Socio-economic factors and mortality among 25-64 year olds followed from 1991 to 1994: the New Zealand Census-Mortality Study.
To measure the association of income, education, occupational class, small area socio-economic deprivation, car access and labour force status with mortality among 25-64 year old males and females using the 1991 census-cohort of the New Zealand Census-Mortality Study. Mortality records for 1991-94 were anonymously and probabilistically linked to 1991 census records, thereby creating a cohort study of all New Zealand census respondents. Odds ratios of mortality comparing categories of each socio-economic factor were calculated using logistic regression. For income, education and deprivation (NZDep91) a modified relative index of inequality (RII(10:90)) was calculated. The RII(10:90) estimates the relative risk of mortality for low socio-economic people (10th percentile rank) compared to high socio-economic people (90 percentile rank) allowing direct comparisons across socio-economic factors. The relative risk of all-cause mortality for 25-64 year old males with an equivalised household income less than $20,000, compared to greater than $50,000, was 2.16 (95% confidence interval 1.99 to 2.34). For females, this relative risk was 1.68 (1.52 to 1.86). Using the RII(10:90) all-cause mortality was 2.22, 1.94 and 1.58 times greater among low compared to high socio-economic males for income, NZDep91 and education, respectively. For females, these RII(10:90) estimates were 1.77, 1.69 and 1.57, respectively. By cause of death, the strongest gradients were observed for respiratory diseases, followed by lung cancer, cardiovascular disease and unintentional injury. For suicide deaths, unemployed males and females had 2.70 (1.84 to 3.95) and 2.86 (1.19 to 6.85) greater rates than the employed. There are strong socio-economic gradients for all-cause mortality and most specific causes of mortality among both males and female adults in New Zealand, regardless of the choice of socio-economic factor. The gradients were strongest for income, followed by small area deprivation and education, and strongest for 'preventable' causes of death.


Charge separation and carrier dynamics in donor-acceptor heterojunction photovoltaic systems.
Electron transfer and subsequent charge separation across donor-acceptor heterojunctions remain the most important areas of study in the field of third-generation photovoltaics. In this context, it is particularly important to unravel the dynamics of individual ultrafast processes (such as photoinduced electron transfer, carrier trapping and association, and energy transfer and relaxation), which prevail in materials and at their interfaces. In the frame of the National Center of Competence in Research "Molecular Ultrafast Science and Technology," a research instrument of the Swiss National Science Foundation, several groups active in the field of ultrafast science in Switzerland have applied a number of complementary experimental techniques and computational simulation tools to scrutinize these critical photophysical phenomena. Structural, electronic, and transport properties of the materials and the detailed mechanisms of photoinduced charge separation in dye-sensitized solar cells, conjugated polymer- and small molecule-based organic photovoltaics, and high-efficiency lead halide perovskite solar energy converters have been scrutinized. Results yielded more than thirty research articles, an overview of which is provided here.


Long-term treatment with citicoline may improve poststroke vascular cognitive impairment.
Cognitive decline after stroke is more common than stroke recurrence. Stroke doubles the risk of dementia and is a major contributor to vascular cognitive impairment and vascular dementia. Nonetheless, few pharmacological studies have addressed vascular cognitive impairment after stroke. We assessed the safety of long-term administration and its possible efficacy of citicoline in preventing poststroke cognitive decline in patients with first-ever ischemic stroke. Open-label, randomized, parallel study of citicoline vs. usual treatment. All subjects were selected 6 weeks after suffering a qualifying stroke and randomized by age, gender, education and stroke type into parallel arms of citicoline (1 g/day) for 12 months vs. no citicoline (control group). Medical management was similar otherwise. All patients underwent neuropsychological evaluation at 1 month, 6 months and 1 year after stroke. Tests results were combined to give indexes of 6 neurocognitive domains: attention and executive function, memory, language, spatial perception, motor speed and temporal orientation. Using adjusted logistic regression models we determined the association between citicoline treatment and cognitive decline for each neurocognitive domain at 6 and 12 months. We recruited 347 subjects (mean age 67.2 years, 186 male (56.6%), mean education 5.7 years); 172 (49.6%) received citicoline for 12 months (no significant differences from controls n = 175). Demographic data, risk factors, initial stroke severity (NIHSS), clinical and etiological classification were similar in both groups. Only 37 subjects (10.7%) discontinued treatment (10.5% citicoline vs. 10.9% control) at 6 months; 30 (8.6%) due to death (16 (9.3%) citicoline vs. 14 (8.0%) control, p = 0.740), 7 lost to follow-up or incorrect treatment, and 4 (2.3%) had adverse events from citicoline without discontinuation. 199 patients underwent neuropsychological evaluation at 1 year. Cognitive functions improved 6 and 12 months after stroke in the entire group but in comparison with controls, citicoline-treated patients showed better outcome in attention-executive functions (OR 1.721, 95% CI 1.065-2.781, p = 0.027 at 6 months; OR 2.379, 95% CI 1.269-4.462, p = 0.007 at 12 months) and temporal orientation (OR 1.780, 95% CI 1.020-3.104, p = 0.042 at 6 months; OR 2.155, 95% CI 1.017-4.566, p = 0.045 at 12 months) during the follow-up. Moreover, citicoline group showed a better functional outcome (modified Rankin scale ≤2) at 12 months (57.3 vs. 48.7%) without statistically significant differences (p = 0.186). Citicoline treatment for 12 months in patients with first-ever ischemic stroke is safe and probably effective in improving poststroke cognitive decline. Citicoline appears to be a promising agent to improve recovery after stroke. Large clinical trials are needed to confirm the net benefit of this therapeutic approach.


Emotion processing, major depression, and functional genetic variation of neuropeptide Y.
Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proven particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD). To determine whether low-expression NPY genotypes are associated with negative emotional processing at 3 levels of analysis. Cross-sectional, case-control study. Academic medical center. Among 44 individuals with MDD and 137 healthy controls, 152 (84%) had an NPY genotype classified as low, intermediate, or high expression according to previously established haplotype-based expression data. Healthy subjects participated in functional magnetic resonance imaging while viewing negative (vs neutral) words (n = 58) and rated positive and negative affect during a pain-stress challenge (n = 78). Genotype distribution was compared between 113 control subjects and 39 subjects with MDD. Among healthy individuals, negatively valenced words activated the medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (P = .03). Whole-brain regression of responses to negative words showed that the rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (P < .05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (P = .002). Low-expression NPY genotypes were overrepresented in subjects with MDD after controlling for age and sex (P = .004). Population stratification did not account for the results. These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including the medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD.


Recent developments in genetic/genomic medicine.
Advances in genetic technology are having a major impact in the clinic, and mean that many perceptions of the role and scope of genetic testing are having to change. Genomic testing brings with it a greater opportunity for diagnosis, or predictions of future diagnoses, but also an increased chance of uncertain or unexpected findings, many of which may have impacts for multiple members of a person's family. In the past, genetic testing was rarely able to provide rapid results, but the increasing speed and availability of genomic testing is changing this, meaning that genomic information is increasingly influencing decisions around patient care in the acute inpatient setting. The landscape of treatment options for genetic conditions is shifting, which has evolving implications for clinical discussions around previously untreatable disorders. Furthermore, the point of access to testing is changing with increasing provision direct to the consumer outside the formal healthcare setting. This review outlines the ways in which genetic medicine is developing in light of technological advances.


A new pathway for medical education.
Physician education in the United States must change to meet the primary care needs of a rapidly transforming health care delivery system. Yet medical schools continue to produce a disproportionate number of hospital-based specialists through a high-cost, time-intensive educational model. In response, the American Osteopathic Association and the American Association of Colleges of Osteopathic Medicine established a blue-ribbon commission to recommend changes needed to prepare primary care physicians for the evolving system. The commission recommends that medical schools, in collaboration with their graduate medical education partners, create a new education model that is based on achievement of competencies without a prescribed number of months of study and incorporates the knowledge and skills needed for a twenty-first-century primary care practice. The course of study would occur within a longitudinal clinical training environment that allows for seamless transition from medical school through residency training.


Klippel-Feil sequence and sleep-disordered breathing in two children.
We report two children with severe sleep-disordered breathing associated with Klippel-Feil sequence. In both patients, minor vertebral anomalies were associated with a major hindbrain anomaly. In one child, the Klippel-Feil sequence had been diagnosed previously, but the hindbrain anomaly was not recognized. Two years later, this child developed fatal obstructive sleep apnea. In the other child, neither the Klippel-Feil sequence nor hindbrain anomaly had been identified before the child's presentation with sleep-disordered breathing characterized by bradypnea and stridor. Because many of the complications of hindbrain anomalies may be amenable to neurosurgical treatment, we recommend that patients with Klippel-Feil sequence be followed for the development of sleep-disordered breathing. Sleep complaints need prompt evaluation with polysomnography, whereas neurologic signs require imaging with attention to the cervicomedullary junction. Unsuspected CNS disorders must be considered in children who present with stridor or serious respiratory disturbances during sleep.


Efficacy of pharmacotherapy and psychotherapy for adult psychiatric disorders: a systematic overview of meta-analyses.
There is debate about the effectiveness of psychiatric treatments and whether pharmacotherapy or psychotherapy should be primarily used. To perform a systematic overview on the efficacy of pharmacotherapies and psychotherapies for major psychiatric disorders and to compare the quality of pharmacotherapy and psychotherapy trials. We searched MEDLINE, EMBASE, PsycINFO, and the Cochrane Library (April 2012, with no time or language limit) for systematic reviews on pharmacotherapy or psychotherapy vs placebo, pharmacotherapy vs psychotherapy, and their combination vs either modality alone. Two reviewers independently selected the meta-analyses and extracted efficacy effect sizes. We assessed the quality of the individual trials included in the pharmacotherapy and psychotherapy meta-analyses with the Cochrane risk of bias tool. The search yielded 45,233 results. We included 61 meta-analyses on 21 psychiatric disorders, which contained 852 individual trials and 137,126 participants. The mean effect size of the meta-analyses was medium (mean, 0.50; 95% CI, 0.41-0.59). Effect sizes of psychotherapies vs placebo tended to be higher than those of medication, but direct comparisons, albeit usually based on few trials, did not reveal consistent differences. Individual pharmacotherapy trials were more likely to have large sample sizes, blinding, control groups, and intention-to-treat analyses. In contrast, psychotherapy trials had lower dropout rates and provided follow-up data. In psychotherapy studies, wait-list designs showed larger effects than did comparisons with placebo. Many pharmacotherapies and psychotherapies are effective, but there is a lot of room for improvement. Because of the multiple differences in the methods used in pharmacotherapy and psychotherapy trials, indirect comparisons of their effect sizes compared with placebo or no treatment are problematic. Well-designed direct comparisons, which are scarce, need public funding. Because patients often benefit from both forms of therapy, research should also focus on how both modalities can be best combined to maximize synergy rather than debate the use of one treatment over the other.


Modulation of Higher-Order Olfaction Components on Executive Functions in Humans.
The prefrontal (PFC) and orbitofrontal cortex (OFC) appear to be associated with both executive functions and olfaction. However, there is little data relating olfactory processing and executive functions in humans. The present study aimed at exploring the role of olfaction on executive functioning, making a distinction between primary and more cognitive aspects of olfaction. Three executive tasks of similar difficulty were used. One was used to assess hot executive functions (Iowa Gambling Task-IGT), and two as a measure of cold executive functioning (Stroop Colour and Word Test-SCWT and Wisconsin Card Sorting Test-WCST). Sixty two healthy participants were included: 31 with normosmia and 31 with hyposmia. Olfactory abilities were assessed using the ''Sniffin' Sticks'' test and the olfactory threshold, odour discrimination and odour identification measures were obtained. All participants were female, aged between 18 and 60. Results showed that participants with hyposmia displayed worse performance in decision making (IGT; Cohen's-d = 0.91) and cognitive flexibility (WCST; Cohen's-d between 0.54 and 0.68) compared to those with normosmia. Multiple regression adjusted by the covariates participants' age and education level showed a positive association between odour identification and the cognitive inhibition response (SCWT-interference; Beta = 0.29; p = .034). The odour discrimination capacity was not a predictor of the cognitive executive performance. Our results suggest that both hot and cold executive functions seem to be associated with higher-order olfactory functioning in humans. These results robustly support the hypothesis that olfaction and executive measures have a common neural substrate in PFC and OFC, and suggest that olfaction might be a reliable cognitive marker in psychiatric and neurologic disorders.


Secure corridor for infraacetabular screws in acetabular fracture fixation-a 3-D radiomorphometric analysis of 124 pelvic CT datasets.
Acetabular fracture surgery is directed toward anatomical reduction and stable fixation to allow for the early functional rehabilitation of an injured hip joint. Recent biomechanical investigations have shown the superiority of using an additional screw in the infraacetabular (IA) region, thereby transfixing the separated columns to strengthen the construct by closing the periacetabular fixation frame. However, the inter-individual existence and variance concerning secure IA screw corridors are poorly understood. This computer-aided 3-D radiomorphometric study examined 124 CT Digital Imaging and Communications in Medicine (DICOM) datasets of intact human pelves (248 acetabula) to visualize the spatial IA corridors as the sum of all intraosseous screw positions. DICOM files were pre-processed using the Amira® 4.2 visualization software. Final corridor computation was accomplished using a custom-made software algorithm. The volumetric measurement data of each corridor were calculated for further statistical analyses. Correlations between the volumetric values and the biometric data were investigated. Furthermore, the influence of hip dysplasia on the IA corridor configuration was analyzed. The IA corridors consistently showed a double-cone shape with the isthmus located at the acetabular fovea. In 97% of male and 91% of female acetabula, a corridor for a 3.5-mm screw could be found. The number of IA corridors was significantly lower in females for screw diameters ≥ 4.5 mm. The mean 3.5-mm screw corridor volume was 16 cm3 in males and 9.2 cm3 in female pelves. Corridor volumes were significantly positively correlated with body height and weight and with the diameter of Köhler's teardrop on standard AP pelvic X-rays. No correlation was observed between hip dysplasia and the IA corridor extent. IA corridors are consistently smaller in females. However, 3.5-mm small fragment screws may still be used as the standard implant because sex-specific differences are significant only with screw diameters ≥ 4.5 mm. Congenital hip dysplasia does not affect secure IA screw insertion. The described method allows 3-D shape analyses with highly reliable results. The visualization of secure IA corridors may support the spatial awareness of surgeons. Volumetric data allow the reliable assessment of individual IA corridors using standard AP X-ray views, which aids preoperative planning.


Subclinical left ventricular dysfunction in women with polycystic ovary syndrome: an observational study.
Cardiac involvement has been increasingly recognized in patients with polycystic ovary syndrome (PCOS). Identification of the earliest asymptomatic impairment of left ventricular (LV) performance may be important in preventing progression to overt heart failure. Our aim was to investigate LV function with different echocardiographic techniques in patients with PCOS. Thirty patients with PCOS and 30 age and body mass index matched healthy subjects were enrolled to this cross-sectional observational study. All subjects underwent echocardiography for assessment of resting LV function as well as two-dimensional speckle tracking echocardiography (2D-STE) and real-time three-dimensional echocardiography (3D-Echo). Global longitudinal strain (GLS) was calculated from 3 standard apical views using 2D-STE. Student t-test, chi-square test, Pearson's, and Spearman's correlation analysis were used for statistical analysis. The early mitral inflow deceleration time (DT), isovolumetric relaxation time (IVRT) and E/Em ratio were increased in the PCOS group (p<0.05 for all). Waist-to-hip ratio, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and low-density lipoprotein (LDL) levels were higher in PCOS group (p<0.05 for all). Significant correlation was observed between DT, IVRT and insulin value, HOMA-IR (p<0.05 for all). On 3D-Echo evaluation, none of the patients in both groups had LV systolic dysfunction with comparable LV ejection fraction and LV volumes. 2D-STE showed that GLS was significantly reduced in the PCOS group compared to control group (-16.78 ± 0.56% vs. -18.36 ± 1.04%, p<0.001). The GLS was found to be negatively correlated with waist-to-hip ratio and LDL values (p<0.05 for all). These results indicate that PCOS may be related to impaired LV systolic function detected by 2D-STE. In addition, PCOS may lead to diastolic dysfunction. Reduced GLS might be an early indicator of cardiac involvement in this patient population.


Toward a simulation and assessment method for the practice of camera-guided rigid bronchoscopy.
We have developed a way to measure performance during a camera-guided rigid bronchoscopy using manikin-based simulation. In an effort to measure contact pressures within the airway during a rigid bronchoscopy, we instrumented pressure sensors in a commercially available bronchoscopy task trainer. Participants were divided into two groups based on self-reported levels of expertise: novice (none to minimal experience in rigid bronchoscopy) and experts (moderate to extensive experience). There was no significant difference between experts and novices in the time taken to complete the rigid bronchoscopy. However, novices touched a greater number of areas than experts, showing that novices induce a higher number of unnecessary soft-tissue contact compared to experts. Moreover, our results show that experts exert significantly less soft tissue pressure compared to novices.


Cell invasion by Neisseria meningitidis requires a functional interplay between the focal adhesion kinase, Src and cortactin.
Entry of Neisseria meningitidis (the meningococcus) into human brain microvascular endothelial cells (HBMEC) is mediated by fibronectin or vitronectin bound to the surface protein Opc forming a bridge to the respective integrins. This interaction leads to cytoskeletal rearrangement and uptake of meningococci. In this study, we determined that the focal adhesion kinase (FAK), which directly associates with integrins, is involved in integrin-mediated internalization of N. meningitidis in HBMEC. Inhibition of FAK activity by the specific FAK inhibitor PF 573882 reduced Opc-mediated invasion of HBMEC more than 90%. Moreover, overexpression of FAK mutants that were either impaired in the kinase activity or were not capable of autophosphorylation or overexpression of the dominant-negative version of FAK (FRNK) blocked integrin-mediated internalization of N. meningitidis. Importantly, FAK-deficient fibroblasts were significantly less invaded by N. meningitidis. Furthermore, N. meningitidis induced tyrosine phosphorylation of several host proteins including the FAK/Src complex substrate cortactin. Inhibition of cortactin expression by siRNA silencing and mutation of critical amino acid residues within cortactin, that encompass Arp2/3 association and dynamin binding, significantly reduced meningococcal invasion into eukaryotic cells suggesting that both domains are critical for efficient uptake of N. meningitidis into eukaryotic cells. Together, these results indicate that N. meningitidis exploits the integrin signal pathway for its entry and that FAK mediates the transfer of signals from activated integrins to the cytoskeleton. A cooperative interplay between FAK, Src and cortactin then enables endocytosis of N. meningitidis into host cells.


Role of tyrosine kinases in norepinephrine-induced contraction of vascular smooth muscle.
We used various probes to examine the involvement of tyrosine kinases in norepinephrine (NE)-induced contractile responses of the isolated rat aorta denuded of endothelium. The putative tyrosine kinase inhibitors, genistein and tyrphostin, significantly inhibited the contractile responses of the aorta to NE but not to potassium chloride (KCl). The protein tyrosine phosphatase inhibitor, sodium orthovanadate, also selectively potentiated the contractile response of the artery to NE. The inhibitory effect of genistein on NE-induced contraction was observed both in the absence and presence of extracellular calcium, which produced phasic and tonic contractile responses, respectively. The effect of genistein was more pronounced on the phasic contraction, suggesting that tyrosine kinases play a greater role in mediating the responses associated with the release of intracellular calcium. Genistein, however, had no effect on contraction elicited by the direct protein kinase C (PKC) activator phorbol 12, 13 dibutyrate (PDB), providing evidence for the lack of involvement of tyrosine kinases in PKC-mediated contractile responses which contribute to the NE-induced tonic contraction. In contrast, genistein attenuated the contraction of the vessel evoked by the direct G-protein activator sodium fluoride (NaF), suggesting the involvement of tyrosine kinases in responses associated with G-protein activation. The data indicate that genistein- and tyrphostin-sensitive tyrosine kinases participate in NE-induced contraction of rat aortic smooth muscle. Although this may involve one or more steps in the signal transduction pathway, the enzymes appear to have a greater role in mediating the responses linked to the release of intracellular calcium and have no roles in certain other processes, including those mediated by PKC activation.


Optimizing rice yields while minimizing yield-scaled global warming potential.
To meet growing global food demand with limited land and reduced environmental impact, agricultural greenhouse gas (GHG) emissions are increasingly evaluated with respect to crop productivity, i.e., on a yield-scaled as opposed to area basis. Here, we compiled available field data on CH4 and N2 O emissions from rice production systems to test the hypothesis that in response to fertilizer nitrogen (N) addition, yield-scaled global warming potential (GWP) will be minimized at N rates that maximize yields. Within each study, yield N surplus was calculated to estimate deficit or excess N application rates with respect to the optimal N rate (defined as the N rate at which maximum yield was achieved). Relationships between yield N surplus and GHG emissions were assessed using linear and nonlinear mixed-effects models. Results indicate that yields increased in response to increasing N surplus when moving from deficit to optimal N rates. At N rates contributing to a yield N surplus, N2 O and yield-scaled N2 O emissions increased exponentially. In contrast, CH4 emissions were not impacted by N inputs. Accordingly, yield-scaled CH4 emissions decreased with N addition. Overall, yield-scaled GWP was minimized at optimal N rates, decreasing by 21% compared to treatments without N addition. These results are unique compared to aerobic cropping systems in which N2 O emissions are the primary contributor to GWP, meaning yield-scaled GWP may not necessarily decrease for aerobic crops when yields are optimized by N fertilizer addition. Balancing gains in agricultural productivity with climate change concerns, this work supports the concept that high rice yields can be achieved with minimal yield-scaled GWP through optimal N application rates. Moreover, additional improvements in N use efficiency may further reduce yield-scaled GWP, thereby strengthening the economic and environmental sustainability of rice systems.


Interaction of heat shock protein 60 (HSP60) with microRNA in Chinese mitten crab during Spiroplasma eriocheiris infection.
Heat shock protein 60 from the Chinese mitten crab Eriocheir sinensis (EsHSP60) was previously identified in relation to Spiroplasma eriocheiris infection by isobaric tags for relative and absolute quantitation labelling followed by liquid chromatography-tandem mass spectrometry. In the present study, to validate the immune function of this protein, the cDNA of the EsHSP60 gene was cloned. Various crab tissues were assessed using real-time PCR, which showed that EsHSP60 transcription occurred in all tissues examined. The expression profiles of EsHSP60 in haemolymph at transcription and protein levels when infected with S. eriocheiris were investigated by real-time PCR and Western blot analysis, respectively. A significant increase of EsHSP60 transcription and protein expression appeared post-injection in response to S. eriocheiris infection when compared to the control group. The double-luciferase reporter gene assay showed that the microRNA PC-533-3p interacted with the 3'-untranslated region of EsHSP60 and inhibited the translation of EsHSP60. The expression profiles of PC-533-3p during S. eriocheiris infection were also investigated by real-time PCR. However, the change tendency of PC-533-3p was opposite to that of the EsHSP60 after S. eriocheiris challenge. These data indicate that the EsHSP60 proteins may play an important role in mediating the immune responses of E. sinensis to an S. eriocheiris challenge.


Data-driven approach for creating synthetic electronic medical records.
New algorithms for disease outbreak detection are being developed to take advantage of full electronic medical records (EMRs) that contain a wealth of patient information. However, due to privacy concerns, even anonymized EMRs cannot be shared among researchers, resulting in great difficulty in comparing the effectiveness of these algorithms. To bridge the gap between novel bio-surveillance algorithms operating on full EMRs and the lack of non-identifiable EMR data, a method for generating complete and synthetic EMRs was developed. This paper describes a novel methodology for generating complete synthetic EMRs both for an outbreak illness of interest (tularemia) and for background records. The method developed has three major steps: 1) synthetic patient identity and basic information generation; 2) identification of care patterns that the synthetic patients would receive based on the information present in real EMR data for similar health problems; 3) adaptation of these care patterns to the synthetic patient population. We generated EMRs, including visit records, clinical activity, laboratory orders/results and radiology orders/results for 203 synthetic tularemia outbreak patients. Validation of the records by a medical expert revealed problems in 19% of the records; these were subsequently corrected. We also generated background EMRs for over 3000 patients in the 4-11 yr age group. Validation of those records by a medical expert revealed problems in fewer than 3% of these background patient EMRs and the errors were subsequently rectified. A data-driven method was developed for generating fully synthetic EMRs. The method is general and can be applied to any data set that has similar data elements (such as laboratory and radiology orders and results, clinical activity, prescription orders). The pilot synthetic outbreak records were for tularemia but our approach may be adapted to other infectious diseases. The pilot synthetic background records were in the 4-11 year old age group. The adaptations that must be made to the algorithms to produce synthetic background EMRs for other age groups are indicated.


Time Matters in Severe Frostbite: Assessment of Limb/Digit Salvage on the Individual Patient Level.
Severe frostbite is associated with high levels of morbidity through loss of digits or limbs. The aim of this study was to examine the salvage rate following severe frostbite injury. Frostbite patients from 2006 to 2014 were identified in the prospectively maintained database at a single urban burn and trauma center. Patients with imaging demonstrating a lack of blood flow in limbs/digits were included in the analysis (N = 73). The Hennepin Frostbite Score was used to quantify frostbite injury and salvage. This score provides a single value to assess each individual patient's salvage rate. The majority of patients with perfusion deficits were male (80%) with an average age of 42 years (range 11-83 years). Patients requiring amputation tended to be older (P = .002), have more tissue impacted by frostbite (P < .001), and experienced a longer time from rewarming to thrombolytic therapy (P = .001). A majority of patients (62%) received thrombolytic treatment. The percentage of patients requiring amputation was lower and the salvage rate was higher in patients treated with thrombolytics; however, the differences failed to reach statistical significance (P = .092 and P = .061, respectively). The rate of salvage decreases as the time from rewarming to thrombolytic therapy increases. Regression analysis demonstrates an additional 26.8% salvage loss with each hour of delayed treatment (P = .006). When the amount of tissue at risk for amputation is included in the model, each hour delay in thrombolytic treatment results in a 28.1% decrease in salvage (P = .011). This study demonstrates a significant decrease in limb/digit salvage with each hour of delayed administration of thrombolytics in patients with severe frostbite.


Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.
Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification. Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119. Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42-72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5%, 92·8-98·2; unadjusted odds ratio 1·00, 95% CI 0·43-2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI -5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3-8·9) given one delayed intensification and six (2·4%, 0·2-4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0-2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one (<1%) treatment-related death, and 74 episodes of grade 3 or 4 toxic effects in 45 patients (17%). Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy. Medical Research Council and Leukaemia and Lymphoma Research.


Hospital Charges and Length of Stay Following Radical Cystectomy in the Enhanced Recovery After Surgery Era.
To report our center's experience with enhanced recovery after surgery (ERAS) pathway for radical cystectomy (RC), specifically evaluating complications, LOS, 30- and 90-day readmissions, and hospital charges. Pathways of this type have been shown to decrease the length of stay (LOS) and postoperative ileus. However, concerns persist that ERAS is costly and increases readmissions. To date, limited studies have evaluated these concerns. Our ERAS protocol was implemented for RC in December 2015. Outcomes in ERAS patients were compared with those in RC patients from the time period before ERAS. Patients were excluded if they underwent concomitant nephroureterectomy. Fifty-six consecutive ERAS patients were compared with 54 pre-ERAS patients. The median charge for index hospitalization was $31,090 in the ERAS group and $35,489 in the pre-ERAS group (P = .036). The median LOS was 5.0 days in the ERAS group and 8.5 days in the pre-ERAS group (P = < .001). The pre-ERAS group had a significantly increased use of nasogastric tube (13.8% vs 30.0%) and parenteral nutrition (6.9% vs 20.4%). The overall complication rate (including infectious, renal, deep vein thrombosis and pulmonary embolism, myocardial infarction and stroke, and respiratory and gastrointestinal-related complications) was similar between the 2 groups (51.7% in the ERAS group and 62.0% in the pre-ERAS group, P = .28). Thirty- and 90-day readmissions also remained similar (19.0% vs 14.8%, P = .55, and 31.0% vs 27.7%, P = .64). The most common readmission reason was infection, specifically urinary tract infection. Implementation of the ERAS pathway at our center resulted in significantly reduced LOS and total hospital charge, with comparable rates of complication and readmission, highlighting the need for ERAS pathways in patients undergoing RC.


Magnetic Mesoporous Silica Nanorods Loaded with Ceria and Functionalized with Fluorophores for Multimodal Imaging.
Multifunctional magnetic nanocomposites based on mesoporous silica have a wide range of potential applications in catalysis, biomedicine, or sensing. Such particles combine responsiveness to external magnetic fields with other functionalities endowed by the agents loaded inside the pores or conjugated to the particle surface. Different applications might benefit from specific particle morphologies. In the case of biomedical applications, mesoporous silica nanospheres have been extensively studied while nanorods, with a more challenging preparation, have attracted much less attention despite the positive impact on the therapeutic performance shown by seminal studies. Here, we report on a sol-gel synthesis of mesoporous rodlike silica particles of two distinct lengths (1.4 and 0.9 μm) and aspect ratios (4.7 and 2.2) using Pluronic P123 as a structure-directing template and rendering ∼1 g of rods per batch. Iron oxide nanoparticles have been synthesized within the pores yielding maghemite (γ-Fe2O3) nanocrystals of elongated shape (∼7 nm × 5 nm) with a [110] preferential orientation along the rod axis and a superparamagnetic character. The performance of the rods as T2-weighted MRI contrast agents has also been confirmed. In a subsequent step, the mesoporous silica rods were loaded with a cerium compound and their surface was functionalized with fluorophores (fluorescamine and Cyanine5) emitting at λ = 525 and 730 nm, respectively, thus highlighting the possibility of multiple imaging modalities. The biocompatibility of the rods was evaluated in vitro in a zebrafish (Danio rerio) liver cell line (ZFL), with results showing that neither long nor short rods with magnetic particles caused cytotoxicity in ZFL cells for concentrations up to 50 μg/ml. We advocate that such nanocomposites can find applications in medical imaging and therapy, where the influence of shape on performance can be also assessed.


Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening.
Defects of mitochondrial oxidative phosphorylation (OXPHOS) are associated with a wide range of clinical phenotypes and time courses. Combined OXPHOS deficiencies are mainly caused by mutations of nuclear genes that are involved in mitochondrial protein translation. Due to their genetic heterogeneity it is almost impossible to diagnose OXPHOS patients on clinical grounds alone. Hence next generation sequencing (NGS) provides a distinct advantage over candidate gene sequencing to discover the underlying genetic defect in a timely manner. One recent example is the identification of mutations in MTFMT that impair mitochondrial protein translation through decreased formylation of Met-tRNA(Met). Here we report the results of a combined exome sequencing and candidate gene screening study. We identified nine additional MTFMT patients from eight families who were affected with Leigh encephalopathy or white matter disease, microcephaly, mental retardation, ataxia, and muscular hypotonia. In four patients, the causal mutations were identified by exome sequencing followed by stringent bioinformatic filtering. In one index case, exome sequencing identified a single heterozygous mutation leading to Sanger sequencing which identified a second mutation in the non-covered first exon. High-resolution melting curve-based MTFMT screening in 350 OXPHPOS patients identified pathogenic mutations in another three index cases. Mutations in one of them were not covered by previous exome sequencing. All novel mutations predict a loss-of-function or result in a severe decrease in MTFMT protein in patients' fibroblasts accompanied by reduced steady-state levels of complex I and IV subunits. Being present in 11 out of 13 index cases the c.626C>T mutation is one of the most frequent disease alleles underlying OXPHOS disorders. We provide detailed clinical descriptions on eleven MTFMT patients and review five previously reported cases.


Open source, open standards, and health care information systems.
Recognition of the improvements in patient safety, quality of patient care, and efficiency that health care information systems have the potential to bring has led to significant investment. Globally the sale of health care information systems now represents a multibillion dollar industry. As policy makers, health care professionals, and patients, we have a responsibility to maximize the return on this investment. To this end we analyze alternative licensing and software development models, as well as the role of standards. We describe how licensing affects development. We argue for the superiority of open source licensing to promote safer, more effective health care information systems. We claim that open source licensing in health care information systems is essential to rational procurement strategy.


A Mutation in the Arabidopsis TFL1 Gene Affects Inflorescence Meristem Development.
We present the initial phenotypic characterization of an Arabidopsis mutation, terminal flower 1-1 (tfl1-1), that identifies a new genetic locus, TFL1. The tfl1-1 mutation causes early flowering and limits the development of the normally indeterminate inflorescence by promoting the formation of a terminal floral meristem. Inflorescence development in mutant plants often terminates with a compound floral structure consisting of the terminal flower and one or two subtending lateral flowers. The distal-most flowers frequently contain chimeric floral organs. Light microscopic examination shows no structural aberrations in the vegetative meristem or in the inflorescence meristem before the formation of floral buttresses. The wild-type appearance of lateral flowers and observations of double mutant combinations of tfl1-1 with the floral morphogenesis mutations apetala 1-1 (ap1-1), ap2-1, and agamous (ag) suggest that the tfl1-1 mutation does not affect normal floral meristems. Secondary flower formation usually associated with the ap1-1 mutation is suppressed in the terminal flower, but not in the lateral flowers, of tfl1-1 ap1-1 double mutants. Our results suggest that tfl1-1 perturbs the establishment and maintenance of the inflorescence meristem. The mutation lies on the top arm of chromosome 5 approximately 2.8 centimorgans from the restriction fragment length polymorphism marker 217.


Type I interferon-mediated autoinflammation due to DNase II deficiency.
Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans.


Pain interference in youth with neurofibromatosis type 1 and plexiform neurofibromas and relation to disease severity, social-emotional functioning, and quality of life.
The physical manifestations of neurofibromatosis type 1 (NF1) can cause chronic pain. This study investigated the impact of pain in youth with NF1 and plexiform neurofibromas (PNs) and its relationship to disease factors, social-emotional functioning, and quality of life (QOL) within a biopsychosocial framework. Caregivers of 59 children and adolescents with NF1 and PNs (6-18 years), and 41 of these youth (10-18 years), completed questionnaires assessing social-emotional functioning and QOL, including an item on pain interference. Measures of disease severity included total PN volume by percent body weight and number of disease complications. Both caregiver (73%) and self-report (59%) ratings indicated that pain interferes with the child's daily functioning despite 33% taking pain medication. Based on caregivers' behavior ratings, more symptoms of anxiety and larger tumor volumes predicted greater pain interference, while greater pain interference, worse depressive symptoms, and more disease complications predicted poorer QOL. As rated by adolescents, more symptoms of anxiety predicted greater pain interference, while greater pain interference and social stress predicted poorer QOL. Further, social-emotional problems mediate the relationship between pain interference and QOL. Thus, pain interferes with daily functioning in the majority of youth with NF1 and PNs even when using pain medication. The impact of pain interference, disease severity, and particularly social-emotional problems on QOL highlights the interaction between physical and psychological states in NF1. Future research and treatment of pain in this population should utilize a biopsychosocial approach and involve multidisciplinary therapies including psychological interventions that target social-emotional functioning.


Early-life exposure to low-dose oxidants can increase longevity via microbiome remodelling in Drosophila.
Environmental stresses experienced during development exert many long-term effects upon health and disease. For example, chemical oxidants or genetic perturbations that induce low levels of reactive oxygen species can extend lifespan in several species. In some cases, the beneficial effects of low-dose oxidants are attributed to adaptive protective mechanisms such as mitohormesis, which involve long-term increases in the expression of stress response genes. Here we show in Drosophila that transient exposure to low concentrations of oxidants during development leads to an extension of adult lifespan. Surprisingly, this depends upon oxidants acting in an antibiotic-like manner to selectively deplete the microbiome of Acetobacter proteobacteria. We demonstrate that the presence of Acetobacter species, such as A. aceti, in the indigenous microbiota increases age-related gut dysfunction and shortens lifespan. This study demonstrates that low-dose oxidant exposure during early life can extend lifespan via microbiome remodelling rather than mitohormesis.


Evaluating the impact of dyslexia laws on the identification of specific learning disability and dyslexia.
Dyslexia is a specific learning disability that impacts word reading accuracy and/or reading fluency. Over half of the states in the USA have passed legislation intended to promote better identification of individuals with dyslexia. To date, no study has been conducted to investigate the potential impact of state laws on the identification of specific learning disability (SLD), and limited data has been presented on the rate at which students in public school settings are identified with dyslexia. The first aim of the current study was to determine if any detectable changes in the identification rates of SLD have occurred in states implementing dyslexia laws because most states do not report number of students identified as dyslexic but rather those students identified with an SLD. The second aim of the study was to characterize the rate of identifying dyslexia in the two states (Texas and Arkansas) that require public schools to report the number of students identified with dyslexia. The third aim was to characterize the identification rate across first to 12th grades. Current SLD rates range from 3.2 to 8.5% in all 50 states. Analysis of SLD prevalence rates did not vary between states with and without dyslexia laws in place. Moreover, there was no change in the identification of SLD once states had implemented these laws. Rates of dyslexia in Arkansas and Texas were less than 5%. Given the persistent levels indicating lack of reading proficiency, our review of data suggests that overall students with dyslexia are being underidentified.


Age-related changes in human blinks. Passive and active changes in eyelid kinematics.
The authors analyzed eyelid kinematics in normal aging subjects to test the hypothesis that eyelid movements exhibit age-related changes and that blink disorders prevalent among the elderly, in turn, represent an outcome of normal aging processes. The electromagnetic search coil technique was used to study blinks in normal human subjects for each decade from 40 to 89 years. Blink metrics (amplitude, peak velocity, and duration), main sequence relationships, and conjugacy were assessed. Mean amplitude and peak velocity of blinks decreased with age for spontaneous blinks and, to a lesser extent, for voluntary blinks. Some but not all, of this decline could be attributed to a peripheral phenomenon, narrowed palpebral fissure width. The spontaneous blink down phase main sequence slope also declined with age. By contrast, blink rate and the coordination of movements of the two eyelids--blink conjugacy--exhibited no change. These data demonstrate that disorders of blink systems typically seen in persons 50 years of age or older occur on a background of normal age-dependent changes in eyelid kinematics. Alterations in main sequence slope imply the operation of central adaptive systems during aging. Reduction in main sequence slope is interpreted as a reduction in aggregate orbicularis oculi motoneuron activity. Such a central neurologic adjustment in the motor output of blink systems may serve to compensate for an age-related increase in blink reflex excitability. Compensatory reduction in the main sequence relationship may offset a potentially hyperexcitable blink reflex, thereby reducing the likelihood of disorders such as blepharospasm. The authors conclude that although there are changes in the kinematics of blinking with age, such changes do not necessarily predispose an aging population to eyelid motility disorders.


Effectiveness of the BOOST-A™ online transition planning program for adolescents on the autism spectrum: a quasi-randomized controlled trial.
The majority of existing transition planning programs are focused on people with a disability in general and may not meet the specific need of adolescents on the autism spectrum. In addition, these interventions focus on specific skills (e.g. job readiness or self-determination) rather than the overall transition planning process and there are methodological limitations to many of the studies determining their effectiveness. The Better OutcOmes & Successful Transitions for Autism (BOOST-A™) is an online program that supports adolescents on the autism spectrum to prepare for leaving school. This study aimed to determine the effectiveness of the BOOST-A™ in enhancing self-determination. A quasi-randomized controlled trial was conducted with adolescents on the autism spectrum enrolled in years 8 to 11 in Australian schools (N = 94). Participants had to have basic computer skills and the ability to write at a year 5 reading level. Participants were allocated to a control (n = 45) or intervention (n = 49) group and participants were blinded to the trial hypothesis. The intervention group used the BOOST-A™ for 12 months, while the control group participated in regular practice. Outcomes included self-determination, career planning and exploration, quality of life, environmental support and domain specific self-determination. Data were collected from parents and adolescents. There were no significant differences in overall self-determination between groups. Results indicated significant differences in favor of the intervention group in three areas: opportunity for self-determination at home as reported by parents; career exploration as reported by parents and adolescents; and transition-specific self-determination as reported by parents. Results provide preliminary evidence that the BOOST-A™ can enhance some career-readiness outcomes. Lack of significant outcomes related to self-determination at school and career planning may be due to the lack of face-to-face training and parents being the primary contacts in the study. Further research is needed to determine effectiveness of the BOOST-A™ related to post-secondary education and employment. Trial registration #ACTRN12615000119594.


Which exercise prescriptions improve quality of life and physical function in patients with cancer during and following treatment? A systematic review and meta-analysis of randomised controlled trials.
Certain exercise prescriptions for patients with cancer may improve self-reported quality of life (QoL) and self-reported physical function (PF). We investigated the effects of exercise on QoL and PF in patients with cancer and studied differences in effects between different intervention-related and exercise-related characteristics. We searched four electronic databases to identify randomised controlled trials investigating exercise effects on QoL and PF in patients with cancer. Pooled effects (Hedges' g) were calculated using Comprehensive Meta-Analysis software. Subgroup analyses were conducted based on intervention dimensions, including timing, duration and delivery mode, and exercise dimensions, including frequency, intensity, type and time (FITT factors). We included 74 exercise arms. Patients who were randomised to exercise interventions had significantly improved QoL (g=0.15, 95% CI (0.10 to 0.20), n=67 exercise arms) and PF (g=0.21, 95% CI (0.15 to 0.27), n=59 exercise arms) compared with patients in control groups. We found a significant between-group difference for exercise delivery mode, with significant beneficial effects for supervised exercise interventions (g=0.20, 95% CI (0.14 to 0.26) for QoL and g=0.27, 95% CI (0.20 to 0.33) for PF), but not for unsupervised interventions (g=0.04, 95% CI (-0.06 to 0.13) for QoL and g=0.09, 95% CI (-0.01 to 0.19) for PF). No statistically significant differences in intervention effects were found for variations in intervention timing, duration or exercise FITT factors. Unsupervised exercise with higher weekly energy expenditure was more effective than unsupervised exercise with lower energy expenditure (z=2.34, p=0.02). Exercise interventions, especially when supervised, have statistically significant and small clinical benefit on self-reported QoL and PF in patients with cancer. Unsupervised exercise intervention effects on PF were larger when prescribed at a higher weekly energy expenditure.


Utility of base deficit for identifying major injury in elder trauma patients.
Early identification of serious injuries is especially important in elders. Base deficit (BD) is an indicator of serious injury in trauma patients. There are limited data to support the utility of BD in elders who have sustained trauma. To assess the diagnostic performance of BD in identifying major injury in elders. This was a prospective, observational, preliminary study. Elder (age 65 years and older) patients with significant injury mechanisms had BD analyzed during initial emergency department resuscitation. Major injury was defined by an Injury Severity Score > or =15, a decrease in hematocrit of more than ten points, or blood transfusion. Patients were stratified into two groups of minor and major injuries. Data were reported as means (+/-SD). Receiver operating characteristic (ROC) curves tested the diagnostic ability of BD to identify major injury. Seventy-four patients were enrolled; the mean (+/-SD) age was 75 (+/-7) years, and 57% were male. Twenty-four patients (32%) had major injury. The mean (+/-SD) for BD in the major injury group (-2.9 [+/-6] mmol/L) was significantly different from that in the minor injury group (0.8 [+/-3] mmol/L), with a mean difference of 3.7 (95% confidence interval = 1.4 to 5.9). ROC curves revealed that BD was able to identify major injury in elder patients (area under the ROC curve, 0.72; 95% confidence interval = 0.60 to 0.85; p = 0.0003). The preliminary data from this study indicate that in trauma patients aged 65 years and older, increased BD at emergency department arrival can predict life-threatening injury.


Racial/ethnic differences in breastfeeding initiation and continuation in the United kingdom and comparison with findings in the United States.
Patterns of breastfeeding vary considerably across different racial/ethnic groups; however, little is known about factors that might explain differences across and within different racial/ethnic groups. Here we examine patterns of breastfeeding initiation and continuation among a racially/ethnically diverse sample of new mothers and compare this with patterns seen in the United States. The effects of demographic, social, economic, and cultural factors on racial/ethnic differences in breastfeeding practices are assessed. The sample includes all singleton infants whose mothers participated in the first survey of the United Kingdom Millennium Cohort Study. Missing data reduced the sample to 17,474 (96%) infants with complete data. After adjustment for demographic, economic, and psychosocial factors, logistic regression models showed that Indian, Pakistani, Bangladeshi, black Caribbean, and black African mothers were more likely to initiate breastfeeding compared with white mothers. Further adjustment for a marker of cultural tradition attenuated these relationships, but all remained statistically significant, suggesting that some of the difference was a consequence of cultural factors. After adjustment for demographic, economic, and psychosocial factors, Indian, Pakistani, Bangladeshi, black Caribbean, and black African mothers were more likely to continue breastfeeding at 3 months compared with white mothers. Additional adjustment for a marker of cultural tradition attenuated the relationship for Indian, Pakistani, Bangladeshi, and black African mothers, but all remained statistically significant. Models run for breastfeeding continuation at 4 and 6 months were consistent with these results. We have shown that in the United Kingdom the highest breastfeeding rates are among black and Asian mothers, which is in stark contrast to patterns in the United States, where the lowest rate is seen among non-Hispanic black mothers. The contrasting racial/ethnic patterns of breastfeeding in the United Kingdom and United States necessitate very different public health approaches to reach national targets on breastfeeding and reduce health disparities. Those who implement future policies aimed at increasing breastfeeding rates need to pay attention to different social, economic, and cultural profiles of all racial/ethnic groups.


Improved cerebral vasomotor reactivity after exercise training in hemiparetic stroke survivors.
Animal studies provide strong evidence that aerobic exercise training positively influences cerebral blood flow, but no human studies support the use of exercise for improving cerebral hemodynamics. This randomized study in stroke survivors assessed the effects of treadmill aerobic exercise training (TM) on cerebral blood flow parameters compared to a control intervention of nonaerobic stretching. Thirty-eight participants (19 in TM group and 19 in control group) with remote stroke (>6 months) and mild to moderate gait deficits completed middle cerebral artery blood flow velocity measurements by transcranial Doppler ultrasonography before and after a 6-month intervention period. Middle cerebral artery blood flow velocity was assessed bilaterally during normocapnia and hypercapnia (6% CO2). Cerebral vasomotor reactivity (cVMR) was calculated as percent change in middle cerebral artery blood flow velocity from normocapnia to hypercapnia (cVMR percent) and as an index correcting percent change for absolute increase in end tidal CO2 (cVMR index). The TM group had significantly larger improvements than did controls for both ipsilesional and contralesional cVMR index (P≤0.05) and contralesional cVMR percent (P≤0.01). Statin users in the TM group (n=10) had higher baseline cVMR and lower training-induced cVMR change, indicating that cVMR change among those not using statins (n=9) primarily accounted for the between-group effects. There was a 19% increase in Vo2 peak for the TM group compared to a 4% decrease in the control group (P<0.01), and peak fitness change correlated with cVMR change (r=0.55; P<0.05). Our data provide the first evidence to our knowledge of exercise-induced cVMR improvements in stroke survivors, implying a protective mechanism against recurrent stroke and other brain-related disorders. Statin use appears to regulate cVMR and the cVMR training response.


Analysis of co-factor function in a glucocorticoid-resistant small cell carcinoma cell line.
Human small cell lung carcinoma (SCLC) tumours exhibit neuroendocrine differentiation, secreting hormones such as ACTH and related peptides. While glucocorticoids inhibit ACTH secretion from the pituitary, this does not occur in SCLC tumours and SCLC cell lines. Failure of glucocorticoids to suppress ACTH peptides is accompanied by a global lack of glucocorticoid action in a number of SCLC cell lines. In the human SCLC cell line, COR L103, activation of a human tyrosine aminotransferase (TAT3)-luciferase reporter gene is resistant to glucocorticoids despite similar glucocorticoid receptor (GR) expression to the glucocorticoid-sensitive A549 human lung cancer cell line; moreover, the GR is free of deleterious mutations. Over-expression of a wild-type GR restores glucocorticoid regulation of TAT3-luciferase, and this is enhanced when the activation function (AF)-2 domain is deleted but much reduced when the AF-1 domain is deleted. This suggests aberrant AF-2 activation domain function. We identified defective steroid receptor co-activator 1 (SRC1) recruitment to the GR AF-2 in COR L103 cells, although SRC1 was successfully recruited to the steroid X receptor with rifampicin, suggesting a defect in the GR. Analysis of other GR C-terminal co-factors identified increased expression of nuclear co-repressor (NCoR) in COR L103 cells. To determine the impact of this, NCoR was over-expressed in A549 cells, where it reduced GR transactivation by 55%. In summary, glucocorticoid resistance is associated with altered SRC protein recruitment and increased expression of NCoR in these SCLC cells, suggesting that glucocorticoid sensitivity may be modified by subtle changes in co-factor recruitment.


Exchangeability of alpha-actinin in living cardiac fibroblasts and muscle cells.
We have investigated the exchangeability of alpha-actinin in various structures of cultured chick cardiac fibroblasts and muscle cells using fluorescent analogue cytochemistry in combination with fluorescence recovery after photobleaching. Living cells were microinjected with tetramethylrhodamine-labeled alpha-actinin, which became localized in cellular structures. Small areas of labeled structures were then photobleached with a laser pulse, and the subsequent recovery of fluorescence was monitored with an image intensifier coupled to an image-processing system. In fibroblasts, fluorescence recovery was studied in stress fibers and in adhesion plaques. Bleached spots in adhesion plaques generally attained complete recovery within 20 min; whereas complete recovery in stress fibers occurred within 30 to 60 min. In muscle cells, alpha-actinin became localized in the Z-lines of sarcomeres, in punctate structures, and in apparently continuous bundle-like structures. Fluorescence recovery in Z-lines, punctate structures, and some bundle-like structures was extremely slow. Complete recovery did not occur within the 6- to 7-h observation period. However, some bundle-like structures recovered completely within 60 min, a rate similar to that of stress fibers in fibroblasts. These results indicate that fluorescently labeled alpha-actinin is more stably associated with structures in muscle cells than in fibroblasts. In addition, different structures within the same cell can display different alpha-actinin exchangeabilities which, in muscle cells, could be developmentally related.


Implantation of vancomycin microspheres in blend with human/rabbit bone grafts to infected bone defects.
In orthopaedic applications, allografts are used for restoration of bone defects. In order to combine the effects of bone repair and to prevent the infection, antibiotic-impregnated bone grafts are under current investigation with promising early results. In this study, to preserve the stability of antibiotics and to provide appropriate release profiles for 4-6 weeks, antibiotic-loaded microspheres were administered in combination with allografts and vancomycin was the antibiotic loaded to microspheres. Particle size, surface characteristics, loading capacity and in vitro release characteristics of the microspheres with and without allografts were determined. In vivo studies were performed on rabbits and antibiotic amount was determined by a fluorescence polarization immunoassay (FPIA) method from synovial fluid sample aspirated. According to the results, although the in vitro study demonstrated effective antibiotic release of vancomycin from antibiotic-impregnated allografts for 5 weeks, in vivo conditions led to an early instability of the antibiotic (in powder form) and contrary to the high initial loading dose an effective release could not be obtained from the allografts after the first week. Following these studies, it was determined that antibiotic release over a minimum inhibitory concentration (MIC) for 6 weeks was realized from vancomycin-loaded microspheres which were implanted in a blend with allografts in bone defects. In conclusion, preservation of the antibiotic in microspheres maintained the bioactivity and provided the controlled antibiotic release, thus implantation of microspheres in a blend with allografts seemed to be a promising carrier system for the orthopaedic applications.


Interleukin-22 Promotes Osteosarcoma Cell Proliferation and Invasion via STAT3 Activation.
BACKGROUND Interleukin-22 (IL-22) is one of the cytokines secreted by T-helper 17 (Th17) cells. It belongs to the IL-10 cytokine family and influences a variety of immune reactions. Studies have indicated that IL-22 can promote cancer progression and metastases. However, the function of IL-22 in osteosarcoma (OS) remains unclear. MATERIAL AND METHODS In this study, the expression of IL-22 in the OS cell line was detected by qRT-PCR. The role of IL-22 in proliferation and invasion in OS cells was tested by MTT and Transwell assays. The protein expression of STAT3, phospho-STAT3, AKT, and phospho-AKT was detected by Western blot analysis. RESULTS The results showed that IL-22 was upregulated in OS cells. IL-22 dose-independently promoted OS cells proliferation and invasion, which could be reversed by IL-22 antibody or STAT3 siRNA. Furthermore, IL-22 exposure of OS cells resulted in dose-independently increased levels of phosphorylated STAT3 protein kinases. Interestingly, IL-22 did not influence the expression of phosphorylated AKT. CONCLUSIONS These results suggest that IL-22 promotes OS cells proliferation and invasion and its effect is mediated by activation of the STAT3 pathway. These findings demonstrate that IL-22 may serve as a promising molecular biomarker for diagnosis and therapy for OS patients.


Gas-uptake pharmacokinetics and biotransformation of 1,1-dichloro-1-fluoroethane (HCFC-141b).
A physiologically based pharmacokinetic model was used to determine the in vivo metabolic constants of the candidate chlorofluorocarbon replacement 1,1-dichloro-1-fluoroethane (HCFC-141b). Rats were exposed by inhalation to HCFC-141b concentrations ranging from 1,000 to 10,000 ppm. Uptake studies of HCFC-141b in the rat indicated the involvement of saturable and first-order components. The in vivo metabolic constants for HCFC-141b were: KM = 7.0 mg liter-1 (59.9 mumol liter-1), Vmax = 0.2 mg kg-1 hr-1 (1.71 mumol kg-1 hr-1), and k = 0.5 hr-1. In rats exposed to HCFC-141b, 2,2-dichloro-2-fluoroethanol was excreted in the urine as its glucuronide conjugate, and the rate of 2,2-dichloro-2-fluoroethanol excretion increased linearly with increasing HCFC-141b exposure concentrations. Diallyl sulfide, a selective, mechanism-based inhibitor of cytochrome P-450 2E1, inhibited the metabolism of HCFC-141b, as indicated by a decreased uptake of HCFC-141b and by a lowered urinary excretion of 2,2-dichloro-2-fluoroethanol in diallyl-sulfide-treated rats. In vitro biotransformation studies with microsomes from rats treated with pyridine, an inducer of cytochrome P-450 2E1, confirmed that cytochrome P-450 2E1 is involved in the metabolism of HCFC-141b. The in vitro metabolic rate constants for the biotransformation of HCFC-141b to 2,2-dichloro-2-fluoroethanol were: KM = 0.39 +/- 0.11 mM and Vmax = 2.08 +/- 0.23 nmol mg protein-1 hr-1.(ABSTRACT TRUNCATED AT 250 WORDS)


Psychosocial effects of physical and verbal abuse in postmenopausal women.
The purpose of this study was to examine the psychological effects of physical and verbal abuse in a cohort of older women. This observational cohort study was conducted at 40 clinical sites nationwide that are part of the Women's Health Initiative (WHI) Observational Study. We surveyed 93,676 women aged 50 to 79 years using the mental health subscales and the combined mental component summary (MCS) score of the RAND Medical Outcomes Study 36-item instrument. At baseline, women reporting exposure to physical abuse only, verbal abuse only, or both physical and verbal abuse had a greater number of depressive symptoms (1.6,1.6, and 3 more symptoms, respectively) and lower MCS scores (4.6, 5.4, and 8.1 lower scores, respectively) than women not reporting abuse. Compared with women who had no exposure to abuse, women had a greater increase in the number of depressive symptoms when they reported a 3-year incident exposure to physical abuse only (0.2; 95% confidence interval [CI], -0.21 to 0.60), verbal abuse only (0.18; 95% CI, 0.11 to 0.24), or both physical and verbal abuse (0.15; 95% CI, -0.05 to 0.36); and they had a decrease in MCS scores when they reported a 3-year incident exposure to physical abuse only (-1.12; 95% CI, -2.45 to 0.12), verbal abuse only (-0.55; 95% CI, -0.75 to -0.34), and both physical and verbal abuse (-0.44; 95% CI, -1.11 to -0.22) even after adjustment for sociodemographic characteristics. Exposure to abuse in older, functionally independent women is associated with poorer mental health. The persistence of these findings suggests that clinicians need to consider abuse exposure in their older female patients who have depressive symptoms. Clinicians caring for older women should identify women at risk for physical and verbal abuse and intervene appropriately.


Integrated genome-scale prediction of detrimental mutations in transcription networks.
A central challenge in genetics is to understand when and why mutations alter the phenotype of an organism. The consequences of gene inhibition have been systematically studied and can be predicted reasonably well across a genome. However, many sequence variants important for disease and evolution may alter gene regulation rather than gene function. The consequences of altering a regulatory interaction (or "edge") rather than a gene (or "node") in a network have not been as extensively studied. Here we use an integrative analysis and evolutionary conservation to identify features that predict when the loss of a regulatory interaction is detrimental in the extensively mapped transcription network of budding yeast. Properties such as the strength of an interaction, location and context in a promoter, regulator and target gene importance, and the potential for compensation (redundancy) associate to some extent with interaction importance. Combined, however, these features predict quite well whether the loss of a regulatory interaction is detrimental across many promoters and for many different transcription factors. Thus, despite the potential for regulatory diversity, common principles can be used to understand and predict when changes in regulation are most harmful to an organism.


[Validity of serum surfactant protein D measurements in a cross-sectional study].
In October, 2008, the method for enzyme-linked immunoassay for serum surfactant protein D (SP-D) was changed from SP-D kit (Yamasa) EIA to SP-D kit (Yamasa) EIA2 in Japan. In our follow-up survey on 144 indium-exposed workers from December, 2008 to June, 2009, SP-D showed systematically higher values compared to the first survey from March to July, 2008. Geometric means (prevalence rate) of serum SP-D of the first and follow-up study were 52.1 ng/mL (4.1%) and 72.1 ng/mL (14.6%), respectively, though serum KL-6 and SP-A were stable. Thus, we examined the validity of the old and new methods. As a result of examining about 200 subjects, the correlation between the two methods was good. However, as a reproducibility examination of about another 300 subjects between the post-measured and the pre-measured values with the same new method at Laboratory A, the differences between vales in each observation are not acceptable. Especially, examinations performed using the lot 804, 805, and 105 at laboratory A showed systematic higher values than others. Various factors might have caused the large measurement bias; in particular, the new method lacks sufficient reproducibility between lots. When observing the chronological change of SP-D, attention must be given in comparisons of serum SP-D after October, 2008 to before that because of the metrology-dependent measurement bias.


A Qualitative Study to Understand the Potential Efficacy of an Information-Based Sugar Reduction Intervention among Low Socioeconomic Individuals in the UK.
Sugar consumption in the UK consistently exceeds recommendations, despite the association it has with poor health outcomes. Low socioeconomic groups are most likely to over-consume sugar, which could exacerbate existing health disparities. Various interventions attempt to reduce the amount of sugar consumed, but their effectiveness is still unclear. This study qualitatively explored the sugar consumption behaviours of individuals experiencing food poverty, and examined how an information-based sugar reduction intervention might influence these behaviours. Eight clients and six volunteers from a food bank in Bristol (UK) completed semi-structured, one-to-one interviews that were thematically analysed. Food bank clients appeared to heavily consume sugar, with little understanding of the associated health effects and limited awareness of the intervention. Consumption behaviours were particularly influenced by personal and psychological factors, such as mental health; in addition to social factors, like familial behaviours and food access issues. It emerged that food bank clients' often-challenging personal circumstances were likely to promote their sugar consumption. Making intervention materials visually appealing and easily comprehendible were found to be important for improving an intervention's reception. Recommendations were developed to improve the efficacy of similar information-based sugar reduction interventions among socioeconomically deprived groups.


Speak up! Speak out! Building HIV and AIDS awareness among Jamaican school children.
The Government of Jamaica, through the Ministry of Health and other ministries, assisted by international funding agencies and members of non-governmental organizations, has diligently led the charge to reduce the incidence ofHIV and AIDS in Jamaica. Yet, the continued escalation in the infection rate attested to the need for education towards the reduction of stigma and discrimination, factors that fuel the spread of the virus. Significant efforts were made to woo corporations in Jamaica to redouble their efforts and provide resources to address the continued escalation of the AIDS epidemic in Jamaica. Scotiabank Jamaica responded with a unique educational initiative. The Scotiabank National Primary Schools HIV and AIDS Debating Competition in 2006-2007 was conducted over a seven-month period. It was opened to primary-level, government and private institutions islandwide. A total of91 institutions competed with each other debating 16 moots (i.e., topics) in 417 debates from the first preliminary rounds through to the final. Moots reflected curricular and extracurricular concerns, emphasized the values of compassion, healthy lifestyles, critical thinking and child rights; they also sent messages of anti-discrimination, and parental and community responsibilities. Whereas communication between the organizers and the schools was sometimes challenging, schools subscribed to the activity (debates) for the awareness it brought and for the potential for developing students. Attempts were also made to raise awareness among teachers, parents and the general community. Feedback at the end acclaimed the debates as a valuable strategy for building awareness as well as development of student potential and unity around a common cause.


Context-dependent enhancer function revealed by targeted inter-TAD relocation.
The expression of some genes depends on large, adjacent regions of the genome that contain multiple enhancers. These regulatory landscapes frequently align with Topologically Associating Domains (TADs), where they integrate the function of multiple similar enhancers to produce a global, TAD-specific regulation. We asked if an individual enhancer could overcome the influence of one of these landscapes, to drive gene transcription. To test this, we transferred an enhancer from its native location, into a nearby TAD with a related yet different functional specificity. We used the biphasic regulation of Hoxd genes during limb development as a paradigm. These genes are first activated in proximal limb cells by enhancers located in one TAD, which is then silenced when the neighboring TAD activates its enhancers in distal limb cells. We transferred a distal limb enhancer into the proximal limb TAD and found that its new context suppresses its normal distal specificity, even though it is bound by HOX13 transcription factors, which are responsible for the distal activity. This activity can be rescued only when a large portion of the surrounding environment is removed. These results indicate that, at least in some cases, the functioning of enhancer elements is subordinated to the host chromatin context, which can exert a dominant control over its activity.


Reproduction of postweaning multisystemic wasting syndrome (PMWS) in immunostimulated and non-immunostimulated 3-week-old piglets experimentally infected with porcine circovirus type 2 (PCV2).
Postweaning multisystemic wasting syndrome (PMWS) in swine is causally associated with the newly recognised pathogen, porcine circovirus type 2 (PCV2). In this study, 3-week-old SPF PCV2-seronegative piglets were inoculated intranasally with PCV2. The effect of immunostimulation on the induction of PMWS was investigated by immunisation with keyhole limpet hemocyanin (KLH) emulsified in incomplete Freunds adjuvant. The study was terminated 5 weeks after inoculation. While disease was not observed in the age-matched controls, two out of five non-immunised PCV2-infected piglets died on postinoculation day (PID) 21, and one was euthanized on PID 25 in moribund condition. These animals had appeared lethargic with persistent fever from PID 12 onwards. The euthanized pig appeared smaller than littermates and suffered from jaundice. At postmortem examination, gastric ulceration, icterus, and liver and thymus atrophy were observed. Furthermore, histological lesions of degenerating hepatocytes and hepatitis in combination with lymphoid depletion and syncytial cells in lymph nodes were consistent with the diagnosis of PMWS. One out of five immunostimulated PCV2-infected piglets was euthanized on PID 22 with convulsions after a period with wasting. This pig was lethargic from PID 14 onwards with persistent fever from PID 8 and transient dyspnoea. No differences in clinical signs, gross pathologic or histological findings were observed for the remaining non-immunostimulated and immunostimulated PCV2-infected piglets. All 10 PCV2-inoculated piglets seroconverted to PCV2 within 14 days after inoculation. By virus isolation, quantitative polymerase chain reaction (Q-PCR), and immunostaining of cryostat sections, it was demonstrated that lymphoid tissue contained abundant PCV2 antigen. Viral DNA load in serum samples was assessed by Q-PCR. All four PMWS-affected piglets had high levels of PCV2 DNA in serum, suggesting that there was a correlation between high levels of viral DNA in serum and the development of PMWS. In conclusion, infection with PCV2 caused PMWS in SPF piglets, however, the immunostimulation did not seem to play a critical role.


Influences of antigen processing on the expression of the T cell repertoire. Evidence for MHC-specific hindering structures on the products of processing.
Two lines of evidence in the current study indicate that antigen processing is a major factor, in addition to MHC binding and T cell repertoire, that determines Ir gene responsiveness and epitope immunodominance. First, immunization with synthetic peptides of myoglobin sequences revealed new reactivities that had not appeared after priming with native myoglobin. For example, B10.S mice (H-2S) immune to equine myoglobin predominantly responded to peptide 102-118, whereas there was little, if any, response to this peptide in B10.BR (H-2k) mice immunized with native equine myoglobin. However, after immunization with the 102-118 peptide, both strains responded to the peptide. After in vitro restimulation, B10.BR T cells responded as well as B10.S T cells. Similarly, some individual 102-118-specific T cell clones from mice of both haplotypes showed similar dose responses and fine specificity patterns. Thus, low responsiveness to this site is due neither to a hole in the repertoire nor to a failure to bind to the appropriate MHC molecule. An alternative explanation was suggested by the observation that, whereas B10.S T cells from peptide 102-118-immune mice responded almost as well to whole myoglobin as to the peptide, the B10.BR T cells from peptide immune mice, while responding well to peptide, were poorly stimulated by whole myoglobin. Thus, the product of natural processing of equine myoglobin probably has hindering structures in the regions flanking the core epitope 102-118 that interfere with presentation by I-Ak but not I-AS. The second line of evidence that processing of native myoglobin may influence the apparent specificity of the T cell response was obtained using the I-Ad-restricted sperm whale myoglobin 102-118-specific clone 9.27. This clone discriminated readily between whole sperm whale myoglobin and equine myoglobin, but it did not distinguish between peptides corresponding to 102-118 of the sperm whale and equine sequences. This distinction between equine peptide and native equine myoglobin could be overcome by artificial "processing" of equine myoglobin with cyanogen bromide. In both sets of experiments, F1 APCs that present the same epitope well to T cells of another haplotype failed to overcome the defect, which was therefore not due to the availability of different processed cleavage fragments in APC of different haplotypes, as would be expected if there were MHC-linked processing. Thus, the differential responses to peptides versus native molecule for both I-Ad- and I-Ak-restricted clones appeared to depend on the restricting molecule used.(ABSTRACT TRUNCATED AT 400 WORDS)


Bipolar II disorder in patients with a current diagnosis of recurrent depression.
The prevalence of bipolar II disorder (BD-II) in Russia has never been studied. Therefore, we sought to identify patients meeting diagnostic criteria for BD-II among patients with a current diagnosis of recurrent depressive disorder (RDD) through the use of the Russian versions of the Hypomania Checklist (HCL-32) and Bipolarity Index scales for differentiating between BD-II and RDD. In a non-interventional diagnostic study, we selected 409 patients aged between 18 and 65 years from two medical settings with (i) a current diagnosis of RDD, (ii) an illness duration of at least three years, and (iii) at least two affective episodes. The diagnosis was based on clinical assessment and confirmed by the Russian version of the Mini International Neuropsychiatric Interview. All patients were assessed by the HCL-32, the Bipolarity Index, and the Personal and Social Performance Scale. Among patients with a current diagnosis of RDD, 40.8% had a diagnosis of bipolar disorder (bipolar I disorder: 4.9%; BD-II: 35.9%). The average time lag from onset to a correct diagnosis of BD-II was 15 years and patients were treated only with antidepressants. The sensitivity of the Russian version of the HCL-32 at the optimal cutoff point (≥14.0) was 83.7%, and its specificity was 71.9%. The Bipolarity Index showed significant differences between the total scores of the patients with BD-II and RDD (31.8 versus 20.2; p < 0.0001). The optimal threshold was ≥22.0 (sensitivity 73.5%; specificity 72.3%). In Russia, diagnostic errors are an important cause of the non-detection of bipolar disorder, particularly BD-II. The Russian version of the HCL-32 and the Bipolarity Index, as additional tools, could be useful for bipolarity screening.


Immunostimulation-Mediated Anti-tumor Activity of Bamboo (Sasa senanensis) Leaf Extracts Obtained Under 'Vigorous' Condition.
Traditional Japanese medicine uses the leaves of Kumaizasa bamboo extracted in hot water at 100°C. For this study, we developed a new, 'vigorous' extraction method involving steps at 100, 121 and 196°C. This procedure not only yielded greater amounts of extract but also with significant increase in immunostimulating activity, which induces activation of human natural killer (NK) cells, macrophages and potent induction of IL-2, IL-12 and IFN-γ in tumor bearing mice. The efficacy of the extract to facilitate phagocytosis and nitric oxide production by mouse peritoneal macrophages was determined and compared with that of 1,3-β-glucan. Anti-tumor activity was evaluated in vivo in several mouse tumor models (S-180, C38 and Meth-A). Oral administration of the extracts was carried out when tumor reached size of approximately 6 mm at concentrations of 0.05% or higher. The extracts significantly suppressed tumor growth in S-180 and C38 tumor models. Overall survival was significantly prolonged in the treatment group than that of control. Activation of macrophages and NK cells by the extracts suggests that the anti-tumor efficacy of the extract is mediated by immunopotentiation. The extracts resolved into three major fractions (F-I, F-II and F-III) in Sephadex gel chromatography. Fraction F-I consists of 1,3-β-glucan and stimulated both macrophages and NK cells suggesting that it may be the primary immunopotentiating factor in suppressing cancer. Fraction F-III has potent free radical scavenging effects and may play an important role in cancer prevention. These results warrant further translation and clinical investigations.


Discoidin domain receptors and their ligand, collagen, are temporally regulated in fetal rat fibroblasts in vitro.
The biochemical regulation of collagen deposition during adult cutaneous wound repair is poorly understood. Likewise, how collagen is perceived and modulated in fetal scarless healing remains unknown. Recently, discoidin domain receptors-1 and 2 (DDR1 and DDR2) with tyrosine kinase activity have been identified as novel receptors for collagen. In light of these findings, it was speculated that the production of collagen receptors DDR1 and DDR2 by fetal fibroblasts may be temporally regulated to correlate with the ontogeny of embryonic scar formation. More specifically, because DDRs directly bind collagen and transmit the signals intracellularly, it was hypothesized that they may play an important role in fetal scarless healing by ultimately regulating and modulating collagen production and organization. As part of a fundamental assessment to elucidate the role of DDRs in scarless fetal wound repair, the endogenous expression of DDR1, DDR2, collagen I, and total collagen, as a function of fetal Sprague-Dawley rat skin fibroblasts of different gestational ages, representing scar-free (<E16.5 days) and scar-forming (>E16.5) periods was determined. Using explanted dermal fibroblasts of gestational days E13.5, E16.5, E18.5, and E21.5 (term gestation = 21.5 days) fetuses (n = 92), [3H]proline incorporation assay and Northern and Western blotting analysis were performed to compare the expressions of these molecules with scar-free and scar-forming stages of embryonic development. These results revealed a pattern of increasing collagen production with increasing gestational ages, whereas DDR1 expression decreased with increasing gestational age. This observation suggests that elevated levels of DDR1 may play an important role in scarless tissue regeneration by early gestation fetal fibroblasts. In contrast, DDR2 was expressed by fetal rat fibroblasts at a similar level throughout gestation. These data demonstrate for the first time the temporal expression of collagen and DDR tyrosine kinases in fetal rat fibroblasts as a function of gestational ages. Overall, these data suggest that differential temporal expression of the above-mentioned molecules during fetal skin development may play an important role in the ontogeny of scar formation. Future studies will involve the characterization of the biomolecular functions of these receptor kinases during fetal wound repair.


Impact of echocardiography on one-month and one-year mortality of intertrochanteric fracture patients.
The aim of this study was to analyze the effects of preoperative echocardiography on patient survival, timing of surgery in length of hospital stay in patients who will undergo hip nailing for an intertrochanteric fracture. The clinical records of the patients who were admitted to a tertiary university hospital with an intertrochanteric femur fracture were retrospectively analyzed. The age, gender, American Society of Anesthesiologists (ASA) score, days to surgery, total hospital stay, cardiac drug prescription/modification, cardiac intervention and presence of an echocardiography assessment including detailed findings were reviewed. Mortality data were accessed from the national civil registration system. 181 (110 women and 71 men; mean age 81 (44-98)) cases were studied whom 65 underwent pre-operative echocardiography. Time to surgery and total hospital stay was 2 days longer at transthoracic echocardiography (TTE) group (p < 0.001). At one month control group survival rate was 93.1% on contrary it was 75.4% at TTE group. One-year survival rates were 77.3% and 55.1% respectively. Likewise mean expected survival time was 21.6 ± 1.03 months for control group and 15.12 ± 1.64 months for TTE group (p < 0.001). Only increased left ventricular end diastolic diameter (LVEDD) was showed to be associated with increasing one-year mortality with a hazard ratio of 10.78 (2.572-45.19) at multivariate model. Cardiac findings and requisite for preoperative TTE and increased LVEDD is a strong predictor for mortality. TTE significantly lengthens the time to surgery. Also LVEDD measurement can be easily performed in the bedside which we believe would save time and reduce mortality. Level III Diagnostic study.


A rapid, flexible method for incorporating controlled antibiotic release into porous polymethylmethacrylate space maintainers for craniofacial reconstruction.
Severe injuries in the craniofacial complex, resulting from trauma or pathology, present several challenges to functional and aesthetic reconstruction. The anatomy and position of the craniofacial region make it vulnerable to injury and subsequent local infection due to external bacteria as well as those from neighbouring structures like the sinuses, nasal passages, and mouth. Porous polymethylmethacrylate (PMMA) "space maintainers" have proven useful in staged craniofacial reconstruction by promoting healing of overlying soft tissue prior to reconstruction of craniofacial bones. We describe herein a method by which the porosity of a prefabricated porous PMMA space maintainer, generated by porogen leaching, can be loaded with a thermogelling copolymer-based drug delivery system. Porogen leaching, space maintainer prewetting, and thermogel loading all significantly affected the loading of a model antibiotic, colistin. Weeks-long release of antibiotic at clinically relevant levels was achieved with several formulations. In vitro assays confirmed that the released colistin maintained its antibiotic activity against several bacterial targets. Our results suggest that this method is a valuable tool in the development of novel therapeutic approaches for the treatment of severe complex, infected craniofacial injuries.


Factors associated with the use of complementary and alternative medicines for prostate cancer by long-term survivors.
To assess whether the use of complementary and alternative medicines therapies (CAMs) for prostate cancer and/or its treatment side effects by long-term survivors is associated with selected socio-demographic, clinical, health-related quality-of-life (HRQOL) and/or psychological factors. The Prostate Cancer Care and Outcomes Study (PCOS) is a population-based cohort study of men with prostate cancer who were aged less than 70 years at diagnosis in New South Wales, Australia. Included in these analyses were men who returned a 10-year follow-up questionnaire, which included questions about CAM use. Validated instruments assessed patient's HRQOL and psychological well-being. Poisson regression with robust variance estimation was used to estimate the adjusted relative risks of current CAM use for prostate cancer according to socio-demographic, clinical, HRQOL and psychological factors. 996 of 1634 (61%) living PCOS participants completed the 10-year questionnaire. Of these 996 men, 168 (17%) were using CAMs for prostate cancer and 525 (53%) were using CAMs for any reason (including prostate cancer). Those using CAM for prostate cancer were more likely to be regular or occasional support group participants (vs. no participation RR = 2.02; 95%CI 1.41-2.88), born in another country (vs. Australian born RR = 1.59; 95%CI 1.17-2.16), have received androgen deprivation treatment (ADT) since diagnosis (RR = 1.60; 95%CI 1.12-2.28) or in the past two years (RR = 2.34; 95%CI 1.56-3.52). CAM use was associated with greater fear of recurrence (RR = 1.29; 95%CI 1.12-1.48), cancer-specific distress (RR = 1.15; 95%CI 1.01-1.30), cancer-specific hyperarousal (RR = 1.17; 95%CI 1.04-1.31), cancer locus of control (RR = 1.16; 95%CI 1.01-1.34) and less satisfaction with medical treatments (RR = 0.86; 95%CI 0.76-0.97), but not with intrusive thinking, cognitive avoidance, depression, anxiety or any HRQOL domains. In this study, about one in six long term prostate cancer survivors used CAMs for their prostate cancer with use centred around ADT, country of birth, distress, cancer control, fear of recurrence and active help seeking.