main contributor to the global score, and was the only score that increased significantly with ARDS severity. However, the posterior score performed worse than the global score in diagnosing ARDS, and it had a positive predictive value of only 50 (41-59)% when using the optimal cutoff. The combined anterolateral score performed as good as the global score (AUROC of 0.91 [0.85-0.97] vs. 0.91 [0.86-0.95]). While the posterior score increases with ARDS severity, its diagnostic accuracy for ARDS is hampered due to an unfavorable signal-to-noise ratio. An 8-region 'anterolateral' score performs as well as the global score and may prove useful to exclude ARDS in invasively ventilated ICU patients.


A Review: Mealtime Difficulties following Frontotemporal Lobar Degeneration.
Frontotemporal lobar degeneration (FTLD) can result in a decline in behavior, language, and motor function. Mealtime disturbances are a common and significant outcome of FTLD. Disturbances during mealtimes can arise from dysphagia or may occur secondary to behavioral changes such as rapid eating, mealtime rigidity, and altered diet preferences. Few studies have comprehensively evaluated eating behavior or dysphagia in individuals presenting with FTLD pathology despite the potential impact on medical safety and individual quality of life. Dysphagia is reported in the late stages of frontotemporal dementia and early in the motor subtypes of FTLD. The identification of dysphagia can alert individuals and medical teams to disease progression and provide insight into the nature and spread of the underlying neuropathology. Improved understanding of eating behaviors can improve individual care and may enhance diagnostic accuracy. Key Message: Aberrant eating behavior and swallowing difficulties are reported in the conditions associated with FTLD neuropathology. The consequences of mealtime disturbances include health risks associated with an increased BMI and aspiration, reduction of an individual's independence, and an increase in caregiver stress and burden. Here we review and summarize the literature on eating behavior and swallow impairments (dysphagia) in each of the syndromes caused by FTLD.


Pre-, intra-, and postoperative management of Robert's uterus.
To demonstrate a minimally invasive approach and management in three different types of Robert's uterus. Video presentation of surgical and ultrasound techniques. University hospital and two private centers. Patients with three types of Robert's uterus; a rare form of septate uterus consisting of non-communicating hemicavity, a contralateral unicornuate uterine cavity in a single uterine body with normal fundus: with large hematometra in the blind hemi-cavity and acute pelvic pain; with an inactive blind hemi-cavity without hematometra and recurrent miscarriages; and with small hematometra in the blind hemi-cavity. Three-dimensional ultrasound with saline infusion sonohysterography and automatic volume calculation software (SonoHySteroAVC) were used for differential diagnosis and surgical planning. Transrectally guided hysteroscopic metroplasty, a incision of myometrium between two parts of cavities by resectoscope and Collin's electrode, were performed and recorded. Sequentional balloon anti-adhesion therapy and three-dimensional ultrasound with saline infusion sonohysterography with SonoHysteroAVC were used in post-operative management. Pre-, intra- and postoperative findings regarding uterine morphology, feasibility of surgery and anatomical and clinical outcomes. A successful unification of non-communicating and communicating uterine cavity parts during surgery, better shape and several times higher volume of uterine cavity, and total elimination of pain associated with obstruction after healing period were recorded. Three-dimensional ultrasound techniques seem to be the best tool for complex pre- and postoperative management of Robert's uterus. Minimally invasive ultrasound-guided hysteroscopic metroplasty should be considered as the first choice of treatment because of the potential for normalization of uterine morphology and function.


Does adhesive capsulitis of the shoulder increase the risk of stroke? A population-based propensity score-matched follow-up study.
A previous population-based study reported an increased risk of stroke after the occurrence of adhesive capsulitis of the shoulder (ACS), but there were substantial imbalances in the distribution of age and pre-existing vascular risk factors between subjects with ACS and without ACS, which might lead to a confounded association between ACS and stroke. The purpose of the present large-scale propensity score-matched population-based follow-up study was to clarify whether there is an increased stroke risk after ACS. We used a logistic regression model that includes age, sex, pre-existing comorbidities and socioeconomic status as covariates to compute the propensity score. A total of 22025 subjects with at least two ambulatory visits with the principal diagnosis of ACS in 2001 was enrolled in the ACS group. The non-ACS group consisted of 22025, propensity score-matched subjects without ACS. The stroke-free survival curves for these 2 groups were compared using the Kaplan-Meier method. Stratified Cox proportional hazard regression with patients matched on propensity score was used to estimate the effect of ACS on the occurrence of stroke. During the two-year follow-up period, 657 subjects in the ACS group (2.98%) and 687 in the non-ACS group (3.12%) developed stroke. The hazard ratio (HR) of stroke for the ACS group was 0.93 compared to the non-ACS group (95% confidence interval [CI], 0.83-1.04, P = 0.1778). There was no statistically significant difference in stroke subtype distribution between the two groups (P = 0.2114). These findings indicate that ACS itself is not associated with an increased risk of subsequent stroke.


The transgenerational effect of maternal and paternal F1 low birth weight on bone health of second and third generation offspring.
Low birth weight programs diseases in adulthood, including adverse bone health. These diseases can have intergenerational and transgenerational origins, whereby transmission to subsequent generations occurs via both parental lines. Uteroplacental insufficiency surgery (Restricted) or sham surgery (Control) was performed on gestational day 18, in F0 Wistar-Kyoto rats. F1 Restricted males and females mated with breeders in order to generate F2 offspring of maternal and paternal lineages. F2 males and females were randomly selected for breeding to generate F3 offspring. F2 and F3 offspring did not have differences in birth weight irrespective of F1 low birth weight and parental line. Maternal line females had minor alterations to trabecular content and density at 6 months, these differences were not sustained at 12 months. Maternal line males had changes to trabecular content at 6 and 12 months; however, differences were no longer present at 16 months. Despite altered bone geometry at 12 and 16 months, bending strength remained unaffected at both ages. Bone health of paternal line females was not affected at 6 and 12 months. Paternal line males at 6 months had changes to trabecular and cortical content; cortical thickness, periosteal circumference and bending strength; however, these differences were no longer sustained at 12 and 16 months. Our data demonstrate that there is no transgenerational transmission of adverse bone health in F2 and F3 offspring, derived from low F1 birth weight females and males. Our results are novel, as bone health across generations and both parental lines has not been investigated in a model of low birth weight due to uteroplacental insufficiency.


T-Box Genes and Developmental Gene Regulatory Networks in Ascidians.
Ascidians are invertebrate chordates with a biphasic life cycle characterized by a dual body plan that displays simplified versions of chordate structures, such as a premetamorphic 40-cell notochord topped by a dorsal nerve cord and postmetamorphic pharyngeal slits. These relatively simple chordates are characterized by rapid development, compact genomes and ease of transgenesis, and thus provide the opportunity to rapidly characterize the genomic organization, developmental function, and transcriptional regulation of evolutionarily conserved gene families. This review summarizes the current knowledge on members of the T-box family of transcription factors in Ciona and other ascidians. In both chordate and nonchordate animals, these genes control a variety of morphogenetic processes, and their mutations are responsible for malformations and developmental defects in organisms ranging from flies to humans. In ascidians, T-box transcription factors are required for the formation and specialization of essential structures, including notochord, muscle, heart, and differentiated neurons. In recent years, the experimental advantages offered by ascidian embryos have allowed the rapid accumulation of a wealth of information on the molecular mechanisms that regulate the expression of T-box genes. These studies have also elucidated the strategies employed by these transcription factors to orchestrate the appropriate spatial and temporal deployment of the numerous target genes that they control.


Supervision of care networks for frail community dwelling adults aged 75 years and older: protocol of a mixed methods study.
The Dutch healthcare inspectorate (IGZ) supervises the quality and safety of healthcare in the Netherlands. Owing to the growing population of (community dwelling) older adults and changes in the Dutch healthcare system, the IGZ is exploring new methods to effectively supervise care networks that exist around frail older adults. The composition of these networks, where formal and informal care takes place, and the lack of guidelines and quality and risk indicators make supervision complicated in the current situation. This study consists of four phases. The first phase identifies risks for community dwelling frail older adults in the existing literature. In the second phase, a qualitative pilot study will be conducted to assess the needs and wishes of the frail older adults concerning care and well-being, perception of risks, and the composition of their networks, collaboration and coordination between care providers involved in the network. In the third phase, questionnaires based on the results of phase II will be sent to a larger group of frail older adults (n=200) and their care providers. The results will describe the composition of their care networks and prioritise risks concerning community dwelling older adults. Also, it will provide input for the development of a new supervision framework by the IGZ. During phase IV, a second questionnaire will be sent to the participants of phase III to establish changes of perception in risks and possible changes in the care networks. The framework will be tested by the IGZ in pilots, and the researchers will evaluate these pilots and provide feedback to the IGZ. The study protocol was approved by the Scientific Committee of the EMGO+institute and the Medical Ethical review committee of the VU University Medical Centre. Results will be presented in scientific articles and reports and at meetings.


Confirmation and elimination of xylose metabolism bottlenecks in glucose phosphoenolpyruvate-dependent phosphotransferase system-deficient Clostridium acetobutylicum for simultaneous utilization of glucose, xylose, and arabinose.
Efficient cofermentation of D-glucose, D-xylose, and L-arabinose, three major sugars present in lignocellulose, is a fundamental requirement for cost-effective utilization of lignocellulosic biomass. The Gram-positive anaerobic bacterium Clostridium acetobutylicum, known for its excellent capability of producing ABE (acetone, butanol, and ethanol) solvent, is limited in using lignocellulose because of inefficient pentose consumption when fermenting sugar mixtures. To overcome this substrate utilization defect, a predicted glcG gene, encoding enzyme II of the D-glucose phosphoenolpyruvate-dependent phosphotransferase system (PTS), was first disrupted in the ABE-producing model strain Clostridium acetobutylicum ATCC 824, resulting in greatly improved D-xylose and L-arabinose consumption in the presence of D-glucose. Interestingly, despite the loss of GlcG, the resulting mutant strain 824glcG fermented D-glucose as efficiently as did the parent strain. This could be attributed to residual glucose PTS activity, although an increased activity of glucose kinase suggested that non-PTS glucose uptake might also be elevated as a result of glcG disruption. Furthermore, the inherent rate-limiting steps of the D-xylose metabolic pathway were observed prior to the pentose phosphate pathway (PPP) in strain ATCC 824 and then overcome by co-overexpression of the D-xylose proton-symporter (cac1345), D-xylose isomerase (cac2610), and xylulokinase (cac2612). As a result, an engineered strain (824glcG-TBA), obtained by integrating glcG disruption and genetic overexpression of the xylose pathway, was able to efficiently coferment mixtures of D-glucose, D-xylose, and L-arabinose, reaching a 24% higher ABE solvent titer (16.06 g/liter) and a 5% higher yield (0.28 g/g) compared to those of the wild-type strain. This strain will be a promising platform host toward commercial exploitation of lignocellulose to produce solvents and biofuels.


Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain.
The vocal control nucleus designated HVc (hyperstriatum ventrale, pars caudalis) of adult female canaries expands in response to systemic testosterone administration, which also induces the females to sing in a male-like manner. We became interested in the possibility of neurogenesis as a potential basis for this phenomenon. Intact adult female canaries were injected with [3H]thymidine over a 2-day period. Some birds were given testosterone implants at various times before thymidine. The birds were sacrificed 5 wk after hormone implantation, and their brains were processed for autoradiography. In parallel control experiments, some birds were given implants of cholesterol instead of testosterone. All birds showed considerable numbers of labeled neurons, glia, endothelia, and ventricular zone cells in and around HVc. Ultrastructural analysis confirmed the identity of these labeled neurons. Cholesterol- and testosterone-treated birds had similar neuronal labeling indices, which ranged from 1.8% to 4.0% in HVc. Thus, neurogenesis occurred in these adults independently of exogenous hormone treatment. Conversely, both glial and endothelial proliferation rates were markedly stimulated by exogenous testosterone treatment. We determined the origin of the thymidine-incorporating neurons by sacrificing two thymidine-treated females soon after their thymidine injections, precluding any significant migration of newly labeled cells. Analysis of these brains revealed no cells of neuronal morphology present in HVc but a very heavily labeled ventricular zone overlying HVc. We conclude that neuronal precursors exist in the HVc ventricular zone that incorporate tritiated thymidine during the S phase preceding their mitosis; after division these cells migrate into, and to some extent beyond, HVc. This ventricular zone neurogenesis seems to be a normally occurring phenomenon in intact adult female canaries.


Rehydration: role for early use of intravenous dextrose.
Acute gastroenteritis is a common reason for children to seek health care. Among the potential complications of acute gastroenteritis, the most common is dehydration. For mild to moderate dehydration, treatment options include oral and intravenous rehydration. Outpatient treatment failure for either method, when it occurs, is often due to persistent nausea and vomiting. Some authorities have suggested that the early administration of dextrose to patients receiving intravenous rehydration may help terminate vomiting and result in fewer outpatient treatment failures. The purpose of this report was to review the evidence supporting the effectiveness of early intravenous dextrose administration in the outpatient management of dehydration in children with acute gastroenteritis.


Pharmacokinetic analysis of enterohepatic circulation of buprenorphine and its active metabolite, norbuprenorphine, in rats.
The pharmacokinetic characteristics of buprenorphine (BN) and its active metabolite, norbuprenorphine (NBN), was investigated using rats. The elimination half-life (t1/2), total body clearance (CLtot), and steady-state volume of distribution (Vdss) of BN (0.6 mg/kg iv dose) in the intact rat were 2.8 hr, 23.3 ml/min/kg, and 4.2 liters/kg, respectively, and those of NBN (0.6 mg/kg iv dose) were 0.9 hr, 35.0 ml/min/kg, and 2.0 liters/kg. Within 24 hr after administration of BN (0.6 mg/kg dose) to the bile-fistula rat, 74.1% of dose was excreted in the bile as BN glucuronide (BN-Glu) and 18.5% as NBN glucuronide (NBN-Glu), and in urine < 3.2% as BN-Glu. After administration of NBN to the bile-fistula rat, 85.1% and 9.1% of the dose were excreted as NGN-Glu in bile and urine, respectively. The existence of the enterohepatic circulation (EHC) of BN and NBN was confirmed by using paired rats: the donor and recipient rats. Within 24 hr after administration of BN (0.6 mg/kg dose) to the donor rat, 58.8% of the dose was reexcreted as NBN-Glu in bile of the recipient and 25.1% as BN-Glu. Based on the results of in vitro metabolism, it was suggested that this increase in the proportion of NBN-Glu in bile observed after one enterohepatic cycling of BN may be due to the first-pass metabolism in the liver. BN was detected in the plasma of the recipient rat after administration of BN, to the donor rat.(ABSTRACT TRUNCATED AT 250 WORDS)


Induced plant defences in biological control of arthropod pests: a double-edged sword.
Biological control is an important ecosystem service delivered by natural enemies. Together with breeding for plant defence, it constitutes one of the most promising alternatives to pesticides for controlling herbivores in sustainable crop production. Especially induced plant defences may be promising targets in plant breeding for resistance against arthropod pests. Because they are activated upon herbivore damage, costs are only incurred when defence is needed. Moreover, they can be more specific than constitutive defences. Nevertheless, inducible defence traits that are harming plant pest organisms may interfere with biological control agents, such as predators and parasitoids. Despite the vast fundamental knowledge on plant defence mechanisms and their effects on natural enemies, our understanding of the feasibility of combining biological control with induced plant defence in practice is relatively poor. In this review, we focus on arthropod pest control and present the most important features of biological control with natural enemies and of induced plant defence. Furthermore, we show potential synergies and conflicts among them and, finally, identify gaps and list opportunities for their combined use in crop protection. We suggest that breeders should focus on inducible resistance traits that are compatible with the natural enemies of arthropod pests, specifically traits that help communities of natural enemies to build up. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.