Potential blood markers as screening tools for subjects with low back pain: an age- and gender-matched cross-sectional analysis.
Introduction: Mechanical and inflammatory factors were suggested as the causes of spine degeneration and low back pain (LBP). Previous studies partly reported the association of LBP with inflammation. However, none of them compared patients with LBP and asymptomatic subjects in terms of complete blood count and inflammatory markers in detail. We aimed to analyze the association of serum white blood cell (WBC) count, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) with chronic LBP by comparing the patients with chronic LBP and age- and gender-matched asymptomatic subjects.Methods: Lumbar intervertebral disc degeneration and vertebral end-plates were evaluated using Pfirrmann grading and Modic classification on lumbar spine magnetic resonance imagings, respectively. Serum WBC counts, CRP levels, and ESRs were recorded from chart reviews.Results: We included 147 patients with chronic LBP and 101 asymptomatic subjects. Patients with chronic LBP had significantly higher serum neutrophil, monocyte, and basophil counts, higher neutrophil-to-lymphocyte ratio, higher ESR and lower serum CRP levels compared to the asymptomatic subjects. Serum monocyte and basophil cell counts and ESR were the most remarkable predictive factors for chronic LBP, severe IVDD, and Modic changes. Higher serum monocyte and basophil cell counts and higher serum ESR above cut-off values of 0.42 x 10^3/uL, 0.025 x 10^3/uL, and 3.5 mm/hour could be used as screening tool for subjects with persistent LBP in primary care.Discussion: Higher serum monocyte and basophil counts and serum ESR above new cut-off values should be alarming to obtain early spinal imaging and to prevent chronicity in patients with LBP.


Liraglutide in diabetes mellitus: More facts and findings.
Liraglutide exert favorable effects on most of the diabetes associated cardiovascular (CV) risk factors and this study was designed to further explore the benefits of liraglutide by observing its effect on plasma sialic acid (PSA) in diabetic rats. A total of 30 streptozotocin induced (50 mg/Kg; i.p.) diabetic rats were randomized into vehicle treated (1 ml/Kg s.c, twice daily) group I, liraglutide treated groups II and III (30 μg/Kg and 150 μg/Kg, twice daily respectively) and studied for 6 weeks. Liraglutide treated groups showed significant reductions in fructosamine levels (p≤0.05) from baseline. Between groups comparison revealed significant difference (p≤.05) at the end point. Similarly, at week 6, liraglutide treated groups showed significantly low levels of PSA compared to baseline (p<0.03 and p<0.005 for group II and III respectively) and control group I (p<0.002 and p<0.001 for group II and III respectively). However, the difference was non-significant between groups II and III (p<0.09). Other parameters including glucose tolerance, fasting plasma glucose (FPG), blood lipids, systolic blood pressure (SBP) and body weight also improved by liraglutide with the group III showing greater improvement. The study concludes that liraglutide produce favourable effects on PSA and may bea useful choice in protecting against diabetes associated CV complications.


Differentially Expressed in Chondrocytes 2 (DEC2) Increases the Expression of IL-1β and Is Abundantly Present in Synovial Membrane in Rheumatoid Arthritis.
Patients with rheumatoid arthritis (RA) have altered circadian rhythm of circulating serum cortisol, melatonin and IL-6, as well as disturbance in the expression of clock genes ARNTL2 and NPAS2. In humans, TNFα increases the expression ARNTL2 and NPAS2 but paradoxically suppresses clock output genes DPB and PER3. Our objective was to investigate the expression of direct clock suppressors DEC1 and DEC2 (BHLHE 40 and 41 proteins) in response to TNFα and investigate their role during inflammation. Cultured primary fibroblasts were stimulated with TNFα. Effects on DEC2 were studied using RT-qPCR and immunofluorescence staining. The role of NF-κB in DEC2 increase was analyzed using IKK-2 specific inhibitor IMD-0354. Cloned DEC2 was transfected into HEK293 cells to study its effects on gene expression. Transfections into primary human fibroblasts were used to confirm the results. The presence of DEC2 was analyzed in (RA) and osteoarthritis (OA) synovial membranes by immunohistochemistry. TNFα increased DEC2 mRNA and DEC2 was mainly detected at nuclei after the stimulus. The effects of TNFα on DEC2 expression were mediated via NF-κB. Overexpression, siRNA and promoter activity studies disclosed that DEC2 directly regulates IL-1β, in both HEK293 cells and primary human fibroblasts. DEC2 was increased in synovial membrane in RA compared to OA. Not only ARNTL2 and NPAS2 but also DEC2 is regulated by TNFα in human fibroblasts. NF-κB mediates the effect on DEC2, which upregulates IL-1β. Circadian clock has a direct effect on inflammation in human fibroblasts.


Sex as a biological variable: Drug use and abuse.
The study of sex as a biological variable is a necessary emphasis across a wide array of endpoints, including basic neuroscience, medicine, mental health, physiology and behavior. The present review summarizes work from clinical and preclinical populations on sex differences in drug use and abuse, ranging from initiation to escalation/dysregulation and from drug cessation/abstinence to relapse. These differences are analyzed in the context of the addiction cycle conceptualization of Koob and his colleagues and address patterns of drug use (binge/intoxication), motivation underlying its use (withdrawal/negative affect) and likelihood and causes of craving and relapse of drug taking (preoccupation/anticipation). Following this overview, an assessment of the basis for the reported sex differences is discussed in the context of the affective (rewarding and aversive) properties of drugs of abuse and how such properties and their balance vary with sex and contribute to drug intake. Finally, the interaction of sex with several experiential (drug history) and subject (age) factors and how these interactions affect reward and aversion are discussed to highlight the importance of understanding such interactions in predicting drug use and abuse. We note that sex as a biological variable remains one of critical evaluation and that such investigations of sex differences in drug use and abuse continue and be expanded to assess all facets of their mediation, including these affective properties, how their balance may be impacted by the multiple conditions under which drugs are taken and how this overall balance affects drug use and addiction vulnerability.


Analysis of 4-1BB ligand (4-1BBL)-deficient mice and of mice lacking both 4-1BBL and CD28 reveals a role for 4-1BBL in skin allograft rejection and in the cytotoxic T cell response to influenza virus.
4-1BB ligand (4-1BBL) is a member of the TNF family expressed on activated APC. 4-1BBL binds to 4-1BB (CD137) on activated CD4 and CD8 T cells and in conjunction with strong signals through the TCR provides a CD28-independent costimulatory signal leading to high level IL-2 production by primary resting T cells. Here we report the immunological characterization of mice lacking 4-1BBL and of mice lacking both 4-1BBL and CD28. 4-1BBL-/- mice mount neutralizing IgM and IgG responses to vesicular stomatitis virus that are indistinguishable from those of wild-type mice. 4-1BBL-/- mice show unimpaired CTL responses to lymphocytic choriomeningitis virus (LCMV) and exhibit normal skin allograft rejection but have a weaker CTL response to influenza virus than wild-type mice. 4-1BBL-/-CD28-/- mice retain the CTL response to LCMV, respond poorly to influenza virus, and exhibit a delay in skin allograft rejection. In agreement with these in vivo results, allogeneic CTL responses of CD28-/- but not CD28+/+ T cells to 4-1BBL-expressing APC are substantially inhibited by soluble 4-1BB receptor as is the in vitro secondary response of CD28+ T cells to influenza virus peptides. TCR-transgenic CD28-/- LCMV glycoprotein-specific T cells are insensitive to the presence of 4-1BBL when a wild-type peptide is used, but the response to a weak agonist peptide is greatly augmented by the presence of 4-1BBL. These results further substantiate the idea that different immune responses vary in their dependence on costimulation and suggest a role for 4-1BBL in augmenting suboptimal CTL responses in vivo.


Safe distances between groundwater-based water wells and pit latrines at different hydrogeological conditions in the Ganges Atrai floodplains of Bangladesh.
Groundwater drawn from shallow tubewells in Bangladesh is often polluted by nearby pit latrines, which are commonly used toilets in rural and sub-urban areas of the country. To determine the minimum safe distance of a tubewell from a pit latrine in different hydrogeological conditions of Bangladesh, 20 monitoring wells were installed at three study sites (Manda, Mohanpur and Bagmara) with the vertical and horizontal distances ranging from 18-47 to 2-15 m, respectively. Water samples were collected three times in three seasons and tested for faecal coliforms (FC) and faecal streptococci (FS) as indicators of contamination. Soil samples were analysed for texture, bulk density and hydraulic conductivity following standard procedures. Sediment samples were collected to prepare lithological logs. When the shallow aquifers at one of the three sites (Mohanpur) were overlained by 18-23-m-thick aquitards, the groundwater of the monitoring wells was found contaminated with a lateral and vertical distances of 2 and 31 m, respectively. However, where the aquitard was only 9 m thick, contamination was found up to lateral and vertical distances of 4.5 and 40.5 m, respectively. The soil textures of all the sites were mainly composed of loam and sandy loam. The hydraulic conductivities in the first aquifer at Manda, Mohanpur and Bagmara were 5.2-7.3, 8.2 and 1.4-15.7 m/h, respectively. The results showed that the safe distance from the tubewell to the pit latrine varied from site to site depending on the horizontal and vertical distances of the tubewell as well as hydrogeological conditions of a particular area.


Proton radiation therapy for chordomas and chondrosarcomas of the skull base.
Local tumor control, patient survival, and treatment failure outcomes were analyzed to assess treatment efficacy in 58 patients in whom fractionated proton radiation therapy (RT) was administered for skull base chordomas and chondrosarcomas. Between March 1992 and January 1998, a total of 58 patients who could be evaluated were treated for skull base tumors, 33 for chordoma and 25 for chondrosarcoma. Following various surgical procedures, residual tumor was detected in 91% of patients; 59% demonstrated brainstem involvement. Target dosages ranged from 64.8 and 79.2 (mean 70.7) Co Gy equivalent. The range of follow up was 7 to 75 months (mean 33 months). In 10 patients (17%) the treatment failed locally, resulting in local control rates of 92% (23 of 25 patients) for chondrosarcomas and 76% (25 of 33 patients) for chordomas. Tumor volume and brainstem involvement influenced control rates. All tumors with volumes of 25 ml or less remained locally controlled, compared with 56% of tumors larger than 25 ml (p = 0.02); 94% of patients without brainstem involvement did not experience recurrence; in patients with brainstem involvement (and dose reduction because of brainstem tolerance constraints) the authors achieved a tumor control rate of 53% (p = 0.04). Three patients died of their disease, and one died of intercurrent disease. Actuarial 5-year survival rates were 100% for patients with chondrosarcoma and 79% for patients with chordoma. Grade 3 and 4 late toxicities were observed in four patients (7%) and were symptomatic in three (5%). High-dose proton RT offers excellent chances of lasting tumor control and survival, with acceptable risks. In this series all small- and medium-sized tumors with no demonstrable brainstem involvement have been controlled; all such patients are alive. Surgical debulking enhanced delivery of full tumoricidal doses, but even patients with large tumors and disease abutting crucial normal structures benefited.


Dynamic hologram recording characteristics in DuPont photopolymers.
Hologram formation and diffusion reactions in photopolymer films are examined at different stages of exposure and at different spatial frequencies. Different properties of the grating formation process are evaluated from efficiency data, including the relative rates of diffusion and photoinitiated polymerization, dye absorption, and residual efficiency enhancement after UV curing. It was also found that gratings with larger periods (approximately 1.4 microm) are susceptible to erasure effects with postexposure laser illumination. In addition, crossed gratings were found to have an extended dynamic range. This effect can have a significant impact on the number of holograms formed with rotational or peristrophic multiplexing.


Correction: The BioRef Infrastructure, a Framework for Real-Time, Federated, Privacy-Preserving, and Personalized Reference Intervals: Design, Development, and Application.
[This corrects the article DOI: 10.2196/47254.].


One-Pot Formal Carboradiofluorination of Alkenes: A Toolkit for Positron Emission Tomography Imaging Probe Development.
We report the first one-pot formal alkene carboradiofluorination reaction employing easily accessible alkenes as both prosthetic group precursors and coupling partners. The methodology features rapid sequential Markovnikov-selective iodofluorination and photoinduced Pd(0/I/II)-catalyzed alkyl Heck reaction as a mild and robust fluorine-18 (18F) radiochemical approach for positron emission tomography (PET) imaging probe development. A new class of prosthetic groups for PET imaging probe synthesis was isolated as iodofluorinated intermediates in moderate to excellent yields. The one-pot formal alkenylfluorination reaction was carried out to produce over 30 analogues of a wide range of bioactive molecules. Further application of the Pd(0/I/II) manifold in PET probe development was illustrated by the direct carbo(radio)fluorination of electron-rich alkenes. The methods were successfully translated to radiolabel a broad scope of medicinally relevant small molecules in generally good radiochemical conversion. The protocol was further optimized to accommodate no-carrier-added conditions with similar efficiency for future (pre)clinical translation. Moreover, the radiosynthesis of prosthetic groups was automated in a radiochemistry module to facilitate its practical use in multistep radiochemical reactions.


The combination of four different clinical decision rules and an age-adjusted D-dimer cut-off increases the number of patients in whom acute pulmonary embolism can safely be excluded.
Four clinical decision rules (CDRs) (Wells score, Revised Geneva Score (RGS), simplified Wells score and simplified RGS) safely exclude pulmonary embolism (PE), when combined with a normal D-dimer test. Recently, an age-adjusted cut-off of the D-dimer (patient's age x 10 μg/l) safely increased the number of patients above 50 years in whom PE could safely be excluded. We validated the age-adjusted D-dimer test and assessed its performance in combination with the four CDRs in patients with suspected PE. A total of 414 consecutive patients with suspected PE who were older than 50 years were included. The proportion of patients in whom PE could be excluded with an 'unlikely' clinical probability combined with a normal age-adjusted D-dimer test was calculated and compared with the proportion using the conventional D-dimer cut-off. We assessed venous thromboembolism (VTE) failure rates during three months follow-up. In patients above 50 years, a normal age-adjusted D-dimer level in combination with an 'unlikely' CDR substantially increased the number of patients in whom PE could be safely excluded: from 13-14% to 19-22% in all CDRs similarly. In patients over 70 years, the number of exclusions was nearly four-fold higher, and the original Wells score excluded most patients, with an increase from 6% to 21% combined with the conventional and age-adjusted D-dimer cut-off, respectively. The number of VTE failures was also comparable in all CDRs. In conclusion, irrespective of which CDR is used, the age-adjusted D-dimer substantially increases the number of patients above 50 years in whom PE can be safely excluded.


MicroRNA-24 antagonism prevents renal ischemia reperfusion injury.
Ischemia-reperfusion (I/R) injury of the kidney is a major cause of AKI. MicroRNAs (miRs) are powerful regulators of various diseases. We investigated the role of apoptosis-associated miR-24 in renal I/R injury. miR-24 was upregulated in the kidney after I/R injury of mice and in patients after kidney transplantation. Cell-sorting experiments revealed a specific miR-24 enrichment in renal endothelial and tubular epithelial cells after I/R induction. In vitro, anoxia/hypoxia induced an enrichment of miR-24 in endothelial and tubular epithelial cells. Transient overexpression of miR-24 alone induced apoptosis and altered functional parameters in these cells, whereas silencing of miR-24 ameliorated apoptotic responses and rescued functional parameters in hypoxic conditions. miR-24 effects were mediated through regulation of H2A histone family, member X, and heme oxygenase 1, which were experimentally validated as direct miR-24 targets through luciferase reporter assays. In vitro, adenoviral overexpression of miR-24 targets lacking miR-24 binding sites along with miR-24 precursors rescued various functional parameters in endothelial and tubular epithelial cells. In vivo, silencing of miR-24 in mice before I/R injury resulted in a significant improvement in survival and kidney function, a reduction of apoptosis, improved histologic tubular epithelial injury, and less infiltration of inflammatory cells. miR-24 also regulated heme oxygenase 1 and H2A histone family, member X, in vivo. Overall, these results indicate miR-24 promotes renal ischemic injury by stimulating apoptosis in endothelial and tubular epithelial cell. Therefore, miR-24 inhibition may be a promising future therapeutic option in the treatment of patients with ischemic AKI.


The cutoff values of visceral fat area and waist circumference for identifying subjects at risk for metabolic syndrome in elderly Korean: Ansan Geriatric (AGE) cohort study.
In Korea, the cutoff values of waist circumference (WC) for the identification of metabolic syndrome (MetS) were suggested to be 90 cm for men and 85 cm for women based on the analysis mainly in middle-aged adults. As aging is associated with increased fat, especially abdominal visceral fat, the cutoff value of WC may differ according to age. In addition, the usefulness of visceral abdominal fat area (VFA) to predict MetS in the elderly has not been studied yet. We aimed to suggest WC and VFA criteria and to compare the predictability of WC and VFA to identify people at risk for MetS. A total of 689 elderly subjects aged>or=63 years (308 men, 381 women) were chosen in this cross-sectional study from an ongoing, prospective, population-based study, the Ansan Geriatric (AGE) cohort study. VFA was measured by single slice abdominal computed tomography scanning. The metabolic risk factors except WC (plasma glucose, blood pressure, serum triglycerides and HDL cholesterol levels) were defined using modified NCEP-ATP III criteria. We estimated the accuracy of VFA and WC for identifying at least two of these factors by receiver operating characteristic (ROC) curve analysis. Two hundred three of 308 men and 280 of 381 women had >or=2 metabolic risk factors. The area under the ROC curve (AUC) value for VFA to predict the presence of >or=2 metabolic risk factors was not significantly different from that for WC (men, 0.735 and 0.750; women, 0.715 and 0.682; AUC values for VFA and WC, respectively). The optimal cutoff points for VFA and WC for predicting the presence of >or=2 metabolic risk factors were 92.6 cm2 and 86.5 cm for men and 88.9 cm2 and 86.5 cm for women. WC had comparable power with VFA to identify elderly people who are at risk for MetS. Elderly Korean men and women had very similar cutoff points for both VFA and WC measurements for estimating the risk of MetS. Age-specific cutoff point for WC might be considered to identify subjects at risk for MetS.


A prospective study of parental history of myocardial infarction and coronary heart disease in women.
Among 121,964 women aged 30-55 years in 1976, 117,156 who were initially free from coronary heart disease provided information on a number of coronary risk factors including parental history of myocardial infarction and were followed prospectively. In 1976, 31,101 (26.5%) reported that at least one parent had suffered a myocardial infarction. Questionnaires in 1978 and 1980 identified women who had developed nonfatal myocardial infarction (n = 132) and angina pectoris (n = 101). Fatal coronary heart disease cases (n = 42) were ascertained by searches of state vital records. The age-adjusted relative risk of nonfatal myocardial infarction for women with a parental history of myocardial infarction less than or equal to 60 years of age compared with women with no family history was 2.8 (95% confidence limits (CL) 1.8, 4.3). For those with a parental history of myocardial infarction greater than 60 years of age, the age-adjusted relative risk of nonfatal myocardial infarction was 1.0 (CL 0.5, 1.8). The age-adjusted relative risks of fatal coronary heart disease were 5.0 (CL 2.7, 9.2) for parental history before age 61 and 2.6 (CL 1.1, 5.8) for parental history after age 60. The corresponding relative risks of angina pectoris were 3.4 (CL 2.2, 5.2) and 1.9 (CL 1.2, 3.2), respectively. These associations were only slightly altered by adjustment for history of hypertension, diabetes, high cholesterol, use of oral contraceptives, menopause, postmenopausal hormone use, obesity, or smoking, in individual stratified analysis or in multivariate analyses. These data support the hypothesis that parental history of myocardial infarction has an independent effect on risk that is not explained solely by individual risk factors.


One week of continuous corticosterone exposure impairs hepatic metabolic flexibility, promotes islet β-cell proliferation, and reduces physical activity in male C57BL/6 J mice.
Clinical glucocorticoid use, and diseases that produce elevated circulating glucocorticoids, promote drastic changes in body composition and reduction in whole body insulin sensitivity. Because steroid-induced diabetes is the most common form of drug-induced hyperglycemia, we investigated mechanisms underlying the recognized phenotypes associated with glucocorticoid excess. Male C57BL/6 J mice were exposed to either 100ug/mL corticosterone (cort) or vehicle in their drinking water. Body composition measurements revealed an increase in fat mass with drastically reduced lean mass during the first week (i.e., seven days) of cort exposure. Relative to the vehicle control group, mice receiving cort had a significant reduction in insulin sensitivity (measured by insulin tolerance test) five days after drug intervention. The increase in insulin resistance significantly correlated with an increase in the number of Ki-67 positive β-cells. Moreover, the ability to switch between fuel sources in liver tissue homogenate substrate oxidation assays revealed reduced metabolic flexibility. Furthermore, metabolomics analyses revealed a decrease in liver glycolytic metabolites, suggesting reduced glucose utilization, a finding consistent with onset of systemic insulin resistance. Physical activity was reduced, while respiratory quotient was increased, in mice receiving corticosterone. The majority of metabolic changes were reversed upon cessation of the drug regimen. Collectively, we conclude that changes in body composition and tissue level substrate metabolism are key components influencing the reductions in whole body insulin sensitivity observed during glucocorticoid administration.


Social motor coordination in unaffected relatives of schizophrenia patients: a potential intermediate phenotype.
Intermediate endophenotypes emerge as an important concept in the study of schizophrenia. Although research on phenotypes mainly investigated cognitive, metabolic or neurophysiological markers so far, some authors also examined the motor behavior anomalies as a potential trait-marker of the disease. However, no research has investigated social motor coordination despite the possible importance of its anomalies in schizophrenia. The aim of this study was thus to determine whether coordination modifications previously demonstrated in schizophrenia are trait-markers that might be associated with the risk for this pathology. Interpersonal motor coordination in 27 unaffected first-degree relatives of schizophrenia patients and 27 healthy controls was assessed using a hand-held pendulum task to examine the presence of interpersonal coordination impairments in individuals at risk for the disorder. Measures of neurologic soft signs, clinical variables and neurocognitive functions were collected to assess the cognitive and clinical correlates of social coordination impairments in at-risk relatives. After controlling for potential confounding variables, unaffected relatives of schizophrenia patients had impaired intentional interpersonal coordination compared to healthy controls while unintentional interpersonal coordination was preserved. More specifically, in intentional coordination, the unaffected relatives of schizophrenia patients exhibited coordination patterns that had greater variability and in which relatives did not lead the coordination. These results show that unaffected relatives of schizophrenia patients, like the patients themselves, also present deficits in intentional interpersonal coordination. For the first time, these results suggest that intentional interpersonal coordination impairments might be a potential motor intermediate endophenotype of schizophrenia opening new perspectives for early diagnosis.


Injury reporting via SMS text messaging in community sport.
The use of text messaging or short message service (SMS) for injury reporting is a recent innovation in sport and has not yet been trialled at the community level. Considering the lack of personnel and resources in community sport, SMS may represent a viable option for ongoing injury surveillance. The aim of this study was to evaluate the feasibility of injury self-reporting via SMS in community Australian football. A total of 4 clubs were randomly selected from a possible 22 men's community Australian football clubs. Consenting players received an SMS after each football round game asking whether they had been injured in the preceding week. Outcome variables included the number of SMS-reported injuries, players' response rates and response time. Poisson regression was used to evaluate any change in response rate over the season and the association between response rate and the number of reported injuries. The sample of 139 football players reported 167 injuries via SMS over the course of the season. The total response rate ranged from 90% to 98%. Of those participants who replied on the same day, 47% replied within 5 min. The number of reported injuries decreased as the season progressed but this was not significantly associated with a change in the response rate. The number of injuries reported via SMS was consistent with previous studies in community Australian football. Injury reporting via SMS yielded a high response rate and fast response time and should be considered a viable injury reporting method for community sports settings.


The action of tumor necrosis factor-alpha on rat mast cells.
Taking into account that cytokine tumor necrosis factor-alpha (TNF-alpha) and mast cells (MC) both are involved in inflammation, it seems of great importance to recognize their relationships. Therefore, we have studied whether recombinant human TNF-alpha (rHuTNF-alpha) can cause histamine secretion from rat peritoneal MC. We have also examined the effect of this cytokine on MC reactivity. We have established that TNF-alpha stimulates rat MC to histamine release in a concentration-dependent manner. TNF-alpha-induced histamine secretion was evoked by concentrations > 10-16 M and reached the maximum rate at a concentration of 10-10 M (histamine release 17.1% +/- 1.9%, mean +/- SEM). We have also noticed that pretreatment of MC with TNF-alpha (in a concentration of 10-16 M) significantly inhibited concanavalin A (ConA)-stimulated release of histamine, with the percent release decreasing to 51% of the control value. Treatment of mast cells with TNF-alpha resulted in a decrease of compound 48/80-dependent histamine release as well (the percent released histamine fell to 85% of the control value). This altered MC responsiveness was reversible. After 120 min of resting time, the MC reactivity came back to the initial values. We have concluded that TNF-alpha appears to be a direct stimulus for MC to release histamine, and it may regulate MC secretory function.


Natural Selection Drives Rapid Functional Evolution of Young Drosophila Duplicate Genes.
Gene duplication is thought to play a major role in phenotypic evolution. Yet the forces involved in the functional divergence of young duplicate genes remain unclear. Here, we use population-genetic inference to elucidate the role of natural selection in the functional evolution of young duplicate genes in Drosophila melanogaster. We find that negative selection acts on young duplicates with ancestral functions, and positive selection on those with novel functions, suggesting that natural selection may determine whether and how young duplicate genes are retained. Moreover, evidence of natural selection is strongest in protein-coding regions and 3' UTRs of young duplicates, indicating that selection may primarily target encoded proteins and regulatory sequences specific to 3' UTRs. Further analysis reveals that natural selection acts immediately after duplication and weakens over time, possibly explaining the observed bias toward the acquisition of new functions by young, rather than old, duplicate gene copies. Last, we find an enrichment of testis-related functions in young duplicates that underwent recent positive selection, but not in young duplicates that did not undergo recent positive selection, or in old duplicates that either did or did not undergo recent positive selection. Thus, our findings reveal that natural selection is a key player in the functional evolution of young duplicate genes, acts rapidly and in a region-specific manner, and may underlie the origin of novel testis-specific phenotypes in Drosophila.


Preventing adhesion of Escherichia coli O157:H7 and Salmonella Typhimurium LT2 on tomato surfaces via ultrathin polyethylene glycol film.
This work deals with adhesion of Escherichia coli O157:H7 and Salmonella enterica subsp. enterica serovar Typhimurium LT2 (S. Typhimurium LT2) on polyethylene glycol (PEG) coated tomato surfaces. PEG coating was characterized by water contact angle technique, scanning electron microscopy, and secondary ion mass spectrometry. It was shown that PEG films could physisorb on the tomato surfaces after the oxygen plasma treatment, which made some outermost layers of the surfaces hydrophilic. Bacterial adhesion on PEG coated tomato surface was studied by standard plate count, fluorescence microscopy, and scanning electron microscopy techniques. Fully covered PEG film reduced the bacterial attachment 90% or more in comparison to the bare tomato surface. The degree of bacterial attachment decreased exponentially with increasing PEG coverage. When desired, PEG film could be removed by rinsing with water. Overall, this work demonstrates the proof-of-concept that an ultrathin film of polyethylene glycol may be used to effectively inhibit the attachment of pathogenic bacteria on tomato surfaces.


Maternal use of alcohol during pregnancy is a risky lifestyle.
Alcohol is a well known teratogen. Its role in causing fetal alcohol syndrome/fetal alcohol effects is well documented. A vast amount of study over the past several decades has finally provided insight into many aspects of its effect. The only effective treatment is complete abstinence from the drug during pregnancy.


Exploiting sequence to control the hydrolysis behavior of biodegradable PLGA copolymers.
Monomer sequence is a potentially powerful but underutilized tool for the control of copolymer properties. Sequence is demonstrated to dramatically affect the hydrolysis profile for the degradation of poly(lactic-co-glycolic acid) (PLGA), a member of the most widely used class of biodegradable polymers employed in biomedical applications. The nearly linear molecular weight loss profile and uniform thermal behavior throughout the course of the hydrolysis differ dramatically from the behavior that is exhibited by random copolymer controls with the same comonomer ratio.


Staff nurse perceptions of health care system changes & nursing management models on client outcomes.
This investigation reports the results of a national survey of staff nurse perceptions of changes in the health care system and nursing management models on client outcomes.


Spherical connective tissue inclusions in epithelial hyperplasia of the breast ("collagenous spherulosis").
Partial myoepithelial differentiation is common in simple epithelial hyperplasia (epitheliosis) of the breast but functional myoepithelial differentiation with basement membrane production is exceedingly rare. A peculiar change of hyaline globules within benign epithelial hyperplasia has been recognised before as "collagenous spherulosis" and type IV collagen has been shown by immunohistochemistry. Another seven cases are described which show the presence of laminin and collagens IV and III within the proliferation. Electron microscopy examination of two cases using material retrieved from the wax block showed varying degrees of myoepithelial differentiation of the cells immediately surrounding the spherules and basal lamina material, including mature collagen fibrils in one case. The degree of myoepithelial differentiation of the cells surrounding the spherules seemed to correlate with the differing types and amounts of extracellular matrix in the spherule. Histopathologists should be aware of this rare change as it may be misinterpreted as in situ carcinoma.


Awareness and Knowledge of Ovarian Cancer Symptoms and Risk Factors: A Survey of Jordanian Women.
Ovarian cancer accounts for 3% of all female cancers and has a high mortality rate among gynecological malignancies. Early diagnosis carries a high survival rate of 93%. So, this study was carried out to assess the knowledge and awareness of Jordanian women about ovarian cancer symptoms and risk factors. A cross-sectional survey design was used; 896 women completed the survey. The mean of total symptoms recognized was low at level of 3.2 ( SD = 2.7) out of 10. The three highest known symptoms among women were as follows: extreme fatigue (43.2%), back pain (42.4%), and persistent pain in pelvic area (40.7%). The most commonly known risk factor was smoking (68.4%), followed by having ovarian cyst(s) (59.7%). Hence, with the absence of an effective screening program, a national awareness campaign is urgently needed to improve the public's understanding of symptoms and risk factors and increasing women's confidence in symptom recognition.


One-year treatment with exenatide vs. insulin glargine: effects on postprandial glycemia, lipid profiles, and oxidative stress.
The objective of the present study was to investigate the effects of one-year treatment with exenatide or Insulin Glargine, followed by a 5-week off-drug period, on postprandial lipidaemia, glycaemia and measures of oxidative stress. Sixty-nine metformin-treated patients with type 2 diabetes were randomised (using apermuted block randomisation scheme stratified by site and baseline HbA(1c) stratum (< or = 8.5% or >8.5%) of which 60 completed (exenatide n=30; Insulin Glargine n=30) the pre-treatment and on-drug meal test. Postprandial glucose, lipids and lipoproteins, and oxidative stress markers were studied at week -1, 51, and after a 5-week off-drug period following a breakfast and lunch mixed-meal containing 50 g fat, 75 g carbohydrates, and 35 g protein. 51-Week exenatide treatment resulted in a significant reduction of prandial glucose, triglycerides, apo-B48, calculated VLDL-C, FFA and MDA excursions whereas Insulin Glargine predominantly reduced fasting glucose, FFA and MDA. Changes in markers of oxidative stress were related to changes in postprandial glucose and triglyceride excursions, independent of treatment arm. All postprandial measures returned to pre-treatment values in both groups after 5-week cessation of study treatment. Exenatide showed beneficial effects on postprandial glycaemia and lipidaemia, and these effects were related to changes in the oxidative stress markers MDA and oxLDL during one year of treatment as compared to Insulin Glargine. Following cessation of both exenatide and Insulin Glargine measures returned to pre-treatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.


Sedation Practice in Extracorporeal Membrane Oxygenation-Treated Patients with Acute Respiratory Distress Syndrome: A Retrospective Study.
Our objective was to characterize sedation management in adult patients with severe respiratory distress syndrome (ARDS) treated with venovenous extracorporeal membrane oxygenation (VV-ECMO). We conducted a retrospective chart review of these patients treated at Toronto General Hospital between January 2012 and October 2015. Medications administered (sedative, analgesic, paralytic, and antipsychotic), sedation depth (Sedation Agitation Scale [SAS] score) delirium assessments, and mobilization were recorded daily. Forty-five adults (33 males, median age 47 years; interquartile range [IQR], 35-56]) with ARDS (median PaO2/FiO2 71; IQR 59-83) because of respiratory infection (91%) were treated with VV-ECMO for a median of 11 days (IQR, 7-17). After ECMO initiation, 96% patients were deeply sedated (SAS score < 3) with continuous infusions of midazolam (49%), propofol (18%), or both (29%) and 98% were receiving opioid infusions (93% fentanyl). Patients were deeply sedated for a median of 6 days (IQR, 3-10) after cannulation before transitioning to intermediate or light sedation (SAS score ≥ 3). Before ECMO discontinuation, 77% of surviving patients were intermediately or lightly sedated, 20% were receiving no sedatives, and 9% were receiving no opioids. During ECMO, 58% had positive delirium assessment and 24% experienced agitation (SAS ≥ 6). During ECMO support, 71% received physical therapy that occurred after a median of 7 days (IQR, 4-12) after cannulation. In conclusion, we found that although patients were deeply sedated for a prolonged duration after VV-ECMO initiation, many were able to safely achieve light sedation and active mobilization.


Structural and biochemical alterations in dendritic spines as key mechanisms for severe mental illnesses.
Severe mental illnesses (SMI) collectively affect approximately 20% of the global population, as estimated by the World Health Organization (WHO). Despite having diverse etiologies, clinical symptoms, and pharmacotherapies, these diseases share a common pathophysiological characteristic: the misconnection of brain areas involved in reality perception, executive control, and cognition, including the corticolimbic system. Dendritic spines play a crucial role in excitatory neurotransmission within the central nervous system. These small structures exhibit remarkable plasticity, regulated by factors such as neurotransmitter tone, neurotrophic factors, and innate immunity-related molecules, and other mechanisms - all of which are associated with the pathophysiology of SMI. However, studying dendritic spine mechanisms in both healthy and pathological conditions in patients is fraught with technical limitations. This is where animal models related to these diseases become indispensable. They have played a pivotal role in elucidating the significance of dendritic spines in SMI. In this review, the information regarding the potential role of dendritic spines in SMI was summarized, drawing from clinical and animal model reports. Also, the implications of targeting dendritic spine-related molecules for SMI treatment were explored. Specifically, our focus is on major depressive disorder and the neurodevelopmental disorders schizophrenia and autism spectrum disorder. Abundant clinical and basic research has studied the functional and structural plasticity of dendritic spines in these diseases, along with potential pharmacological targets that modulate the dynamics of these structures. These targets may be associated with the clinical efficacy of the pharmacotherapy.


Push for Center Learning via Orthogonalization and Subspace Masking for Person Re-Identification.
Person re-identification aims to identify whether pairs of images belong to the same person or not. This problem is challenging due to large differences in camera views, lighting and background. One of the mainstream in learning CNN features is to design loss functions which reinforce both the class separation and intra-class compactness. In this paper, we propose a novel Orthogonal Center Learning method with Subspace Masking for person re-identification. We make the following contributions: 1) we develop a center learning module to learn the class centers by simultaneously reducing the intra-class differences and inter-class correlations by orthogonalization; 2) we introduce a subspace masking mechanism to enhance the generalization of the learned class centers; and 3) we propose to integrate the average pooling and max pooling in a regularizing manner that fully exploits their powers. Extensive experiments show that our proposed method consistently outperforms the state-of-the-art methods on large-scale ReID datasets including Market-1501, DukeMTMC-ReID, CUHK03 and MSMT17.


Improving performance in a contracted physician network.
Health care organizations face significant performance challenges. Achieving desired results requires the highest level of partnership with independent physicians. Tufts Health Plan invited medical directors of its affiliated groups to participate in a leadership development process to improve clinical, service, and business performance. The design included performance review, gap analysis, priority setting, improvement work plans, and defining the optimum practice culture. Medical directors practiced core leadership capabilities, including building a shared context, getting physician buy-in, and managing outliers. The peer learning environment has been sustained in redesigned medical directors' meetings. There has been significant performance improvement in several practices and enhanced relations between the health plan and medical directors.


Postoperative radiotherapy in prostate cancer: Analysis of prognostic factors in a series of 282 patients.
To assess the outcomes of patients treated with postoperative RT in relation to the possible prognostic factors. Postoperative radiotherapy (RT) has been proved to reduce the risk of biochemical recurrence in high-risk prostate cancer patients. Baseline prostate specific antigen (PSA), pathological Gleason score (GS), positive surgical margins, nodal status and seminal vesicle invasion are independent predictors of biochemical relapse. The clinical records of 282 patients who underwent postoperative RT were retrospectively reviewed. The prognostic value of postoperative PSA, preoperative risk class, nodal status, pathological GS, margins status, and administration of hormonal therapy (HT) was analyzed. Postoperative RT was delivered with a median dose to the prostatic fossa of 66 Gy (range 50-72) in 1.8-2 Gy/fraction. Median follow-up was 23.1 months (range 6-119). Five-year actuarial biochemical disease-free survival (bDFS) and overall survival rates were 76% and 95%, respectively. Higher bDFS was found for patients with postoperative PSA <0.02 ng/ml (p = 0.03), low preoperative risk class (p = 0.01), pN0 (p = 0.003), GS 4-6 (p = 0.0006), no androgen deprivation therapy (p = 0.02), and irrespective of surgical margin status (p = 0.10). Multivariate analysis showed that postoperative PSA and Gleason score had a significant impact on bDFS (p = 0.039 and p = 0.05, respectively). Postoperative RT with a dose of 66 Gy offers an acceptable toxicity and an optimal disease control after radical prostatectomy in patients with different risk features. A postoperative PSA >0.02 ng/ml could be considered as a prognostic factor and a tool to select patients at risk for progression.


Adaptive evolution in rodent seminal vesicle secretion proteins.
Proteins involved in reproductive fitness have evolved unusually rapidly across diverse groups of organisms. These reproductive proteins show unusually high rates of amino acid substitutions, suggesting that the proteins have been subject to positive selection. We sought to identify seminal fluid proteins experiencing adaptive evolution because such proteins are often involved in sperm competition, host immunity to pathogens, and manipulation of female reproductive physiology and behavior. We performed an evolutionary screen of the mouse prostate transcriptome for genes with elevated evolutionary rates between mouse and rat. We observed that secreted rodent prostate proteins evolve approximately twice as fast as nonsecreted proteins, remarkably similar to findings in the primate prostate and in the Drosophila male accessory gland. Our screen led us to identify and characterize a group of seminal vesicle secretion (Svs) proteins and to show that the gene Svs7 is evolving very rapidly, with many amino acid sites under positive selection. Another gene in this group, Svs5, showed evidence of branch-specific selection in the rat. We also found that Svs7 is under selection in primates and, by using three-dimensional models, demonstrated that the same regions have been under selection in both groups. Svs7 has been identified as mouse caltrin, a protein involved in sperm capacitation, the process responsible for the timing of changes in sperm activity and behavior, following ejaculation. We propose that the most likely explanation of the adaptive evolution of Svs7 that we have observed in rodents and primates stems from an important function in sperm competition.


Role of transcription factors Ad4bp/SF-1 and DAX-1 in steroidogenesis and spermatogenesis in human testicular development and idiopathic azoospermia.
Ad4bp/SF-1 and DAX-1 are orphan members of the nuclear hormone receptor superfamily of transcription factors. In order to obtain better understandings of human testicular steroidogenesis and spermatogenesis, we examined the expression levels of both factors in human normal and idiopathic azoospermic testes and investigated their physical meaning. First, we examined the expression level of Ad4bp/SF-1 and DAX-1 by quantitative reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry and western blotting analysis using eight normal human testicular tissues from infants to adults. Second, we performed quantitative RT-PCR using testicular biopsy samples obtained from 22 idiopathic azoospermic patients to examine the expression of Ad4bp/SF-1 and DAX-1, and analysed the correlation between the expression levels of both factors and the serum hormone levels or histological evaluation to study their potential correlation with steroidogenesis and spermatogenesis on idiopathic azoospermia. The expression levels of both factors in the normal testes increased with testicular development. Ad4bp/SF-1 was abundantly expressed in Leydig cell, whereas DAX-1 was expressed in Sertoli cells. The expression level of Ad4bp/SF-1 in idiopathic azoospermic patients testes positively correlated with serum testosterone (P < 0.05). The average expression levels of DAX-1 mRNA for patients with maturation arrest (0.39 +/- 0.19) and Sertoli cell-only syndrome (0.13 +/- 0.08) were lower than that with hypospermatogenesis (1.60 +/- 1.32) and normal spermatogenesis (1.30 +/- 1.41). Ad4bp/SF-1 is important for the maintenance of steroidogenesis in the human testis. DAX-1 plays a critical role in spermatogenesis in the human testis, and Sertoli cell-only syndrome and maturation arrest may result from abnormal Sertoli cell function that disrupts the normal progression of spermatogenesis.


Investigation of Within-Tablet Dynamics for Extended Release of a Poorly Soluble Basic Drug from Hydrophilic Matrix Tablets Using ATR-FTIR Imaging.
Hydrophilic matrices are an effective option for oral controlled release but can face challenges in terms of bioavailability and efficacy when used in conjunction with poorly soluble, weakly basic drugs. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) imaging provides dynamic information relating to the location and chemical nature of both the sustained release matrix and the active pharmaceutical ingredient (API) during hydration/dissolution. In this study, we have identified a model system combining itraconazole (IT), a poorly soluble, weakly basic API that has pKa in the physiological range, and hydroxypropyl methylcellulose, which is a commonly used oral tablet matrix. This system was investigated to determine the swelling kinetics at different pH values at a fixed ionic strength and to facilitate the study of the influence of hydrating media pH on the drug particle movement (translocation). Using ATR-FTIR imaging, we were able to show that gel layer formation and swelling were independent of pH but highly dependent on the ionic strength of the hydrating medium in placebo tablets. When the ionic strength was fixed, gel layer formation and radial swelling were both shown to be pH-dependent when IT was incorporated into the matrix. This was verified using optical imaging. The chemical specificity of ATR-FTIR imaging permitted the observation of transformational changes of IT from the free base to the ionized form in the tablet core during hydration. This phenomenon was shown to be greater at pH 1.5 than at pH 7. ATR-FTIR imaging was able to follow drug particle translocation at both pH 1.5 and pH 7; however, the extent of migration away from the tablet core was shown to be greater at lower pH. The location of the translocated particles within the gel layer was different between the two studied pH values, with particles being located close to the swelling front at pH 7 and within the diffusion front at pH 1.5. In both pH environments, the translocated IT particles were shown to be predominantly in the free base form. No evidence of fully solubilized IT was observed in the surrounding medium because of the inherent aqueous solubility of IT being below the instrument detection limits. This work highlighted the value of utilizing a chemically specific spectroscopic tool to increase the understanding of the nature of the factors affecting the release of a pH-dependent, poorly soluble drug from a hydrophilic matrix at different pH values and permitted greater insights into what happens inside the polymer matrix during drug release.


Diagnosis and treatment of prostate cancer in renal-transplant recipients.
The incidence and treatment of prostate cancer in male renal-transplant patients has not been extensively evaluated. With the aging of the renal-transplant population, the diagnosis and management of prostate cancer in these patients needs further evaluation. In this study, we conducted a retrospective review of data from 498 male renal-transplant patients to evaluate the prevalence, treatment, and outcome of prostate cancer in this population. Of the 498 male renal-transplant patients, nine were diagnosed with prostate cancer. A prostate specific antigen (PSA) screening program was not utilized, and these patients were diagnosed based on a prostate digital rectal examination and/or elevated PSA. The median age at transplantation was 55 years, and the median age at the diagnosis of prostate cancer was 63.6 years. One patient was treated with androgen ablation alone, four patients were with radiation alone, and four patients were treated with a combination of androgen ablation and external radiation. Twelve skin malignancies occurred in five of the patients with prostate cancer. Our patient population was preferentially treated with radiation therapy rather than radical prostatectomy. Seven of these treated patients are currently being followed and have good control of the disease. Two of the seven patients are on dialysis because of chronic allograft nephropathy. One patient was lost to follow-up, and one died with extensive metastasis, paraplegia, and renal failure. The incidence of diagnosed prostate cancer in patients with renal transplant will increase because of systematic PSA screening. The recommended current treatment modality depends on the Gleason grade, stage, PSA levels, and associated comorbid conditions. A combination of radiation treatment with androgen ablation provides good control of the disease while preserving renal function.


Bilateral autogenous breast reconstruction using perforator free flaps: a single center's experience.
The authors present a single center's experience in bilateral breast reconstruction using perforator free flaps. The aim of this study was to show their indications, surgical technique, and results. A series of 53 patients underwent this procedure between February of 1996 and October of 2002. The surgical procedures were performed on patients with bilateral breast cancer (11 patients), patients with unilateral breast cancer and contralateral prophylactic mastectomy (22 patients), patients who had undergone bilateral prophylactic mastectomy (18 patients), a patient with Poland's syndrome, and a patient whose aesthetic breast augmentation had failed. Primary and secondary bilateral breast reconstructions were done in 18 and four patients, respectively. Eighteen patients who had earlier undergone breast reconstruction with implants had a tertiary breast reconstruction. Combined reconstruction (primary with secondary and primary with tertiary reconstruction) was done in 13 patients. Ninety-eight deep inferior epigastric perforator flaps and eight superior gluteal artery perforator flaps were used. The average operative time was 10 hours (range, 8 to 14.5 hours) for the simultaneous bilateral reconstruction. Total flap necrosis occurred in two cases (one deep inferior epigastric perforator flap and one superior gluteal artery perforator flap). Partial flap necrosis was not encountered, and fat necrosis was found in one deep inferior epigastric perforator flap (1 percent). Two pulmonary infections, one deep vein thrombosis, and one cardiac arrhythmia occurred as postoperative complications. The mean hospital stay was 9 days (range, 6 to 20 days). Abdominal bulging was reported in one patient. There were no recurrent disease or cancer manifestations, with an average follow-up of 3.5 years. This series clearly shows that perforator flaps are reliable and useful tools for bilateral breast reconstruction. This technique decreases the donor-site morbidity and offers an excellent aesthetic and long-term outcome and high patient satisfaction.


Limits for oxygen and substrate transport in mammals.
Environmental oxygen is transported by the respiratory cascade to the site of oxidation in active tissues. Under conditions of heavy exercise, it is ultimately the working skeletal muscle cells that set the aerobic demand because over 90 % of energy is spent in muscle cells. The pathways for oxygen and substrates converge in muscle mitochondria. In mammals, a structural limitation of carbohydrate and lipid transfer from the microvascular system to the muscle cells is reached at a moderate work intensity (i.e. at 40-50 % of VO2max). At higher work rates, intracellular substrate stores must be used for oxidation. Because of the importance of these intracellular stores for aerobic work, we find larger intramyocellular substrate stores in 'athletic' species as well as in endurance-trained human athletes. The transfer limitations for carbohydrates and lipids at the level of the sarcolemma imply that the design of the respiratory cascade from lungs to muscle mitochondria reflects primarily oxygen demand. Comparative studies indicate that the oxidative capacity of skeletal muscle tissue, and hence maximal oxygen demand, is adjusted by varying mitochondrial content. At the level of microcirculatory oxygen supply, it is found that muscle tissue capillarity is adjusted to muscle oxygen demand but that the capillary erythrocyte volume also plays a role. Oxygen delivery by the heart has long been recognized to be a key link in the oxygen transport chain. In allometric variation it is heart rate and in adaptive variation it is essentially stroke volume, and hence heart size, that determines maximal cardiac output. Again, haematocrit is an important variable that allows the heart of athletic species to generate higher flux rates for oxygen. The pulmonary gas exchanger offers only a negligible resistance to oxygen flux to the periphery. However, in contrast to all other steps in the respiratory cascade, the lungs have only a minimal phenotypical plasticity and appear, therefore, to be built with considerable structural redundancy in all but the most athletic species. Because of the lack of malleability, the lungs may ultimately become limiting for VO2max when adaptive processes have maximized O2 flux through the malleable downstream elements of the respiratory system: the heart, microcirculation and muscle mitochondria.


Peroxide-mediated chromatin remodelling of a nuclear factor kappa B site in the mouse inducible nitric oxide synthase promoter.
Hepatocyte expression of iNOS (inducible nitric oxide synthase) and synthesis of nitric oxide convey protective antioxidant functions in models of sepsis, shock and reperfusion. However, the underlying redox-sensitive mechanisms that regulate hepatocyte expression of iNOS and its antioxidant functions are largely unknown. Activity of the transcription factor NF-kappaB (nuclear factor kappaB) is known to be redox-modulated. In this regard, the mouse hepatocyte iNOS promoter has NF-kappaB-binding sites at nt -1044 to -1034 and at nt -114 to -104, which are considered to be critical for iNOS expression in response to pro-inflammatory cytokine stimulation. The relative contribution of these two NF-kappaB-binding sites in the mouse iNOS promoter to hepatocyte iNOS promoter activity in the context of oxidative stress has not been characterized previously. In addition, although the cis - and trans -regulatory factors controlling mouse hepatocyte iNOS expression have been well-characterized, the local changes in chromatin structure that accompany activation of iNOS gene transcription have not been considered. In the present study, we demonstrate that (1) in the absence of exogenous oxidative stress, the NF-kappaB site at nt -114 is inactive and (2) peroxide-mediated oxidative stress induces hyperacetylation and enhanced accessibility of the restriction enzyme to this NF-kappaB region. Our results suggest that chromatin structural changes activate this NF-kappaB site and increase interleukin-1beta-stimulated iNOS expression in the presence of oxidative stress.


A clinical and radiographic comparison of two hardware systems used to treat jones fracture of the fifth metatarsal.
There is a broad variation in the type and size of screws used for Jones fractures. Therefore, a screw implant specifically designed for the operative treatment of a Jones fracture has been developed. The purpose of this retrospective study was to compare the clinical and radiographic results of patients treated with a screw specifically designed for this fracture to a group treated with a traditional screw. Forty-seven patients underwent surgery (47 feet) for a Jones fracture between 1999 and 2007, performed by 4 foot and ankle fellowship-trained orthopaedic surgeons at one institution. Twenty-six patients (26 feet) were treated with the indication-specific screw (group I), while 21 patients (21 feet) were operated on with the traditional screw (group II). All patients were retrospectively reviewed for either radiographic signs of union or an adverse event. Radiographic parameters were evaluated by 2 independent observers, which included Torg's classification system (intramedullary sclerosis, cortical hypertrophy, periosteal reaction), hardware failure, with an endpoint of healing or nonunion. Of 47 patients, 40 were available for clinical follow-up, and functional outcomes with VAS pain scores at final follow-up visit were compared. Additional procedures (bone grafting), complications, and adverse events were recorded. The results were analyzed using Fisher's exact tests and independent t test with a significance level of .05. The average age of the patients was 43.8 years, with a mean clinical follow-up of 37 months (range of 6 to 105 months). Preoperative films were classified according to the Torg classification system and did not demonstrate any difference between group I and group II, with respect to the type of Jones fracture. There was no significant difference found between the 2 groups as related to fracture union, but there was a higher number of adverse events in group II as compared with group I (P = .03). The adverse events included 2 implant failures, 1 intraoperative fracture, and 1 symptomatic hardware, all requiring further surgical interventions. All adverse events occurred within an average of 2 months after surgery. Clinically, there were no statistically significant differences between the 2 systems in regard to limitations in activity, shoe-wear modifications, recovery time, satisfaction, and willingness to repeat the surgery. The VAS pain scales (0-100) were equivalent; average VAS pain of group II was reported as 9 (range, 0-33), as compared to the VAS pain of patients in group I averaging 11 (range, 0-47). In our retrospective series, comparing 2 differing instrumentation systems in treating Jones fractures, both groups were found to progress to radiographic union above 95%. Although there was a statistically greater number of adverse events in the traditional hardware system (group II), clinically both groups had similar outcomes with good results. Level III, retrospective comparative series.


Avosentan for overt diabetic nephropathy.
In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.


Hyperpolarized [1-13 C] pyruvate as a possible diagnostic tool in liver disease.
Introduction of hyperpolarized magnetic resonance in preclinical studies and lately translation to patients provides new detailed in vivo information of metabolic flux in organs. Hyperpolarized magnetic resonance based on 13 C enriched pyruvate is performed without ionizing radiation and allows quantification of the pyruvate conversion products: alanine, lactate and bicarbonate in real time. Thus, this methodology has a promising potential for in vivo monitoring of energetic alterations in hepatic diseases. Using 13 C pyruvate, we investigated the metabolism in the porcine liver before and after intravenous injection of glucose. The overall mean lactate to pyruvate ratio increased significantly after the injection of glucose whereas the bicarbonate to pyruvate ratio was unaffected, representative of the levels of pyruvate entering the tricarboxylic acid cycle. Similarly, alanine to pyruvate ratio did not change. The increased lactate to pyruvate ratio over time showed an exponential correlation with insulin, glucagon and free fatty acids. Together, these data, obtained by hyperpolarized 13 C magnetic resonance spectroscopy and by blood sampling, indicate a hepatic metabolic shift in glucose utilization following a glucose challenge. Our findings demonstrate the capacity of hyperpolarized 13 C magnetic resonance spectroscopy for quantifying hepatic substrate metabolism in accordance with well-known physiological processes. When combined with concentration of blood insulin, glucagon and free fatty acids in the blood, the results indicate the potential of hyperpolarized magnetic resonance spectroscopy as a future clinical method for quantification of hepatic substrate metabolism.


Optical Sensors for Bacterial Detection.
Analytical devices for bacterial detection are an integral part of modern laboratory medicine, as they permit the early diagnosis of diseases and their timely treatment. Therefore, special attention is directed to the development of and improvements in monitoring and diagnostic methods, including biosensor-based ones. A promising direction in the development of bacterial detection methods is optical sensor systems based on colorimetric and fluorescence techniques, the surface plasmon resonance, and the measurement of orientational effects. This review shows the detecting capabilities of these systems and the promise of electro-optical analysis for bacterial detection. It also discusses the advantages and disadvantages of optical sensor systems and the prospects for their further improvement.


Risks and opportunities for plastic surgeons in a widening cosmetic medicine market: future demand, consumer preferences, and trends in practitioners' services.
The American Society of Plastic Surgeons and the American Society for Aesthetic Plastic Surgery launched a joint Cosmetic Medicine Task Force to address the growing trend of non-plastic surgeons entering the cosmetic medicine field. The task force commissioned two surveys in 2007 to determine consumer attitudes about choosing cosmetic medicine providers and to learn about the cosmetic services that plastic surgeons offer. The first survey obtained responses from 1015 women who had undergone a cosmetic procedure or were considering having one within 2 years. The second survey obtained responses from 260 members of the two societies. Compared with other practitioners, plastic surgeons enjoy higher rates of satisfaction among their patients who undergo noninvasive procedures. Injectables present a particularly promising market for plastic surgeons. Half of consumers surveyed said they were very concerned about complications associated with injectables, and generally, the higher the perceived risk of the procedure, the higher the likelihood that a patient would choose a plastic surgeon to perform it. In addition, injectables were among the noninvasive treatments most frequently being considered by consumers. However, almost half of consumers said that if they had a positive experience with a non-plastic surgeon core provider for a noninvasive procedure, that physician would likely be their first choice for a surgical procedure. These findings suggest that plastic surgeons, and especially those who are building young practices, must expand their offerings of nonsurgical cosmetic services to remain at the core of the cosmetic medicine field.


The prevalence of caries and tooth loss among participants in the Hispanic Community Health Study/Study of Latinos.
The Hispanic and Latino population is projected to increase from 16.7 percent to 30.0 percent by 2050. Previous U.S. national surveys had minimal representation of Hispanic and Latino participants other than Mexicans, despite evidence suggesting that Hispanic or Latino country of origin and degree of acculturation influence health outcomes in this population. In this article, the authors describe the prevalence and mean number of cavitated, decayed and filled surfaces, missing teeth and edentulism among Hispanics and Latinos of different national origins. Investigators in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)-a multicenter epidemiologic study funded by the National Heart, Lung, and Blood Institute with funds transferred from six other institutes, including the National Institute of Dental and Craniofacial Research-conducted in-person examinations and interviews with more than 16,000 participants aged 18 to 74 years in four U.S. cities between March 2008 and June 2011. The investigators identified missing, filled and decayed teeth according to a modified version of methods used in the National Health and Nutrition Examination Survey. The authors computed prevalence estimates (weighted percentages), weighted means and standard errors for measures. The prevalence of decayed surfaces ranged from 20.2 percent to 35.5 percent, depending on Hispanic or Latino background, whereas the prevalence of decayed and filled surfaces ranged from 82.7 percent to 87.0 percent, indicating substantial amounts of dental treatment. The prevalence of missing teeth ranged from 49.8 percent to 63.8 percent and differed according to Hispanic or Latino background. Significant differences in the mean number of decayed surfaces, decayed or filled surfaces and missing teeth according to Hispanic and Latino background existed within each of the age groups and between women and men. Oral health status differs according to Hispanic or Latino background, even with adjustment for age, sex and other characteristics. These data indicate that Hispanics and Latinos in the United States receive restorative dental treatment and that practitioners should consider the association between Hispanic or Latino origin and oral health status. This could mean that dental practices in areas dominated by patients from a single Hispanic or Latino background can anticipate a practice based on a specific pattern of treatment needs.


Tobacco cessation via doctors of chiropractic: results of a feasibility study.
There is a sizeable and growing body of empirical literature on the effects of physician advice to quit smoking. Because of the association between tobacco use and the health problems that may provoke referral to chiropractic care, doctors of chiropractic (DCs) may be able to give patients personalized proximal health feedback that may motivate them to quit. However, DCs have not been utilized in this role. The primary aim of this study was to design and refine a brief office-based tobacco intervention for use within chiropractic settings. This study was conducted in 20 private chiropractic practices in 2 phases: (a) intervention development, in which we created and focus tested practitioner and patient materials, and (b) feasibility, in which we evaluated the impact of the intervention on 210 tobacco-using chiropractic patients. Analyses were conducted on 156 patients who exclusively smoked cigarettes. Using an intent-to-treat approach, assuming all nonresponders to be smokers, 13 (8.3%) reported 7-day abstinence at 6 weeks, 22 (14.1%) at the 6-month follow-up, and 35 (22.4%) at the 12-month assessment. Eleven participants (7.1%) reported prolonged abstinence at the 6-month follow-up, and 15 (9.6%) reported prolonged abstinence at 12 months. To our knowledge, this is the first study to refine a brief office-based treatment for tobacco dependence for use in chiropractic settings. The results of this study were promising and will lead to a randomized clinical trial. If found to be effective, this model could be disseminated to chiropractic practitioners throughout the United States.


Combination of EGFR Inhibitor Lapatinib and MET Inhibitor Foretinib Inhibits Migration of Triple Negative Breast Cancer Cell Lines.
Triple-negative breast cancer (TNBC) is the most challenging subtype to treat due to the lack of estrogen receptor, progesterone receptor, and HER2 expression, which excludes the usage of directed targeted therapy against them. Promising therapeutic targets are the hepatocyte growth factor receptor (MET) and epidermal growth factor receptor (EGFR), which expression is frequently elevated in TNBC. Inhibitors of these receptors used as monotherapy are often ineffective. Due to that, we studied the efficacy of combined therapy targeting MET and EGFR simultaneously. Two TNBC cell lines were treated with lapatinib (a dual EGFR and HER2 inhibitor), foretinib (a MET inhibitor), or a combination of the two. After the inhibitors treatment, we verified the cell viability (XTT assay), distribution of the cell cycle phases, the activation of signaling pathways (Western blotting), distribution of invadopodia, fluorescent gelatin digestion (immunofluorescence), and the invasion capacity of cells. A combination of foretinib and lapatinib effectively reduced the viability of examined cells, led to G2/M arrest and reduction of pAKT. There was also a decreasein number of invadopodia formed by cells, their ability to digest gelatin and reduction of cells migration/invasion capacity. Therapy targeting of both EGFR and MET receptors was much more effective against tested cells than monotherapy. We selected a combination of drugs that could be successfully used against this breast cancer subtype.


A continuum model for platelet plug formation and growth.
When the wall of a blood vessel is damaged, the immediate response of the body to prevent blood loss is the creation of a platelet plug. The process is both chemical (platelets are chemically activated to adhere to the injured wall) and mechanical (platelets are convected by blood flow, which interacts with the forming plug). A continuum model for platelet plug formation and growth is presented in this work, which allows to study the interaction between platelet plug morphology and local haemodynamics. The numerical framework consists of two parts: a biochemical model combined with a new plug growth model. The biochemical model is a system of convection-diffusion-reaction equations, each of which represents the dynamics of platelets and chemicals involved in the plug formation process. The plug growth model defines the plug interface displacement based on the outcome of the biochemical model, that is, on the number of deposited bounded platelets on the injured part of the vessel wall. Results for different cases are shown, together with a comparison between the sole biochemical model and the complete model that includes plug growth. The framework opens the way to the development of continuum models for full blood clot formation and growth in physiologically relevant configurations.


Effect of normoglycemia before conception on early pregnancy hormone profiles.
Insulin-dependent diabetic women have been shown to have subnormal hormone levels in the first trimester of pregnancy. To determine whether these abnormalities were the result of poor diabetes control, testosterone, androstenedione, human chorionic gonadotropin (HCG), and prolactin were studied longitudinally in diabetic women made normoglycemic before conception (N = 11) and normal (N = 6) control subjects beginning at the fifth week of gestation. HCG levels rose normally in all 11 diabetic and six control subjects and then declined as expected, with peak levels between 8 and 12 wk of gestation. Prolactin levels similarly rose significantly (P less than 0.00001) during the period studied. Plasma androstenedione did not increase during the course of this study, but testosterone levels increased significantly (P = 0.0001). Androgen levels were consistently higher in diabetic subjects despite the normoglycemic state, although the differences reached statistical significance at only one point. This study demonstrates that when normoglycemia is achieved before conception, HCG and prolactin are normal at 5 wk after the last menstrual period. The possibility that androgen levels may be higher in insulin-requiring diabetic women, perhaps due to peripheral hyperinsulinemia, should be explored.


Usefulness of the mini nutritional assessment in predicting the nutritional status of patients with liver cancer in Taiwan.
Liver cancer patients are confronted with the additional risk of malnutrition because the disease is often associated with hepatitis, liver cirrhosis, and metabolic disturbances. Nutritional intervention can improve treatment outcome, but early detection is important. This study aimed to determine whether the Mini Nutritional Assessment (MNA) could effectively rate the nutritional status of patients with liver cancer in Taiwan. A total of 300 patients were evaluated for nutritional status with two modified versions of the MNA in short and long forms. MNA-Taiwan Version 1 adopted population-specific anthropometric cutpoints, whereas Version 2 replaced mid-arm and calf circumferences in place of body mass index. Predicted statuses were compared to results predicted by the Council on Nutrition Appetite Questionnaire (CNAQ) and analyzed for correlations with biochemical or cancer status parameters. Results showed that both versions of the MNA were effective in predicting nutritional status, and predictions by the short forms agreed well with those by the long forms. The nutritional scores correlated well with hemoglobin, serum albumin, C-reactive protein, r-glutamyl transpeptidase, TNM (tumor, node, metastasis) staging, and severity of cirrhosis. These results suggest that the MNA can be an effective tool for assessing the nutritional status of patients with liver cancer.


Dentinogenesis imperfecta in children with osteogenesis imperfecta: a clinical and ultrastructural study.
The aim of this study was to assess the correlation between osteogenesis imperfecta (OI) and dentinogenesis imperfecta (DI) from both a clinical and histological point of view, particularly clarifying the structural and ultrastructural dentine changes. Sixteen children (6-12 years aged) with diagnosis of OI were examined for dental alterations referable to DI. For each patient, the OI type (I, III, or IV) was recorded. Extracted or normally exfoliated primary teeth were subjected to a histological examination (to both optical microscopy and confocal laser-scanning microscopy). A total of ten patients had abnormal discolourations referable to DI: four patients were affected by OI type I, three patients by OI type III, and three patients by OI type IV. The discolourations, yellow/brown or opalescent grey, could not be related to the different types of OI. Histological exam of primary teeth showed severe pathological change in the dentin, structured into four different layers. A collagen defect due to odontoblast dysfunction was theorized to be on the base of the histological changes. There is no correlation between the type of OI and the type of discolouration. The underlying dentinal defect seems to be related to an odontoblast dysfunction.


Adverse Drug Event-Related Admissions to a Pediatric Emergency Unit.
The objectives of this study were to analyze adverse drug events (ADEs) related to admissions to a pediatric emergency unit and to identify the associated risk factors. This was a prospective study. Demographic data and details of medications were collected for each patient admitted. Case studies were performed by clinical pharmacists and the clinical team to discuss whether the admission was due to an ADE and to characterize the ADE. Multivariate logistic regression was used for statistical analysis. In total, 1708 pediatric patients were included in this study. Adverse drug events were the cause of hospital admission in 12.3% of the studied population. The majority of patients presenting with an ADE were in the age group of 0 to 5 years (61.6%), had a mean ± SD age of 4.9 ± 3.9 years, were female (51.2%), were Caucasian (72.0%), and had infectious disorders (49.3%). High frequencies of medication errors (68.8%), use of drugs to treat respiratory disorders (27.7%), and ADEs of mild severity (75.3%) were reported. The risk of being admitted to the pediatric emergency unit for any ADE increased in cases of neurological (odds ratio [OR], 4.63; 95% confidence interval [CI], 2.38-8.99), dermatological (OR, 3.16; 95% CI, 1.93-5.18), and respiratory (OR, 3.02; 95% CI, 1.89-4.83) disorders. A high frequency of ADE-related admissions to the pediatric emergency unit was observed. The risk of being admitted to the pediatric emergency unit for any ADE increased in cases of neurological, dermatological, and respiratory disorders. Clinical pharmacists play an important role in the identification of ADEs and the education of child caregivers and health care providers concerning pediatric medication.


Binding of Campylobacter jejuni FliW Adjacent to the CsrA RNA-Binding Pockets Modulates CsrA Regulatory Activity.
Campylobacter jejuni CsrA is an mRNA-binding, post-transcriptional regulator that controls many metabolic- and virulence-related characteristics of this important pathogen. In contrast to E. coli CsrA, whose activity is modulated by binding to small non-coding RNAs (sRNAs), C. jejuni CsrA activity is controlled by binding to the CsrA antagonist FliW. In this study, we identified the FliW binding site on CsrA. Deletion of the C-terminus of C. jejuni CsrA, which is extended relative to sRNA-binding CsrA proteins, abrogated FliW binding. Bacterial two-hybrid experiments were used to assess the interaction of FliW with wild-type CsrA and mutants thereof, in which every amino acid was individually mutated. Two CsrA mutations (V51A and N55A) resulted in a significant decrease in FliW binding. The V51A and N55A mutants also showed a decrease in CsrA-FliW complex formation, as assessed by size-exclusion chromatography and surface plasmon resonance. These residues were highly conserved in bacterial species containing CsrA orthologs whose activities are predicted to be regulated by FliW. The location of FliW binding was immediately adjacent to the two RNA-binding sites of the CsrA homodimer, suggesting the model that FliW binding to CsrA modulates its ability to bind to its mRNA targets either by steric hindrance, electrostatic repulsion, or by altering the overall structure of the RNA-binding sites.


Fear-Conditioning to Unpredictable Threats Reveals Sex and Strain Differences in Rat Fear-Potentiated Startle (FPS).
Fear-potentiated startle (FPS) has been widely used to study fear processing in humans and rodents. Human studies showed higher startle amplitudes and exaggerated fear reactivity to unpredictable vs. predictable threats in individuals suffering from post-traumatic stress disorder (PTSD). Although human FPS studies use both sexes, a surprisingly limited number of rodent FPS studies use females. Here we investigate the effects of signal-threat contingency, signal-threat order and threat predictability on FPS in both sexes. We use a classic fear-conditioning protocol (100% contingency of cue and shock pairings, with forward conditioning such that the cue co-terminates with the shock) and compare it to modified fear-conditioning protocols (70% contingency; backward conditioning; or cue and shock un-paired). Although there are no sex differences in the startle amplitudes when corrected for body weight, females consistently demonstrate higher shock reactivity during fear-conditioning. Both sexes and strains demonstrate comparable levels of cued, non-cued, and contextual fear in the classic FPS and FPS following fear-conditioning with 70% contingency or backward order (cue co-starts with shock). However, in the classic FPS, Sprague-Dawley females show reduced proportion between cued fear and cue-elicited vigilant state than males. Lastly, a prominent sex difference is uncovered following unpredictable fear-conditioning (cue and shock un-paired), with Wistar, but not Sprague-Dawley, females showing significantly higher startle overall during the FPS recall, regardless of trial type, and higher contextual fear than males. This striking sex difference in processing unpredictable threats in rodent FPS might help to understand the mechanisms underlying higher incidence of PTSD in women.


Synthesis and biophysical properties of (L)-aTNA based G-quadruplexes.
Novel G-quadruplex structures are constructed by acyclic (L)-threninol nucleic acid and their synthesis and biophysical properties are described. Pyrene excimer fluorescence and circular dichroism (CD) data revealed that four strands of aTNA are oriented in antiparallel direction.


The forgotten people in British public health: a national neglect of the dying, bereaved and caregivers.
The clinical and social epidemiology of living with a life-threatening or life-limiting illness, frail ageing, long-term caregiving, and grief and bereavement is well documented in the palliative care, psycho-oncology and psychiatric literature but this investigation asks what interest exists from the mainstream public health sector in these health and illness experiences. This paper reports a content analysis of 7 key British public health journals, 14 major public health textbooks and 3 public health websites employing key word and synonym searches to assess the size and quality of interest in populations related to ageing, dying, caregiving, and grief and bereavement. Compared with other public health issues, such as obesity and tobacco use, for examples, interest in the social experience and epidemiology of end-of-life experiences is extremely low. Reasons for this lack of interest are explored.


An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia.
Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation.


Adhesin expression in matched nasopharyngeal and middle ear isolates of nontypeable Haemophilus influenzae from children with acute otitis media.
The HMW1 and HMW2 proteins, Hia, and hemagglutinating pili are important adherence factors in nontypeable Haemophilus influenzae. To gain insight into the relative importance of these adhesins in nasopharyngeal colonization and localized respiratory tract disease, we assessed their expression in matched nasopharyngeal and middle ear isolates of nontypeable H. influenzae from 17 children with acute otitis media. In all patients, including 11 with bilateral disease, the matched isolates were isogenic based on total protein profiles and genomic fingerprints. Of the nasopharyngeal isolates, 14 expressed only HMW1/HMW2-like proteins, 1 expressed only Hia, 1 expressed only pili, and 1 expressed both Hia and pili. Further analysis revealed concordance between nasopharyngeal isolates and the matched middle ear isolates for expression of the HMW1/HMW2-like proteins and Hia. In contrast, in the two children whose nasopharynges were colonized by piliated organisms, the corresponding middle ear isolates were nonpiliated and could not be enriched for piliation. Nevertheless, Southern analysis revealed that these two middle ear isolates contained all five hif genes required for pilus biogenesis and had no evidence of major genetic rearrangement. In summary, the vast majority of isolates of nontypeable H. influenzae associated with acute otitis media express HMW1/HMW2-like proteins, with expression present in both the nasopharynx and the middle ear. A smaller fraction of nasopharyngeal isolates express pili, while isogenic strains recovered from the middle ear are often refractory to enrichment for piliation. We speculate that the HMW adhesins and Hia are important at multiple steps in the pathogenesis of otitis media while pili contribute to early colonization and then become dispensable.


Insulin requirements in non-critically ill hospitalized patients with diabetes and steroid-induced hyperglycemia.
Steroid-induced hyperglycemia is common in hospitalized patients with diabetes mellitus. Guidelines for glucose management in this setting are lacking. We conducted a retrospective chart review of non-critically ill patients with diabetes receiving steroids, hospitalized from January 2009 to October 2012. Fifty-eight patients were identified from 247 consults. Multivariable linear regression was used to assess median daily insulin requirements of normoglycemic patients compared with hyperglycemic patients. Of the 58 total patients included in our study, 20 achieved normoglycemia during admission (patient-day weighted mean blood glucose [PDWMBG] level = 154 ± 16 mg/dL) and 38 remained hyperglycemic (PDWMBG level = 243 ± 39 mg/dL; P < 0.001). There were no differences between the 2 patient groups in age, sex, race, body weight, renal function, HbA1c level, glucose-altering medications, diabetes type, or disease duration. Following multivariable adjustment, compared with hyperglycemic patients, normoglycemic patients required similar units of basal insulin (median interquartile range [IQR])(23.6 [17.9, 31.2] vs 20.1 [16.5, 24.4]; P = 0.35); higher units of nutritional insulin (45.5 [34.2, 60.4] vs 20.1 [16.4, 24.5]; P < 0.001]; and lower units of correctional insulin (5.8 [4.1, 8.1] vs 13.0 [10.2, 16.5]; P < 0.001]). Patients achieving normoglycemia required a significantly lower percentage of correction insulin (total daily dose [TDD]: 7.4% vs 23.4%; P < 0.001) and a higher percentage of nutritional insulin (TDD: 58.1% vs 36.2%; P <0.001) than hyperglycemic patients. There was no difference in the TDD per kilogram, TDD per milligram hydrocortisone dose, or TDD per milligram hydrocortisone dose per kilogram weight between the 2 groups. The data suggest that non-critically ill patients with hyperglycemia receiving steroids require a higher percentage of TDD insulin therapy as nutritional insulin to achieve normoglycemia.


[Marital norm, reality and satisfaction in middle-aged couples: why are wives less satisfied than husbands?].
The purpose of this study was to investigate recent changes in marital norm and reality in middle-aged couples, and how marital reality, as perceived by oneself, was associated with their demographic variables, as well as their marital satisfaction. A questionnaire was administered, and 277 pairs of middle-aged, nuclear-family couples participated. Main findings were as follows. First, factor analysis of marital reality variables extracted three factors: love each other, respect for the husband's life style, and respect for wife's life style. Second, concerning the wife's education and income, 'respect for the wife's life style' was highest among highly educated double income couples. Third, 'love each other' was the most important predictor of marital satisfaction for both husbands and wives. Finally, 'respect for the husband's the life style' was associated with husband's satisfaction, while that for the wife's was not with wife's marital satisfaction.


Meta-analysis: factors affecting placebo response rate in the irritable bowel syndrome.
Irritable bowel syndrome (IBS) is a functional disorder of the gastrointestinal tract with a significant placebo response. To conduct a systematic review and meta-analysis examining the magnitude of placebo response rate in treatment trials for IBS. MEDLINE, EMBASE and the Cochrane central register of controlled trials were searched to identify randomized controlled trials (RCTs) comparing pharmacological therapies with placebo in adult IBS patients. Studies reported either global assessment of IBS symptom cure or improvement or abdominal pain cure or improvement. Data were extracted as intention-to-treat analyses with drop-outs assumed to be treatment failures and pooled using a random-effects model. Proportion of placebo patients experiencing symptom improvement or resolution was reported with a 95% confidence interval (CI). Effect of trial characteristics on magnitude of placebo response was examined. In all, 73 RCTs were eligible, including 8364 patients with IBS allocated to placebo. Pooled placebo response rate across all RCTs was 37.5% (95% CI 34.4-40.6%). Rates were higher in European RCTs, RCTs that used physician-reported outcomes and RCTs using shorter duration of therapy. Placebo response rates across RCTs of pharmacological therapies in IBS were high. Future research should identify patient characteristics predicting placebo response.


Natriuretic peptides in the management of solid organ transplantation associated acute kidney injury: a systematic review and meta-analysis.
Randomized controlled trials involving natriuretic peptide administration in solid organ transplantation setting have shown inconsistent effects for renal endpoints. We conducted a systematic review and meta-analysis of these trials to ascertain the role of natriuretic peptides in the management of solid organ transplantation associated acute kidney injury (AKI). MEDLINE, EMBASE, and Google scholar were searched independently by two authors for randomized trials evaluating renal effects of natriuretic peptides in solid organ transplantation settings. Two reviewers independently assessed the studies for eligibility and extracted the relevant data. The pooled estimate showed that natriuretic peptide administration is associated with a reduction in AKI requiring dialysis (odds ratio = 0.50 [0.26-0.97]), a statistically nonsignificant trend toward improvement in posttransplant creatinine clearance (weighted mean difference = 5.5 mL/min, [-1.3 to 12.2 mL/min]), and reduction in renal replacement requirement duration (weighted mean difference -44.0 hours, [-60.5 to -27.5 hours]). There were no mortality events and no adverse events related to natriuretic peptides. In conclusion, administration of natriuretic peptides in solid organ transplantation may be associated with significant improvements in renal outcomes. These observations need to be confirmed in an adequately powered, prospective multicenter study.


Bistable or oscillating state depending on station and temperature in three-station glycorotaxane molecular machines.
High-yield, straightforward synthesis of two- and three-station [2]rotaxane molecular machines based on an anilinium, a triazolium, and a mono- or disubstituted pyridinium amide station is reported. In the case of the pH-sensitive two-station molecular machines, large-amplitude movement of the macrocycle occurred. However, the presence of an intermediate third station led, after deprotonation of the anilinium station, and depending on the substitution of the pyridinium amide, either to exclusive localization of the macrocycle around the triazolium station or to oscillatory shuttling of the macrocycle between the triazolium and monosubstituted pyridinium amide station. Variable-temperature (1)H NMR investigation of the oscillating system was performed in CD(2)Cl(2). The exchange between the two stations proved to be fast on the NMR timescale for all considered temperatures (298-193 K). Interestingly, decreasing the temperature displaced the equilibrium between the two translational isomers until a unique location of the macrocycle around the monosubstituted pyridinium amide station was reached. Thermodynamic constants K were evaluated at each temperature: the thermodynamic parameters DeltaH and DeltaS were extracted from a Van't Hoff plot, and provided the Gibbs energy DeltaG. Arrhenius and Eyring plots afforded kinetic parameters, namely, energies of activation E(a), enthalpies of activation DeltaH( not equal), and entropies of activation DeltaS( not equal). The DeltaG values deduced from kinetic parameters match very well with the DeltaG values determined from thermodynamic parameters. In addition, whereas signal coalescence of pyridinium hydrogen atoms located next to the amide bond was observed at 205 K in the oscillating rotaxane and at 203 K in the two-station rotaxane with a unique location of the macrocycle around the pyridinium amide, no separation of (1)H NMR signals of the considered hydrogen atoms was seen in the corresponding nonencapsulated thread. It is suggested that the macrocycle acts as a molecular brake for the rotation of the pyridinium-amide bond when it interacts by hydrogen bonding with both the amide NH and the pyridinium hydrogen atoms at the same time.