Safety of compounded calcium chloride admixtures for peripheral intravenous administration in the setting of a calcium gluconate shortage.
Calcium gluconate is preferred over calcium chloride for intravenous (IV) repletion of calcium deficiencies in the inpatient setting. In the setting of a national shortage of IV calcium gluconate, our institution implemented a compounded calcium chloride admixture for IV administration. The objective of this analysis is to evaluate the peripheral infusion site safety of compounded IV calcium chloride admixtures in adult inpatients. A total of 222 patients, encompassing 224 inpatient admissions, from April to June 2011 were retrospectively reviewed. Sterile preparations of calcium chloride in 5% dextrose (600 mg/250 mL and 300 mg/100 mL) were used during the study time period. Adverse infusion site reactions were assessed using an institutional infiltration and phlebitis grading system. A total of 333 doses were administered peripherally. In all, 4 (1.8%) patients experienced a moderate to severe infusion site reaction, with 3 due to phlebitis and 1 due to infiltration. Naranjo Nomogram for Adverse Drug Reaction Assessment classified all 4 reactions to have a possible link to calcium chloride administration. Peripheral administration of compounded calcium chloride admixtures in 5% dextrose is associated with a low incidence of IV infusion site reactions and can be considered as an alternative in the event of a calcium gluconate shortage.


Neuronal Differentiation of Induced Pluripotent Stem Cells on Surfactant Templated Chitosan Hydrogels.
The development of effective tissue engineering materials requires careful consideration of several properties beyond biocompatibility, including permeability and mechanical stiffness. While surfactant templating has been used for over a decade to control the physical properties of photopolymer materials, the potential benefit of this technique with regard to biomaterials has yet to be fully explored. Herein we demonstrate that surfactant templating can be used to tune the water uptake and compressive modulus of photo-cross-linked chitosan hydrogels. Interestingly, templating with quaternary ammonium surfactants also hedges against property fluctuations that occur with changing pH. Further, we demonstrate that, after adequate surfactant removal, these materials are nontoxic, support the attachment of induced pluripotent stem cells and facilitate stem cell differentiation to neuronal phenotypes. These results demonstrate the utility of surfactant templating for optimizing the properties of biomaterials intended for a variety of applications, including retinal regeneration.


Oral Supplementation with Algal Sulphated Polysaccharide in Subjects with Inflammatory Skin Conditions: A Randomised Double-Blind Placebo-Controlled Trial and Baseline Dietary Differences.
We examined the effect of a dietary seaweed extract-sulfated xylorhamnoglucuronan (SXRG84)-on individuals with inflammatory skin conditions. A subgroup analysis of a larger trial was undertaken, where 44 participants with skin conditions were enrolled in a double-blind placebo-controlled crossover design. Subjects ingested either SXRG84 extract (2 g/day) for six weeks and placebo for six weeks, or vice versa. At baseline, six- and twelve-weeks inflammatory markers and the gut microbiota were assessed, as well as skin assessments using the dermatology quality of life index (DQLI), psoriasis area severity index (PASI) and visual analogue scales (VAS). There were significant differences at weeks six and twelve for pro-inflammatory cytokines IFN-γ (p = 0.041), IL-1β (p = 0.030), TNF-α (p = 0.008) and the anti-inflammatory cytokine IL-10 (p = 0.026), determined by ANCOVA. These cytokines were all significantly higher at six weeks post placebo compared to twelve weeks post placebo followed by SXRG84 treatment. A total of 23% of participants reported skin improvements, as measured by VAS (mean difference 3.1, p = 0.0005) and the DQLI score (mean difference -2.0, p = 0.049), compared to the 'non-responders'. Thus, the ingestion of SXRG84 for 6 weeks reduced inflammatory cytokines, and a subset of participants saw improvements.


Comparative characteristics of laryngeal-resident mesenchymal stromal cell populations isolated from distinct sites in the rat larynx.
Although tissue-resident mesenchymal stromal cells (MSCs) in the larynx have been described, their distinct characteristics and roles have not been thoroughly explored. Therefore, we investigated stem cell characteristics and regenerative potentials of single clonal populations isolated from rat epiglottic mucosa (EM), lamina propria (LP), and macula flava (MF) to determine whether they comprised laryngeal tissue-resident stem cells. Single clonal laryngeal cells were isolated following microdissection of the EM, LP, and MF from the rat larynx. Several clonal populations from the three laryngeal subsites were selected and expanded in vitro. We compared the stem cell characteristics of self-renewal and differentiation potential, as well as the cell surface phenotypes and gene expression profiles, of laryngeal MSC-like cells to that of bone marrow MSCs (BM-MSCs). We also investigated the regenerative potential of the laryngeal cells in a radiation-induced laryngeal injury animal model. Self-renewing, clonal cell populations were obtained from rat EM, LP, and MF. EM-derived and LP-derived clonal cells had fibroblast-like features, while MF-resident clonal cells had stellate cell morphology and lipid droplets containing vitamin A. All laryngeal clonal cell populations had MSC-like cell surface marker expression (CD29, CD44, CD73, and CD90) and the potential to differentiate into bone and cartilage cell lineages; EM-derived and MF-derived cells, but not LP-derived cells, were also able to differentiate into adipocytes. Clonal cells isolated from the laryngeal subsites exhibited differential extracellular matrix-related gene expression. We found that the mesenchymal and stellate cell-related genes desmin and nestin were enriched in laryngeal MSC-like cells relative to BM-MSCs (P < 0.001). Growth differentiation factor 3 (GDF3) and glial fibrillary acidic protein (GFAP) transcript and protein levels were higher in MF-derived cells than in other laryngeal populations (P < 0.001). At 4 weeks after transplantation, laryngeal MF-derived and EM-derived cells contributed to laryngeal epithelial and/or glandular regeneration in response to radiation injury. These results suggest that cell populations with MSC characteristics reside in the EM, LP, and MF of the larynx. Laryngeal MSC-like cells contribute to regeneration of the larynx following injury; further investigation is needed to clarify the differential roles of the populations in laryngeal tissue regeneration, as well as the clinical implications for the treatment of laryngeal disease.


The inflammatory response in the regression of lumbar disc herniation.
Lumbar disc herniation (LDH) is highly associated with inflammation in the context of low back pain. Currently, inflammation is associated with adverse symptoms related to the stimulation of nerve fibers that may lead to pain. However, inflammation has also been indicated as the main factor responsible for LDH regression. This apparent controversy places inflammation as a good prognostic indicator of spontaneous regression of LDH. This review addresses the molecular and cellular mechanisms involved in LDH regression, including matrix remodeling and neovascularization, in the scope of the clinical decision on conservative versus surgical intervention. Based on the evidence, a special focus on the inflammatory response in the LDH context is given, particularly in the monocyte/macrophage role. The phenomenon of spontaneous regression of LDH, extensively reported in the literature, is therefore analyzed here under the perspective of the modulatory role of inflammation.


Lateral buccotomy for removal of a supernumerary cheek tooth in a horse.
A 3-year-old female Standardbred was admitted for evaluation of a firm swelling on the right side located rostral to the facial crest and a firm intraoral swelling located rostral to the erupted cheek teeth. Examination of skull radiographs revealed a supernumerary cheek tooth rostral to the erupted third premolar. The supernumerary tooth was removed via lateral buccotomy. The horse did not have complications after surgery and resumed racing. Lateral buccotomy should be considered for removal of rostrally located maxillary or mandibular cheek teeth. Supernumerary cheek teeth can be found in locations in the upper dental arcade, other than caudal to the last molar.


[Methylmercury causes diffuse damage to the somatosensory cortex: how to diagnose Minamata disease].
The first acute case of methylmercury (MeHg) poisoning by the consumption of fish arose in Minamata, Japan, in 1953. It was officially recognized and called Minamata disease (MD) in 1956. There are still arguments about the definition of MD in terms of its associated clinical symptoms and lesions even 50 years after the initial recognition of MD. Studies on this MD epidemic are reviewed along with its historical background. Since MeHg dispersed from Minamata to the Shiranui Sea, residents living around the sea had been exposed to low-dose MeHg through fish consumption for about 20 years (at least from 1950 to 1968). These chronic MeHg poisoning patients complained of paresthesia at the distal parts of their extremities and around the lips even 30 years after the cessation of exposure to MeHg of anthropogenic origin. The persisting somatosensory disorders after the discontinuation of exposure to MeHg were induced by diffuse damage to the somatosensory cortex, but not by damage to the peripheral nervous system, as previously believed. Based on these findings, symptoms and lesions in MeHg poisoning are reappraised.


[6]-gingerol: a novel AT₁ antagonist for the treatment of cardiovascular disease.
Considering the prevalence of cardiovascular disease in public health and the limited validated therapeutic options, this study aimed to find novel compounds targeting the angiotensin II type 1 receptor, accepted as a therapeutic target in cardiovascular disease. A small library consisting of 89 compounds from 39 Chinese herbs was profiled using a cell-based calcium mobilization assay which was developed and characterized for high-throughput screening. [6]-Gingerol derived from Zingiber officinale Roscoe (ginger) was identified as a novel angiotensin II type 1 receptor antagonist, with an IC50 value of 8.173 µM. The hit was further tested by a specificity assay indicating that it had no antagonistic effects on other evaluated GPCRs, such as endothelin receptors. The major ingredient of ginger, [6]-gingerol, could inhibit angiotensin II type 1 receptor activation, which partially clarified the mechanism of ginger regulating blood pressure and strengthening heart in the cardiovascular system.


Pyridoxal phosphate-dependent neonatal epileptic encephalopathy.
Pyridox(am)ine-5'-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5'-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant treatment but responsive to pyridoxal phosphate is described. Pyridoxal phosphate should be considered in neonatal epileptic encephalopathy unresponsive to pyridoxine.


Integrated electrooptic laser deflector.
An integrated optical laser deflector employing the electrooptic effect is analyzed and shown to provide continuous angular deflection in one dimension. The angle of deflection is found to vary linearly with applied voltage. Because of the integrated optical configuration, significant deflection angles can be obtained for relatively low values of applied voltage. The presence of the deflector configuration within a thin-film cavity is shown to reduce the voltage required for a specific deflection. Waveguide mode coupling resulting from the induced refractive index variation is considered and found to be negligible for typical waveguide parameters.


Learning about happiness from persons with Down syndrome: feeling the sense of joy and contentment.
One well-known stereotype about persons with Down syndrome is that they are relentlessly "happy." Although some individuals with Down syndrome seem to possess an unusual personality aspect that calls out the best in others, this aspect should be viewed as distinct from the traditional stereotype. Many people with Down syndrome have shattered popular expectations of what they might accomplish, society still has lowered expectations for them. In this paper I seek to identify those characteristics that offer genuine and thoughtful joyfulness among these individuals. Happiness is closely aligned with a sense of peace, well-being, and/or contentment. A more appropriate contention is the idea that a rare and potent trait holds within it true enrichment and peace among individuals with Down syndrome.


The Effects of Ivacaftor on Bone Density and Microarchitecture in Children and Adults with Cystic Fibrosis.
Cystic fibrosis (CF) transmembrane conductance (CFTR) dysfunction may play a role in CF-related bone disease (CFBD). Ivacaftor is a CFTR potentiator effective in improving pulmonary and nutritional outcomes in patients with the G551D-CFTR mutation. The effects of ivacaftor on bone health are unknown. To determine the impact of ivacaftor on bone density and microarchitecture in children and adults with CF. Prospective observational multiple cohort study. Outpatient clinical research center within a tertiary academic medical center. Three cohorts of age-, race-, and gender-matched subjects were enrolled: 26 subjects (15 adults and 11 children) with CF and the G551D-CFTR mutation who were planning to start or had started treatment with ivacaftor within 3 months (Ivacaftor cohort), 26 subjects with CF were not treated with ivacaftor (CF Control cohort), and 26 healthy volunteers. All treatments, including Ivacaftor, were managed by the subjects' pulmonologists. Bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT), areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) and bone turnover markers at baseline, 1, and 2 years. Cortical volume, area, and porosity at the radius and tibia increased significantly in adults in the Ivacaftor cohort. No significant differences were observed in changes in aBMD, trabecular microarchitecture, or estimated bone strength in adults or in any outcome measures in children. Treatment with ivacaftor was associated with increases in cortical microarchitecture in adults with CF. Further studies are needed to understand the implications of these findings.


Does long-term exposure to gel-filled silicone implants increase the risk of relapse after breast cancer?
An increased risk of cancer and autoimmune diseases associated with gel-filled silicone implants, debated by FDA experts since 1991, has given rise to a profusion of literature on the subject. However, such effects have not been adequately investigated in patients with breast cancer. In a previous report we compared 146 breast cancer patients with gel-filled silicone implants for breast reconstruction to 146 control patients in whom no reconstruction had been performed. The observed results were reassuring, as the evolution of the disease after 10 years was better in the reconstruction group than in the control group. We now report the end results of this study with a median follow-up of 13 years after the breast reconstruction (range, 10-20 years). The relative risks of detrimental events were estimated with Cox's Proportional Hazards Model, with stratification according to age at diagnosis. The risks of locoregional recurrences and distant metastasis were significantly lower in the BR group than in the control group. The risks of death, of a second breast cancer and of a second primary cancer at a site other than the breast were not significantly different between the two groups of patients. Long-term follow-up of patients exposed to gel-filled silicone implants confirms the absence of detrimental effects after breast cancer. The power of our study is, however, below that required to detect a very slight increase in the risks studied.


The effects of immune protein CD3ζ development and degeneration of retinal neurons after optic nerve injury.
Major histocompatibility complex (MHC) class I molecules and their receptors play fundamental roles in neuronal death during diseases. T-cell receptors (TCR) function as MHCI receptor on T-cells and both MHCI and a key component of TCR, CD3ζ, are expressed by mouse retinal ganglion cells (RGCs) and displaced amacrine cells. Mutation of these molecules compromises the development of RGCs. We investigated whether CD3ζ regulates the development and degeneration of amacrine cells after RGC death. Surprisingly, mutation of CD3ζ not only impairs the proper development of amacrine cells expressing CD3ζ but also those not expressing CD3ζ. In contrast to effects of MHCI and its receptor, PirB, on other neurons, mutation of CD3ζ has no effect on RGC death and starburst amacrine cells degeneration after optic nerve crush. Thus, unlike MHCI and PirB, CD3ζ regulates the development of RGCs and amacrine cells but not their degeneration after optic nerve crush.


Targeting the Noncoding Genome: Superenhancers Meet Their Kryptonite.
<b/> In this study, McKeown and colleagues carried out a genome-wide characterization and stratification of the enhancer landscape in acute myeloid leukemia (AML). The authors' analysis led to the discovery of a novel RARA superenhancer found in a subset of patients with AML, rendering these leukemia cells highly sensitive to SY-1425, a highly potent RARA agonist able to induce myeloid differentiation in these high-expressing RARA AML subtypes. Cancer Discov; 7(10); 1065-6. ©2017 AACR.See related article by McKeown et al., p. 1136.


Living and Regenerative Material Encapsulating Self-Assembled Shewanella oneidensis-CdS Hybrids for Photocatalytic Biodegradation of Organic Dyes.
Reductive biodegradation by microorganisms has been widely explored for detoxifying recalcitrant contaminants; however, the biodegradation capacity of microbes is limited by the energy level of the released electrons. Here, we developed a method to self-assemble Shewanella oneidensis-CdS nanoparticle hybrids with significantly improved reductive biodegradation capacity and constructed a living material by encapsulating the hybrids in hydrogels. The material confines the nano-bacteria hybrids and protects them from environmental stress, thus improving their recyclability and long-term stability (degradation capacity unhindered after 4 weeks). The developed living materials exhibited efficient photocatalytic biodegradation of various organic dyes including azo and nitroso dyes. This study highlights the feasibility and benefits of constructing self-assembled nano-bacteria hybrids for bioremediation and sets the stage for the development of novel living materials from nano-bacteria hybrids.


Clinical Usefulness of Echocardiographic Measurement of Proximal Aortic Diameter in Early Differentiation Between Type A Acute Aortic Dissection and ST-Segment-Elevation Myocardial Infarction.
Background Contradictions between management modalities of type A acute aortic dissection (TAAAD) and ST-elevation-myocardial infarction (STEMI) may result in clinical catastrophe. Therefore, we aimed to explore which 2-dimensional echocardiography (2DE) findings are optimal for differentiating TAAAD from STEMI. Methods and Results This study included 340 patients with STEMI and 340 patients with TAAAD who underwent 2DE in the emergency department between 2012 and 2021. The proximal ascending aorta (PAA) diameter and other echocardiographic parameters were analyzed. PAA diameters were measured at 4 levels in the parasternal view: Valsalva, the sinotubular junction (STJ), the PAA at 1 cm above the STJ, and the PAA at 2 cm above the STJ. Receiver-operating characteristic curve analysis showed that Valsalva, STJ, PAA at 1 cm above the STJ, and PAA at 2 cm above the STJ were significant predictors of TAAAD (areas under the curve: 0.777, 0.924, 0.965, and 0.975, respectively; P<0.001) with the respective cutoff values of 39.4, 38.5, 39.8, and 41.2 mm. Multivariable analysis suggested that all 2DE parameters were significant predictors of TAAAD. Among the 2DE parameters examined, the incorporation of PAA at 2 cm above the STJ to clinical indicators exhibited the most significant diagnostic capability (C-statistics, 0.97; net reclassification improvement, 1.81; integrated discrimination improvement, 0.61). When only TAAAD with coronary malperfusion and STEMI were analyzed, the diagnostic utility of PAA at 1 cm above the STJ was evident (C-statistics, 0.99; net reclassification improvement, 1.79; integrated discrimination improvement, 0.67), with PAA at 2 cm above the STJ ranking second in diagnostic significance (C-statistics, 0.99; net reclassification improvement, 1.12; integrated discrimination improvement, 0.66). Conclusions PAA measurements were the most beneficial for diagnosing TAAAD in all 2DE findings and TAAAD from STEMI.


Guanidine hydrochloride inhibits the generation of prion "seeds" but not prion protein aggregation in yeast.
[PSI(+)] strains of the yeast Saccharomyces cerevisiae replicate and transmit the prion form of the Sup35p protein but can be permanently cured of this property when grown in millimolar concentrations of guanidine hydrochloride (GdnHCl). GdnHCl treatment leads to the inhibition of the replication of the [PSI(+)] seeds necessary for continued [PSI(+)] propagation. Here we demonstrate that the rate of incorporation of newly synthesized Sup35p into the high-molecular-weight aggregates, diagnostic of [PSI(+)] strains, is proportional to the number of seeds in the cell, with seed number declining (and the levels of soluble Sup35p increasing) in the presence of GdnHCl. GdnHCl does not cause breakdown of preexisting Sup35p aggregates in [PSI(+)] cells. Transfer of GdnHCl-treated cells to GdnHCl-free medium reverses GdnHCl inhibition of [PSI(+)] seed replication and allows new prion seeds to be generated exponentially in the absence of ongoing protein synthesis. Following such release the [PSI(+)] seed numbers double every 20 to 22 min. Recent evidence (P. C. Ferreira, F. Ness, S. R. Edwards, B. S. Cox, and M. F. Tuite, Mol. Microbiol. 40:1357-1369, 2001; G. Jung and D. C. Masison, Curr. Microbiol. 43:7-10, 2001), together with data presented here, suggests that curing yeast prions by GdnHCl is a consequence of GdnHCl inhibition of the activity of molecular chaperone Hsp104, which in turn is essential for [PSI(+)] propagation. The kinetics of elimination of [PSI(+)] by coexpression of a dominant, ATPase-negative allele of HSP104 were similar to those observed for GdnHCl-induced elimination. Based on these and other data, we propose a two-cycle model for "prionization" of Sup35p in [PSI(+)] cells: cycle A is the GdnHCl-sensitive (Hsp104-dependent) replication of the prion seeds, while cycle B is a GdnHCl-insensitive (Hsp104-independent) process that converts these seeds to pelletable aggregates.


Confounding T-wave inversion.
In the medical community, the nonspecific finding of T-wave inversion warrants further investigation. An electrocardiogram may be an essential component of a surgical risk evaluation. Patients who show a T-wave inversion on a preoperative electrocardiogram require further investigation to distinguish between pathological and benign T-wave inversion. Optimizing patients' safety during the perioperative experience is the ultimate clinical outcome.


Molecular frustration: a hypothesis for regulation of viral infections.
The recent revolution in imaging techniques and results from RNA footprinting in situ reveal how the bacteriophage MS2 genome regulates both particle assembly and genome release. We have proposed a model in which multiple packaging signal (PS) RNA-coat protein (CP) contacts orchestrate different stages of a viral life cycle. Programmed formation and release of specific PS contacts with CP regulates viral particle assembly and genome uncoating during cell entry. We hypothesize that molecular frustration, a concept introduced to understand protein folding, can be used to better rationalize how PSs function in both particle assembly and genome release. More broadly this concept may explain the directionality of viral life cycles, for example, the roles of host cofactors in HIV infection. We propose that this is a universal principle in virology that explains mechanisms of host-virus interaction and suggests diverse therapeutic interventions.


Electrode polarization effects on interfacial kinetics of ionic liquid at graphite surface: An extended lagrangian-based constant potential molecular dynamics simulation study.
Computational models including electrode polarization can be essential to study electrode/electrolyte interfacial phenomena more realistically. We present here a constant-potential classical molecular dynamics simulation method based on the extended Lagrangian formulation where the fluctuating electrode atomic charges are treated as independent dynamical variables. The method is applied to a graphite/ionic liquid system for the validation and the interfacial kinetics study. While the correct adiabatic dynamics is achieved with a sufficiently small fictitious mass of charge, static properties have been shown to be almost insensitive to the fictitious mass. As for the kinetics study, electrical double layer (EDL) relaxation and ion desorption from the electrode surface are considered. We found that the polarization slows EDL relaxation greatly whereas it has little impact on the ion desorption kinetics. The findings suggest that the polarization is essential to estimate the kinetics in nonequilibrium processes, not in equilibrium. © 2019 Wiley Periodicals, Inc.


Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias.
Some critics argue that bias from population stratification (the mixture of individuals from heterogeneous genetic backgrounds) undermines the credibility of epidemiologic studies designed to estimate the association between a genotype and the risk of disease. We investigated the degree of bias likely from population stratification in U.S. studies of cancer among non-Hispanic Caucasians of European origin. An expression of the confounding risk ratio-the ratio of the effect of the genetic factor on risk of disease with and without adjustment for ethnicity-is used to measure the potential relative bias from population stratification. We first use empirical data on the frequency of the N-acetyltransferase (NAT2) slow acetylation genotype and incidence rates of male bladder cancer and female breast cancer in non-Hispanic U.S. Caucasians with ancestries from eight European countries to assess the bias in a hypothetical population-based U.S. study that does not take ethnicity into consideration. Then, we provide theoretical calculations of the bias over a large range of allele frequencies and disease rates. Ignoring ethnicity leads to a bias of 1% or less in our empirical studies of NAT2. Furthermore, evaluation of a wide range of allele frequencies and representative ranges of cancer rates that exist across European populations shows that the risk ratio is biased by less than 10% in U.S. studies except under extreme conditions. We note that the bias decreases as the number of ethnic strata increases. There will be only a small bias from population stratification in a well-designed case-control study of genetic factors that ignores ethnicity among non-Hispanic U.S. Caucasians of European origin. Further work is needed to estimate the effect of population stratification within other populations.


Do patients with diabetes and low socioeconomic status receive less care and have worse outcomes? A national study.
The objective of the study was to assess the influence of socioeconomic status (SES) on the care of patients with diabetes. Quality indicators for patients who were taking medication for diabetes were established. Overall compliance with the quality indicators, as well as prevalence of diabetes by age, were obtained from a national database. Patients with national tax exemptions (used as a marker for low SES) were compared to those without. Of 4,110,852 citizens aged 18-74, 210,988 (5.1%) were receiving medication for diabetes. The prevalence of diabetes reached 19.9% in people aged 65-74. 495,392 citizens had an exemption, and they had a higher prevalence of diabetes that those who did not (15.4% vs. 3.7%). Patients with an exemption had a higher rate of having a yearly HbA1c done, a yearly LDL level done, a yearly eye exam, a yearly urinary protein exam, of being treated with insulin for an elevated HbA1c than those without an exemption. In patients with an exemption there was a lower percentage with an HbA1c less than 7%, a higher percentage with an HbA1c greater than 9%, and a lower percentage with an LDL less than 130. Multivariate analysis showed that exemption status was a predictor of better performance on process measures (LDL test done, OR-1.03, 95% CI 1.01-1.06, HbA1c test done, OR 1.03, 95% CI- 1.01-1.05) and of worse outcomes (high LDL, OR 0.92, 95% CI, 0.90-0.95 and high HbA1c, OR, 0.85, 95% CI, 0.83-0.87). In a country with universal healthcare, patients from a lower SES had an increased prevalence of diabetes and had greater adherence to preventive healthcare measures However, they were less successful in meeting target treatment goals.


Reversed siderophores as antimalarial agents. II. Selective scavenging of Fe(III) from parasitized erythrocytes by a fluorescent derivative of desferal.
We introduce here a fluorescent derivative of desferrioxamine B (DFO) that retains the high affinity of the parent compound and displays a powerful inhibition of intraerythrocytic Plasmodium falciparum growth. NBD-DFO was synthesized by coupling 7-Nitrobenz-2-oxa-1,3-diazole (NBD) to the terminal amino group of DFO. The NBD group at this position renders the DFO molecule more lipophilic and imparts to it fluorescent properties. The novel NBD-DFO probe displays a unique combination of chemical and biological properties, such as 1) improved and selective permeation properties across membranes of P. falciparum-infected erythrocytes, 2) improved efficacy as an inhibitor of intraerythrocytic P. falciparum growth (including multidrug-resistant strains), 3) demonstrable Fe3+ scavenging within parasitized red cells, and 4) usefulness as a sensitive and versatile analytical tool for quantitative assessment of Fe3+ and for following iron-scavenging processes, because the fluorescence of NBD-DFO is demonstrably quenched upon complexation with Fe3+.


Geographical differences in upper abdominal resectional surgery and high-volume procedures in Sweden during 2009-2011.
Upper abdominal surgery comprises many different procedures, from major resectional surgery on the esophagus, stomach, liver, and pancreas, to high-volume operations such as cholecystectomy and bariatric surgery. The aim of the present study was to evaluate geographical differences, if any, in number of procedures performed per capita among the 6 healthcare regions and the 21 Swedish counties, responsible for the health care of its inhabitants. Data on resectional surgery and high-volume procedures were collected for the study period (2009-2011) from the Swedish National Patient Register. Annual number of procedures and procedures performed per 100,000 inhabitants was registered based on the place of residence of patients. In the six healthcare regions, the number of resections per 100,000 inhabitants on the esophagus varied from 1.8 to 3.9, stomach 5.3-6.7, liver 6.7-13.2, and pancreas 4.9-8.3. Corresponding figures for cholecystectomies were 146.7-191.3 and for bariatric surgery 33.1-97.4. The southeast region had the highest incidence of major resectional surgery, except for gastric resections. A high number of cholecystectomies were performed in all regions. Bariatric surgery was most common in the Stockholm region. At county level, the variations were larger, particularly for liver surgery and high-volume procedures. Significant geographical differences were observed between the six healthcare regions and at county level, when studying the number of procedures performed per 100,000 inhabitants. We believe that this reflects local traditions in selection of patients for resectional surgery and differences in capacity for meeting the high demand for bariatric surgery.


Lack of correlation of postmortem vitreous humor calcium concentration with antemortem serum calcium concentration.
Although results of several studies measuring calcium concentrations in vitreous humor have been published, comparisons of postmortem vitreous calcium with antemortem serum calcium have not been made. In a study of 30 cases in which antemortem calcium results were available, the mean vitreous calcium concentration was 6.8 mg/dL. There was no significant change in vitreous calcium postmortem nor significant correlation between vitreous calcium and antemortem serum calcium. Experimental observations suggest that vitreous calcium is regulated by an active transport mechanism. Vitreous calcium measurements do not appear to be useful in evaluating suspected antemortem abnormalities of serum calcium.


Machine learning plastic deformation of crystals.
Plastic deformation of micron-scale crystalline solids exhibits stress-strain curves with significant sample-to-sample variations. It is a pertinent question if this variability is purely random or to some extent predictable. Here we show, by employing machine learning techniques such as regression neural networks and support vector machines that deformation predictability evolves with strain and crystal size. Using data from discrete dislocations dynamics simulations, the machine learning models are trained to infer the mapping from features of the pre-existing dislocation configuration to the stress-strain curves. The predictability vs strain relation is non-monotonic and exhibits a system size effect: larger systems are more predictable. Stochastic deformation avalanches give rise to fundamental limits of deformation predictability for intermediate strains. However, the large-strain deformation dynamics of the samples can be predicted surprisingly well.


From plasticity to a renormalization group.
The marginally rigid state is a candidate paradigm for what makes granular material a state of matter distinct from both liquid and solid. The coordination number is identified as a discriminating characteristic, and for rough-surfaced particles we show that the low values predicted are indeed approached in simple two-dimensional experiments. We show calculations of the stress transmission, suggesting that this is governed by local linear equations of constraint between the stress components. These constraints can in turn be related to the generalized forces conjugate to the motion of grains rolling over each other. The lack of a spatially coherent way of imposing a sign convention on these motions is a problem for scaling up the equations, which leads us to attempt a renormalization-group calculation. Finally, we discuss how perturbations propagate through such systems, suggesting a distinction between the behaviour of rough and smooth grains.


Fully discharging phases. A new approach to biphasic waveforms for external defibrillation.
Phase-2 voltage and maximum pulse width are dependent on phase-1 pulse characteristics in a single-capacitor biphasic waveform. The use of 2 separate output capacitors avoids these limitations and may allow waveforms with lower defibrillation thresholds. A previous report also suggested that the optimal tilt may be >70%. This study was designed to determine an optimal biphasic waveform by use of a combination of 2 separate and fully (95% tilt) discharging capacitors. We performed 2 external defibrillation studies in a pig ventricular fibrillation model. In group 1, 9 waveforms from a combination of 3 phase-1 capacitor values (30, 60, and 120 microF) and 3 phase-2 capacitor values (0=monophasic, 1/3, and 1.0 times the phase-1 capacitor) were tested. Biphasic waveforms with phase-2 capacitors of 1/3 times that of phase 1 provided the highest defibrillation efficacy (stored energy and voltage) compared with corresponding monophasic and biphasic waveforms with the same capacitors in both phases except for waveforms with a 30-microF phase-1 capacitor. In group 2, 10 biphasic waveforms from a combination of 2 phase-1 capacitor values (30 and 60 microF) and 5 phase-2 capacitor values (10, 20, 30, 40, and 50 microF) were tested. In this range, phase-2 capacitor size was more critical for the 30-microF phase-1 than for the 60-microF phase-1 capacitor. The optimal combinations of fully discharging capacitors for defibrillation were 60/20 and 60/30 microF. Conclusions-Phase-2 capacitor size plays an important role in reducing defibrillation energy in biphasic waveforms when 2 separate and fully discharging capacitors are used.


Significance of MMP-9 expression and MMP-9 polymorphism in prostate cancer.
The aim of the study was to assess the expression of the MMP-9 gene and -1562 C/T polymorphism in MMP-9 gene promoter in relation to clinicopathological parameters in predicting the clinical outcome of prostate cancer patients. A total of 82 patients with histopathologically diagnosed prostate cancer were enrolled in the study. MMP-9 gene expression was assessed by reverse transcription-PCR method. MMP-9 (-1562 C/T) polymorphism variants were determined by the polymerase chain reaction-based restriction fragment length polymorphism method. MMP-9 expression and MMP-9 -1562 polymorphism variants in relation to disease pathological stage (P = 0.006; P <0.0001, respectively), as well as to prognostic group (P = 0.019; P <0.0001, respectively), were statistically significant. Only MMP-9 -1562 polymorphism variants in relation to tumor differentiation grade (P = 0.044) were found to be statistically significant. Positive MMP-9 gene expression was associated with 5-year survival rate of prostate cancer patients with pathological stage III (P = 0.036) and for the patients in prognostic group III (P = 0.012). Patients with tumor differentiation grade G2 and with the identified CC variant had a significantly longer survival time than patients with the identified TT variant (P = 0.007). MMP-9 gene expression and MMP-9 -1562 polymorphism variants were associated with prostate cancer pathological stage and prognostic group. MMP-9 -1562 polymorphism CC variant was associated with prostate cancer tumor differentiation grade. Five-year survival analysis showed the relationship between MMP-9 gene expression and pathological stage III, as well as prognostic group III, whereas MMP-9 -1562 polymorphism variants, with tumor differentiation grade G2.


MiR-181a contributes to bufalin-induced apoptosis in PC-3 prostate cancer cells.
Bufalin is a major active compound of cinobufacini, which comes from dried toad venom and has been used for treatments of various cancers in China for many years. A number of studies have demonstrated that bufalin can induce apoptosis in some cancers. However, effects and mechanism of bufalin on prostate cancer cells remain unknown. Apoptosis assay was measured by the annexin-V/PI flow cytometric assay. Western blot was used to measure Caspase-3 and Bcl-2. qRT-PCR was used to measure the relative expression of miR-181a. Bufalin was found to induce the expression of miR-181a, a small non-coding RNA believed to induce apoptosis by repressing its target gene, BCL-2. In prostate cancer PC-3cell line, bufalin-induced apoptosis can be largely attenuated by a miR-181a inhibitor, which blocked bufalin-induced Bcl-2 reduction and caspase-3 activation. Our dataindicatedthat miR-181a mediates bufalin-induced apoptosis in PC-3 cells. Thus, we presented here a new pharmacological mechanism for bufalin in anti-tumor therapy.


Effect of ruboxistaurin (RBX) On visual acuity decline over a 6-year period with cessation and reinstitution of therapy: results of an open-label extension of the Protein Kinase C Diabetic Retinopathy Study 2 (PKC-DRS2).
The PKC-DRS2 was a Phase 3, randomized, double-masked, placebo (PBO)-controlled, 3-year study of the effect of 32 mg/day of ruboxistaurin (RBX), an orally administered protein kinase C inhibitor, on vision loss in patients with moderate to severe nonproliferative diabetic retinopathy. Ruboxistaurin reduced the occurrence of sustained moderate visual loss (SMVL; ≥15-letter decline in visual acuity sustained for the last 6 months of study participation) from 9.1% in the PBO group (N = 340) to 5.5% in the RBX group (N = 345, P = 0.034). This study evaluates the primary end point of SMVL in a 2-year open-label extension (OLE) of the PKC-DRS2, which began a median of 466 days (range, 263-1,296 days) after the conclusion of PKC-DRS2. Visual acuity was measured by certified examiners using the Early Treatment Diabetic Retinopathy Study chart. Of the 514 patients who completed PKC-DRS2, 366 did so in the 32 study centers participating in the OLE, and of these, 203 (55%) enrolled in the OLE for treatment with 32 mg/day of RBX for 2 years. Of the 203 enrolled in the OLE, 100 had previously been treated with PBO (prior PBO subgroup) and 103 had been treated with RBX (prior RBX subgroup). PKC-DRS2 baseline patient and ocular characteristics were well matched between these two subgroups and were similar to the PKC-DRS2 patient population as a whole. Using the PKC-DRS2 baseline as the starting point, SMVL occurred in 6% of the prior PBO subgroup during the PKC-DRS2, increasing to 26% by the end of the OLE. However, in the prior RBX subgroup, SMVL occurred in only 4% and 8% during the PKC-DRS2 and by the end of the OLE, respectively (P < 0.001 for difference at the end of the OLE). In the prior PBO subgroup, mean visual acuity declined from 79.6 letters at PKC-DRS2 baseline to 73.1 letters at OLE end point (-6.5 letters). In the prior RBX subgroup, this loss was 2.7 letters (79.8 to 77.1) over the same period (P = 0.02). Over a 6-year study period incorporating 3 years of a rigorously placebo-controlled trial, approximately 1 year off treatment and 2-year OLE where all groups received therapy, those patients with greatest RBX exposure (∼5 years) experienced less SMVL compared with those in the original PBO group (∼2-year RBX exposure).


Red to far-red ratio correction in plant growth chambers - growth responses and influence of thermal load on garden pea.
Plant growth chambers are commonly used to minimize environmental variation but the light sources used vary considerably from natural light and from each other. Incandescent globes are often used to add more far-red light, with the aim of producing a more natural red to far-red ratio (R:FR), but also add to thermal load. High-intensity discharge lamps are often used to produce higher irradiances, more akin to natural light, but the thermal implications are rarely considered because air temperature is controlled. This paper examines the spectral properties and thermal implications of growth chamber light sources and takes a whole-plant physiology approach, by examining growth responses of a photoperiodic pea line (Pisum sativum L. cv. Torsdag) in the same growth chamber type under different light sources - in essence using plants to study the controlled environments rather than vice-versa. High R:FR delayed flowering and inhibited internode extension in pea. However, the addition of far-red-rich incandescent globes in the proportions provided in the growth chambers (400-500 W) did little to reduce R:FR, did not induce earlier flowering and actually further inhibited internode length. Leaflet size and yield were significantly reduced. While air temperature was maintained at 20 degrees C in all experiments, radiant temperature was significantly higher under high irradiance and/or with incandescent added, and soil temperatures were elevated. Growth responses under these lights were similar to the effect caused by elevating the air temperature. An alternative method of controlling R:FR, without thermal load implications, using light-emitting diodes is described.


Cash transfers and domestic violence.
Violence against women is a major health and human rights problem yet there is little rigorous evidence as to how to reduce it. We take advantage of the randomized roll-out of Ecuador's cash transfer program to mothers to investigate how an exogenous increase in a woman's income affects domestic violence. We find that the effect of a cash transfer depends on a woman's education and on her education relative to her partner's. Our results show that for women with greater than primary school education a cash transfer significantly decreases psychological violence from her partner. For women with primary school education or less, however, the effect of a cash transfer depends on her education relative to her partner's. Specifically, the cash transfer significantly increases emotional violence in households where the woman's education is equal to or more than her partner's.


Silver delivery approaches in the management of partial thickness burns: A systematic review and indirect treatment comparison.
Silver-containing products play an important role in the management of burn wound infections. We sought to compare the efficacy of commonly used silver delivery approaches including nanocrystalline silver, silver-impregnated hydrofiber dressing, and silver-impregnated foam dressing as the main products in the management of partial thickness burns. A systematic review was performed by searching PubMed, EMBASE, Cochrane, and other databases to identify relevant randomized controlled trials and observational studies. Due to the paucity of direct head-to-head trials, an indirect treatment comparison was performed. The use of nanocrystalline silver was associated with a statistically significant reduction in length of stay when compared to silver-impregnated hydrofiber dressing (p = 0.027) and a shorter time to healing when compared to silver-impregnated foam dressing (p = 0.0328). There were no statistically significant differences in infection rates and surgical procedures between nanocrystalline silver, silver-impregnated hydrofiber dressing, and silver-impregnated foam dressing; however, nanocrystalline silver was found to be the most beneficial for all the outcomes, including infection rates and surgical procedures, according to the Monte Carlo simulation method. In conclusion, current evidence from the published literature suggests that where the clinical and microbiological priority is to get in control of infection quickly it would seem prudent to use the most potent silver delivery system, which is nanocrystalline silver. Nanocrystalline silver may offer both clinical and economic benefits compared to alternative treatments in the management of patients with mixed burns that are at high risk of infection.


[Atrial fibrillation process studied in clinical practice by using statistical analysis methods].
The results of studying the electrical activity of the atria in 53 patients with cardiac fibrillation by means of a special digital computer system are discussed. On the strength of the aggregate of amplitude, rate, and morphological characteristics, three varieties of fibrillation waves are distinguished. It is shown that in the absence of cardiotropic therapy, the principal regular features in the distribution of the ff waves according to the frequency ranges are preserved in one and the same patients for a long period of time. A characteristic dynamics of changes in atrial activity during treatment with preparations of digitalis was disclosed, which may be an additional criterion of digitalization. A connection was revealed between the changes in atrial activity during treatment with digitalis preparations and the characteristic dynamics of the ventricular rhythm structure. The absence of such correlative connection may be evidence of the possible occurrence of atrioventricular block after restoration of the sinus rhythm.


Allergic contact dermatitis.
Allergic contact dermatitis is a frequent inflammatory skin disease. The suspected diagnosis is based on clinical symptoms, a plausible contact to allergens and a suitable history of dermatitis. Differential diagnoses should be considered only after careful exclusion of any causal contact sensitization. Hence, careful diagnosis by patch testing is of great importance. Modifications of the standardized test procedure are the strip patch test and the repeated open application test. The interpretation of the SLS (sodium lauryl sulfate) patch test as well as testing with the patients' own products and working materials are potential sources of error. Accurate patch test reading is affected in particular by the experience and individual factors of the examiner. Therefore, a high degree of standardization and continuous quality control is necessary and may be supported by use of an online patch test reading course made available by the German Contact Dermatitis Research Group. A critical relevance assessment of allergic patch test reactions helps to avoid relapses and the consideration of differential diagnoses. Any allergic test reaction should be documented in an allergy ID card including the INCI name, if appropriate. The diagnostics of allergic contact dermatitis is endangered by a seriously reduced financing of patch testing by the German statutory health insurances. Restrictive regulations by the German Drug Law block the approval of new contact allergens for routine patch testing. Beside the consistent avoidance of allergen contact, temporary use of systemic and topical corticosteroids is the therapy of first choice.


Characteristics of a paediatric low vision population in a private eye hospital in India.
While private hospitals provide an important access point for low vision services for children in urban India, little is known about this service delivery route. A cross sectional survey was done of consecutive records of 220 children presenting at a newly opened paediatric low vision centre in a private eye hospital in Hyderabad. On presentation, 49% of the children were classified as moderately visually impaired, 31% were severely visually impaired and 20% were blind. The four major causes of visual impairment were the hereditary/genetic conditions of congenital glaucoma, hereditary macular degeneration, retinitis pigmentosa and albinism. Approach magnification was sufficient for required near tasks in all pre-school children and about 50% of school children. Provision of a distance refraction decreased the prevalence of severe visual impairment and blindness by 31%. The most commonly prescribed low vision devices were spectacles indicating a key role for optometry in the management of visual impairment in Indian children. Establishment of low vision clinics in existing Indian eye hospitals using associated optometric staff would be a cost effective method to minimise visual impairment in Indian children.


The effect of chronic periodontitis on the development of atherosclerosis: review of the literature.
Although research has demonstrated that odontogenic foci of infection can be dangerous to the function of other organs, a direct relationship between orofacial infections and systemic health has not been proved. Recently, bacterial and viral organisms involved in chronic inflammatory processes have also been regarded as risk factors for atherosclerosis. Periodontitis is one of the most common chronic bacterial infections. One of the first researchers to indicate a relationship between orofacial infections and atherosclerosis were Mattila et al. In 1989 they published a paper which identified periodontal disease as an independent predictor of the risk of myocardial infarction. For over ten years several authors have discussed the correlation between oral infections, and periodontal disease in particular, and the occurrence of coronary heart disease, myocardial infarction, and ischemic stroke. A review of the knowledge of the effects of periodontal disease on the development of atheromatous plaque is presented here. No scientific evidence was found to prove a direct association between odontogenic infections and atherosclerosis. However, such a relationship is probable in the light of the reviewed articles. Reliable markers should be sought which could accurately indicate the effect of periodontal disease on the condition of the arteries.


Nutrigenomic effect of conjugated linoleic acid on growth and meat quality indices of growing rabbit.
Conjugated linoleic acid was detected in rabbit caecotrophs, due to the presence of microbial lipid activity in rabbit cecum. However, the effect of CLA as a functional food in growing rabbit is not well established. Therefore, this study was conducted to determine the effect of CLA on production, meat quality, and its nutrigenomic effect on edible parts of rabbit carcass including skeletal muscle, liver, and adipose tissue. Therefore, seventy five weaned V-Line male rabbits, 30 days old, were randomly allocated into three dietary treatments receiving either basal control diet, diet supplemented with 0.5% (CLAL), or 1% CLA (CLAH). Total experimental period (63 d) was segmented into 7 days adaptation and 56 days experimental period. Dietary supplementation of CLA did not alter growth performance, however, the fat percentage of longissimus lumborum muscle was decreased, with an increase in protein and polyunsaturated fatty acids (PUFA) percentage. Saturated fatty acids (SFA) and mono unsaturated fatty acids (MUFA) were not increased in CLA treated groups. There was tissue specific sensing of CLA, since subcutaneous adipose tissue gene expression of PPARA was downregulated, however, CPT1A tended to be upregulated in liver of CLAL group only (P = 0.09). In skeletal muscle, FASN and PPARG were upregulated in CLAH group only (P ≤0.01). Marked cytoplasmic vacuolation was noticed in liver of CLAH group without altering hepatocyte structure. Adipocyte size was decreased in CLA fed groups, in a dose dependent manner (P <0.01). Cell proliferation determined by PCNA was lower (P <0.01) in adipose tissue of CLA groups. Our data indicate that dietary supplementation of CLA (c9,t11-CLA and t10,c12- CLA) at a dose of 0.5% in growing rabbit diet produce rabbit meat rich in PUFA and lower fat % without altering growth performance and hepatocyte structure.


Beyond quality of life: a cross sectional study on the mental health of patients with chronic kidney disease undergoing dialysis and their caregivers.
Patients with terminal chronic kidney disease (CKDT) requiring renal replacement therapies (RRT) undergo important changes in living habits and frequently need caregiving. These patients and their caregivers are risk groups for the development of physical and psychological symptoms. This study aimed to evaluate the prevalence of anxiety, depression, stress, fatigue, social support, and quality of life in patients with CKD and their caregivers. This cross sectional study was conducted with 21 patients and their caregivers, from January to September 2015. We included patients aged over 18 years, with at least 6 months on dialysis treatment, and caregivers who were family members. The participants' social, demographic, clinical, laboratory, and psychological variables were evaluated. A descriptive analysis and an examination of the association between patients and caregivers were performed. Among patients, we observed that 38.1% had symptoms that indicated anxiety and depression. The average score for practical social support was 3.15 ± 0.769 and that for emotional social support was 3.16 ± 0.79. As for fatigue, 14.3% of patients reported being 'extremely tired' and 14.3% reported that they engaged in all the activities they usually performed before the illness. Further, 57.1% presented stress, and of these, 66.7% were at the resistance stage, with predominance of psychological symptoms in 60.0%. The quality of life domain in terms of functional capacity (FC) presented a correlation with haemoglobin level (r = 0.581, p = 0.006) and non-anaemic patients presented better FC. Among caregivers, we observed symptoms that indicated anxiety and depression in 33.3% of the sample. Caregivers exhibited an average score of 2.88 ± 0.77 for practical social support and 3.0 ± 0.72 for emotional social support. Further, 14.3% reported being 'extremely tired' and 28.8% reported that they engaged in all activities that they usually performed before the patient's illness. When comparing the two groups (patients vs. caregivers), we observed that they presented similar results for the presence of anxiety, depression, and fatigue. Caregivers received less social support than patients did. Both groups presented similar predominance of stress levels; however, patients presented more predominance of psychological symptoms. With reference to quality of life, patients and caregivers presented similar results on the social aspects, vitality, mental health, and mental domains. The mental health characteristics of patients and caregivers were similar, and within the context of dialysis for renal disease, both must undergo specific interventions.


Five-year follow-up of a posterior chamber phakic intraocular lens with a central hole for correction of myopia.
To evaluate intermediate and long-term visual outcomes and safety of a phakic intraocular posterior chamber lens with a central hole (ICL V4c) for myopic eyes. Retrospective, consecutive case study of patients that uneventfully received a ICL V4c for myopia correction, with a 5-year postoperative follow-up. Department of Ophthalmology, Goethe University Frankfurt, Germany. From 241 eyes that underwent ICL implantation, we included 45 eyes with a mean age at surgery of 33 years ± 6 (18-48 years), with a 5 years follow-up. CDVA improved from 0.05logMAR ± 0.15 CDVA preoperatively to - 0.00 ± 0,07 at 5 years and did not change significantly from 3 to 5 years' time (p = 0.266). The mean spherical equivalent (SE) improved from -10.13D ± 3.39 to - 0.45D ± 0.69. The change in endothelial cell count showed a mean decrease of 1.9% per year throughout the follow-up. Safety and efficacy index were 1.16 and 0.78, respectively. Cataract formation was seen in 2 of 241 eyes (0.8%), but in none of the 45 eyes that finished the 5-year follow-up. Our data show a good intermediate and long-term stability, efficiency, and safety of ICL V4c phakic lenses in myopic eyes comparable to other known literature.


Association between neighbourhood deprivation and hypertension in a US-wide Cohort.
Socioeconomic status (SES) at the individual level is associated with hypertension risk. Less is known about neighbourhood level SES or how neighbourhood and individual level SES may jointly affect hypertension risk. The Area Deprivation Index (ADI) includes 17 census-based measures reflecting neighbourhood SES. The ADI was linked to enrolment addresses of 47 329 women in the Sister Study cohort and categorised as ≤10% (low deprivation), 11%-20%, 21%-35%, 36%-55% and >55% (high deprivation). Hypertension was defined as either high systolic (≥140 mm Hg) or diastolic (≥90 mm Hg) blood pressure or taking antihypertensive medication. We used log binomial regression to investigate the cross-sectional association between ADI and hypertension and evaluated interactions between ADI and race/ethnicity and between ADI and individual SES. The highest ADI level of >55% was associated with increased prevalence of hypertension, compared with the lowest level of ADI≤10%, in a model adjusted for age, race/ethnicity, educational attainment and annual household income (prevalence ratio=1.26, 95% CI 1.21 to 1.32). We observed interaction between race/ethnicity and ADI (interaction contrast ratio (ICR)=1.9; 95% CI 0.94 to 2.8 comparing non-Hispanic Black women with ADI >55% to non-Hispanic White women with ADI≤10%) and between household income and ADI (ICR 0.38; 95% CI 0.12 to 0.65 comparing participants with household income ≤US$49 999 and ADI>55% to those with household income >US$100 000 and ADI≤10%). These findings suggest that neighbourhood deprivation measured by ADI may be a risk factor for hypertension and that ADI may act synergistically with race/ethnicity and individual household income to contribute to hypertension.


Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease.
There have been important advances in defining effector mechanisms for several human autoimmune diseases. However, for most human autoimmune diseases, the induction stage is less well defined and there are very few clues on etiology. Our laboratory has focused on defining the molecular basis of autoantibody recognition and epitope modification in primary biliary cirrhosis (PBC). Our work has demonstrated that antibodies to mitochondria, the hallmark of disease, are directed against a very conserved site of pyruvate dehydrogenase, the E2 subunit of pyruvate dehydrogenase (PDC-E2). We have also demonstrated that several chemical xenobiotics, chosen based on quantitative structural activity relationship analysis and rigorous epitope analysis, when coupled to the lysine residue that normally binds the lipoic acid cofactor of PDC-E2, reacts as well or better to PBC sera than native autoantigen. In the present studies, we immunized C57BL/6 mice with one such xenobiotic, 2-octynoic acid, coupled to bovine serum albumin and we followed the mice for 24 weeks. Animals were studied for appearance of histologic lesions as well as appearance of antibodies to PDC-E2, serum levels of tumor necrosis factor-alpha and interferon-gamma, and splenic and liver lymphoid phenotyping by flow cytometry. Mice immunized with 2-octynoic acid manifest autoimmune cholangitis, typical mitochondrial autoantibodies, increased liver lymphoid cell numbers, an increase in CD8(+) liver infiltrating cells, particularly CD8(+) T cells that coexpress CD44, and finally an elevation of serum tumor necrosis factor-alpha and interferon-gamma. these data provide a persuasive argument in favor of an environmental origin for human PBC.


Timing, storage, and comparison of stimulus duration engage discrete anatomical components of a perceptual timing network.
The temporal discrimination paradigm requires subjects to compare the duration of a probe stimulus to that of a sample previously stored in working or long-term memory, thus providing an index of timing that is independent of a motor response. However, the estimation process itself comprises several component cognitive processes, including timing, storage, retrieval, and comparison of durations. Previous imaging studies have attempted to disentangle these components by simply measuring brain activity during early versus late scanning epochs. We aim to improve the temporal resolution and precision of this approach by using rapid event-related functional magnetic resonance imaging to time-lock the hemodynamic response to presentation of the sample and probe stimuli themselves. Compared to a control (color-estimation) task, which was matched in terms of difficulty, sustained attention, and motor preparation requirements, we found selective activation of the left putamen for the storage ("encoding") of stimulus duration into working memory (WM). Moreover, increased putamen activity was linked to enhanced timing performance, suggesting that the level of putamen activity may modulate the depth of temporal encoding. Retrieval and comparison of stimulus duration in WM selectively activated the right superior temporal gyrus. Finally, the supplementary motor area was equally active during both sample and probe stages of the task, suggesting a fundamental role in timing the duration of a stimulus that is currently unfolding in time.


Equilibrium unfolding mechanism of chicken muscle triose phosphate isomerase.
Triose phosphate isomerase (TIM) was prepared and purified from chicken breast muscle. The equilibrium unfolding of TIM by urea was investigated by following the changes of intrinsic fluorescence and circular dichroism spectroscopy, and the equilibrium thermal unfolding by differential scanning calorimetry (DSC). Results show that the unfolding of TIM in urea is highly cooperative and no folding intermediate was detected in the experimental conditions used. The thermodynamic parameters of TIM during its urea induced unfolding were calculated as DeltaG degrees =3.54 kcal.mol(-1), and m(G) = 0.67 kcal.mol(-1)M(-1), which just reflect the unfolding of dissociated folded monomer to fully unfolded monomer transition, while the dissociation energy of folded dimer to folded monomer is probe silence. DSC results indicate that TIM unfolding follows an irreversible two-state step with a slow aggregation process. The cooperative unfolding ratio, DeltaH(cal)/DeltaH(vH), was measured close to 2, indicating that the two subunits of chicken muscle TIM unfold independently. The van't Hoff enthalpy, DeltaH(vH), was estimated as about 200 kcal.mol(-1). These results support the unfolding mechanism with a folded monomer formation before its tertiary structure and secondary structure unfolding.


Production of fimbrial adhesins K99 and F41 by enterotoxigenic Escherichia coli as a function of growth-rate domain.
The production of fimbrial adhesins K99 and F41 by enterotoxigenic Escherichia coli has been measured in steady-state chemostat experiments at various specific growth rates (microseconds) and in a recycling fermentor across a range of mu values falling to less than 0.004 h-1. It has been demonstrated that the production of K99 and F41 fimbriae is correlated with mu both in aerobic and anaerobic chemostat experiments. A significant production of fimbriae was only detected at mu values higher than 0.2 h-1. This behavior was further examined by culturing the bacteria in a recycling fermentor with complete biomass retention. It could be shown that the production of K99 and F41 fimbriae only occurred during balanced growth, with a high biomass yield at mu values higher than 0.04 h-1 corresponding to mass doubling times (td) of less than 17 h. The production of both fimbriae halted during balanced growth with a lower biomass yield (at mu values between 0.012 and 0.04 h-1 corresponding to td values between 17 and 58 h) and unbalanced stringent growth (at mu values lower than 0.012 h-1 or td values higher than 58 h). The external pH of the medium greatly influenced the production of both K99 and F41 fimbriae. At pH values lower than 7, the production of fimbriae was strongly inhibited. Also, at pH values higher than 7, a decrease in production was observed. The consequences of the observed phenomena for the pathogenic behavior of this E. coli strain are discussed.


The stress protein BAG3 stabilizes Mcl-1 protein and promotes survival of cancer cells and resistance to antagonist ABT-737.
Members of the Bcl-2 family of proteins are important inhibitors of apoptosis in human cancer and are targets for novel anticancer agents such as the Bcl-2 antagonists, ABT-263 (Navitoclax), and its analog ABT-737. Unlike Bcl-2, Mcl-1 is not antagonized by ABT-263 or ABT-737 and is considered to be a major factor in resistance. Also, Mcl-1 exhibits differential regulation when compared with other Bcl-2 family members and is a target for anticancer drug discovery. Here, we demonstrate that BAG3, an Hsp70 co-chaperone, protects Mcl-1 from proteasomal degradation, thereby promoting its antiapoptotic activity. Using neuroblastoma cell lines, with a defined Bcl-2 family dependence, we found that BAG3 expression correlated with Mcl-1 dependence and ABT-737 resistance. RNA silencing of BAG3 led to a marked reduction in Mcl-1 protein levels and overcame ABT-737 resistance in Mcl-1-dependent cells. In ABT-737-resistant cells, Mcl-1 co-immunoprecipitated with BAG3, and loss of Mcl-1 after BAG3 silencing was prevented by proteasome inhibition. BAG3 and Mcl-1 were co-expressed in a panel of diverse cancer cell lines resistant to ABT-737. Silencing BAG3 reduced Mcl-1 protein levels and overcame ABT-737 resistance in several of the cell lines, including triple-negative breast cancer (MDA-MB231) and androgen receptor-negative prostate cancer (PC3) cells. These studies identify BAG3-mediated Mcl-1 stabilization as a potential target for cancer drug discovery.


Teriparatide attenuates scarring around murine cranial bone allograft via modulation of angiogenesis.
Nearly all bone fractures in humans can deteriorate into a non-union fracture, often due to formation of fibrotic tissue. Cranial allogeneic bone grafts present a striking example: although seemingly attractive for craniofacial reconstructions, they often fail due to fibrosis at the host-graft junction, which physically prevents the desired bridging of bone between the host and graft and revitalization of the latter. In the present study we show that intermittent treatment with recombinant parathyroid hormone-analogue (teriparatide) modulates neovascularization feeding in the graft surroundings, consequently reducing fibrosis and scar tissue formation and facilitates osteogenesis. Longitudinal inspection of the vascular tree feeding the allograft has revealed that teriparatide induces formation of small-diameter vessels in the 1st week after surgery; by the 2nd week, abundant formation of small-diameter blood vessels was detected in untreated control animals, but far less in teriparatide-treated mice, although in total, more blood capillaries were detected in the animals that were given teriparatide. By that time point we observed expression of the profibrogenic mediator TGF-β in untreated animals, but negligible expression in the teriparatide-treated mice. To evaluate the formation of scar tissue, we utilized a magnetization transfer contrast MRI protocol to differentiate osteoid tissue from scar tissue, based on the characterization of collagen fibers. Using this method we found that significantly more bone matrix was formed in animals given teriparatide than in control animals. Altogether, our findings show how teriparatide diminishes scarring, ultimately leading to superior bone graft integration.


Is tisseel a viable option in posterior lamellar keratoplasty?
It is well known that Tisseel Fibrin Sealant provides an excellent tissue adhesive. However, its thick and viscuous nature makes it nearly impossible to apply it in a uniform and thin layer. We propose applying the sealant phase as a dry powder and polymerizing it in-vivo by exposing it to thrombin solution after a graft has been placed. For each experiment two rabbit corneal buttons were affixed to each other using either Tisseel or thrombin plus dry fibrinogen component, the tensile strength of the bond was then tested in the tension box. Balanced salt solution was used as an aqueous substitute. Tisseel was demonstrated to create significant adhesive tensile force (expressed as N/m) between corneal buttons (P < 10). Using only the dry fibrinogen component followed by injection of the thrombin solution directly into the balanced salt solution did not significantly alter the strength of the bond (P = 0.18). The use of the dry fibrinogen component followed by injection of thrombin solution into the balanced salt solution, without the accompanying fibrinolysis inhibitor, is equally effective in adhesive strength when compared to complete Tisseel. This technique may be used in lamellar corneal surgery, although there would be potential difficulties with its application in the in vivo setting.


Fate of Per- and Polyfluoroalkyl Substances from Durable Water-Repellent Clothing during Use.
To make outdoor clothing water- or dirt-repellent, durable water-repellent (DWR) coatings based on side-chain fluorinated polymers (SFPs) are used. During use of outdoor clothing, per- and polyfluoroalkyl substances (PFASs) can be emitted from the DWR to the environment. In this study, the effects of aging, washing, and tumble drying on the concentration of extractable PFASs in the DWR of perfluorohexane-based short-chain SFPs (FC-6 chemistry) and of perfluorooctane-based long-chain SFPs (FC-8 chemistry) were assessed. For this purpose, polyamide (PA) and polyester (PES) fabrics were coated with FC-6- and FC-8-based DWRs. Results show that aging of the coated fabrics causes an increase in concentration and formation of perfluoroalkyl acids (PFAAs). The effect of aging on the volatile PFASs depends on the type of fabric. Washing causes a decrease in PFAA concentrations, and in general, volatile PFASs are partly washed out of the textiles. However, washing can also increase the extractable concentration of volatile PFASs in the fabrics. This effect becomes stronger by a combination of aging and washing. Tumble drying does not affect the PFAS concentrations in textiles. In conclusion, aging and washing of fabrics coated with the DWR based on SFPs release PFASs to the environment.


Effect of ropivacaine skull block on perioperative outcomes in patients with supratentorial brain tumors and comparison with remifentanil: a pilot study.
Skull blockade for craniotomy may result in the reduction of sympathetic stimulation associated with the application of head pins ("pinning"), improvement in intraoperative hemodynamic stability, and a decrease in intraoperative anesthetic requirements. Postoperative benefits may include a decrease in pain, in analgesic requirements, and in the incidence of nausea and vomiting. The authors examined the potential benefits of a skull block in patients in whom a maintenance anesthetic consisting of sevoflurane and a titratable remifentanil infusion was used. In other studies examining the ability of a skull block to improve perioperative outcomes, investigators have not used remifentanil. Thirty patients presenting for resection of a supratentorial tumor were prospectively enrolled. Patients were randomized into 2 groups as follows: 14 patients (skull block group) received a skull block with 0.5% ropivacaine at least 15 minutes prior to pinning, whereas the remaining 16 patients (control group) did not. Patients in the skull block group did not have a significant increase in blood pressure or heart rate with placement of head pins, whereas patients in the control group did. Nevertheless, there was no difference in blood pressure variability between the groups. The mean intraoperative concentration of sevoflurane (1.0% in both groups, p = 0.703) and remifentanil (0.163 microg/kg/min compared with 0.205 microg/kg/min, p = 0.186) used was similar in both groups. During the postoperative period, there was no difference in the 1-, 2-, or 4-hour visual analog scale scores; in the need for postoperative narcotic analgesia (0.274 morphine equivalent mg/kg compared with 0.517 morphine equivalent mg/kg, p = 0.162); or in the incidence of nausea or vomiting. Prospective analysis of perioperative skull blockade failed to demonstrate significant benefit in patients treated with a remifentanil infusion.


Functional diversification of duplicated chalcone synthase genes in anthocyanin biosynthesis of Gerbera hybrida.
• Chalcone synthase (CHS) is the key enzyme in the first committed step of the flavonoid biosynthetic pathway and catalyzes the stepwise condensation of 4-coumaroyl-CoA and malonyl-CoA to naringenin chalcone. In plants, CHS is often encoded by a small family of genes that are temporally and spatially regulated. Our earlier studies have shown that GCHS4 is highly activated by ectopic expression of an MYB-type regulator GMYB10 in gerbera (Gerbera hybrida). • The tissue- and development-specific expression patterns of three gerbera CHS genes were examined. Virus-induced gene silencing (VIGS) was used to knock down GCHS1 and GCHS4 separately in gerbera inflorescences. • Our data show that GCHS4 is the only CHS encoding gene that is expressed in the cyanidin-pigmented vegetative tissues of gerbera cv Terraregina. GCHS3 expression is pronounced in the pappus bristles of the flowers. Expression of both GCHS1 and GCHS4 is high in the epidermal cells of gerbera petals, but only GCHS1 is contributing to flavonoid biosynthesis. • Gerbera contains a family of three CHS encoding genes showing different spatial and temporal regulation. GCHS4 expression in gerbera petals is regulated post-transcriptionally, at the level of either translation elongation or protein stability.


Mitochondrial Translocation of P66Shc Aggravates Cisplatin-induced AKI by Promoting Ferroptosis.
The objective of this study is to evaluate the regulatory mechanism between P66Shc and ferroptosis in cisplatin-induced acute kidney injury (CP-AKI). A CP-AKI model was constructed both in vivo and in vitro using C57BL/6 mice and HK-2 cells, respectively. Renal histopathological injury, reactive oxygen species (ROS), and apoptosis were detected. Some parameters of ferroptosis (e.g. 4HNE and GPX4) and the expression of P66Shc/ P-P66Shc both in mitochondria and cytoplasm were tested. In in vitro studies, HK-2 cells were incubated with CP (50 uM); additionally, Fer1 and P66Shc siRNA were applied to explore the molecular regulatory mechanism of P66Shc in ferroptosis. The levels of mitochondrial ROS, apoptosis and the expression of 4HNE,GPX4, P66Shc, and P-P66Shc were tested. Furthermore, the mitochondrial translocation of P66Shc was detected. CP treatment caused elevation of Scr, BUN and renal MDA levels and decreased renal SOD, GSH-PX and GPX4 levels. CP enhanced the expression of 4HNE, P66Shc and P-P66Shc both in vivo and in vitro. Renal oxidative stress and apoptosis were significantly increased in CP-AKI mice. Electron microscopy examination indicated obvious mitochondria injury in renal tubular cells of CP-AKI mice. The level of ferroptosis and the translocation of P-P66Shc from the cytoplasm to mitochondria were significantly increased in HK-2 cells under CP condition, and these effects were obviously blocked by P66Shc siRNA treatment. Conversely, pretreatment with the ferroptosis inhibitor (Fer1) had no effect on the expression and mitochondria translocation of PP66Shc under CP condition. Mitochondrial translocation of P66Shc could result in mitochondrial injury and lipid peroxide accumulation, which ultimately led to ferroptosis and aggravated CPinduced AKI.


Impact of Rigidity on Molecular Self-Assembly.
Rigid, cage-like molecules, like diamondoids, show unique self-assembly behavior, such as templating 1-D nanomaterial assembly via pathways that are typically blocked for such bulky substituents. We investigate molecular forces between diamondoids to explore why molecules with high structural rigidity exhibit these novel assembly pathways. The rigid nature of diamondoids significantly lowers configurational entropy, and we hypothesize that this influences molecular interaction forces. To test this concept, we calculated the distance-dependent impact of entropy on assembly using molecular dynamics simulations. To isolate pairwise entropic and enthalpic contributions to assembly, we considered pairs of molecules in a thermal bath, fixed at set intermolecular separations but otherwise allowed to freely move. By comparing diamondoids to linear alkanes, we draw out the impact of rigidity on the entropy and enthalpy of pairwise interactions. We find that linear alkanes actually exhibit stronger van der Waals interactions than diamondoids at contact, because the bulky structure of diamondoids induces larger net atomic separations. Yet, we also find that diamondoids pay lower entropic penalties when assembling into contact pairs. Thus, the cage-like shape of diamondoids introduces an enthalpic penalty at contact, but the penalty is counterbalanced by entropic effects. Investigating the distance dependence of entropic forces provides a mechanism to explore how rigidity influences molecular assembly. Our results show that low entropic penalties paid by diamondoids can explain the effectiveness of diamondoids in templating nanomaterial assembly. Hence, tuning molecular rigidity can be an effective strategy for controlling the assembly of functional materials, such as biomimetic surfaces and nanoscale materials.


OLIG2 is an in vivo bookmarking transcription factor in the developing neural tube in mouse.
Cells possess intrinsic features that are inheritable via epigenetic regulation, such as DNA methylation and histone modification. These inheritable features maintain a unique gene expression pattern, underlying cellular memory. Because of the degradation or displacement of mitotic chromosomes, most transcription factors do not contribute to cellular memory. However, accumulating in vitro evidence indicates that some transcription factors can be retained in mitotic chromosomes called as bookmarking. Such transcription factors may contribute to a novel third mechanism of cellular memory. Since most findings of transcription factor bookmarking have been reported in vitro, little is currently known in vivo. In the neural tube of mouse embryos, we discovered that OLIG2, a basic helix loop helix (bHLH) transcription factor that regulates proliferation of neural progenitors and the cell fate of motoneurons and oligodendrocytes, binds to chromatin through every cell cycle including M-phase. OLIG2 chromosomal localization coincides with mitotic cell features such as the phosphorylation of histone H3, KI67, and nuclear membrane breakdown. Chromosomal localization of OLIG2 is regulated by an N-terminus triple serine motif. Photobleaching analysis revealed slow OLIG2 mobility, suggesting a high affinity of OLIG2 to DNA. In Olig2 N-terminal deletion mutant mice, motoneurons and oligodendrocyte progenitor numbers are reduced in the neural tube, suggesting that the bookmarking regulatory domain is important for OLIG2 function. We conclude that OLIG2 is a de novo in vivo bookmarking transcription factor. Our results demonstrate the presence of in vivo bookmarking in a living organism and illustrate a novel function of transcription factors.


Prevalence of femoroacetabular impingement and effect of training frequency on aetiology in paediatric football players.
The aim of this study was to determine the prevalence of asymptomatic radiographic findings of femoroacetabular impingement (FAI) in paediatric football players in different age groups and to investigate aetiological factors. Paediatric male athletes between 10 and 17 years of age from 8 soccer teams were recruited. In addition to an annual control check-up, anteroposterior pelvis and frog-leg radiographs as well as the curriculum vitae of the athletes, their injuries, and real-time complaints were recorded. The alpha angle, lateral centre-edge angle, Tönnis angle, and collodiaphyseal angle were measured and morphological abnormalities were noted. There were 214 male football players with a mean age of 13.4 ± 3.2 years included in the study. In the morphological analysis of hips, there was FAI in 30% of the athletes. In the analysis of FAI prevalence in 3 subgroups based on age (Group 1: 10-12 years [ n = 25], Group 2: 13-15 years [ n = 104], Group 3: 16-17 years [ n = 85]), there was 0% FAI in Group 1, 19.1% in Group 2 and 60% in Group 3. In the analysis of aetiological factors, there was no significant difference between the right and left hips of players regarding alpha angles and FAI prevalence. However, the prevalence of FAI was higher in players who had been playing football for 3 years or more and who had been training for 12.5 hours/week or more. Training for 12.5 hours or more per week in paediatric football players doubled the risk development of FAI morphology.


In situ study of abundant expression of proinflammatory chemokines and cytokines in pulmonary granulomas that develop in cynomolgus macaques experimentally infected with Mycobacterium tuberculosis.
Tuberculosis remains a major public health problem worldwide. Chemokines and cytokines organize and direct infiltrating cells to sites of infection, and these molecules likely play crucial roles in granuloma formation and maintenance. To address this issue, we used in situ hybridization (ISH) to measure chemokine and cytokine mRNA expression levels and patterns directly in lung tissues from cynomolgus macaques (Macaca fascicularis) experimentally infected with a low dose of virulent Mycobacterium tuberculosis. We examined more than 300 granulomas and observed abundant expression of gamma interferon (IFN-gamma)-inducible chemokine mRNAs (CXCL9/monokine induced by IFN-gamma, CXCL10/IFN-gamma-inducible protein, and CXCL11/IFN-gamma-inducible T-cell alpha-chemoattractant) within solid and caseous granulomas, and there was only minimal expression in nongranulomatous regions of tissue. The mRNA expression patterns of IFN-gamma and tumor necrosis factor alpha were examined in parallel, and the results revealed that cytokine mRNA(+) cells were abundant and generally localized to the granulomas. Mycobacterial 16S rRNA expression was also measured by ISH, and the results revealed that there was localization predominantly to the granulomas and that the highest signal intensity was in caseous granulomas. We observed several granulomatous lesions with exceptionally high levels of RNA for mycobacterial 16S rRNA, IFN-gamma, and IFN-gamma-inducible chemokines, suggesting that the local presence of mycobacteria is partially responsible for the upregulation of IFN-gamma-inducible chemokines and recruitment of CXCR3(+) cells, which were also abundant in granulomatous lesions. These results suggest that expression of CXCR3 ligands and the subsequent recruitment of CXCR3(+) cells are involved in granuloma formation and maintenance.


Factors Affecting Death Anxiety in Patients Undergoing Open Heart Surgery: A Cross-Sectional Study.
After the operation, death anxiety of patients is affected by many factors. This study aims to investigate the factors affecting death anxiety of patients undergoing open heart surgery. A descriptive, cross-sectional study. Data were collected using the 'Introductory Information Form,' the 'Templer's Death Anxiety Scale,' and the 'Spiritual Well-being Scale.' This study was conducted with 313 intensive care patients. The mean scores of the patients on the "Death Anxiety Scale" were moderate (7.96 (4.28)). According to the study findings, age, gender, length of stay in the intensive care unit, and spiritual well-being were found to be important predictors of death anxiety (F (4,308) = 16.149, p < .001). Considering gender differences in nursing care, it is thought that the intensive care period will be shortened, the level of spiritual well-being will increase and death anxiety will decrease.


Out-of-pocket health expenditures and antimicrobial resistance in low-income and middle-income countries: an economic analysis.
The decreasing effectiveness of antimicrobial agents is a growing global public health concern. Low-income and middle-income countries are vulnerable to the loss of antimicrobial efficacy because of their high burden of infectious disease and the cost of treating resistant organisms. We aimed to assess if copayments in the public sector promoted the development of antibiotic resistance by inducing patients to purchase treatment from less well regulated private providers. We analysed data from the WHO 2014 Antibacterial Resistance Global Surveillance report. We assessed the importance of out-of-pocket spending and copayment requirements for public sector drugs on the level of bacterial resistance in low-income and middle-income countries, using linear regression to adjust for environmental factors purported to be predictors of resistance, such as sanitation, animal husbandry, and poverty, and other structural components of the health sector. Our outcome variable of interest was the proportion of bacterial isolates tested that showed resistance to a class of antimicrobial agents. In particular, we computed the average proportion of isolates that showed antibiotic resistance for a given bacteria-antibacterial combination in a given country. Our sample included 47 countries (23 in Africa, eight in the Americas, three in Europe, eight in the Middle East, three in southeast Asia, and two in the western Pacific). Out-of-pocket health expenditures were the only factor significantly associated with antimicrobial resistance. A ten point increase in the percentage of health expenditures that were out-of-pocket was associated with a 3·2 percentage point increase in resistant isolates (95% CI 1·17-5·15; p=0·002). This association was driven by countries requiring copayments for drugs in the public health sector. Of these countries, moving from the 20th to 80th percentile of out-of-pocket health expenditures was associated with an increase in resistant bacterial isolates from 17·76% (95% CI 12·54-22·97) to 36·27% (31·16-41·38). Out-of-pocket health expenditures were strongly correlated with antimicrobial resistance in low-income and middle-income countries. This relation was driven by countries that require copayments on drugs in the public sector. Our data suggest cost-sharing of antimicrobials in the public sector might drive demand to the private sector in which supply-side incentives to overprescribe are probably heightened and quality assurance less standardised. National Institutes of Health.


The impact of malnutrition on quality of life in patients with systemic sclerosis.
Our objective was to investigate the prevalence of malnutrition in patients with systemic sclerosis (SSc) and its impact on their quality of life (QoL). One hundred and twenty-nine patients with SSc underwent clinical evaluation and were screened with the Malnutrition Universal Screening Tool (MUST). Malnutrition was defined as MUST score ≥2.To investigate QoL, all patients completed the Short Form 36 Questionnaire and the Scleroderma Health Assessment Questionnaire. The data were analyzed with IBM SPSS® Statistics by using χ2/Fisher's test, Mann-Whitney U test, correlation, and linear regression analysis. One hundred and twenty-nine patients were included in this study (mean age was 59.1 ± 13.8 years, 90.7% women). The prevalence of malnutrition was 10.9%. Age and disease duration were not significantly different between malnourished and well-nourished patients. All QoL scores (except bodily pain and self-reported health) were significantly impaired in malnourished patients. Furthermore, the Scleroderma Health Assessment Score score which assesses disease-specific QoL was significantly higher in the malnourished patients (1.6 ± 0.73 compared to 0.91 ± 0.61 in well-nourished patients; p = 0.001), reflecting a lower QoL due to disease-specific impairments. Severe malnutrition in SSc patients is associated with reduced QoL. Standardized nutritional screening should routinely be conducted to identify the risk of malnutrition in order to enable an intervention with multimodal treatment and avoid the serious consequences associated with severe malnutrition.


Generation of a mouse line expressing Cre recombinase in glycinergic interneurons.
In caudal regions of the CNS, glycine constitutes the major inhibitory neurotransmitter. Here, we describe a mouse line that expresses Cre recombinase under the control of a BAC transgenic glycine transporter 2 (GlyT2) promoter fragment. Mating of GlyT2-Cre mice with the Cre reporter mouse lines Rosa26/LacZ and Rosa26/YFP and analysis of double transgenic offsprings revealed strong transgene activity in caudal regions of the central nervous system, i.e., brain stem and spinal cord. Some additional Cre expression was observed in cortical and cerebellar regions. In brain stem and spinal cord, Cre expressing cells were identified as glycinergic interneurons by staining with GlyT2- and glycine-immunoreactive antibodies; here, >80% of the glycine-immunoreactive cells expressed the Cre reporter protein. These data indicate that GlyT2-Cre mice are a useful tool for the genetic manipulation of glycinergic interneurons.


Immunoglobulin heavy chain mRNA in mitogen-stimulated B cells.
This paper relates the synthesis of DNA, immunoglobulin and heavy chain (H) mRNA in murine spleen cells following activation of B cells with lipopolysaccharide from E. coli (LPS). Spleen cells (CBA/H mice) were cultivated with 10% FCS and 10 mug LPS/ml. 4 h pulses with [3H]thymidine showed that DNA synthesis was stimulated within the first day following LPS activation and exhibited a sharp peak at 24 h. The shape of the DNA synthesis curve suggests that the cells susceptible to LPS stimulation are activated in a synchronous manner. Stimulation of H-chain mRNA (H-mRNA) synthesis proceeded rapidly (within 6 h of LPS addition) and peaked around 24 h, in parallel to DNA synthesis. The H-mRNA was isolated and quantitated by making use of its interaction with IgG[1, 2]. The actual level of H-mRNA in the culture increased threefold during the first 24 h and then doubled within the next 48 h. Estimates of the actual number of H-mRNA were approximately 200 molecules H-m-RNA/cell on day 0 rising to 1800/cell on day 3. In such a mixed cell population these figures will be accurate only within a factor of 2-3 (at least 35% B cells in spleen cell suspensions at the commencement of the culture, with up to 35-60% of plasma blasts by day 3 and 4 of LPS treatment). Translation of the lymphoid cell mRNA in oocytes from Xenopus laevis demonstrated that stimulation of H-mRNA synthesis was restricted to mu-mRNA, although some gamma-mRNA was present in the original spleen cells. High levels of synthesis of immunoglobulin followed after a lag period of about 24 h following LPS addition peaking after 48 and 72 h; the proportional Ig production relative to total protein synthesis reached 26% on days 3 and 4. Stimulation of Ig production was limited to IgM. Rapid stimulation of mitosis and H-mRNA synthesis thus precedes the maximum synthesis of Ig molecules, suggesting a translational block on H-mRNA during cell maturation. There was no apparent block on the transport of H-mRNA from the nucleus during early stages of activation.


Depression leads to incident vascular disease: evidence for the relevance to primary care.
Depression is a known risk factor for vascular disease in community cohorts and in large, system-wide, health care databases. It is not known if the association between depression and incident vascular disease exists when patient data is restricted to depression presenting in primary care. Data were from a medical record registry capturing all primary care encounters at a large academic medical practice from 2008 to 2013. From 27,225 registry patients, we identified 7383 patients free of vascular disease for 18 months prior to baseline. ICD-9-CM codes were used to define depression and vascular disease. Volume of health care use, demographics and comorbid diagnoses were obtained from the patient data registry. Cox proportional hazard models with time dependent covariates were computed to measure the association between depression and incident vascular disease before and after adjusting for covariates. Of the 7383 patients initially free of vascular disease, 14% were diagnosed with depression and 8.6% developed vascular disease. Incident vascular disease was significantly (P < 0.01) higher among patients with depression (12.7%) compared to those without depression (7.9%). In the unadjusted model, depression was associated with a 49% increased risk of developing vascular disease (odds ratio [OR] = 1.49; 95% confidence interval [CI]: 1.19-1.86) and this association remained significant after adjusting for all potential confounders (OR = 1.28; 95% CI: 1.02-1.62). The association between depression and incident vascular disease is observed in patients diagnosed and managed by primary care physicians. Primary care physicians have an opportunity to impact this association. Guidelines for primary care providers are needed to prompt aggressive depression treatment and vascular disease screening.


hERG1 channels modulate integrin signaling to trigger angiogenesis and tumor progression in colorectal cancer.
Angiogenesis is a potential target for cancer therapy. We identified a novel signaling pathway that sustains angiogenesis and progression in colorectal cancer (CRC). This pathway is triggered by β1 integrin-mediated adhesion and leads to VEGF-A secretion. The effect is modulated by the human ether-à-go-go related gene 1 (hERG1) K(+) channel. hERG1 recruits and activates PI3K and Akt. This in turn increases the Hypoxia Inducible Factor (HIF)-dependent transcription of VEGF-A and other tumour progression genes. This signaling pathway has novel features in that the integrin- and hERG1-dependent activation of HIF (i) is triggered in normoxia, especially after CRC cells have experienced a hypoxic stage, (ii) involves NF-kB and (iii) is counteracted by an active p53. Blocking hERG1 switches this pathway off also in vivo, by inhibiting cell growth, angiogenesis and metastatic spread. This suggests that non-cardiotoxic anti-hERG1 drugs might be a fruitful therapeutic strategy to prevent the failure of anti-VEGF therapy.