Association between diabetes, diabetes treatment and risk of developing endometrial cancer.
A growing body of evidence suggests that diabetes is a risk factor for endometrial cancer incidence. However, most of these studies used case-control study designs and did not adjust for obesity, an established risk factor for endometrial cancer. In addition, few epidemiological studies have examined the association between diabetes treatment and endometrial cancer risk. The objective of this study was to assess the relationships among diabetes, diabetes treatment and endometrial cancer risk in postmenopausal women participating in the Women's Health Initiative (WHI). A total of 88 107 postmenopausal women aged 50-79 years who were free of cancer and had no hysterectomy at baseline were followed until date of endometrial cancer diagnosis, death, hysterectomy or loss to follow-up, whichever came first. Endometrial cancers were confirmed by central medical record and pathology report review. Multivariate Cox proportional hazards regression models were used to estimate hazard ratios (HRs) (95% confidence interval (CI)) for diagnosis of diabetes and metformin treatment as risk factors for endometrial cancer. Over a mean of 11 years of follow-up, 1241 endometrial cancers developed. In the primary analysis that focused on prevalent diabetes at enrolment, compared with women without diabetes, women with self-reported diabetes, and the subset of women with treated diabetes, had significantly higher risk of endometrial cancer without adjusting for BMI (HR=1.44, 95% CI: 1.13-1.85 for diabetes, HR=1.57, 95% CI: 1.19-2.07 for treated diabetes). However after adjusting for BMI, the associations between diabetes, diabetes treatment, diabetes duration and the risk of endometrial cancer became non-significant. Elevated risk was noted when considering combining diabetes diagnosed at baseline and during follow-up as time-dependent exposure (HR=1.31, 95% CI: 1.08-1.59) even after adjusting for BMI. No significant association was observed between metformin use and endometrial cancer risk. Our results suggest that the relationship observed in previous research between diabetes and endometrial cancer incidence may be largely confounded by body weight, although some modest independent elevated risk remains.


Reduced specificity in emotion judgment in people with autism spectrum disorder.
There is a conflicting literature on facial emotion processing in autism spectrum disorder (ASD): both typical and atypical performance have been reported, and inconsistencies in the literature may stem from different processes examined (emotion judgment, face perception, fixations) as well as differences in participant populations. Here we conducted a detailed investigation of the ability to discriminate graded emotions shown in morphs of fear-happy faces, in a well-characterized high-functioning sample of participants with ASD and matched controls. Signal detection approaches were used in the analyses, and concurrent high-resolution eye-tracking was collected. Although people with ASD had typical thresholds for categorical fear and confidence judgments, their psychometric specificity to detect emotions across the entire range of intensities was reduced. However, fixation patterns onto the stimuli were typical and could not account for the reduced specificity of emotion judgment. Together, our results argue for a subtle and specific deficit in emotion perception in ASD that, from a signal detection perspective, is best understood as a reduced specificity due to increased noise in central processing of the face stimuli.


Major depressive disorder during pregnancy: Psychiatric medications have minimal effects on the fetus and infant yet development is compromised.
Psychotropic medication use and psychiatric symptoms during pregnancy each are associated with adverse neurodevelopmental outcomes in offspring. Commonly, studies considering medication effects do not adequately assess symptoms, nor evaluate children when the effects are believed to occur, the fetal period. This study examined maternal serotonin reuptake inhibitor and polypharmacy use in relation to serial assessments of five indices of fetal neurobehavior and Bayley Scales of Infant Development at 12 months in N = 161 socioeconomically advantaged, non-Hispanic White women with a shared risk phenotype, diagnosed major depressive disorder. On average fetuses showed the expected development over gestation. In contrast, infant average Bayley psychomotor and mental development scores were low (M = 84.10 and M = 89.92, range of normal limits 85-114) with rates of delay more than 2-3 times what would be expected based on this measure's normative data. Controlling for prenatal and postnatal depressive symptoms, prenatal medication effects on neurobehavioral development were largely undetected in the fetus and infant. Mental health care directed primarily at symptoms may not address the additional psychosocial needs of women parenting infants. Speculatively, prenatal serotonin reuptake inhibitor exposure may act as a plasticity rather than risk factor, potentially enhancing receptivity to a nonoptimal postnatal environment in some mother-infant dyads.


The myth of the total institution: Written narratives of patients' views of sanatorium care 1908-1959.
Drawing on written narratives by 72 former sanatorium patients, this article explores, from patients' perspectives, the nature of the relationships between patients and staff in a Swedish sanatorium during the first half of the twentieth century. These narratives are discussed in the context of the total institution. This article suggests that this phenomenon was marked by inconsistencies that can be understood in terms of its situational and contradictory characteristics. Simultaneously, these narratives are in opposition to the assumption of the static and powerless patient adapted only to suit the logic of the institution.


A ternary nanofibrous scaffold potential for central nerve system tissue engineering.
In the present research, a ternary polycaprolactone (PCL)/gelatin/fibrinogen nanofibrous scaffold for tissue engineering application was developed. Through this combination, PCL improved the scaffold mechanical properties; meanwhile, gelatin and fibrinogen provided more hydrophilicity and cell proliferation. Three types of nanofibrous scaffolds containing different fibrinogen contents were prepared and characterized. Morphological study of the nanofibers showed that the prepared nanofibers were smooth, uniform without any formation of beads with a significant reduction in nanofiber diameter after incorporation of fibrinogen. The chemical characterization of the scaffolds confirmed that no chemical reaction occurred between the scaffold components. The tensile test results of the scaffolds showed that increasing in fibrinogen content led to a decrease in mechanical properties. Furthermore, adipose-derived stem cells were employed to evaluate cell-scaffold interaction. Cell culture results indicated that higher cell proliferation occurred for the higher amount of fibrinogen. Statistical analysis was also carried out to evaluate the significant difference for the obtained results of water droplet contact angle and cell culture. Therefore, the results confirmed that PCL/gel/fibrinogen scaffold has a good potential for tissue engineering applications including central nerve system tissue engineering. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2394-2401, 2018.


Prolonged survival of tumor-bearing rats with repetitive low-dose recombinant tumor necrosis factor.
Tumor necrosis factor may be a mediator of the syndrome of cancer cachexia. Tachyphylaxis or tolerance to the cachectic effects of recombinant tumor necrosis factor (rTNF) has been previously described. In this study, we investigate whether repetitive exposure to rTNF can induce similar tolerance in tumor-bearing (TB) rats and ameliorate cachexia induced by the tumor. In experiment 1, non-tumor-bearing (NTB) and TB rats were randomized to either escalating low doses of rTNF or saline i.p. twice daily for 9 consecutive days. NTB rats treated with rTNF demonstrated a significant decline in food intake and weight change (P less than 0.00001) but soon developed tolerance to the cachectic effects of rTNF; they consumed significantly more food than on the first day of treatment and had weight change similar to NTB rats treated with saline. TB rats treated with rTNF showed a similar significant decline in food intake and weight change (P less than 0.0001) and also demonstrated similar tolerance to the cachectic effects of rTNF with continued treatment. Following treatment, TB rats that had been treated with rTNF ate significantly more and lost less weight than TB rats that had been treated with saline (P less than 0.00001). rTNF treatment of TB rats also demonstrated antineoplastic activity, as estimated tumor weight of tumors from rats treated with rTNF were significantly less than controls (P = 0.003). The anticachexia and antineoplastic effects of rTNF resulted in prolonged survival of TB rats treated with rTNF compared to control TB rats (P = 0.015). Experiment 2 utilized two different rTNF treatment regimens in TB rats: one group received 12 days of escalating doses of rTNF, and another group received 15 days of rTNF treatment. TB rats treated with rTNF again had a significantly greater food intake (P less than 0.00001) and delayed weight loss (P = 0.0001) posttreatment that was further augmented by additional doses of rTNF. Antineoplastic activity of rTNF was less clear, and overall tumor growth curves were not affected by rTNF treatment. Survival of TB rats treated with rTNF was again significantly increased in a dose-dependent manner (P = 0.006). Repeated administration of low doses of rTNF to TB rats induces mild reduction in tumor growth, tolerance to the cachectic effects of rTNF that results in tolerance to the cachectic effects of tumor, and prolongation of survival.


Mutational analysis of amino acid residues involved in IgE-binding to the Malassezia sympodialis allergen Mala s 11.
The yeast Malassezia sympodialis, which is an integral part of the normal cutaneous flora, has been shown to elicit specific IgE- and T-cell reactivity in atopic eczema (AE) patients. The M. sympodialis allergen Mala s 11 has a high degree of amino acid sequence homology to manganese superoxide dismutase (MnSOD) from Homo sapiens (50%) and Aspergillus fumigatus (56%). Humoral and cell-mediated cross-reactivity between MnSOD from H. sapiens and A. fumigatus has been demonstrated. Taken together with the recent finding that human MnSOD (hMnSOD) can act as an autoallergen in AE patients sensitised to M. sympodialis, we hypothesized that cross-reactivity could also occur between hMnSOD and Mala s 11, endogenous hMnSOD thus being capable of stimulating an immune response through molecular mimicry. Herein we demonstrate that recombinant Mala s 11 (rMala s 11) is able to inhibit IgE-binding to recombinant hMnSOD and vice versa, indicating that these two homologues share common IgE-binding epitopes and providing an explanation at a molecular level for the autoreactivity to hMnSOD observed in AE patients sensitised to Mala s 11. Using molecular modelling and mapping of identical amino acids exposed on the surface of both Mala s 11 and hMnSOD we identified four regions each composed of 4-5 residues which are potentially involved in IgE-mediated cross-reactivity. Mutated rMala s 11 molecules were produced in which these residues were altered. Native-like folding was verified by enzymatic activity tests and circular dichroism. The rMala s 11 mutants displayed lower IgE-binding in comparison to wild-type rMala s 11 using plasma from AE patients. In particular, mutation of the residues E29, P30, E122 and K125 lowered the IgE-binding to Mala s 11. The results of this study provide new insights in the molecular basis underlying the cross-reactivity between Mala s 11 and hMnSOD.


A psychophysical measurement and analysis of motion perception in normal and binocularly deprived monkeys.
To measure psychophysically the thresholds for motion detection in the nasal and temporal directions under monocular viewing conditions in monkeys reared under conditions of daily alternating monocular occlusion (AMO). The hypothesis was that motion perception would be asymmetric with more sensitivity for motion in the nasal direction. Three monkeys subjected to AMO (AMO monkeys) and three normal monkeys were studied. All were trained with operant conditioning techniques to discriminate coherent from random motion in a random dot display. The percentage of dots in the display that moved either left or right was varied. Thresholds for motion detection of nasally directed and temporally directed stimuli were measured to determine whether the motion perception of AMO monkeys was asymmetric, as predicted. A two-factor analysis of variance revealed a statistically significant difference between treatment groups (normal versus AMO) and directions (nasal versus temporal) and a significant interaction. The interaction was due to a significant difference between nasal and temporal directions for the AMO group, but no significant difference for the normal group. Planned comparisons were performed based on each animal's best eye (eye most sensitive to nasal motion) and worst eye (eye least sensitive to temporal motion). No significant differences were found between the two groups in the best eyes' responses to the nasal direction, but the worst eyes' responses in the temporal direction were significantly poorer in the AMO group. A neural model that can account for these findings is based on a Hebbian teacher located in the nucleus of the optic tract that strengthens connections of a subpopulation of directionally selective cortical neurons. AMO rearing results in asymmetric motion perception. Thresholds for detecting nasally directed motion are normal, whereas thresholds for detecting temporally directed motion are deficient. These results demonstrate that motion-processing mechanisms in primates exhibit experience-dependent developmental neural plasticity. The locus of the neural plasticity could be a subpopulation of directionally selective neurons in the striate cortex (V1).


Butterbur, a herbal remedy, attenuates adenosine monophosphate induced nasal responsiveness in seasonal allergic rhinitis.
Butterbur (BB) or Petasites hybridus, a herbal remedy, exhibits in vitro inhibition of cysteinyl leukotriene biosynthesis. However, no placebo-controlled studies have been performed to evaluate the effectiveness of BB on objective outcomes such as nasal provocation testing in seasonal allergic rhinitis (SAR). Twenty patients with grass-pollen-sensitized SAR were randomized in a double-blind, cross-over manner to receive for 2 weeks either BB 50 mg twice daily or placebo (PL) twice daily during the grass pollen season. Nasal adenosine monophosphate (AMP) challenge (the primary outcome) was administered as a single 400 mg/mL dose after each randomized treatment. Spontaneous recovery following AMP challenge (area under the response time profile curve as % x min+/-SEM) was significantly attenuated (P=0.028) with BB (584+/-289) compared to PL (1438+/-240); mean difference: 854 (95% CI 95-1614), and the maximum % peak nasal inspiratory flow reduction from baseline following AMP challenge was significantly blunted (P=0.036) with BB (30+/-4) compared to PL (43+/-5); mean difference: 13 (95% CI 1-25). BB exhibited protection against AMP-induced nasal responsiveness during the grass pollen season in sensitized patients. This is turn may explain its potential clinical efficacy in patients with SAR.


NDMA formation by chloramination of ranitidine: kinetics and mechanism.
The kinetics of decomposition of the pharmaceutical ranitidine (a major precursor of NDMA) during chloramination was investigated and some decomposition byproducts were identified by using high performance liquid chromatography coupled with mass spectrometry (HPLC-MS). The reaction between monochloramine and ranitidine followed second order kinetics and was acid-catalyzed. Decomposition of ranitidine formed different byproducts depending on the applied monochloramine concentration. Most identified products were chlorinated and hydroxylated analogues of ranitidine. In excess of monochloramine, nucleophilic substitution between ranitidine and monochloramine led to byproducts that are critical intermediates involved in the formation of NDMA, for example, a carbocation formed from the decomposition of the methylfuran moiety of ranitidine. A complete mechanism is proposed to explain the high formation yield of NDMA from chloramination of ranitidine. These results are of great importance to understand the formation of NDMA by chloramination of tertiary amines.


LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor.
Cellular cholesterol levels reflect a balance between uptake, efflux, and endogenous synthesis. Here we show that the sterol-responsive nuclear liver X receptor (LXR) helps maintain cholesterol homeostasis, not only through promotion of cholesterol efflux but also through suppression of low-density lipoprotein (LDL) uptake. LXR inhibits the LDL receptor (LDLR) pathway through transcriptional induction of Idol (inducible degrader of the LDLR), an E3 ubiquitin ligase that triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. LXR ligand reduces, whereas LXR knockout increases, LDLR protein levels in vivo in a tissue-selective manner. Idol knockdown in hepatocytes increases LDLR protein levels and promotes LDL uptake. Conversely, adenovirus-mediated expression of Idol in mouse liver promotes LDLR degradation and elevates plasma LDL levels. The LXR-Idol-LDLR axis defines a complementary pathway to sterol response element-binding proteins for sterol regulation of cholesterol uptake.


Increasing doses of inhaled corticosteroids compared to adding long-acting inhaled beta2-agonists in achieving asthma control.
Combination therapy with inhaled corticosteroids (ICSs) and long-acting beta(2)-agonists (LABAs), or treatment with high doses of ICSs alone improves asthma control when therapy with low-dose ICSs is not sufficient. However, it is not known which of these treatment options is more effective in sustaining asthma control. To evaluate the effect of increasing the ICS dosage vs adding LABAs on the time spent with well-controlled asthma or poorly controlled asthma. Post hoc analysis of the Formoterol and Corticosteroid Establishing Therapy study, which compared a fourfold increase in the budesonide dose with and without formoterol. Time with well-controlled asthma was improved by 19% (95% confidence interval [CI], 3 to 35%; p = 0.017) by adding formoterol, 24 microg/d, to therapy with budesonide, 200 microg/d, compared to 2% (95% CI, -9 to 12%; p = 0.76) with therapy with budesonide, 800 microg/d, alone. Time with well-controlled asthma was further improved by 29% (95% CI, 13 to 47%; p < 0.001) by adding formoterol to therapy with budesonide, 800 microg/d. Time with poorly controlled asthma was significantly reduced using the same interventions by 43% (95% CI, 25 to 57%), 22% (95% CI, 7 to 44%), and 50% (95% CI, 30 to 64%), respectively. Adding formoterol to budesonide was significantly more effective in increasing time with well-controlled asthma when compared to increasing the budesonide dose fourfold (increase, 16%; 95% CI, 1 to 33%; p = 0.035), with a trend for a greater reduction in time with poor control (decrease, 21%; 95% CI, -5 to 42%). The addition of formoterol to therapy with low-dose budesonide increases the probability of well-controlled asthma compared to a substantial increase in the dose of an ICS.


Interlaboratory comparison of PCR-based identification and genogrouping of Neisseria meningitidis.
Twenty clinical samples (18 cerebrospinal fluid samples and 2 articular fluid samples) were sent to 11 meningococcus reference centers located in 11 different countries. Ten of these laboratories are participating in the EU-MenNet program (a European Union-funded program) and are members of the European Monitoring Group on Meningococci. The remaining laboratory was located in Burkina Faso. Neisseria meningitidis was sought by detecting several meningococcus-specific genes (crgA, ctrA, 16S rRNA, and porA). The PCR-based nonculture method for the detection of N. meningitidis gave similar results between participants with a mean sensitivity and specificity of 89.7 and 92.7%, respectively. Most of the laboratories also performed genogrouping assays (siaD and mynB/sacC). The performance of genogrouping was more variable between laboratories, with a mean sensitivity of 72.7%. Genogroup B gave the best correlation between participants, as all laboratories routinely perform this PCR. The results for genogroups A and W135 were less similar between the eight participating laboratories that performed these PCRs.


Simplified procedures for applying the polymerase chain reaction to routinely fixed paraffin wax sections.
The polymerase chain reaction was applied to the analysis of DNA contained in archival paraffin wax embedded material. DNA suitable for the reaction was obtained from these tissues by simple extraction methods, without previous dewaxing of tissue sections. When compared with unfixed material, the reaction efficiency was compromised, so that an increased number of amplification cycles were required to produce equivalent amounts of amplified product. This in turn led to an increase in amplification artefacts, which can be minimised by a simple modification of the standard reaction. Amplification of relatively large DNA fragments was not always successful, and it seems prudent to bear this in mind when designing oligonucleotide primers which are to be used for the amplification of archival material. The efficiency of the procedure can be improved by dividing the amplification cycles into two parts: this reduces the amount of reagent needed, is relatively simple and inexpensive, and can be performed in one working day.


An optimization model for reducing typhoid cases in developing countries without increasing public spending.
This article considers the investment case for using the Vi polysaccharide vaccine in developing countries from two perspectives: reducing typhoid cases and limiting new health care spending. A case study is presented using data from South and Southeast Asia. The purpose of the paper, however, is to draw broad implications that may apply to developing countries in general. Typical consumer demand functions developed from stated preference household surveys in South and Southeast Asia are used to predict probabilities of adults and children purchasing typhoid vaccinations at different prices. These functions are incorporated in a formal mathematical model. Using data from the recent literature for South and Southeast Asia for typhoid incidence, Vi vaccine effectiveness, public cost of illness, and vaccination program cost, three mass vaccination policy alternatives are evaluated: charging adults and children different (optimal) prices, charging uniform prices, and providing free vaccines. Assuming differential pricing is politically feasible, different vaccine prices for children and adults would maximize the number of typhoid cases avoided from a mass vaccination program if the public sector faces a budget constraint on spending for the vaccination program. However, equal prices for children and adults produce very similar results, and they might be more readily accepted by the community. Alternatively, if vaccines are free, the number of cases is not significantly reduced compared to either pricing policy, but a large external financial contribution from government or donors would be required. A Monte Carlo simulation explores the effects of uncertain parameters on vaccination program outcomes.


CXCL12-CXCR4 signalling plays an essential role in proper patterning of aortic arch and pulmonary arteries.
Chemokine CXCL12 (stromal derived factor 1: SDF1) has been shown to play important roles in various processes of cardiovascular development. In recent avian studies, CXCL12 signalling has been implicated in guidance of cardiac neural crest cells for their participation in the development of outflow tract and cardiac septum. The goal of this study is to investigate the extent to which CXCL12 signalling contribute to the development of aortic arch and pulmonary arteries in mammals. Novel Cxcl12-LacZ reporter and conditional alleles were generated. Using whole mount X-gal staining with the reporter allele and vascular casting techniques, we show that the domain branching pattern of pulmonary arteries in Cxcl12-null mice is completely disrupted and discordant with that of pulmonary veins and airways. Cxcl12-null mice also displayed abnormal and superfluous arterial branches from the aortic arch. The early steps of pharyngeal arch remodelling in Cxcl12-null mice appeared to be unaffected, but vertebral arteries were often missing and prominent aberrant arteries were present parallel to carotid arteries or trachea, similar to aberrant vertebral artery or thyroid ima artery, respectively. Analysis with computed tomography not only confirmed the results from vascular casting studies but also identified abnormal systemic arterial supply to lungs in the Cxcl12-null mice. Tie2-Cre mediated Cxcr4 deletion phenocopied the Cxcl12-null phenotypes, indicating that CXCR4 is the primary receptor for arterial patterning, whereas Cxcl12 or Cxcr4 deletion by Wnt1-Cre did not affect aortic arch patterning. CXCL12-CXCR4 signalling is essential for the correct patterning of aortic arches and pulmonary arteries during development. Superfluous arteries in Cxcl12-null lungs and the aortic arch infer a role of CXCL12 in protecting arteries from uncontrolled sprouting during development of the arterial system.


N-acetylcysteine for treatment of autism, a case report.
There are a limited number of Food and Drug Administration (FDA)-approved medications for the treatment of autism. Meanwhile, oxidative stress and neuroinflammation are supposed to play a causative role in autism. N-acetylcysteine may provide cystine, a precursor for glutathione (GSH), which is an important antioxidant factor in the brain. We here report a child with autism, whose symptoms were markedly decreased after taking oral N-acetylcysteine 800 mg/day, in three divided doses. His social interaction was significantly increased. The score of social impairment on a visual analog scale decreased from 10 to 6 in the two-month trial. The aggressive behaviors decreased from 10 to 3. This case suggests that N-acetylcysteine may decrease some symptoms of autism.


The Genderqueer Identity (GQI) Scale: Measurement and validation of four distinct subscales with trans and LGBQ clinical and community samples in two countries.
Background: Non-binary gender measurement has grown out of a need for accurate representation in scholarship and public health services available to a diverse gender population. Aims: The Genderqueer Identity Scale (GQI) was developed to allow for a multidimensional assessment of genderqueer identity, including non-binary identity, socially constructed versus essentialist gender, theoretical awareness of gender concepts, and gender fluidity. The GQI was designed to assess gender identity across a full spectrum of gender, at any age after mid-adolescence, and at various stages of gender identity development, including prior to, during, and after a gender transition, where applicable. Two of the GQI subscales focus on intrapersonal processes, while two focus on interpersonal processes. Methods: The measure was piloted and refined across four distinct samples: a U.S. university based LGBT sample, consecutive clinical referrals at the Center of Expertise on Gender Dysphoria in Amsterdam, the Netherlands, a Dutch LGB community sample, and an online survey forum (LGBTQ). Results: The first exploratory factor analysis identified minor potential adjustments, which were refined and retested. Researchers evaluated and cross-validated the hypothesized factor structure and determined that the three factor GQI subscales and the unidimensional Gender Fluidity measure yielded internally consistent and valid scores among transgender individuals seeking clinical treatment and LGB individuals within a community setting. The exploratory and confirmatory factor analyses provide evidence of good reliability, construct validity, and internal consistency of all four subscales. Discussion: The subscales were appropriate across a spectrum of gender identities and can be taken in the same form over time and across gender transition statuses, making them suitable for clinical evaluation and community based longitudinal research with trans-identified or gender nonconforming persons. The development of the GQI fills critical gaps in gender-related measurement including the ability to assess multiple dimensions of gender identity, and to assess gender identity across time.


Adaptive mutations in sugar metabolism restore growth on glucose in a pyruvate decarboxylase negative yeast strain.
A Saccharomyces cerevisiae strain carrying deletions in all three pyruvate decarboxylase (PDC) genes (also called Pdc negative yeast) represents a non-ethanol producing platform strain for the production of pyruvate derived biochemicals. However, it cannot grow on glucose as the sole carbon source, and requires supplementation of C2 compounds to the medium in order to meet the requirement for cytosolic acetyl-CoA for biosynthesis of fatty acids and ergosterol. In this study, a Pdc negative strain was adaptively evolved for improved growth in glucose medium via serial transfer, resulting in three independently evolved strains, which were able to grow in minimal medium containing glucose as the sole carbon source at the maximum specific rates of 0.138, 0.148, 0.141 h(-1), respectively. Several genetic changes were identified in the evolved Pdc negative strains by genomic DNA sequencing. Among these genetic changes, 4 genes were found to carry point mutations in at least two of the evolved strains: MTH1 encoding a negative regulator of the glucose-sensing signal transduction pathway, HXT2 encoding a hexose transporter, CIT1 encoding a mitochondrial citrate synthase, and RPD3 encoding a histone deacetylase. Reverse engineering of the non-evolved Pdc negative strain through introduction of the MTH1 (81D) allele restored its growth on glucose at a maximum specific rate of 0.053 h(-1) in minimal medium with 2% glucose, and the CIT1 deletion in the reverse engineered strain further increased the maximum specific growth rate to 0.069 h(-1). In this study, possible evolving mechanisms of Pdc negative strains on glucose were investigated by genome sequencing and reverse engineering. The non-synonymous mutations in MTH1 alleviated the glucose repression by repressing expression of several hexose transporter genes. The non-synonymous mutations in HXT2 and CIT1 may function in the presence of mutated MTH1 alleles and could be related to an altered central carbon metabolism in order to ensure production of cytosolic acetyl-CoA in the Pdc negative strain.


Effective leadership and decision-making in animal groups on the move.
For animals that forage or travel in groups, making movement decisions often depends on social interactions among group members. However, in many cases, few individuals have pertinent information, such as knowledge about the location of a food source, or of a migration route. Using a simple model we show how information can be transferred within groups both without signalling and when group members do not know which individuals, if any, have information. We reveal that the larger the group the smaller the proportion of informed individuals needed to guide the group, and that only a very small proportion of informed individuals is required to achieve great accuracy. We also demonstrate how groups can make consensus decisions, even though informed individuals do not know whether they are in a majority or minority, how the quality of their information compares with that of others, or even whether there are any other informed individuals. Our model provides new insights into the mechanisms of effective leadership and decision-making in biological systems.


Myocardial protection by nanomaterials formulated with CHIR99021 and FGF1.
The mortality of patients suffering from acute myocardial infarction is linearly related to the infarct size. As regeneration of cardiomyocytes from cardiac progenitor cells is minimal in the mammalian adult heart, we have explored a new therapeutic approach, which leverages the capacity of nanomaterials to release chemicals over time to promote myocardial protection and infarct size reduction. Initial screening identified 2 chemicals, FGF1 and CHIR99021 (a Wnt1 agonist/GSK-3β antagonist), which synergistically enhance cardiomyocyte cell cycle in vitro. Poly-lactic-co-glycolic acid nanoparticles (NPs) formulated with CHIR99021 and FGF1 (CHIR + FGF1-NPs) provided an effective slow-release system for up to 4 weeks. Intramyocardial injection of CHIR + FGF1-NPs enabled myocardial protection via reducing infarct size by 20%-30% in mouse or pig models of postinfarction left ventricular (LV) remodeling. This LV structural improvement was accompanied by preservation of cardiac contractile function. Further investigation revealed that CHIR + FGF1-NPs resulted in a reduction of cardiomyocyte apoptosis and increase of angiogenesis. Thus, using a combination of chemicals and an NP-based prolonged-release system that works synergistically, this study demonstrates a potentially novel therapy for LV infarct size reduction in hearts with acute myocardial infarction.


A novel RET kinase-beta-catenin signaling pathway contributes to tumorigenesis in thyroid carcinoma.
The RET receptor tyrosine kinase has essential roles in cell survival, differentiation, and proliferation. Oncogenic activation of RET causes the cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) and is a frequent event in sporadic thyroid carcinomas. However, the molecular mechanisms underlying RET's potent transforming and mitogenic signals are still not clear. Here, we show that nuclear localization of beta-catenin is frequent in both thyroid tumors and their metastases from MEN 2 patients, suggesting a novel mechanism of RET-mediated function through the beta-catenin signaling pathway. We show that RET binds to, and tyrosine phosphorylates, beta-catenin and show that the interaction between RET and beta-catenin can be direct and independent of cytoplasmic kinases, such as SRC. As a result of RET-mediated tyrosine phosphorylation, beta-catenin escapes cytosolic down-regulation by the adenomatous polyposis coli/Axin/glycogen synthase kinase-3 complex and accumulates in the nucleus, where it can stimulate beta-catenin-specific transcriptional programs in a RET-dependent fashion. We show that down-regulation of beta-catenin activity decreases RET-mediated cell proliferation, colony formation, and tumor growth in nude mice. Together, our data show that a beta-catenin-RET kinase pathway is a critical contributor to the development and metastasis of human thyroid carcinoma.


Evaluation of Three Block Anesthesia Methods for Pain Management During Mandibular Third Molar Extraction: A Meta-analysis.
A patient's pain during mandibular third molar extraction often creates problems for a dental surgeon and can also cause immense patient discomfort, such as decreased quality of life, serious complications, or even danger to the patients' lives. Effective pain management is therefore of great importance. Conventional block anesthesia method often fails to control such pain completely during an operation. Therefore, two available alternatives, Gow-Gates (G-G) and Vazirani-Akinosi (V-A) methods, have been developed. However, the results of current studies regarding their effectiveness and safety are somewhat ambiguous. The use of G-G and V-A techniques is therefore restricted. This study did a comprehensive review of the relevant research and finally 7 RCTs were included. The results of this meta-analysis indicate that both G-G and V-A techniques have a lower risk of positive aspiration. G-G technique also evidenced a higher success rate than the conventional method. V-A was faster while the G-G technique in contrast had a slower onset time than the conventional technique. In terms of the measurement of analgesic success, however, the V-A method was statistically indistinguishable from conventional techniques. These findings will hopefully endow clinicians with the knowledge required to make appropriate choices for effective anesthesia during lower third molar extraction.


Prevalence of antibodies against hantaviruses in serum and saliva of adults living or working on farms in Yorkshire, United Kingdom.
Hantaviruses are an established cause of haemorrhagic fever with renal syndrome (HFRS) in Europe. Following a confirmed case of HFRS in the UK, in an individual residing on a farm in North Yorkshire and the Humber, a tidal estuary on the east coast of Northern England, and the subsequent isolation of a Seoul hantavirus from rats trapped on the patient's farm, it was considered appropriate to further investigate the public health risk of this virus in the region. Of a total 119 individuals tested, nine (7.6%) were seropositive for hantavirus antibodies. Seven of the seropositive samples showed a stronger reaction to Seoul and Hantaan compared to other clinically relevant hantaviruses. Observation of rodents during the day, in particular mice, was associated with a reduced risk of seropositivity. In addition to one region known to be at risk following an acute case, five further potential risk areas have been identified. This study supports recently published evidence that hantaviruses are likely to be of public health interest in the region.


Nocardiosis in transplant recipients.
Nocardiosis is a rare opportunistic infection caused by Nocardia spp., an aerobic actinomycete, that mainly affects patients with cell-mediated immunity defects, such as transplant recipients. Despite recent progress regarding Nocardia identification and changes in taxonomic assignment, many challenges remain for the diagnosis or management of nocardiosis. This opportunistic infection affects 0.04 to 3.5 % of patients with solid organ or hematopoietic stem cell transplantation, depending on the organ transplanted, cytomegalovirus (CMV) infection, corticosteroids dose and calcineurin inhibitors level. Nocardiosis diagnosis relies on appropriate clinical, radiological and microbiological workup that includes the sampling of an accessible involved site and molecular microbiology tools. In parallel, extensive clinical and radiological evaluations are mandatory, including brain imaging, even in the absence of neurological signs. In transplanted patients, differential diagnosis is challenging, with co-infections reported in 20 to 64 % of cases. As the antibiotic susceptibility pattern varies among species, the antimicrobial regimen before species identification should rely on the association of antibiotics active on all species of Nocardia. Bactericidal antibiotics are required in cases of severe or disseminated disease. Furthermore, in transplant recipients, combination therapy is difficult to manage because of cumulative toxicity and interactions with immunosuppressive agents. Because of a high recurrence rate, antibiotic therapy should be prescribed for 6 to 12 months.


Developments in the management of bone metastases with interventional radiology.
Interventional radiology has known an exponential growth in the last years. Technological advances of the last decades, have made it possible to use new treatments on a larger scale, with safe and effective results. They could be considered as palliative treatments for painful lesions but also curative procedures, as single treatment or specially in combination with other techniques (surgery, radiation and oncology therapies, etc.).The main diffuse techniques are those of thermal ablation that destroy the target lesion through the heat; however there are also endovascular therapies that destroy the target tissue thanks to devascularization. Finally the is also the possibility to stabilize pathological fractures or impending fractures. In this paper all the most diffuse and effective techniques are reviewed and also a discussion of the main indications is done, with an analisys of the success and complications rates.


Plasma levels of β2-microglobulin are associated with atherosclerosis in patients with systemic lupus erythematosus: a cross-sectional cohort study.
Objective The objective of this paper is to examine the association between plasma levels of β2-microglobulin (β2MG), a protein previously associated with atherosclerosis, and the presence of carotid plaque (CP) or coronary artery calcium (CAC) in a cross-sectional cohort study of patients with systemic lupus erythematosus (SLE). Methods Patients with SLE were enrolled between June 2013 and May 2014. The presence of CP and CAC was assessed with ultrasonography and computed tomography scan, respectively. The presence of CP or CAC in the SLE patients was analyzed with respect to plasma levels of β2MG and renal function expressed as the estimated glomerular filtration rate (eGFR). Results The study cohort consisted of 147 patients, 89% women and 95% Caucasians. The median age was 46 (range: 21-75) years with a median disease duration of 14 years. CP and CAC was observed in 29 (20%) and 57 (39%) of patients, respectively. CP or CAC was seen in 62 (42%) patients and was associated with the highest quartile of plasma β2MG in patients with eGFR ≥ 90 ml/min/1.73 m2; OR = 18 (95% CI: 1.7-181). β2MG adjusted for eGFR was also associated with presence of CP or CAC in the total cohort. The exclusion of 25 patients with a prior history of cardiovascular disease did not change the observed associations. Conclusion In this study, we found significant associations between imaging markers of atherosclerosis and high plasma levels of plasma β2MG. These data suggest that β2MG is a candidate for further study as a biomarker for atherosclerosis in SLE.


Cognitive control mechanisms revealed by ERP and fMRI: evidence from repeated task-switching.
We investigated the extent to which a common neural mechanism is involved in task set-switching and response withholding, factors that are frequently confounded in task-switching and go/no-go paradigms. Subjects' brain activity was measured using event-related electrical potentials (ERPs) and event-related functional MRI (fMRI) neuroimaging in separate studies using the same cognitive paradigm. Subjects made compatible left/right keypress responses to left/right arrow stimuli of 1000 msec duration; they switched every two trials between responding at stimulus onset (GO task-green arrows) and stimulus offset (WAIT task-red arrows). With-holding an immediate response (WAIT vs. GO) elicited an enhancement of the frontal N2 ERP and lateral PFC activation of the right hemisphere, both previously associated with the "no-go" response, but only on switch trials. Task-switching (switch vs. nonswitch) was associated with frontal N2 amplification and right hemisphere ventrolateral PFC activation, but only for the WAIT task. The anterior cingulate cortex (ACC) was the only brain region to be activated for both types of task switch, but this activation was located more rostrally for the WAIT than for the GO switch trials. We conclude that the frontal N2 ERP and lateral PFC activation are not markers for withholding an immediate response or switching tasks per se, but are associated with switching into a response-suppression mode. Different regions within the ACC may be involved in two processes integral to task-switching: processing response conflict (rostral ACC) and overcoming prior response suppression (caudal ACC).


Liquid/vapor-induced reversible dynamic structural transformation of a three-dimensional Cu-based MOF to a one-dimensional MOF showing gate adsorption.
A new 3D metal-organic framework (MOF), in which 2D layers are interlaced to form a 3D architecture, was synthesized by a reaction of Cu(BF4)2 and 1,3-bis(4-pyridyl)propane (bpp) in a water/1-hexanol solvent system, and the crystal structure of the MOF was successfully solved. The MOF is reversibly transformed to a 1D chain MOF, which shows gate adsorption properties. The dynamic transformation gives crystal size reduction resulting in a slight change in CO2 adsorption isotherms. The 1D MOF shows selective adsorption/separation properties on benzene and its analogues with similar sizes and shapes (benzene, toluene, and cyclohexane).


The role of nodes in arsenic storage and distribution in rice.
Knowledge of arsenic (As) accumulation in rice (Oryza sativa L.) is important for minimizing As transfer to the food chain. The aim of this study was to investigate the role of rice nodes in As storage and distribution. Synchrotron μX-ray fluorescence (μ-XRF) was used to map As distribution in the top node and internode of a lsi2 mutant defective in silicon/arsenite efflux carrier and its wild-type (WT) grown in soil. Lsi2 expression in different tissues during grain filling was investigated by quantitative RT-PCR. Arsenite or dimethylarsinic acid (DMA) was supplied to excised panicles to investigate the roles of Lsi2 and phytochelatins (PC) in As distribution. μ-XRF mapping revealed As storage in the phloem of different vascular bundles in the top node and internode. Soil-grown plants of lsi2 had markedly decreased As accumulation in the phloem compared with the WT. Lsi2 was strongly expressed, not only in the roots but also in the nodes. When excised panicles were exposed to As(III), the lsi2 mutant distributed more As to the node and flag leaf but less As to the grain compared with the WT, while there was no significant difference in DMA distribution. Inhibition of PC synthesis by l-buthionine-sulphoximine decreased As(III) deposition in the top node but increased As accumulation in the grain and flag leaf. The results suggest that rice nodes serve as a filter restricting As(III) distribution to the grain. Furthermore, Lsi2 plays a role in As(III) distribution in rice nodes and phytochelatins are important compounds for As(III) storage in the nodes.


Synthetic and structural studies of phosphine coordinated boronium salts.
The reaction of BrH2B·SMe2 with primary and secondary phosphines affords a range of boronium salts of the form [H2B(PR3)2]Br (PR3 = PHCy21; PHPh2, 2; PH2Cy, 3), which have been fully characterised including solid-state determinations. Reactions of bulky tertiary phosphines, e.g., PCy3 and PPh3, with BrH2B·SMe2 do not proceed beyond the phosphine-stabilised bromoborane adducts, however, the smaller tertiary phosphine PMe2Ph readily proceeds to form [H2B(PMe2Ph)2]Br (4). The formation of the unsymmetrical boronium salts [H2B(PH2Cy)(PHCy2)]Br (5) and [H2B(PHCy2)(PHPh2)]Br (6) was observed by in situ NMR spectroscopy, however, the compounds were found to spontaneously disproportionate to their respective homophosphine boronium cations, even on prolonged storage in solution at -78 °C. Di- and triphosphines were found to form ring-closed boronium salts to afford [H2B(κ2-P,P'-diphosphine)]Br (diphosphine = dppe, 7; dcpe, 8; dmpe, 9; dppf, 10; dppf with [AsF6]- counterion, 11; amphos, 12). The analogous methodology with Br2HB·SMe2 proved less generally applicable due to an accessible decomposition pathway being available to boronium salts bearing primary and secondary phosphines, leading to the formation of phosphonium salts, although [BrHB(dcpe)]Br (13), [BrHB(PMe2Ph)2]Br (14) and [BrHB(amphos)]Br (15) were synthesised with varying degrees of success. Reaction of BrH2B·SMe2 with diphars afforded the boronium salt [H2B(κ2-P,P'-diphars)]Br (16), which featured two pendant arsine arms. Similarly, triphos was found to react with BrH2B·SMe2 to give [H2B(κ2-P,P'-triphos)]Br (17), which featured a pendant phosphine arm. Substitution of the bromide counter anion with either hexafluoroarsenate or hexfluoroantimonate anions revealed weak hydrogen bonds between the P-H bonds of the boronium cations and the anions, that appeared through NMR studies to be retained in solution (where hydrogen bonding order was determined to be Br- > [SbF6]-/[AsF6]-). This was further demonstrated by comparison of solid-state structures and solution NMR data of 1 with [H2B(PHCy2)2][SbF6] (18), 4 with [H2B(PMe2Ph)2][AsF6] (19) and 17 with [H2B(triphos)][AsF6] (20).


Pharmacokinetics of Nilotinib in Pediatric Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia or Acute Lymphoblastic Leukemia.
We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment. Fifteen patients (aged 1-<18 years) with CML resistant to or intolerant of imatinib and/or dasatinib (n = 11) or Ph+ ALL relapsed on or refractory to standard therapy (n = 4) enrolled in this phase I study. Nilotinib (230 mg/m2 twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients. The area under the concentration-time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70-1.06]. Body surface area-adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04-1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Ph+ ALL achieved complete remission. Nilotinib 230 mg/m2 twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Ph+ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.


Essential Medicines in Universal Health Coverage: A Scoping Review of Public Health Law Interventions and How They Are Measured in Five Middle-Income Countries.
Very few studies exist of legal interventions (national laws) for essential medicines as part of universal health coverage in middle-income countries, or how the effect of these laws is measured. This study aims to critically assess whether laws related to universal health coverage use five objectives of public health law to promote medicines affordability and financing, and to understand how access to medicines achieved through these laws is measured. This comparative case study of five middle-income countries (Ecuador, Ghana, Philippines, South Africa, Ukraine) uses a public health law framework to guide the content analysis of national laws and the scoping review of empirical evidence for measuring access to medicines. Sixty laws were included. All countries write into national law: (a) health equity objectives, (b) remedies for users/patients and sanctions for some stakeholders, (c) economic policies and regulatory objectives for financing (except South Africa), pricing, and benefits selection (except South Africa), (d) information dissemination objectives (ex. for medicines prices (except Ghana)), and (e) public health infrastructure. The 17 studies included in the scoping review evaluate laws with economic policy and regulatory objectives (n = 14 articles), health equity (n = 10), information dissemination (n = 3), infrastructure (n = 2), and sanctions (n = 1) (not mutually exclusive). Cross-sectional descriptive designs (n = 8 articles) and time series analyses (n = 5) were the most frequent designs. Change in patients' spending on medicines was the most frequent outcome measure (n = 5). Although legal interventions for pharmaceuticals in middle-income countries commonly use all objectives of public health law, the intended and unintended effects of economic policies and regulation are most frequently investigated.


Nonfouling textiles with tunable antimicrobial activity based on a zwitterionic polyamine finish.
Antimicrobial finishes for textiles and other surfaces that act without the release of biocides to the environment (contact biocides) or by inhibiting microbial adhesion (antifouling action) are viewed as promising and environmentally friendly alternatives to current products. We have used polyvinylamine polymers that were functionalized with zwitterionic sulfobetaine side chains with different degrees of substitution (DS) for the finishing of poly(ethylene terephthalate) (PET) and cotton fabrics in a water-based pad-dry-cure process. After washing with different surfactants, a stable finish with total polymer add-ons of 0.2-0.5 wt% was achieved. The finished textiles efficiently inhibited the adhesion of proteins and bacteria to the surface even with a small DS as low as 20%. Textiles finished with polymers with a low DS also showed significant antibacterial activity, most notably against Staphylococcus aureus. Accordingly, textile finishes with either pure antiadhesive (DS > 50%) or combined antiadhesive and antibacterial properties (DS = 20-50%) are accessible using this approach.


Field method comparison between passive air samplers and continuous monitors for Vocs and NO2 in El Paso, Texas.
This study evaluates the performance of Model 3300 Ogawa Passive Nitrogen Dioxide (NO2) Samplers and 3M 3520 Organic Vapor Monitors (OVMs) by comparing integrated passive sampling concentrations to averaged hourly NO2 and volatile organic compound (VOC) measurements at two sites in El Paso, TX. Sampling periods were three time intervals (3-day weekend, 4-day weekday, and 7-day weekly) for three consecutive weeks. OVM concentrations were corrected for ambient pressure to account for higher elevation. Precise results (< 5% relative standard deviation, RSD) were found for NO2 measurements from collocated Ogawa samplers. Reproducibility was lower from duplicate OVMs for BTEX (benzene, toluene, ethylbenzene, and xylene isomers) VOCs (> or = 77% RSD for 2-day samples) with better precision for longer sampling periods. Comparison of Ogawa NO2 samplers with chemiluminescence measurements averaged over the same time period suggested potential calibration problems with the chemiluminescence analyzer. For BTEX species, generally good agreement was obtained between OVMs and automated-gas chromatograph (auto-GC) measurements. The OVMs successfully tracked increasing levels of VOCs recorded by the auto-GCs. However, except for toluene, OVM BTEX measurements generally exceeded their continuous counterparts with a mean bias of 5-10%. Although interpretation of the study results was limited due to small sample sizes, diffusion barrier influences caused by shelters that housed OVMs and differences in sampling heights between OVMs and auto-GC inlet may explain the overestimation.


Clinical efficacy and tolerability of direct-acting antivirals in elderly patients with chronic hepatitis C.
There is a lack of evidence-based data on aged patients with newer direct-acting antivirals (DAAs) and with shorter duration of treatment regimens involving DAAs with or without ribavirin (RBV) and pegylated interferon (Peg IFN). Medical records of 240 patients treated with DAAs with or without Peg IFN and RBV between January 2013 and July 2015 were retrospectively analyzed. Patients were divided into two groups: patients aged 65 years and older (N=84) and patients aged younger than 65 years (N=156). Pretreatment baseline patient characteristics, treatment efficacy, factors affecting sustained virologic response at 12 weeks after treatment, and adverse reactions were compared between the groups. No statistically significant difference was observed with end of treatment response (98.8 vs. 98%, P=0.667) and sustained virologic response at 12 weeks after treatment (93.1 vs. 94.1%, P=0.767) between patients aged 65 and older and those younger than 65 years of age. Fatigue was the most common adverse event recorded (32.5%), followed by anemia (19.6%), leukopenia (11.7%), thrombocytopenia (10%), skin rash (8.3%), and headache (7.9%). The RBV dose was reduced in eight (8%) patients and four patients discontinued the RBV treatment because of severe anemia. RBV dose reduction or discontinuation did not reach statistical significance (P=0.913). Increased fibrosis, cirrhosis, aspartate aminotransferase, alanine aminotransferase, hemoglobin, and platelet levels seem to affect the sustained virologic response in the elderly. Twelve (6.28%) patients failed to respond to treatment and the failure rate was not significant (P=0.767) between the groups. DAAs with or without IFN and RBV in the standard recommended 12 or 24-week treatment regimens are effective, well tolerated, and may be safely extended to elderly patients infected with chronic hepatitis C.


Matrix effects in human urine analysis using multi-targeted liquid chromatography-tandem mass spectrometry.
Different sample preparation methods were tested for human urine for the subsequent analysis with a LC-MS/MS multimethod to quantify 65 micropollutants (pesticides, pharmaceuticals, personal care products, industrial chemicals and metabolites) within the general population. Direct injection of diluted urine revealed highly variable and often severe signal suppression for nearly all analytes at relevant concentration levels during electrospray ionization. Urine samples were highly variable in their total organic carbon (500-10,000mgL(-1)) and creatinine (0.35-13mM) content as well as in electrical conductivity (3-19mScm(-1)) but these differences did not correlate clearly with the strength of matrix effects. Therefore, matrix removal by solid phase extraction was intended and different mixed-mode sorbents were tested. Results showed poor apparent recoveries likely due to insufficient separation of target analytes and matrix compounds for all tested sorbents. The wide variability and high concentration levels of urine constituents strongly affect electrospray ionization as well as recovery during extraction at the sub-microgram per liter level. Especially, the hydrophobic interaction at the hydrophilic-lipophilic-balanced sorbent was affected. It is concluded that the urine matrix is too strong, too diverse and too variable to allow one sample preparation method for the very diverse analytes of a LC-MS/MS multimethod. Instead dedicated methods appear more promising.


MKP-1 knockout does not prevent glucocorticoid-induced bone disease in mice.
Glucocorticoid-induced osteoporosis (GCOP) is predominantly caused by inhibition of bone formation, resulting from a decrease in osteoblast numbers. Employing mouse (MBA-15.4) and human (MG-63) osteoblast cell lines, we previously found that the glucocorticoid (GC) dexamethasone (Dex) inhibits cellular proliferation as well as activation of the MAPK/ERK signaling pathway, essential for mitogenesis in these cells, and that both these effects could be reversed by the protein tyrosine phosphatase (PTP) inhibitor vanadate. In a rat model of GCOP, the GC-induced changes in bone formation, mass, and strength could be prevented by vanadate cotreatment, suggesting that the GC effects on bone were mediated by one or more PTPs. Employing phosphatase inhibitors, qRT-PCR, Western blotting, and overexpression/knockdown experiments, we concluded that MKP-1 was upregulated by Dex, that this correlated with the dephosphorylation of ERK, and that it largely mediated the in vitro effects of GCs on bone. To confirm the pivotal role of MKP-1 in vivo, we investigated the effects of the GC methylprednisolone on the quantitative bone histology of wild-type (WT) and MKP-1 homozygous knockout (MKP-1(-/-)) mice. In WT mice, static bone histology revealed that GC administration for 28 days decreased osteoid surfaces, volumes, and osteoblast numbers. Dynamic histology, following time-spaced tetracycline labeling, confirmed a significant GC-induced reduction in osteoblast appositional rate and bone formation rate. However, identical results were obtained in MKP-1 knockout mice, suggesting that in these animals upregulation of MKP-1 by GCs cannot be regarded as the sole mediator of the GC effects on bone.


Gender-specific associations between perceived and objective neighbourhood crime and metabolic syndrome.
Much research has considered the relationship between neighbourhood crime and physical activity, but few studies have assessed clinical outcomes consequent to behaviour, such as cardiometabolic risk. Fewer still have simultaneously assessed perceived and objective measures of crime. Perceptions of crime and actual victimisation vary according to gender; thus, this study sought to assess: 1) correspondence between perceived and objective neighbourhood crime; and 2) gender-specific associations between perceived and reported crime and metabolic syndrome, representing cardiometabolic risk. The indirect effect of neighbourhood crime on metabolic syndrome via walking was additionally evaluated. An Australian population-based biomedical cohort study (2004-2007) collected biomedical, socio-demographic, and neighbourhood perceptions data from n = 1,172 urban-dwelling, adults. Area-level reported crime rates were standardised and linked to individual data based on participants' residential location. Correspondence between actual and perceived crime measures was assessed using Pearson correlation coefficients. Cross-sectional associations between crime and metabolic syndrome were analysed using generalised estimating equations regression models accounting for socio-demographic factors and area-level income. Correspondence between perceived and objective crime was small to medium among men and women (r = 0.17 to 0.33). Among men, metabolic syndrome was related to rates of violent (OR = 1.21, 95% CI 1.08-1.35) and total crime (OR = 1.17, 95% CI 1.04-1.32), after accounting for perceived crime. Among women, metabolic syndrome was related to perceived crime (OR = 1.35, 95% CI 1.14-1.60) after accounting for total reported crime. Among women, there were indirect effects of perceived crime and property crime on metabolic syndrome through walking. Results indicate that crime, an adverse social exposure, is linked to clinical health status. Crime rates, and perceptions of crime and safety, differentially impact upon cardiometabolic health according to gender. Social policy and public health strategies targeting crime reduction, as well as strategies to increase perceptions of safety, have potential to contribute to improved cardiometabolic outcomes.


Proposing an algorithm for treatment of different manifestations of neuro-Behcet's disease.
"Neuro-Behcet's disease" (NBD) is the constellation of neurologic manifestations as a direct consequence of Behcet's disease usually confirmed by imaging studies and/or cerebrospinal fluid analysis. The authors propose a therapeutic algorithm for neuro-Behcet's disease based upon pathological, clinical, prognostic, and medico-economical issues based on available evidences. The authors divide anti-NBD armamentarium to first-line, second-line, and experimental drugs. These drugs should be administered hierarchically in treatment of parenchymal manifestations of neuro-Behcet's disease. First-line drug include corticosteroids, azathioprine, methotrexate, and cyclophosphamide. Second-line drugs are tumor necrosis factor (TNF) alpha blocking drugs, interferon-alpha, chlorambucil, and mycophenolate mofenil. Experimental drugs include other "targeted therapies" than anti-TNF antibodies, tolerization therapy and stem cell transplantation. Cerebral venous sinus thrombosis associated with Behcet's disease should be treated by short-term corticosteroids and anticoagulation with or without immunosuppressive drugs.


A Smart Health Platform for Measuring Health and Well-Being Improvement in People With Dementia and Their Informal Caregivers: Usability Study.
Dementia is a neurodegenerative chronic condition characterized by a progressive decline in a person's memory, thinking, learning skills, and the ability to perform activities of daily living. Previous research has indicated that there are many types of technology interventions available in the literature that have shown promising results in improving disease progression, disease management, and the well-being of people with dementia (PwD) and their informal caregiver, thus facilitating dementia care and living. Technology-driven home care interventions, such as Connected Health (CH), could offer a convenient and low-cost alternative to traditional home care, providing an informal caregiver with the support they may need at home while caring for a PwD, improving their physical and mental well-being. This study aimed (1) to create a multidimensional profile for evaluating the well-being progression of the PwD-informal caregiver dyad for a year during their use of a CH platform, designed for monitoring PwD and supporting their informal caregivers at home, and (2) to conduct a long-term follow-up using the proposed well-being profile at different time-interval evaluations. The PwD-informal caregiver well-being profile was created based on the World Health Organization International Classification of Functioning considering the following outcomes: functional status, cognitive status, and quality of life for the PwD and mental well-being, sleeping quality, and burden for the informal caregiver. Over a year, comprehensive assessments of these outcomes were conducted every 3 months to evaluate the well-being of PwD-informal caregivers, using international and standardized validated questionnaires. Participants' demographic information was analyzed using descriptive statistics and presented as means and SDs. A nonparametric Friedman test was used to analyze the outcome changes and the progression in the PwD-caregiver dyads and to determine if those changes were statistically significant. There were no significant changes in the well-being of PwD or their caregivers over the year of follow-up, with the majority of the PwD-caregiver dyads remaining stable. The only instances in which significant changes were observed were the functional status in the PwD and sleep quality in their caregivers. In each of these measures, post hoc pairwise comparisons did not indicate that the changes observed were related to the deployment of the CH platform. The follow-up of this population of PwD and their informal caregivers has shown that disease progression and physical and mental well-being do not change significantly during the time, being a slow and gradual process. The well-being profile created to analyze the potential impact of the CH platform on the PwD-informal caregiver dyad well-being, once validated, could be used as a future tool to conduct the same analyses with other CH technologies for this population. RR2-10.2196/13280.


[Palliative aspects in clinical acute and emergency medicine as well as intensive care medicine : Consensus paper of the DGIIN, DGK, DGP, DGHO, DGfN, DGNI, DGG, DGAI, DGINA and DG Palliativmedizin].
The integration of palliative medicine is an important component in the treatment of various advanced diseases. While a German S3 guideline on palliative medicine exists for patients with incurable cancer, a recommendation for non-oncological patients and especially for palliative patients presenting in the emergency department or intensive care unit is missing to date. Based on the present consensus paper, the palliative care aspects of the respective medical disciplines are addressed. The timely integration of palliative care aims to improve quality of life and symptom control in clinical acute and emergency medicine as well as intensive care.


[Methods for studying tumor cell migration and invasiveness].
Migration and invasiveness are phenotypic characteristics of cells that contribute to physiological processes, such as wound healing or embryogenesis and they are involved in serious pathological processes, namely in tumor cell metastasis. Availability of methods for studying migration and invasiveness of the cells is important for understanding molecular basis of these processes. In the case of cancer, migration, invasiveness and metastatic potential of tumor cells are key factors that determine clinical prognosis of the patients. This communication provides an overview of in vitro and in vivo methods which are used to study cell migration, invasion and metastasis. In vitro meth-ods for studying cell migration include simple two dimensional assays (scratch - wound assay and the assay based on the effect of hepatocyte growth factor) and methods based on chemotaxis (Dunns chamber, videomicroscopy of cells, the use of carriers with chemoattractants). Methods for studying both cell migration and invasiveness in vitro include more complex systems based on the principle of the Boyden chamber (transwell migration/ invasive test, analysis of cell migration and invasion in xCELLigence system, confocal microscopy based approaches) as well as analysis of cell migration in microchannels. Our overview of in vivo methods provides an introduction into model organisms and methods used in this field, with an emphasis on the study of cancer metastasis in mouse models. The methods described in this review are mainly involved in larger research projects aiming at developing new diagnostic and therapeutic approaches in oncology.


From sauropsids to mammals and back: New approaches to comparative cortical development.
Evolution of the mammalian neocortex (isocortex) has been a persisting problem in neurobiology. While recent studies have attempted to understand the evolutionary expansion of the human neocortex from rodents, similar approaches have been used to study the changes between reptiles, birds, and mammals. We review here findings from the past decades on the development, organization, and gene expression patterns in various extant species. This review aims to compare cortical cell numbers and neuronal cell types to the elaboration of progenitor populations and their proliferation in these species. Several progenitors, such as the ventricular radial glia, the subventricular intermediate progenitors, and the subventricular (outer) radial glia, have been identified but the contribution of each to cortical layers and cell types through specific lineages, their possible roles in determining brain size or cortical folding, are not yet understood. Across species, larger, more diverse progenitors relate to cortical size and cell diversity. The challenge is to relate the radial and tangential expansion of the neocortex to the changes in the proliferative compartments during mammalian evolution and with the changes in gene expression and lineages evident in various sectors of the developing brain. We also review the use of recent lineage tracing and transcriptomic approaches to revisit theories and to provide novel understanding of molecular processes involved in specification of cortical regions.


Why do the numbers of laboratory animal procedures conducted continue to rise? An analysis of the Home Office Statistics of Scientific Procedures on Living Animals: Great Britain 2005.
The publication of the Statistics of Scientific Procedures on Living Animals: Great Britain 2005 once again provides evidence that the levels of animal experimentation in Great Britain are rising, the underlying reason for this being the continued and increasing reliance on genetically modified animals as model systems. There has been a gradual increase in fundamental research, as applied toxicological studies have declined. Of particular concern is the impact that the forthcoming REACH legislation will have and the apparent lack of urgency in facing up to this challenge. The major issues arising from the Statistics are discussed, including the increases in rabbit and primate procedures. The potential of newly validated and emerging techniques to counteract these worrying trends are also considered.


Overcoming Symmetry Mismatch in Vaccine Nanoassembly through Spontaneous Amidation.
Matching of symmetry at interfaces is a fundamental obstacle in molecular assembly. Virus-like particles (VLPs) are important vaccine platforms against pathogenic threats, including Covid-19. However, symmetry mismatch can prohibit vaccine nanoassembly. We established an approach for coupling VLPs to diverse antigen symmetries. SpyCatcher003 enabled efficient VLP conjugation and extreme thermal resilience. Many people had pre-existing antibodies to SpyTag:SpyCatcher but less to the 003 variants. We coupled the computer-designed VLP not only to monomers (SARS-CoV-2) but also to cyclic dimers (Newcastle disease, Lyme disease), trimers (influenza hemagglutinins), and tetramers (influenza neuraminidases). Even an antigen with dihedral symmetry could be displayed. For the global challenge of influenza, SpyTag-mediated display of trimer and tetramer antigens strongly induced neutralizing antibodies. SpyCatcher003 conjugation enables nanodisplay of diverse symmetries towards generation of potent vaccines.


The Association between Glyceraldehyde-Derived Advanced Glycation End-Products and Colorectal Cancer Risk.
A large proportion of colorectal cancers are thought to be associated with unhealthy dietary and lifestyle exposures, particularly energy excess, obesity, hyperinsulinemia, and hyperglycemia. It has been suggested that these processes stimulate the production of toxic reactive carbonyls from sugars such as glyceraldehyde. Glyceraldehyde contributes to the production of a group of compounds known as glyceraldehyde-derived advanced glycation end-products (glycer-AGEs), which may promote colorectal cancer through their proinflammatory and pro-oxidative properties. The objective of this study nested within a prospective cohort was to explore the association of circulating glycer-AGEs with risk of colorectal cancer. A total of 1,055 colorectal cancer cases (colon n = 659; rectal n = 396) were matchced (1:1) to control subjects. Circulating glycer-AGEs were measured by a competitive ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (95% CI), adjusting for potential confounding factors, including smoking, alcohol, physical activity, body mass index, and diabetes status. Elevated glycer-AGEs levels were not associated with colorectal cancer risk (highest vs. lowest quartile, 1.10; 95% CI, 0.82-1.49). Subgroup analyses showed possible divergence by anatomical subsites (OR for colon cancer, 0.83; 95% CI, 0.57-1.22; OR for rectal cancer, 1.90; 95% CI, 1.14-3.19; Pheterogeneity = 0.14). In this prospective study, circulating glycer-AGEs were not associated with risk of colon cancer, but showed a positive association with the risk of rectal cancer. Further research is needed to clarify the role of toxic products of carbohydrate metabolism and energy excess in colorectal cancer development.


A robust neuromuscular system protects rat and human skeletal muscle from sarcopenia.
Declining muscle mass and function is one of the main drivers of loss of independence in the elderly. Sarcopenia is associated with numerous cellular and endocrine perturbations, and it remains challenging to identify those changes that play a causal role and could serve as targets for therapeutic intervention. In this study, we uncovered a remarkable differential susceptibility of certain muscles to age-related decline. Aging rats specifically lose muscle mass and function in the hindlimbs, but not in the forelimbs. By performing a comprehensive comparative analysis of these muscles, we demonstrate that regional susceptibility to sarcopenia is dependent on neuromuscular junction fragmentation, loss of motoneuron innervation, and reduced excitability. Remarkably, muscle loss in elderly humans also differs in vastus lateralis and tibialis anterior muscles in direct relation to neuromuscular dysfunction. By comparing gene expression in susceptible and non-susceptible muscles, we identified a specific transcriptomic signature of neuromuscular impairment. Importantly, differential molecular profiling of the associated peripheral nerves revealed fundamental changes in cholesterol biosynthetic pathways. Altogether our results provide compelling evidence that susceptibility to sarcopenia is tightly linked to neuromuscular decline in rats and humans, and identify dysregulation of sterol metabolism in the peripheral nervous system as an early event in this process.


Eliminating child labour in Malawi: a British American Tobacco corporate responsibility project to sidestep tobacco labour exploitation.
To examine British American Tobacco and other tobacco industry support of the Eliminating Child Labour in Tobacco Growing Foundation. Analyses of internal tobacco industry documents and ethnographic data. British American Tobacco co-founded the Eliminating Child Labour in Tobacco Growing Foundation (ECLT) in October 2000 and launched its pilot project in Malawi. ECLT's initial projects were budgeted at US2.3 million dollars over four years. Labour unions and leaf dealers, through ECLT funds, have undertook modest efforts such as building schools, planting trees, and constructing shallow wells to address the use of child labour in tobacco farming. In stark contrast, the tobacco companies receive nearly US40 million dollars over four years in economic benefit through the use of unpaid child labour in Malawi during the same time. BAT's efforts to combat child labour in Malawi through ECLT was developed to support the company's "corporate social responsibility agenda" rather than accepting responsibility for taking meaningful steps to eradicate child labour in the Malawi tobacco sector. In Malawi, transnational tobacco companies are using child labour projects to enhance corporate reputations and distract public attention from how they profit from low wages and cheap tobacco.


Chestnuts bred for blight resistance depart nursery with distinct fungal rhizobiomes.
Restoration of the American chestnut (Castanea dentata) is underway using backcross breeding that confers chestnut blight disease resistance from Asian chestnuts (most often Castanea mollissima) to the susceptible host. Successful restoration will depend on blight resistance and performance of hybrid seedlings, which can be impacted by below-ground fungal communities. We compared fungal communities in roots and rhizospheres (rhizobiomes) of nursery-grown, 1-year-old chestnut seedlings from different genetic families of American chestnut, Chinese chestnut, and hybrids from backcross breeding generations as well as those present in the nursery soil. We specifically focused on the ectomycorrhizal (EcM) fungi that may facilitate host performance in the nursery and aid in seedling establishment after outplanting. Seedling rhizobiomes and nursery soil communities were distinct and seedlings recruited heterogeneous communities from shared nursery soil. The rhizobiomes included EcM fungi as well as endophytes, putative pathogens, and likely saprobes, but their relative proportions varied widely within and among the chestnut families. Notably, hybrid seedlings that hosted few EcM fungi hosted a large proportion of potential pathogens and endophytes, with possible consequences in outplanting success. Our data show that chestnut seedlings recruit divergent rhizobiomes and depart nurseries with communities that may facilitate or compromise the seedling performance in the field.


Deer, wolves, and people: costs, benefits and challenges of living together.
Human-driven species annihilations loom as a major crisis. However the recovery of deer and wolf populations in many parts of the northern hemisphere has resulted in conflicts and controversies rather than in relief. Both species interact in complex ways with their environment, each other, and humans. We review these interactions in the context of the ecological and human costs and benefits associated with these species. We integrate scattered information to widen our perspective on the nature and perception of these costs and benefits and how they link to each other and ongoing controversies regarding how we manage deer and wolf populations. After revisiting the ecological roles deer and wolves play in contemporary ecosystems, we explore how they interact, directly and indirectly, with human groups including farmers, foresters, shepherds, and hunters. Interactions with deer and wolves generate various axes of tension, posing both ecological and sociological challenges. Resolving these tensions and conflicts requires that we address key questions using integrative approaches: what are the ecological consequences of deer and wolf recovery? How do they influence each other? What are the social and socio-ecological consequences of large deer populations and wolf presence? Finally, what key obstacles must be overcome to allow deer, wolves and people to coexist? Reviewing contemporary ecological and sociological results suggests insights and ways to improve our understanding and resolve long-standing challenges to coexistence. We should begin by agreeing to enhance aggregate benefits while minimizing the collective costs we incur by interacting with deer and wolves. We should also view these species, and ourselves, as parts of integrated ecosystems subject to long-term dynamics. If co-existence is our goal, we need deer and wolves to persevere in ways that are compatible with human interests. Our human interests, however, should be inclusive and fairly value all the costs and benefits deer and wolves entail including their intrinsic value. Shifts in human attitudes and cultural learning that are already occurring will reshape our ecological interactions with deer and wolves.


Therapeutic action of ketogenic enteral nutrition in obese and overweight patients: a retrospective interventional study.
Ketogenic enteral nutrition (KEN™) is a modification of Blackburn's protein-sparing modified fast, using a hypocaloric, ketogenic liquid diet. The study is about ketogenic enteral nutrition (KEN) in overweight and obese patients receiving a short treatment of the nutritional solution as a 24-h infusion. It is a retrospective analysis that examines safety, weight loss and body composition changes after three sequential 10-day cycles of KEN therapy. Anthropometric and bio-impedance data from 629 patients who underwent KEN were collected before and after completing a 10-day cycle. The study focuses on the change in outcomes from the first cycle to the second cycle and from the first cycle to the third cycle. The following outcomes were explored: weight, waist circumference, BMI, fat mass, lean mass, dry lean mass, phase angle, wellness marker, water mass as a percentage of total body weight. Statistical tests were used to test for significant differences between paired cycle 1 and cycle 2 outcomes and also between paired cycle 1 and cycle 3 outcomes. Where changes in outcomes between timepoints were found to be normally distributed, the paired t test was used, whereas where the changes in outcomes had skewed distributions, the Wilcoxon signed-rank test was used. Linear regression was used to examine associations between changes in both phase angle and BMR/weight with percentage weight change. Initially the simple relationship between variables was examined, and subsequently multiple linear regression was used to re-examine the relationships after adjusting for two pre-specified confounding variables. The results suggested significant changes for all analyzed parameters. There were significant decreases in weight, waist circumference, BMI, fat mass, lean mass, dry lean mass and phase angle. Quantitative changes in lean mass and dry lean mass were minor changes with respect to changes in fat mass. When considering the change from cycle 1 to cycle 3, there was a significant association between change in BMR/weight and change in weight, which remained significant after adjusting for changes in phase angle, fat mass and waist circumference. A one-unit increase in BMR/weight was associated with a 2.4% reduction in weight. There was no significant association between change in phase angle from cycle 1 to cycle 3 in the simple analysis. However, after adjustments greater change in phase angle was associated with a greater weight loss. KEN treatment was overall well tolerated. Results might be restricted to a British cohort only and should not be universally applied. Long-term results need to be explored in controlled studies. KEN treatment is safe, well tolerated and results in rapid fat loss without detriment to dry lean mass.


Leukoaraiosis and collateral blood flow in stroke patients with anterior circulation large vessel occlusion.
Leukoaraiosis and collateral blood flow are processes that involve small vessels, the former related to flow within the deep perforating arterioles and the latter involving the small, cortical pial-pial connections, both of which are independently used to predict cerebrovascular events and treatment outcomes. The aim of this study was to investigate their relationship to each other. We retrospectively reviewed patients who underwent mechanical thrombectomy for stroke with pre-procedural CT imaging within 24 hours of the onset of symptoms. Leukoaraiosis was graded by the total Fazekas score on non-contrast CT, periventricular white matter (PVWM) and deep white matter (DWM) scores, both ranging from 0 to 3. Collateral cerebral blood flow was measured by the American Society of Interventional and Therapeutic Radiology/Society of Interventional Radiology (ASITN/SIR) collateral scale. 178 patients were included with a mean age of 67.6±14.8 years. We found an inverse relationship between total Fazekas score and collateral flow (p<0.0001). Among patients with good collaterals, 75.1% had total Fazekas scores of 0-2, compared with 36.6% of patients with moderate collaterals and 32.7% of patients with poor collaterals with total Fazekas scores of 0-2. Mean Fazekas scores were 1.6±1.5, 3.1±1.5 and 3.4±1.6 for good, moderate and poor collaterals, respectively (p<0.0001). On multivariate analysis, total Fazekas score was the only variable independently associated with collateral status (p<0.0001). Increasing severity of leukoaraiosis is associated with poor collateral grade among ischemic stroke patients with anterior circulation large vessel occlusion. These findings suggest that leukoaraiosis may be a marker for global cerebrovascular dysfunction.


Expression of avian Pax1 and Pax9 is intrinsically regulated in the pharyngeal endoderm, but depends on environmental influences in the paraxial mesoderm.
Pax1 and Pax9 represent a subfamily of paired-box-containing genes. In vertebrates, Pax1 and Pax9 transcripts have been found specifically in mesodermal tissues and the pharyngeal endoderm. Pax1 expression in the sclerotomes has been shown to be indispensable for proper formation of the axial skeleton, but expression of Pax1 in the endoderm has not been studied in detail. We have cloned the chick homologue of the murine Pax9 gene. Our results show that transcripts of Pax1 and Pax9 are first detectable in the prospective foregut endoderm of headfold-stage avian embryos. Endodermal expression correlates with the highly proliferative zones of the folding foregut and evaginating pharyngeal pouches. In later stages, Pax1 and Pax9 are expressed in overlapping but distinct patterns within the developing sclerotomes and limb buds. From grafting experiments we conclude that activation of pharyngeal Pax1 and Pax9 expression is an intrinsic property of the endoderm, not requiring midline structures or head mesoderm. In contrast, notochord is required to induce Pax1 in competent sclerotomes. Here we show that in vitro there is a cranio-caudal gradient of inductive capacity in the notochord. This coincides with the graded expression of Pax1 and Pax9 along the cranio-caudal axis in 2- to 3-day-old embryos. Furthermore, paraxial head mesoderm shows no competence to express Pax1. Finally, in vitro we find counteracting influences on notochord signaling by lateral tissues (lateral plate, intermediate mesoderm), leading to an inhibition of Sonic hedgehog (Shh) expression in notochord and floor plate, as well as Pax1 and Pax9 expression in sclerotomes. Taken together, our results demonstrate that different mechanisms regulate expression of Pax1 and Pax9 in foregut and sclerotome, but suggest a common function for both genes in the two tissues that is promoting proliferation and preventing fusion of neighboring blastemas.


A real-life comparative effectiveness study into the addition of antibiotics to the management of asthma exacerbations in primary care.
Asthma exacerbations are major contributors to asthma morbidity and mortality. They are usually managed with bronchodilators and oral corticosteroids (OCS), but clinical trial evidence suggests that antibiotics could be beneficial. We aimed to assess whether treatment of asthma exacerbations with antibiotics in addition to OCS improved outcomes in larger, more representative routine-care populations. A retrospective comparative effectiveness study into managing asthma exacerbations with OCS alone versus OCS plus antibiotics was conducted using the Optimum Patient Care Research Database. The dataset included 28 637 patients; following propensity score matching 20 024 adults and 4184 children were analysed. Antibiotics in addition to OCS were prescribed for the treatment of asthma exacerbations in 45% of adults and 32% of children. Compared to OCS alone, OCS plus antibiotics was associated with reduced risk of having an asthma/wheeze consultation in the following 2 weeks (children hazard ratio (HR) 0.84 (95% CI 0.73-0.96), p=0.012; adults HR 0.86 (95% CI 0.81-0.91), p<0.001), but an increase in risk of a further OCS prescription for a new/ongoing exacerbation within 6 weeks in adults (HR 1.11 (95% CI 1.01-1.21), p=0.030), but not children. Penicillins, but not macrolides, were associated with a reduction in the odds of a subsequent asthma/wheeze consultation compared to OCS alone, in both adults and children. Antibiotics were frequently prescribed in relation to asthma exacerbations, contrary to guideline recommendations. Overall, the routine addition of antibiotics to OCS in the management of asthma exacerbations appeared to confer little clinical benefit, especially when considering the risks of antibiotic overuse.


Autonomic dysfunction in psoriatic arthritis.
Autonomic nervous system (ANS) involvement has been studied in systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjogren's syndrome, and ankylosing spondylitis but still has not been studied in psoriatic arthritis (PsA). The aim of this study was to investigate the prevalence and the nature of autonomic neuropathy in patients with PsA. Sixteen patients of PsA and 15 age and sex matched control subjects were studied prospectively using a battery of noninvasive tests. Cardiovascular autonomic neuropathy (CAN) was diagnosed by applying four cardiovascular reflex tests, and peripheral sympathetic autonomic function was assessed by Sudoscan. Patients with PsA had significantly higher heart rate response to standing (p = 0.01), blood pressure response to standing (p = 0.02), and Sudoscan (p = 0.01) when compared with healthy controls. Fifty percent (n = 8) of the patients with PsA had at least two or more abnormal CAN parasympathetic dysfunction; of these, 18.75% (n = 3) of the patients had abnormal parasympathetic and sympathetic dysfunction, 68.7% (n = 11) and 25% (n = 4) of the patients had at least one abnormal parasympathetic and sympathetic parameters, respectively, and 37.5% (n = 6) of the patients had moderate sudomotor dysfunction. About 18.7% (n = 3) of our parasympathetic dysfunction patients had autonomic symptoms. None of healthy volunteers had abnormal ANS dysfunction. Heart rate response significantly correlated with erythrocyte sedimentation rate (p < 0.05) and C-reactive protein (p < 0.05) levels. In conclusion, cardiovascular autonomic and peripheral sympathetic neuropathy occurs in PsA. Parasympathetic function is more commonly found to be abnormal than sympathetic function. There is no correlation of peripheral sympathetic dysfunction with cardiovascular autonomic neuropathy.


Mixed infections and In Vivo evolution in the human fungal pathogen Cryptococcus neoformans.
Koch's postulates are criteria establishing a causal relationship between a microbe and a disease that lead to the assumption that diseases are caused by a single strain or its evolved forms. Cryptococcus neoformans is a life-threatening human fungal pathogen responsible for an estimated 1 million cases of cryptococcosis/year, predominantly meningoencephalitis. To assess the molecular diversity of clinical isolates and gain knowledge of C. neoformans biology in the host, we analyzed clinical cultures collected during the prospective CryptoA/D study. Using molecular analysis of unpurified isolates, we demonstrated that mixed infections in humans are more common than previously thought, occurring in almost 20% of patients diagnosed with cryptococcosis. These mixed infections are composed of different mating types, serotypes, and/or genotypes. We also identified genetically related haploid and diploid strains in the same patients. Experimental infections and quantitative PCR show that these ploidy changes can result from endoreplication (duplication of DNA content) and that shuttling between haploid and diploid states can occur, suggesting in vivo evolution. Thus, the concept of one strain/one infection does not hold true for C. neoformans and may apply to other environmentally acquired fungal pathogens. Furthermore, the possibility of mixed and/or evolving infections should be taken into account when developing therapeutic strategies against these pathogens.


Male sexual polymorphism, alternative reproductive tactics, and androgens in combtooth blennies (pisces: blenniidae).
In species in which intense intermale competition for the access to females is present males of lower competitive ability may adopt alternative reproductive tactics (ART) to get access to mates. These ART translate in many cases into male sexual polymorphism, with individuals following distinctly different tactics. Usually two alternative male morphs can be recognized in species with ART: (1) bourgeois males that compete for access to mates invest in typically male behaviors, such as building elaborated nests or displaying ornaments; and (2) parasitic males that take advantage of the success of the bourgeois males in attracting females and attempt "sneaker" fertilizations (e.g., sneaker and satellite males). In combtooth blennies (Blenniidae) the co-occurrence of ART and male sexual polymorphism has been described for two temperate species: the peacock blenny, Salaria pavo, and the Azorean rock-pool blenny, Parablennius sanguinolentus parvicornis. Interestingly, while in the peacock blenny the alternative male morph adopts a sneaker tactic, in the rock-pool blenny parasitic males act as satellites to nest-holder males. Thus, this variation in the ART expressed in these two closely related species allows for a comparative study of the proximate and ultimate factors affecting the expression of the two ART. In this article we summarize the available information on androgen levels in bourgeois and parasitic males of natural populations of the two species and of recent studies on the effect of exogenous administration of androgens on tactic switching in parasitic males of the two species. The information is discussed within the frame of the relative plasticity hypothesis, which predicts that plastic alternative morphs should show differences in hormone levels and that the administration of sex steroids should be effective in promoting the switch from the parasitic to bourgeois tactic. The evidence is only partly consistent with this hypothesis. Alternatively, a social transduction hypothesis that better fits the available data on androgens and ART in teleost is proposed. It states that the observed differences in androgen levels between alternative morphs should not be interpreted as an organization vs activation effect of steroids, but rather as the limited vs lifelong responsiveness of the neuroendocrine axis to social regulation.


Gene expression changes triggered by exposure of Haemophilus influenzae to novobiocin or ciprofloxacin: combined transcription and translation analysis.
The responses of Haemophilus influenzae to DNA gyrase inhibitors were analyzed at the transcriptional and the translational level. High-density microarrays based on the genomic sequence were used to monitor the expression levels of >80% of the genes in this bacterium. In parallel the proteins were analyzed by two-dimensional electrophoresis. DNA gyrase inhibitors of two different functional classes were used. Novobiocin, as a representative of one class, inhibits the ATPase activity of the enzyme, thereby indirectly changing the degree of DNA supercoiling. Ciprofloxacin, a representative of the second class, obstructs supercoiling by inhibiting the DNA cleavage-resealing reaction. Our results clearly show that different responses can be observed. Treatment with the ATPase inhibitor Novobiocin changed the expression rates of many genes, reflecting the fact that the initiation of transcription for many genes is sensitive to DNA supercoiling. Ciprofloxacin mainly stimulated the expression of DNA repair systems as a response to the DNA damage caused by the stable ternary complexes. In addition, changed expression levels were also observed for some genes coding for proteins either annotated as "unknown function" or "hypothetical" or for proteins not directly involved in DNA topology or repair.