Health plan policies and programs for colorectal cancer screening: a national profile.
A consensus has emerged that average-risk adults 50 years of age or older should be screened for colorectal cancer (CRC). To describe health plans' coverage policies, guidelines, and organized programs to promote CRC screening. Review of data from the National Cancer Institute Survey of Colorectal Cancer Screening Practices, administered to a national sample of health plans in 1999-2000. The survey inquired about coverage policies for fecal occult blood testing, sigmoidoscopy, colonoscopy, and double-contrast barium enema; the nature of any guidelines the plan had issued to its providers on CRC screening; and systems for recruiting patients into screening and for tracking and reporting the results of screening and follow-up procedures. Of 346 eligible health plans, 180 (52%) responded. Nearly all health plans covered at least 1 CRC screening modality. Plans were most likely to cover fecal occult blood testing (97%) and least likely to cover colonoscopy (57%). Sixty-five percent had issued guidelines on CRC screening to providers. One quarter had a mechanism to remind patients that they are due for CRC screening, but fewer had systems for prompting providers, contacting noncompliant patients, or tracking completion of screening. Health plans have the ability to provide organizational infrastructure for a broad range of preventive services to well-defined populations. However, few health plans had all 3 essential CRC screening delivery components--coverage, guidelines, and tracking systems--in place in 1999-2000.


Outcomes of surgery for chronic exertional compartment syndrome in a military population.
To determine the outcome following fasciectomy for chronic exertional compartment syndrome (CECS) in the UK military, and the association between presurgical intramuscular pressure (IMP) and outcome. All patients who underwent fasciectomy for anterior CECS were identified between 2007 and 2010. Presurgery and postsurgery military medical grading for leg function was extracted from the medical records system. The Wilcoxon signed-rank test compared grades before and after surgery. Spearman's rank correlation examined the relationship between IMP and outcome. Presurgery and postsurgery grading was available for 63% of patients. These patients had significantly better leg function after surgery (Z=-3.63, p<0.001). Of these, 49% improved by at least one grade, 36% showed no improvement in grading and 15% had a poorer outcome. There were no significant correlations between IMP and outcome. A large proportion of patients do not return to full fitness following fasciectomy in the military population. This is in line with a recent study in the US military, but conflicts with most civilian reports. The reasons for these differences are not clear. Furthermore, the lack of a relationship between IMP and outcome questions the role of pressure in this condition. These results suggest that the role of postoperative rehabilitation protocols and other conservative options should be explored.


Incidence and trends of prostate cancer in Karachi South, 1995-2002.
Cancer prostate (CaP) is a commonly diagnosed cancer in western men, but there is sparse information about the demographics of this malignancy in Pakistan. The study objective was to provide an overview of CaP in Karachi, Pakistan. Epidemiological data of 282 incident CaP cases registered at Karachi Cancer Registry (KCR) during 1st January 1995 to 31st December 2002 were reviewed. Incidence and trends were studied in 2 time periods, 1995-7 and 1998-2002. In 1995-7, CaP accounted for approximately 3.4% of the cancers in males and ranked 8th in hierarchy with an age standardized incidence rate (ASR) world and crude incidence rate (CIR) per 100,000 of 6.0 and 2.8 respectively. During 1998-2002, CaP accounted 4.6% of the cancers, ranked 4th with an ASR world and CIR per 100,000 of 10.1 and 4.4. Thus an approximate 60% increase was observed between 1995 and 2002. Mean ages of the patients were 67.0 and 67.4 years. Age-specific curves showed a gradual increase in risk from the fifth decade onwards. A marginal down staging was also observed in period 2, more apparent in the more educated Mohajir and Punjabi ethnicities. Karachi falls into a low risk region for CaP, with a rapidly increasing incidence and a marginal down staging. The probable reasons for the lower incidence are a low life expectancy, lack of availability or accessibility to health care and lack of public awareness. Implementation of CaP screening and public health education is a necessity today. The low incidence of CaP in Pakistan may be an artefact!


Chlorogenic Acid: The Conceivable Chemosensitizer Leading to Cancer Growth Suppression.
New paradigm in cancer pathogenesis revealed that microenvironmental conditions significantly contribute to cancer. Hence, Warburg stated that cancer is a metabolic disease. Chlorogenic acid (CGA) is a polyphenol that is found abundantly in coffee. This compound has proven ability in ameliorating some metabolic diseases through various pathways. This article will elaborate the potency of CGA as a chemosensitizer in suppressing tumor growth through a metabolic pathway. AMPK pathway is the main cell metabolic pathway that is activated by CGA in some studies. Moreover, CGA inhibited EGFR/PI3K/mTOR, HIF, VEGF pathways and MAPK/ERK pathway that may suppress tumor cell growth. Furthermore, CGA induced intracellular DNA damage and topoisomerase I- and II-DNA complexes formation that plays a key role in apoptosis. Conclusively, based on the ability of CGA in activate and inhibit some important pathways in cancer metabolism, it may act as a chemosensitizing agent leading to cancer growth suppression.


Serodiagnosis of Schistosoma mansoni with microsomal adult worm antigen in an enzyme-linked immunosorbent assay using a standard curve developed with a reference serum pool.
A standardized microtest plate enzyme-linked immunosorbent assay was developed using the microsomal fraction of adult worms of Schistosoma mansoni (MAMA) as antigen. The standard reference serum pool was prepared from acutely and chronically infected rhesus monkeys and was shown to be appropriate as a standard for measuring the levels of reactivity of the unknowns. The standard serum pool was arbitrarily designated as having 100 activity units per microliter. The levels of reactivity of the unknowns were expressed as activity units per microliter. Serum specimens were obtained from 190 patients infected with S. mansoni in the Caribbean, South America, and Africa. Serum was obtained from small numbers of patients infected with S. haematobium, S. japonicum, or S. mekongi. Controls were 136 patients with other helminthic infections, 142 patients with protozoal or other diseases with liver involvement, and 81 healthy serum donors. The J index (or predictability) of the assay was calculated to determine the significant level of reactivity. The assay has a predictability of 95% for both patients with S. mansoni infections and those with other infections. The sensitivity of the assay for S. mansoni infections was 96%, and the specificity (in terms of cross-reactions with infections with other parasite genera or with other liver diseases) was 99%. The heterologous Schistosoma species showed a markedly lower level of reactivity, with an overall sensitivity of 55%. This is in accord with the species-specificity previously recognized in MAMA, and emphasizes the need for standard reference pools of human sera prepared from patients infected with single species of each of the Schistosoma. Use of these pools in assays with antigens of the respective schistosome species would allow optimum serologic evaluation.


Assessing the organizational context for EBP implementation: the development and validity testing of the Implementation Climate Scale (ICS).
Although the importance of the organizational environment for implementing evidence-based practices (EBP) has been widely recognized, there are limited options for measuring implementation climate in public sector health settings. The goal of this research was to develop and test a measure of EBP implementation climate that would both capture a broad range of issues important for effective EBP implementation and be of practical use to researchers and managers seeking to understand and improve the implementation of EBPs. Participants were 630 clinicians working in 128 work groups in 32 US-based mental health agencies. Items to measure climate for EBP implementation were developed based on past literature on implementation climate and other strategic climates and in consultation with experts on the implementation of EBPs in mental health settings. The sample was randomly split at the work group level of analysis; half of the sample was used for exploratory factor analysis (EFA), and the other half was used for confirmatory factor analysis (CFA). The entire sample was utilized for additional analyses assessing the reliability, support for level of aggregation, and construct-based evidence of validity. The EFA resulted in a final factor structure of six dimensions for the Implementation Climate Scale (ICS): 1) focus on EBP, 2) educational support for EBP, 3) recognition for EBP, 4) rewards for EBP, 5) selection for EBP, and 6) selection for openness. This structure was supported in the other half of the sample using CFA. Additional analyses supported the reliability and construct-based evidence of validity for the ICS, as well as the aggregation of the measure to the work group level. The ICS is a very brief (18 item) and pragmatic measure of a strategic climate for EBP implementation. It captures six dimensions of the organizational context that indicate to employees the extent to which their organization prioritizes and values the successful implementation of EBPs. The ICS can be used by researchers to better understand the role of the organizational context on implementation outcomes and by organizations to evaluate their current climate as they consider how to improve the likelihood of implementation success.


Cognitive and behavioral therapy for insomnia increases the use of continuous positive airway pressure therapy in obstructive sleep apnea participants with comorbid insomnia: a randomized clinical trial.
Insomnia and obstructive sleep apnea (OSA) commonly co-occur which makes OSA difficult to treat with continuous positive airway pressure (CPAP). We conducted a randomized controlled trial in participants with OSA and co-occurring insomnia to test the hypothesis that initial treatment with cognitive and behavioral therapy for insomnia (CBT-i), versus treatment as usual (TAU) would improve insomnia symptoms and increase subsequent acceptance and use of CPAP. One hundred and forty-five participants with OSA (apnea-hypopnea index ≥ 15) and comorbid insomnia were randomized to either four sessions of CBT-i, or TAU, before commencing CPAP therapy until 6 months post-randomization. Primary between-group outcomes included objective average CPAP adherence and changes in objective sleep efficiency by 6 months. Secondary between-group outcomes included rates of immediate CPAP acceptance/rejection, and changes in; sleep parameters, insomnia severity, and daytime impairments by 6 months. Compared to TAU, participants in the CBT-i group had 61 min greater average nightly adherence to CPAP (95% confidence interval [CI] = 9 to 113; p = 0.023, d = 0.38) and higher initial CPAP treatment acceptance (99% vs. 89%; p = 0.034). The CBT-i group showed greater improvement of global insomnia severity, and dysfunctional sleep-related cognitions by 6 months (both: p < 0.001), and greater improvement in sleep impairment measures immediately following CBT-i. There were no between-group differences in sleep outcomes, or daytime impairments by 6 months. In OSA participants with comorbid insomnia, CBT-i prior to initiating CPAP treatment improves CPAP use and insomnia symptoms compared to commencing CPAP without CBT-i. OSA patients should be evaluated for co-occurring insomnia and considered for CBT-i before commencing CPAP therapy. Treating comorbid insomnia with obstructive sleep apnea (COMSIA) study: A new treatment strategy for patients with combined insomnia and sleep apnea, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365184 Australian New Zealand Clinical Trials Registry: ACTRN12613001178730. Universal Trial Number: U1111-1149-4230.


Piperine from the fruits of Piper longum with inhibitory effect on monoamine oxidase and antidepressant-like activity.
A bioassay-guided isolation of the ethanol extract from the fruits of Piper longum yielded a known piperidine alkaloid, piperine, as a monoamine oxidase (MAO) inhibitor. Piperine showed an inhibitory effect against MAO-A (IC50 value: 20.9 microM) and MAO-B (IC50 value: 7.0 microM). Kinetic analyses by a Lineweaver-Burk plot clearly indicated that piperine competitively inhibited MAO-A and MAO-B with Ki values of 19.0+/-0.9 microM and 3.19+/-0.5 microM, respectively. The inhibition by piperine was found to be reversible by dialysis of the incubation mixture. In addition, the immobility times in the tail suspension test were significantly reduced by piperine, similar to that of the reference antidepressant fluoxetine, without accompanying changes in ambulation when assessed in an open-field. These results suggest that piperine possesses potent antidepressant-like properties that are mediated in part through the inhibition of MAO activity, and therefore represent a promising pharmacotherapeutic candidate as an antidepressant agent.


Association between gastrointestinal tract infections and glycated hemoglobin in school children of poor neighborhoods in Port Elizabeth, South Africa.
Low- and middle-income countries are facing a dual disease burden with infectious diseases (e.g., gastrointestinal tract infections) and non-communicable diseases (e.g., diabetes) being common. For instance, chronic parasite infections lead to altered immune regulatory networks, anemia, malnutrition, and diarrhea with an associated shift in the gut microbiome. These can all be pathways of potential relevance for insulin resistance and diabetes. The aim of this study was to investigate the association between common gastrointestinal tract infections and glycemia in children from non-fee paying schools in South Africa. We conducted a cross-sectional survey among 9- to 14-year-old school children in Port Elizabeth. Stool and urine samples were collected to assess infection status with parasitic worms (e.g., Ascaris lumbricoides, Enterobius vermicularis, and Trichuris trichiura), intestinal protozoa (e.g., Cryptosporidium parvum and Giardia intestinalis), and the bacterium Helicobacter pylori. Glycated hemoglobin (HbA1c) was measured in finger prick derived capillary blood. All children at schools with a high prevalence of helminth infections and only infected children at the schools with low infection rates were treated with albendazole. The association of anthelmintic treatment with changes in HbA1c 6 months after the drug intervention was also investigated. A high prevalence of 71.8% of prediabetes was measured in this group of children, with only 27.8% having HbA1c in the normal range. H. pylori was the predominant infectious agent and showed an independent positive association with HbA1c in a multivariable regression analysis (β = 0.040, 95% confidence interval (CI) 0.006-0.073, p<0.05). No association of HbA1c with either any other infectious agent or albendazole administration was found. The role of H. pylori in diabetes needs confirmation in the context of longitudinal treatment interventions. The specific effect of other gastrointestinal tract infections on glycemia remains unclear. Future studies should integrate the measurement of biomarkers, including immunological parameters, to shed light on the potential mediating mechanisms between parasite infections and diabetes.


Essential tremor: predictors of disease progression in a clinical cohort.
To examine the utility of baseline factors to predict disease progression among a clinical cohort of patients diagnosed with essential tremor. Tremor Rating Scale (TRS). A clinical series of 128 consecutive patients diagnosed with essential tremor was included for study. 45 (35%) patients had at least one follow-up exam (mean = 3.6 years). Baseline predictive factors examined included age, age at onset of symptoms, disease duration, sex, handedness, total tremor rating score, asymmetric tremor ratings, location of initial tremor onset, use of drugs for movement disorders, ETOH responsiveness of tremor, association of head or neck tremor, history of depression, familial history of essential tremor, Parkinson's disease, Alzheimer's disease and other movement disorders. On average, the TRS total score increased by <1 point per year before the first visit to the clinic and by about 2 points per year during the observed study period. The increase of 2 points per year during the observed study period represented an approximate 12% annual change from the mean TRS total score at the first clinic visit. Significant (p<0.05) predictive factors associated with increased tremor severity at the initial clinic visit included older age, longer disease duration, use of movement disorder drugs and the presence of voice tremor (r = 0.24, 0.27, 0.25, 0.19). The major factors associated with an increase in tremor severity from the initial clinic visit to the last follow up included asymmetrical tremor ratings, unilateral initial tremor onset and longer follow-up duration (r = 0.32, 0.31, 0.30). Multivariate regression analysis accounted for about 17-30% of the variance in tremor ratings (p<0.05). Essential tremor is a slow, progressive disease. The rate of disease progression and the factors associated with disease progression may vary throughout the disease course.


Breast self examination and breast cancer stage at diagnosis.
The relationship between breast self examination (BSE) and breast cancer stage at diagnosis was examined in 616 women aged 15-59 years. Differences in tumour characteristics between those not practising BSE and those practising but not taught were small and inconstant. However, women who had both practised and had been taught BSE had more favourable tumours than the non-practising group. The difference was most marked in terms of tumour size and the involvement of axillary nodes. The proportions of women in the non-BSE and taught-BSE groups with each characteristic were respectively: size less than or equal to 2 cm 33% and 45%, T1 clinical stage 27% and 42%, and N0 pathological stage 37% and 50%. This advantage to taught-BSE women persisted after adjustment for the identified confounding factors of age, social class and oral contraceptive use. The likely impact on breast cancer mortality is difficult to assess, although the potential benefit of the lead time gained must not be ignored when assessing the costs and benefits of BSE.


Localization and distribution of tissue type and urokinase type plasminogen activators and their inhibitors Type 1 and 2 in human and rhesus monkey fetal membranes.
Fetal membranes consist of 10 distinct layers including components of amnion, chorion and decidua, the latter being of maternal origin. They form mechanically integrated sheets capable of retaining amniotic fluid and play an essential role in protecting fetal growth and development in the pregnant uterus. The extracellular matrix, substrate for plasminogen activators (PAs), is an important supportive framework of the fetal membranes. Fetal membranes from women with preterm premature rupture of membranes may differ in their protease activity compared with normal membranes. To identify the presence of PAs and their inhibitors (PAI) and their possible role in the process of fetal membrane rupture, this study investigated the distribution and localization of both protein and mRNA for tissue (t) and urokinase (u) PA and their inhibitors type 1 (PAI-1) and type 2 (PAI-2) in amniochorion of human and rhesus monkey using conventional and confocal immunofluorescence microscopy. In situ hybridization analysis showed that the distribution and localization of mRNAs for tPA, uPA, PAI-1 and PAI-2 were similar in the fetal membranes of human and rhesus monkey; no obvious species difference was observed. Evidence of tPA mRNA was detected in amniotic epithelium, trophoblast cells and nearly all cells of the decidual layer. Strong expression of uPA mRNA was noted in the decidual cells which increased in intensity as the abscission point was approached. Weak staining in chorion laeve trophoblast was also detected. In situ hybridization experiments showed PAI-1 mRNA to be concentrated mainly in the decidual cells, some of which were interposed into the maternal-facing edge of the chorion laeve. Maximal labelling of the decidua occurred towards the zone of abscission. Weak expression of PAI-1 mRNA was also noted in some cells of the chorion laeve. The distribution of PAI-2 mRNA in amniochorion was also concentrated in the cells of the decidual layer, maximum expression of the mRNA was in the level of abscission. No detectable amount of mRNAs for tPA, uPA, PAI-1 and PAI-2 was found in the fibroblast, reticular and spongy layers. Distribution of the proteins of tPA, uPA and PAI-1 in the fetal membranes of these two species was consistent with the distribution of their mRNA. Anti-PAI-2 immunofluorescence was found to be strongly concentrated in the amniotic epithelium, but PAI-2 mRNA was negative in this layer, suggesting that the epithelium-associated PAI-2 is not of epithelial origin. These findings suggest that a local fibrinolysis in fetal membranes generated by precisely balanced expression of PAs and their inhibitors via paracrine or autocrine mechanisms may play an essential role in fetal membrane development, maturation and in membrane rupture. Following an analysis of the distribution and synthesis of activators and inhibitors it was found that they may play a role in abscission during the third stage of labour.


Distinct genetic and immunological features in patients with onset of IDDM before and after age 40.
Young age at onset is a relevant parameter associated with a rapid progression of IDDM. Our major aim was to define differences between IDDM patients with age at diagnosis > 40 years and adult IDDM with onset at a younger age. The correlation between islet-related antibodies (islet cell antibodies [ICAs] and antibodies [Abs] to GAD and the tyrosine phosphatase IA2), T-cell responses to GAD peptides and HLA class II isotypes was investigated in 23 IDDM patients 12-38 years of age at onset (group 1), 24 patients with IDDM > 40 years of age at onset (group 2), and 12 healthy control subjects. ICAs were measured by indirect immunofluorescence, and GAD-Ab and IA2-Ab were measured by immunoprecipitation tests. T-cell responses against GAD peptides, which had been identified as typical for IDDM, were tested by 5-day proliferation assays. HLA class II alleles were typed by polymerase chain reaction. ICAs and GAD-Abs were more prevalent in IDDM patients than in control subjects (P < 0.001), but only IDDM group 1 had IA2-Abs (P < 0.001 compared with IDDM group 2 and control subjects). Moreover, antibody combinations differed between IDDM patients of groups 1 and 2. T-cell responses to GAD peptides were seen in 67% of IDDM group 1 and in 71% of IDDM group 2 (P < 0.02 compared with control subjects). IDDM patients of group 1 were more frequently DR4+/DQ8+ and less frequently DR2+/DQ0602+ compared with IDDM patients of group 2 (P < 0.05). Our data provide strong evidence for humoral and cellular autoimmunity in adult IDDM patients with onset both before and after 40 years of age. However, late-onset differs from young-onset IDDM with respect to Ab profiles, especially a lack of IA2-Ab, and HLA class II types. These findings have consequences for the diagnostic strategy for identifying slow-onset IDDM in individuals after 40 years of age.


Meta-analysis of quantification methods shows that archaea and bacteria have similar abundances in the subseafloor.
There is no universally accepted method to quantify bacteria and archaea in seawater and marine sediments, and different methods have produced conflicting results with the same samples. To identify best practices, we compiled data from 65 studies, plus our own measurements, in which bacteria and archaea were quantified with fluorescent in situ hybridization (FISH), catalyzed reporter deposition FISH (CARD-FISH), polyribonucleotide FISH, or quantitative PCR (qPCR). To estimate efficiency, we defined "yield" to be the sum of bacteria and archaea counted by these techniques divided by the total number of cells. In seawater, the yield was high (median, 71%) and was similar for FISH, CARD-FISH, and polyribonucleotide FISH. In sediments, only measurements by CARD-FISH in which archaeal cells were permeabilized with proteinase K showed high yields (median, 84%). Therefore, the majority of cells in both environments appear to be alive, since they contain intact ribosomes. In sediments, the sum of bacterial and archaeal 16S rRNA gene qPCR counts was not closely related to cell counts, even after accounting for variations in copy numbers per genome. However, qPCR measurements were precise relative to other qPCR measurements made on the same samples. qPCR is therefore a reliable relative quantification method. Inconsistent results for the relative abundance of bacteria versus archaea in deep subsurface sediments were resolved by the removal of CARD-FISH measurements in which lysozyme was used to permeabilize archaeal cells and qPCR measurements which used ARCH516 as an archaeal primer or TaqMan probe. Data from best-practice methods showed that archaea and bacteria decreased as the depth in seawater and marine sediments increased, although archaea decreased more slowly.


Assessing malaria transmission in a low endemicity area of north-western Peru.
Where malaria endemicity is low, control programmes need increasingly sensitive tools for monitoring malaria transmission intensity (MTI) and to better define health priorities. A cross-sectional survey was conducted in a low endemicity area of the Peruvian north-western coast to assess the MTI using both molecular and serological tools. Epidemiological, parasitological and serological data were collected from 2,667 individuals in three settlements of Bellavista district, in May 2010. Parasite infection was detected using microscopy and polymerase chain reaction (PCR). Antibodies to Plasmodium vivax merozoite surface protein-119 (PvMSP1₁₉) and to Plasmodium falciparum glutamate-rich protein (PfGLURP) were detected by ELISA. Risk factors for exposure to malaria (seropositivity) were assessed by multivariate survey logistic regression models. Age-specific antibody prevalence of both P. falciparum and P. vivax were analysed using a previously published catalytic conversion model based on maximum likelihood for generating seroconversion rates (SCR). The overall parasite prevalence by microscopy and PCR were extremely low: 0.3 and 0.9%, respectively for P. vivax, and 0 and 0.04%, respectively for P. falciparum, while seroprevalence was much higher, 13.6% for P. vivax and 9.8% for P. falciparum. Settlement, age and occupation as moto-taxi driver during previous year were significantly associated with P. falciparum exposure, while age and distance to the water drain were associated with P. vivax exposure. Likelihood ratio tests supported age seroprevalence curves with two SCR for both P. vivax and P. falciparum indicating significant changes in the MTI over time. The SCR for PfGLURP was 19-fold lower after 2002 as compared to before (λ1 = 0.022 versus λ2 = 0.431), and the SCR for PvMSP1₁₉ was four-fold higher after 2006 as compared to before (λ1 = 0.024 versus λ2 = 0.006). Combining molecular and serological tools considerably enhanced the capacity of detecting current and past exposure to malaria infections and related risks factors in this very low endemicity area. This allowed for an improved characterization of the current human reservoir of infections, largely hidden and heterogeneous, as well as providing insights into recent changes in species specific MTIs. This approach will be of key importance for evaluating and monitoring future malaria elimination strategies.


Exploring copper nanostructures as highly uniform and reproducible substrates for plasmon-enhanced fluorescence.
The unique properties of metallic nanostructures of coinage metals that can sustain localized surface plasmon resonances (LSPR) put them at the centre of plasmon-enhanced phenomena. The theory of plasmonic phenomena based on LSPR is well-established. However, the fabrication of plasmonic substrates, reproducibly, is still challenging for applications in surface-enhanced Raman scattering (SERS) and surface-enhanced fluorescence (SEF). In this work we describe well-ordered copper nanostructures (CuNSs), produced by electrodeposition and nanosphere lithography, as active substrates for SEF. After a detailed spectroscopic and microscopic characterization, CuNSs are successfully applied as SEF-active substrates using a well-known perylene derivative as a target molecule. The signal reproducibility from CuNS substrates was established by comparing the results against those obtained from a simply roughened Cu substrate. Under optimal conditions, signal variability is around 4%.


Feasibility and Safety of Hydrogen Gas Inhalation for Post-Cardiac Arrest Syndrome - First-in-Human Pilot Study.
Hydrogen gas inhalation (HI) ameliorates cerebral and cardiac dysfunction in animal models of post-cardiac arrest syndrome (PCAS). HI for human patients with PCAS has never been studied. Between January 2014 and January 2015, 21 of 107 patients with out-of-hospital cardiac arrest achieved spontaneous return of circulation. After excluding 16 patients with specific criteria, 5 patients underwent HI together with target temperature management (TTM). No undesirable effects attributable to HI were observed and 4 patients survived 90 days with a favorable neurological outcome. HI in combination with TTM is a feasible therapy for patients with PCAS. (Circ J 2016; 80: 1870-1873).


Alternative Outpatient Chemotherapy Scheduling Method to Improve Patient Service Quality and Nurse Satisfaction.
Optimal scheduling and calendar management in an outpatient chemotherapy unit is a complex process that is driven by a need to focus on safety while accommodating a high degree of variability. Primary constraints are infusion times, staffing resources, chair availability, and unit hours. We undertook a process to analyze our existing management models across multiple practice settings in our health care system, then developed a model to optimize safety and efficiency. The model was tested in one of the community chemotherapy units. We assessed staffing violations as measured by nurse-to-patient ratios throughout the workday and at key points during treatment. Staffing violations were tracked before and after the implementation of the new model. The new model reduced staffing violations by nearly 50% and required fewer chairs to treat the same number of patients for the selected clinic day. Actual implementation results indicated that the new model leveled the distribution of patients across the workday with an 18% reduction in maximum chair utilization and a 27% reduction in staffing violations. Subsequently, a positive impact on peak pharmacy workload reduced delays by as much as 35 minutes. Nursing staff satisfaction with the new model was positive. We conclude that the proposed optimization approach with regard to nursing resource assignment and workload balance throughout a day effectively improves patient service quality and staff satisfaction.


Age-Stratified Profiles of Serum IL-6, IL-10, and TNF-α Cytokines Among Kenyan Children with Schistosoma haematobium, Plasmodium falciparum, and Other Chronic Parasitic Co-Infections.
In a study of children having polyparasitic infections in a Schistosoma haematobium-endemic area, we examined the hypothesis that S. haematobium-positive children, compared with S. haematobium-negative children (anti-soluble worm antigen preparation [SWAP] negative and egg negative) have increased systemic production of pro-inflammatory cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α) and decreased down-regulatory IL-10. A total of 804 children, 2-19 years of age, were surveyed between July and December 2009 and tested for S. haematobium, Plasmodium falciparum, filariasis, and soil-transmitted helminth infections. Plasma levels of IL-6, TNF-α, and IL-10 were compared for S. haematobium-positive and S. haematobium-negative children, adjusting for malaria, filaria, and hookworm co-infections, and for nutritional status, age group, sex, and geographic location. IL-10 was significantly elevated among children infected with S. haematobium, showing bimodal peaks in 7-8 and 13-14 years age groups. IL-10 was also higher among children who were acutely malnourished, whereas IL-10 levels were lower in the presence of S. haematobium-filaria co-infection. After adjustment for co-factors, IL-6 was significantly elevated among children of 5-6 years and among those with P. falciparum infection. Lower levels of IL-6 were found in malaria-hookworm co-infection. High levels of TNF-α were found in children aged 11-12 years regardless of infection status. In addition, village of residence was a strong predictor of IL-6 and IL-10 plasma levels. In adolescent children infected with S. haematobium, there is an associated elevation in circulating IL-10 that may reduce the risk of later morbidity. Although we did not find a direct link between S. haematobium infection and circulating pro-inflammatory IL-6 and TNF-α levels, future T-cell stimulation studies may provide more conclusive linkages between infection and cytokine responses in settings that are endemic for multiple parasites and multiple co-infections.


Protein fiber linear dichroism for structure determination and kinetics in a low-volume, low-wavelength couette flow cell.
High-resolution structure determination of soluble globular proteins relies heavily on x-ray crystallography techniques. Such an approach is often ineffective for investigations into the structure of fibrous proteins as these proteins generally do not crystallize. Thus investigations into fibrous protein structure have relied on less direct methods such as x-ray fiber diffraction and circular dichroism. Ultraviolet linear dichroism has the potential to provide additional information on the structure of such biomolecular systems. However, existing systems are not optimized for the requirements of fibrous proteins. We have designed and built a low-volume (200 microL), low-wavelength (down to 180 nm), low-pathlength (100 microm), high-alignment flow-alignment system (couette) to perform ultraviolet linear dichroism studies on the fibers formed by a range of biomolecules. The apparatus has been tested using a number of proteins for which longer wavelength linear dichroism spectra had already been measured. The new couette cell has also been used to obtain data on two medically important protein fibers, the all-beta-sheet amyloid fibers of the Alzheimer's derived protein Abeta and the long-chain assemblies of alpha1-antitrypsin polymers.


Association of Weight Loss in Ambulatory Care Settings With First Diagnosis of Lung Cancer in the US.
Lung cancer, the US's leading cause of cancer death, is often diagnosed following presentation to health care settings with symptoms, and many patients present with late-stage disease. To investigate the association between weight loss and subsequent diagnosis of incident lung cancer in an ambulatory care population and to assess whether recorded weight change had higher odds of lung cancer diagnosis than objective measurements. This case-control study included patients visiting a US academic medical center between January 1, 2012, and December 31, 2019. Data were derived from US ambulatory care electronic health records from the University of Washington Medical Center linked to the local Surveillance, Epidemiology, and End Results cancer registry. Cases were identified from patients who had a primary lung cancer diagnosis between 2012 and 2019; controls were matched on age, sex, smoking status, and presenting to the same type of ambulatory clinic as cases. Data were analyzed from March 2022 through January 2023. Continuous and categorical weight change were assessed. Odds ratios estimating the likelihood of a diagnosis of lung cancer were calculated using univariable and multivariable conditional logistic regression. A total of 625 patients aged 40 years or older with a first primary lung cancer diagnosis and 4606 matched controls were included (1915 [36.6%] ages 60 to 69 years; 418 [8.0%] Asian, 389 [7.4%] Black, 4092 [78.2%] White). In unadjusted analyses, participants with weight loss of 1% to 3% (odds ratio [OR], 1.12; 95% CI, 0.88-1.41), 3% to 5% (OR, 1.36; 95% CI, 0.99-1.88), or 5% to 10% (OR, 1.23; 95% CI, 0.82-1.85) over a 2-year period did not have statistically significantly increased risk of lung cancer diagnosis compared with those who maintained a steady weight. However, participants with weight loss of 10% to 50% had more than twice the odds of a lung cancer diagnosis (OR, 2.27; 95% CI, 1.27-4.05). Most categories of weight loss showed significant associations with an increased risk of lung cancer diagnosis for at least 6 months prior to diagnosis. Patients who had weight loss both recorded in clinicians' notes and measured had higher odds of lung cancer compared with patients who had only recorded (OR, 1.26; odds; 95% CI, 1.04-1.52) or measured (OR, 8.53; 95% CI, 6.99-10.40) weight loss. In this case-control study, weight loss in the prior 6 months was associated with incident lung cancer diagnosis and was present whether weight loss was recorded as a symptom by the clinician or based on changes in routinely measured weight, demonstrating a potential opportunity for early diagnosis. The association between measured and recorded weight loss by clinicians presents novel results for the US.


Vision-Based Control of a Handheld Surgical Micromanipulator with Virtual Fixtures.
Performing micromanipulation and delicate operations in submillimeter workspaces is difficult because of destabilizing tremor and imprecise targeting. Accurate micromanipulation is especially important for microsurgical procedures, such as vitreoretinal surgery, to maximize successful outcomes and minimize collateral damage. Robotic aid combined with filtering techniques that suppress tremor frequency bands increases performance; however, if knowledge of the operator's goals is available, virtual fixtures have been shown to further improve performance. In this paper, we derive a virtual fixture framework for active handheld micromanipulators that is based on high-bandwidth position measurements rather than forces applied to a robot handle. For applicability in surgical environments, the fixtures are generated in real-time from microscope video during the procedure. Additionally, we develop motion scaling behavior around virtual fixtures as a simple and direct extension to the proposed framework. We demonstrate that virtual fixtures significantly outperform tremor cancellation algorithms on a set of synthetic tracing tasks (p < 0.05). In more medically relevant experiments of vein tracing and membrane peeling in eye phantoms, virtual fixtures can significantly reduce both positioning error and forces applied to tissue (p < 0.05).


Contemporary methods for detection of microbial infections in transplanted tissues.
Infective processes developing after transplantation are diagnosed mainly in the specimens harvested from blood and exudates. Not much attention has been focused on identification of microorganisms present in the graft or penetrating the graft from the recipient. Although a progress has been made with respect to detection of viruses there is still little knowledge on the pathological role of bacteria, transplanted together with the graft or acquired from the recipient, in evoking or enhancing the rejection reaction (heterologous immune response). Recently developing molecular techniques allow us to detect bacterial genetic materials in clinical specimens. This article reviews commonly used methods for detection, identification and typing bacterial pathogens. It focuses on specific and universal methods based on gene sequencing, PCR and techniques based on polymorphic DNA. We also present the examples of genes and microorganisms analysed in laboratories. Together with conventional microbiological methods the molecular tests can serve as a key for better understanding the bacterial presence in tissues, not necessarily causing inflammation, quite often being commensal, but also evoking host reaction under certain so far not defined circumstances.


Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors.
Effective cancer immunotherapy requires the release of a broad spectrum of tumor antigens in the context of potent immune activation. We show here that a cDNA library of normal tissue, expressed from a highly immunogenic viral platform, cures established tumors of the same histological type from which the cDNA library was derived. Immune escape occurred with suboptimal vaccination, but tumor cells that escaped the immune pressure were readily treated by second-line virus-based immunotherapy. This approach has several major advantages. Use of the cDNA library leads to presentation of a broad repertoire of (undefined) tumor-associated antigens, which reduces emergence of treatment-resistant variants and also permits rational, combined-modality approaches in the clinic. Finally, the viral vectors can be delivered systemically, without the need for tumor targeting, and are amenable to clinical-grade production. Therefore, virus-expressed cDNA libraries represent a novel paradigm for cancer treatment addressing many of the key issues that have undermined the efficacy of immuno- and virotherapy to date.


Supplementation with lutein or lutein plus green tea extracts does not change oxidative stress in adequately nourished older adults.
Epigallocatechin gallate, a major component of green tea polyphenols, protects against the oxidation of fat-soluble antioxidants including lutein. The current study determined the effect of a relatively high but a dietary achievable dose of lutein or lutein plus green tea extract on antioxidant status. Healthy subjects (50-70 years) were randomly assigned to one of two groups (n=20 in each group): (1) a lutein (12 mg/day) supplemented group or (2) a lutein (12 mg/day) plus green tea extract (200 mg/day) supplemented group. After 2 weeks of run-in period consuming less than two servings of lightly colored fruits and vegetables in their diet, each group was treated for 112 days while on their customary regular diets. Plasma carotenoids including lutein, tocopherols, flavanols and ascorbic acid were analyzed by HPLC-UVD and HPLC-electrochemical detector systems; total antioxidant capacity by fluorometry; lipid peroxidation by malondialdehyde using a HPLC system with a fluorescent detector and by total hydroxyoctadecadienoic acids using a GC/MS. Plasma lutein, total carotenoids and ascorbic acid concentrations of subjects in either the lutein group or the lutein plus green tea extract group were significantly increased (P<.05) at 4 weeks and throughout the 16-week study period. However, no significant changes from baseline in any biomarker of overall antioxidant activity or lipid peroxidation of the subjects were seen in either group. Our results indicate that an increase of antioxidant concentrations within a range that could readily be achieved in a healthful diet does not affect in vivo antioxidant status in normal healthy subjects when sufficient amounts of antioxidants already exist.


[Clopidogrel-associated thrombotic thrombocytopenic purpura].
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that is a rare complication of thienopyridine treatment, especially clopidogrel. Here we report a case of clopidogrel-associated TTP. A 77-year-old male initially complained of petechiae on his legs 6 weeks after clopidogrel treatment following coronary artery stenting. He was admitted 4 weeks later with slurred speech and low-grade fever. Laboratory findings showed severe thrombocytopenia, hemolytic anemia with fragmented red cells, renal dysfunction and severe deficiency of ADAMTS13 activity with the presence of the inhibitor. Based on the clinical course and laboratory findings, he was diagnosed with TTP and underwent plasma exchange, followed by improvement of symptoms and laboratory abnormalities after 7 courses of plasma exchange. Nevertheless, the patient died of sepsis due to perforated small intestinal diverticulitis 89 days after admission. Thienopyridine-associated TTP usually occurs within 12 weeks after initiation of the therapy. Physicians should therefore be aware of this fatal complication associated with clopidogrel therapy and frequent blood tests, every 2 weeks during the first 12 weeks, is recommended for early diagnosis.


Mathematical models of pancreatic islet size distributions.
The islets of Langerhans, ranging in size from clusters of a few cells to several thousand cells, are scattered near large blood vessels. While the β-cell mass in mammals is proportional to body weight, the size ranges of islets are similar between species with different body sizes, possibly reflecting an optimal functional size. The large range of islet sizes suggests a stochastic developmental process. It is not fully understood how islets develop to reach such size distributions, and how their sizes change under certain physiological and pathological conditions such as development, pregnancy, aging, obesity, and diabetes. The lack of a high-resolution in vivo imaging technique for pancreatic islets implies that the only data available to elucidate the dynamics of islet development are cross-sectional quantifications of islet size distributions. In this review, we infer biological processes affecting islet morphology in the large by examining changes of islet size distributions. Neonatal islet formation and growth is shown as a particular example of developing a mathematical model of islet size distribution. Application of this modeling to elucidate islet changes under other conditions is also discussed.


Pattern of total and regional lung function in subjects with bronchoconstriction induced by 15-me PGF2 alpha.
Closing volume (single breath nitrogen test), regional ventilation and perfusion (using intravenous xenon-133), and total lung function (TLC, VC, and FEV) were measured before and after intramuscular administration of 250 mug 15-methyl prostaglandin F2alpha (15-me PGF2alpha) in 10 healthy women. The cardiac output was measured with the Minnesota impedance cardiograph model 304A and the transthoracic impedance was used as an expression of the thoracic fluid volume. The slope of the alveolar plateau on the closing volume tracing showed a 271% increase 20 minutes after the prostaglandin administration, at which time the closing volume per cent (CV%) had decreased (P less than 0-01) and the closing capacity (CC%) had increased (P less than 0-05). Vital capacity (VC) decreased (P less than 0-01), residual volume (RV) increased (P less than 0-01), and the total lung capacity (TLC) remained unchanged. The maximal decrease (9%) in FEV1 was seen after 20 minutes. All these measurements except the slope of the alveolar plateau returned to control levels after 60 minutes. The redistribution of regional ventilation was more pronounced than that of the regional pulmonary blood flow. No change was observed in cardiac output and transthoracic impedance. None of the patients experienced any dyspnoea. Our results are consistent with a more pronounced effect of prostaglandin F2alpha on the small airways (the alveolar plateau) than on the larger airways (FEV1). In cases where an increase in the slope of the alveolar plateau is observed, the closing volume per cent should not be used as a measurement of the lung disease. It is concluded that the single breath nitrogen test (N2 closing volume) is more sensitive than the conventional tests.


Validation of housekeeping genes for gene expression studies in Symbiodinium exposed to thermal and light stress.
Unicellular photosynthetic algae (dinoflagellate) from the genus Symbiodinium live in mutualistic symbiosis with reef-building corals. Cultured Symbiodinium sp. (clade C) were exposed to a range of environmental stresses that included elevated temperatures (29°C and 32°C) under high (100 μmol quanta m(-2) s(-1) Photosynthetic Active Radiation) and low (10 μmol quanta m(-2) s(-1)) irradiances. Using real-time RT-PCR the stability of expression for the nine selected putative housekeeping genes (HKGs) was tested. The most stable expression pattern was identified for cyclophilin and S-adenosyl methionine synthetase (SAM) followed by S4 ribosomal protein (Rp-S4), Calmodulin (Cal), and Cytochrome oxidase subunit 1 (Cox), respectively. Thermal stress alone resulted in the highest expression stability for Rp-S4 and SAM, with a minimum of two reference genes required for data normalization. For Symbiodinium exposed to both, light and thermal stresses, at least five reference genes were recommended by geNorm analysis. In parallel, the expression of Hsp90 for Symbiodinium in culture and in symbiosis within coral host (Acropora millepora) was evaluated using the most stable HKGs. Our results revealed a drop in Hsp90 expression after an 18 h-period and a 24 h-period of exposure to elevated temperatures indicating the similar Hsp90 expression profile in symbiotic and non-symbiotic environments. This study provides the first list of the HKGs and will provide a useful reference in future gene expression studies in symbiotic dinoflagellates.


Accelerated High Spatial Resolution Diffusion-Weighted Imaging.
Acquisition of a series of anisotropically oversampled acquisitions (so-called anisotropic "snapshots") and reconstruction in the image space has recently been proposed to increase the spatial resolution in diffusion weighted imaging (DWI), providing a theoretical 8x acceleration at equal signal-to-noise ratio (SNR) compared to conventional dense k-space sampling. However, in most works, each DW image is reconstructed separately and the fact that the DW images constitute different views of the same anatomy is ignored. In addition, current approaches are limited by their inability to reconstruct a high resolution (HR) acquisition from snapshots with different subsets of diffusion gradients: an isotropic HR gradient image cannot be reconstructed if one .of its anisotropic snapshots is missing, for example due to intra-scan motion, even if other snapshots for this gradient were successfully acquired. In this work, we propose a novel multi-snapshot DWI reconstruction technique that simultaneously achieves HR reconstruction and local tissue model estimation while enabling reconstruction from snapshots containing different subsets of diffusion gradients, providing increased robustness to patient motion and potential for acceleration. Our approach is formalized as a joint probabilistic model with missing observations, from which interactions between missing snapshots, HR reconstruction and a generic tissue model naturally emerge. We evaluate our approach with synthetic simulations, simulated multi-snapshot scenario and in vivo multi-snapshot imaging. We show that (1) our combined approach ultimately provides both better HR reconstruction and better tissue model estimation and (2) the error in the case of missing snapshots can be quantified. Our novel multi-snapshot technique will enable improved high spatial characterization of the brain connectivity and microstructure in vivo.


Selective degradation of transcripts during meiotic maturation of mouse oocytes.
There is massive destruction of transcripts during the maturation of mouse oocytes. The objective of this project was to identify and characterize the transcripts that are degraded versus those that are stable during the transcriptionally silent germinal vesicle (GV)-stage to metaphase II (MII)-stage transition using a microarray approach. A system for oocyte transcript amplification using both internal and 3'-poly(A) priming was utilized to minimize the impact of complex variations in transcript polyadenylation prevalent during this transition. Transcripts were identified and quantified using the Affymetrix Mouse Genome 430 v2.0 GeneChip. The significantly changed and stable transcripts were analyzed using Ingenuity Pathways Analysis and GenMAPP/MAPPFinder to characterize the biological themes underlying global changes in oocyte transcripts during maturation. It was concluded that the destruction of transcripts during the GV to MII transition is a selective rather than promiscuous process in mouse oocytes. In general, transcripts involved in processes that are associated with meiotic arrest at the GV-stage and the progression of oocyte maturation, such as oxidative phosphorylation, energy production, and protein synthesis and metabolism, were dramatically degraded. In contrast, transcripts encoding participants in signaling pathways essential for maintaining the unique characteristics of the MII-arrested oocyte, such as those involved in protein kinase pathways, were the most prominent among the stable transcripts.


Perceived exercise barriers explain exercise participation in Australian women treated for breast cancer better than perceived exercise benefits.
This study aimed to determine the effect of perceived exercise benefits and barriers on exercise levels among women who have been treated for breast cancer and have not participated in a formal exercise intervention. This was an anonymous, national, online cross-sectional survey study. Four hundred thirty-two women treated for breast cancer completed an online survey covering their treatment and demographic background, current exercise levels, and perceived exercise benefits and barriers. Each perceived benefit and barrier was considered in a binary logistic regression against reported exercise levels to ascertain significant relationships and associative values (odds ratio [OR]). Agreement with 16 out of 19 exercise barriers was significantly related to being more likely to report insufficient exercise levels, whereas agreement with 6 out of 15 exercise benefits was significantly related to being less likely to report insufficient levels of exercise. Feeling too weak, lacking self-discipline, and not making exercise a priority were the barriers with the largest association to insufficient exercise levels (OR=10.97, 95% confidence interval [CI]=3.90, 30.86; OR=8.12, 95% CI=4.73, 13.93; and OR=7.43, 95% CI=3.72, 14.83, respectively). Conversely, exercise enjoyment, improved feelings of well-being, and decreased feelings of stress and tension were the top 3 benefits associated with being less likely to have insufficient exercise levels (OR=0.21, 95% CI=0.11, 0.39; OR=0.21, 95% CI=0.07, 0.63; and OR=0.31, 95% CI=0.15, 0.63, respectively). Self-reported data measures were used to collect exercise data. Targeting exercise barriers specific to women treated for breast cancer may improve exercise participation levels in this cohort. Awareness of the impact of exercise barriers identified in the present study will enable physical therapists to better plan exercise interventions that support all women treated for breast cancer.


Public Healthcare Entitlements and Healthcare Utilisation among the Older Population in Ireland.
The use of direct out-of-pocket payments to finance general practitioner (GP) care by the majority of the population in Ireland is unusual in a European context. Currently, approximately 40% of the population have means-tested access to free GP care, while the remainder must pay the full out-of-pocket cost. In this paper, we use data from The Irish Longitudinal Study on Ageing (TILDA) to examine the impact of the current system of public healthcare entitlements on GP utilisation among the older population. Using difference-in-difference propensity score matching methods, we find significant effects of changes in public healthcare entitlements on GP utilisation (i.e. introducing user fees reduces utilisation, while removing them increases utilisation). There is limited evidence of offset effects on other types of healthcare utilisation. The results have direct implications for current Irish health policy, and add to the international literature on the effects of insurance on healthcare utilisation. Copyright © 2016 John Wiley & Sons, Ltd.


Identification of carbohydrate metabolism genes in the metagenome of a marine biofilm community shown to be dominated by gammaproteobacteria and bacteroidetes.
Polysaccharides are an important source of organic carbon in the marine environment and degradation of the insoluble and globally abundant cellulose is a major component of the marine carbon cycle. Although a number of species of cultured bacteria are known to degrade crystalline cellulose, little is known of the polysaccharide hydrolases expressed by cellulose-degrading microbial communities, particularly in the marine environment. Next generation 454 Pyrosequencing was applied to analyze the microbial community that colonizes and degrades insoluble polysaccharides in situ in the Irish Sea. The bioinformatics tool MG-RAST was used to examine the randomly sampled data for taxonomic markers and functional genes, and showed that the community was dominated by members of the Gammaproteobacteria and Bacteroidetes. Furthermore, the identification of 211 gene sequences matched to a custom-made database comprising the members of nine glycoside hydrolase families revealed an extensive repertoire of functional genes predicted to be involved in cellulose utilization. This demonstrates that the use of an in situ cellulose baiting method yielded a marine microbial metagenome considerably enriched in functional genes involved in polysaccharide degradation. The research reported here is the first designed to specifically address the bacterial communities that colonize and degrade cellulose in the marine environment and to evaluate the glycoside hydrolase (cellulase and chitinase) gene repertoire of that community, in the absence of the biases associated with PCR-based molecular techniques.


Nuclear condensation of cyclic adenosine monophosphate responsive element-binding protein in discrete murine brain structures.
We have directed a polyclonal antibody against an oligo-peptide (123-136) of the transcription factor cyclic AMP responsive element-binding protein (CREB) including the serine residue at 133. Rabbit sera were purified by ammonium sulfate precipitation, followed by affinity chromatography to homogeneity on one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. The purified antibody not only induced marked supershift of CREB binding, without affecting binding of activator protein-1 on gel retardation electrophoresis, but also differentiated between CREB and CREB phosphorylated at serine133 in brain nuclear fractions on Western blotting. Immunoreactive CREB was detected in both cytosolic and nuclear fractions of discrete murine brain structures but was more highly condensed in cerebellum than in neocortex and hippocampus. Incubation of brain nuclear fractions led to a marked export of immunoreactive CREB in a temperature-dependent manner, whereas the temperature-dependent export activity was significantly lower in cerebellum than in other brain structures. Suppression of general new protein synthesis by cycloheximide (500 mg/kg, i.p.) in vivo resulted in a significant decrease in the nuclear CREB level, with a concomitant increase in the cytosolic level in hippocampus, but not in cerebellum. These results suggest that the nuclear export activity might vary from region to region in murine brains through a hitherto unidentified mechanism other than the nuclear localization signal, to result in different nuclear condensation ratios for subsequent elicitation of differential transcriptional activities by the constitutive transcription factor CREB in the nucleus.


Spinal TNF-α impedes Fbxo45-dependent Munc13-1 ubiquitination to mediate neuropathic allodynia in rats.
Presynaptic active zone proteins play a crucial role in regulating synaptic plasticity. Although the ubiquitin-proteasome system underlying the degradation of the presynaptic active zone protein is well established, the contribution of this machinery to regulating spinal plasticity during neuropathic pain development remains unclear. Here, using male Sprague Dawley rats, we demonstrated along with behavioral allodynia, neuropathic injury induced a marked elevation in the expression levels of an active zone protein Munc13-1 in the homogenate and synaptic plasma membrane of the ipsilateral dorsal horn. Moreover, nerve injury-increased Munc13-1 expression was associated with an increase in the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in ipsilateral dorsal horn neurons. This neuropathic injury-induced accumulation of Munc13-1 colocalized with synaptophysin but not homer1 in the dorsal horn. Focal knockdown of spinal Munc13-1 expression attenuated behavioral allodynia and the increased frequency, not the amplitude, of mEPSCs in neuropathic rats. Remarkably, neuropathic injury decreased spinal Fbxo45 expression, Fbxo45-Munc13-1 co-precipitation, and Munc13-1 ubiquitination in the ipsilateral dorsal horn. Conversely, focal knockdown of spinal Fbxo45 expression in naive animals resulted in behavioral allodynia in association with similar protein expression and ubiquitination in the dorsal horn as observed with neuropathic injury rats. Furthermore, both neuropathic insults and intrathecal injection of tumor necrosis factor-α (TNF-α) impeded spinal Fbxo45-dependent Munc13-1 ubiquitination, which was reversed by intrathecal TNF-α-neutralizing antibody. Our data revealed that spinal TNF-α impedes Fbxo45-dependent Munc13-1 ubiquitination that accumulates Munc13-1 in the presynaptic area and hence facilitates the synaptic excitability of nociceptive neurotransmission underlying neuropathic pain.


Determination of the epitope of an inhibitory antibody to proliferating cell nuclear antigen.
Proliferating cell nuclear antigen (PCNA) is an essential component for the normal processive DNA synthesis by DNA polymerase delta and is also required for DNA excision repair. Human PCNA autoantisera has been shown to inhibit the function of PCNA in vitro, in contrast to induced antibodies. A monoclonal IgG2 PCNA antibody, 74B1, that effectively inhibited DNA replication in vitro was identified. The inhibitory effect was dose dependent and using synthetic overlapping peptides of PCNA the 74B1 epitope was mapped to aa 121-135, a region of the PCNA protein containing the interdomain connector implicated in intermolecular interactions. Interestingly, a neighboring and partly overlapping peptide, aa 111-125, contains an immunodominant region recognized by a number of monoclonal PCNA antibodies with no inhibitory effect on DNA synthesis. The 74B1 antibody is a potentially useful antibody in future studies of PCNA and its interaction in complexes associated with cell cycle progress, DNA replication, and DNA repair.


Novel technique for repairing posterior medial meniscus root tears using porcine knees and biomechanical study.
Transtibial pullout suture (TPS) repair of posterior medial meniscus root (PMMR) tears was shown to achieve good clinical outcomes. The purpose of this study was to compare biomechanically, a novel technique designed to repair PMMR tears using tendon graft (TG) and conventional TPS repair. Twelve porcine tibiae (n = 6 each) TG group: flexor digitorum profundus tendon was passed through an incision in the root area, created 5 mm postero-medially along the edge of the attachment area. TPS group: a modified Mason-Allen suture was created using no. 2 FiberWire. The tendon grafts and sutures were threaded through the bone tunnel and then fixed to the anterolateral cortex of the tibia. The two groups underwent cyclic loading followed by a load-to-failure test. Displacements of the constructs after 100, 500, and 1000 loading cycles, and the maximum load, stiffness, and elongation at failure were recorded. The TG technique had significantly lower elongation and higher stiffness compared with the TPS. The maximum load of the TG group was significantly lower than that of the TPS group. Failure modes for all specimens were caused by the suture or graft cutting through the meniscus. Lesser elongation and higher stiffness of the constructs in TG technique over those in the standard TPS technique might be beneficial for postoperative biological healing between the meniscus and tibial plateau. However, a slower rehabilitation program might be necessary due to its relatively lower maximum failure load.


Monitoring of the process of composting of kitchen waste in an institutional scale worm farm.
Vermicomposting provides an alternative method of managing waste that is ecofriendly and cost-effective. The Environmental Technology Centre (ETC) at Murdoch University and St. John of God Hospital (SJOG) signed a Memorandum of Understanding (MOU) to install a vermiculture system in SJOG to treat some of the organic waste generated by the on site kitchen facility. This is an effort made by SJOG to reduce the amount of organic waste sent to landfill each year and to treat the waste on site as part of a recycling/reuse program. The study is aimed at scientifically monitoring vermicomposting process and to understand the optimum management requirements to improve the operation of an institutional scale worm farm. In addition, an experiment was conducted to investigate the suitability of bedding materials: horse manure, cow manure, peat coir, and natural bedding (vermicast). The species of earthworms used in this experiment were Red (Lumbricus rubellus), Tiger (Eisenia fetida), and Blue (Lumbricus excavatus). The pH, temperature, worm population and quality of castings were tested in different beds. Results indicated that vermicast was the best bedding for vermicomposting, and there were no significant difference between the performances of the other three beds. However, it can be concluded that the bedding material of horse manure, cow manure, and peat coir were successfully established well within the experimental period of eight weeks, and cow manure with the lowest C:N ratio produced the best quality bedding. As using vermicast for the initial bedding creates a very high capital cost these organic substrates provide cost-effective alternative. Therefore they would be quite appropriate to initiate an institutional scale worm farm.


Filter design for optical pattern recognition: multicriteria optimization approach.
A method of constructing optimal multicriteria filters for optical pattern recognition is presented. In the particular case of synthetic discriminant function filters, this method is illustrated for double-optimization criteria, and filters that are not overspecialized are obtained, in contrast with traditional techniques. Furthermore, a rigorous comparison between different filters, with respect to the considered criteria, is provided with this approach.


IL13 variants are associated with total serum IgE and early sensitization to food allergens in children with atopic dermatitis.
Increased total and specific serum immunoglobulin E (IgE) levels are common characteristics of atopic diseases and their basal production is proposed to be under strong genetic control. Interleukin 13 (IL13) variants have been consistently associated with total serum IgE levels in white populations with a strongest association in non-atopics. The aim of this study was to test the IL13 p.R130Q and c.1-1111C>T variants in children with atopic dermatitis (AD) for associations with total serum IgE and early sensitization to common food and inhalant allergens and with asthma. We included 453 children with AD [participants of the Early Treatment of the Atopic Child (ETAC) study] that were followed from the age of 12-24 months for 3 yr. Total and specific IgE were determined at four time points. We genotyped the IL13 p.R130Q and c.1-1111C>T variants by melting curve analysis. In children up to 4 yr of age, the 130Q allele was related to slightly higher total IgE levels compared to heterozygotes and 130R homozygotes. More importantly, both IL13 variants were significantly associated with sensitization to food allergens, with most significant results for sensitization to egg (p = 0.0001). Although early sensitization to hen's egg represents a strong risk factor for subsequent sensitization to inhalant allergens and asthma, the investigated IL13 variants were not associated with these phenotypes at the age of 48-60 months. In summary IL13 variants contribute to elevated levels of total serum IgE in young atopic children and are strongly associated with sensitization to food allergens, particularly to hen's egg. These findings suggest that IL13 variants play a major role not only in non-cognate but also in allergen specific IgE synthesis.


The change of HCN1/HCN2 mRNA expression in peripheral nerve after chronic constriction injury induced neuropathy followed by pulsed electromagnetic field therapy.
Neuropathic pain is usually defined as a chronic pain state caused by peripheral or central nerve injury as a result of acute damage or systemic diseases. It remains a difficult disease to treat. Recent studies showed that the frequency of action potentials in nociceptive afferents is affected by the activity of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN) family. In the current study, we used a neuropathy rat model induced by chronic constriction injury (CCI) of sciatic nerve to evaluate the change of expression of HCN1/HCN2 mRNA in peripheral nerve and spinal cord. Rats were subjected to CCI with or without pulsed electromagnetic field (PEMF) therapy. It was found that CCI induced neural cell degeneration while PEMF promoted nerve regeneration as documented by Nissl staining. CCI shortened the hind paw withdrawal latency (PWL) and hind paw withdrawal threshold (PWT) and PEMF prolonged the PWL and PWT. In addition, CCI lowers the expression of HCN1 and HCN2 mRNA and PEMF cannot restore the expression of HCN1 and HCN2 mRNA. Our results indicated that PEMF can promote nerve regeneration and could be used for the treatment of neuropathic pain.


Quantum control of molecular vibrational and rotational excitations in a homonuclear diatomic molecule: a full three-dimensional treatment with polarization forces.
The optimal control of the vibrational excitation of the hydrogen molecule [Balint-Kurti et al., J. Chem. Phys. 122, 084110 (2005)] utilizing polarization forces is extended to three dimensions. The polarizability of the molecule, to first and higher orders, is accounted for using explicit ab initio calculations of the molecular electronic energy in the presence of an electric field. Optimal control theory is then used to design infrared laser pulses that selectively excite the molecule to preselected vibrational-rotational states. The amplitude of the electric field of the optimized pulses is restricted so that there is no significant ionization during the process, and a new frequency sifting method is used to simplify the frequency spectrum of the pulse. The frequency spectra of the optimized laser pulses for processes involving rotational excitation are more complex than those relating to processes involving only vibrational excitation.


A 12-year retrospective analytic study of the implant survival rate in 177 consecutive maxillary sinus augmentation procedures.
This retrospective study sought to demonstrate the outcome of maxillary sinus elevation surgery in a series of 177 procedures performed over 12 years and to determine the existence of variables that could independently predict implant survival. A retrospective descriptive and analytic study of a series of maxillary sinus elevation procedures performed between 1996 and 2007 was undertaken. The sample was composed of patients with severe atrophy of the posterior maxilla who had been rehabilitated with osseointegrated implants placed in grafted maxillary sinuses. Several features of the patients (smoking habit, presence of comorbidities, and previous oral carcinoma) and of the surgical procedure (grafting material, associated procedures, associated materials, simultaneous/delayed implant placement, and complications) related to implant survival or failure were monitored during the follow-up period. Implant survival and the existence of variables that could predict implant survival independently were analyzed statistically. One hundred seventy-seven sinus augmentation procedures were performed in 119 consecutive patients (mean age 50.02 years; SD 11.5). Of the 272 implants placed in sinus-augmented regions, 19 were lost. The mean follow-up period was 60.7 months (SD 36.5). The overall cumulative implant survival rate was 93% after 5 years. The multivariate analysis showed that the presence of complications related to the sinus augmentation procedure (membrane perforation and sinusitis) and peri-implantitis were factors in predicting implant failure. On the basis of this retrospective analysis, it might be concluded that sinus augmentation is a very versatile procedure. Its efficacy and predictability in terms of implant survival rate is extremely high and independent of the graft material, surgical technique, associated comorbidities, smoking habits, and timing of implant placement. Complications such as membrane perforation, sinusitis, and peri-implantitis appeared to influence implant failure.


Response of balloon-expandable endoprosthetic metallic stents subjected to over-expansion in vitro.
We attempted to evaluate the in vitro behavior and performance of balloon-expandable endoprosthetic metallic stents subjected to over-expansion (OE). Seventy-two balloon-expandable endoprosthetic stents, representing 22 models from six manufacturers, were overexpanded in vitro. Stents were initially expanded to their maximum manufacturer- recommended diameter and then over-expanded incrementally to their endpoints. Endpoints for OE were either stent disarticulation or an inability to undergo further expansion despite balloon insufflation to maximum burst pressure. Measurements of stent dimensions were recorded at each overexpanded diameter and comparisons were made to manufacturer's specifications. A total of 288 balloon-driven expansions were performed on 72 stents. Sixteen stents were expanded to large diameters (> or = 16 mm), 20 stents underwent OE of 50% or greater. One model tended to disarticulate after OE greater than 50%. There were five models that had a tendency to disarticulate after minimal OE. Five models were resistant to OE (25% or less OE) but did not disarticulate. Nearly all stents showed some degree of foreshortening with OE, while 36 stents underwent foreshortening of 30% or more. Models that are not recommended for OE include Intrastent, Intrastent DoubleStrut, NIR Royale and Omniflex. Good candidates for OE include Intrastent DoubleStrut LD, Palmaz large, Medtronic Extra Support Biliary Plus and Medtronic Flexible Biliary. Palmaz XL remains the only model available for expansion from 20 to 28 mm in diameter. For the remaining stents, OE is possible, however, caution should be used.


Validation of the appropriate use criteria for percutaneous coronary intervention in patients with stable coronary artery disease (from the COURAGE trial).
Establishing the validity of appropriate use criteria (AUC) for percutaneous coronary intervention (PCI) in the setting of stable ischemic heart disease can support their adoption for quality improvement. We conducted a post hoc analysis of 2,287 Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation trial patients with stable ischemic heart disease randomized to PCI with optimal medical therapy (OMT) or OMT alone. Within appropriateness categories, we compared rates of death, myocardial infarction, revascularization subsequent to initial therapy, and angina-specific health status as determined by the Seattle Angina Questionnaire in patients randomized to PCI + OMT to those randomized to OMT alone. A total of 1,987 patients (87.9%) were mapped to the 2012 publication of the AUC, with 1,334 (67.1%) classified as appropriate, 551 (27.7%) uncertain, and 102 (5.1%) as inappropriate. There were no significant differences between PCI and OMT alone in the rate of mortality and myocardial infarction by appropriateness classification. Rates of revascularization were significantly lower in patients initially receiving PCI + OMT who were classified as appropriate (hazard ratio 0.65; 95% confidence interval 0.53 to 0.80; p <0.001) or uncertain (hazard ratio 0.49; 95% confidence interval 0.32 to 0.76; p = 0.001). Furthermore, among patients classified as appropriate by the AUC, Seattle Angina Questionnaire scores at 1 month were better in the PCI-treated group compared with the medical therapy group (80 ± 23 vs 75 ± 24 for angina frequency, 73 ± 24 vs 68 ± 24 for physical limitations, and 68 ± 23 vs 60 ± 24 for quality of life; all p <0.01), with differences generally persisting through 12 months. In contrast, health status scores were similar throughout the first year of follow-up in PCI + OMT patients compared with OMT alone in patients classified as uncertain or inappropriate. In conclusion, these findings support the validity of the AUC in efforts to improve health care quality through optimal use of PCI.


Personalized laboratory medicine: a patient-centered future approach.
In contrast to population-based medical decision making, which emphasizes the use of evidence-based treatment strategies for groups of patients, personalized medicine is based on optimizing treatment at the level of the individual patient. The creation of molecular profiles of individual patients was made possible by the advent of "omics" technologies, based on high throughput instrumental techniques in combination with biostatistics tools and artificial intelligence. The goal of personalized laboratory medicine is to use advanced technologies in the process of preventive, curative or palliative patient management. Personalized medicine does not rely on changes in concentration of a single molecular marker to make a therapeutic decision, but rather on changes of a profile of markers characterizing an individual patient's status, taking into account not only the expected response to treatment of the disease but also the expected response of the patient. Such medical approach promises a more effective diagnostics with more effective and safer treatment, as well as faster recovery and restoration of health and improved cost effectiveness. The laboratory medicine profession is aware of its key role in personalized medicine, but to empower the laboratories, at least an enhancement in cooperation between disciplines within laboratory medicine will be necessary.


Cerebrospinal fluid biomarker candidates associated with human WNV neuroinvasive disease.
During the last decade, the epidemiology of WNV in humans has changed in the southern regions of Europe, with high incidence of West Nile fever (WNF) cases, but also of West Nile neuroinvasive disease (WNND). The lack of human vaccine or specific treatment against WNV infection imparts a pressing need to characterize indicators associated with neurological involvement. By its intimacy with central nervous system (CNS) structures, modifications in the cerebrospinal fluid (CSF) composition could accurately reflect CNS pathological process. Until now, few studies investigated the association between imbalance of CSF elements and severity of WNV infection. The aim of the present study was to apply the iTRAQ technology in order to identify the CSF proteins whose abundances are modified in patients with WNND. Forty-seven proteins were found modified in the CSF of WNND patients as compared to control groups, and most of them are reported for the first time in the context of WNND. On the basis of their known biological functions, several of these proteins were associated with inflammatory response. Among them, Defensin-1 alpha (DEFA1), a protein reported with anti-viral effects, presented the highest increasing fold-change (FC>12). The augmentation of DEFA1 abundance in patients with WNND was confirmed at the CSF, but also in serum, compared to the control individual groups. Furthermore, the DEFA1 serum level was significantly elevated in WNND patients compared to subjects diagnosed for WNF. The present study provided the first insight into the potential CSF biomarkers associated with WNV neuroinvasion. Further investigation in larger cohorts with kinetic sampling could determine the usefulness of measuring DEFA1 as diagnostic or prognostic biomarker of detrimental WNND evolution.


The importance of the intracortical canal network for murine bone mechanics.
As shown by recent data bone strength estimation can greatly be improved by including microarchitectural parameters in the analysis. Our previous results showed that intracortical canals (the living space of the vasculature and/or remodeling units) are a major contributor to cortical tissue porosity, and therefore, can be linked to mechanical bone properties. Consequently, the goal of this study was to investigate the importance of the intracortical canal network for murine bone mechanics. To study intracortical canals within murine femoral bone, we used a mouse model, including two mouse strains, C57BL/6J-Ghrhr(lit)/J (B6-lit/+) and C3.B6-Ghrhr(lit)/J (C3.B6-lit/+) representing low and high bone mass, respectively. The intracortical canal network was assessed by synchrotron radiation-based micro-computed tomography and the mechanical bone properties were derived from three-point bending experiments. Multiple linear regression models were built to explain the variation in ultimate force, work to fracture, and stiffness in terms of the morphometric parameters. The power to explain the variation in bone mechanics was increased significantly for most mechanical measures when including morphometric parameters of intracortical canals in addition to macroscopic morphometric measures. Specifically, we could derive generalized (mouse strain-independent) models for ultimate force, where the incorporation of intracortical canals in addition to macroscopic bone measures improved the explained variation in ultimate force considerably, which was confirmed by an increase in adjusted R(2) of 73% and 8% for B6-lit/+ and C3.B6-lit/+, respectively. Further, we observed that the heterogeneity of the morphometric measures for the individual canal branches play an important role for explaining the variation in ultimate force. Finally, the current study provides strong evidence that work to fracture of murine bone, which is triggered critically by microcracks, is affected by intracortical canals. In summary, the study suggests that the intracortical canal network is important for bone mechanics.


IER-START nomogram for prediction of three-month unfavorable outcome after thrombectomy for stroke.
The applicability of the current models for predicting functional outcome after thrombectomy in strokes with large vessel occlusion (LVO) is affected by a moderate predictive performance. We aimed to develop and validate a nomogram with pre- and post-treatment factors for prediction of the probability of unfavorable outcome in patients with anterior and posterior LVO who received bridging therapy or direct thrombectomy <6 h of stroke onset. We conducted a cohort study on patients data collected prospectively in the Italian Endovascular Registry (IER). Unfavorable outcome was defined as three-month modified Rankin Scale (mRS) score 3-6. Six predictors, including NIH Stroke Scale (NIHSS) score, age, pre-stroke mRS score, bridging therapy or direct thrombectomy, grade of recanalization according to the thrombolysis in cerebral ischemia (TICI) grading system, and onset-to-end procedure time were identified a priori by three stroke experts. To generate the IER-START, the pre-established predictors were entered into a logistic regression model. The discriminative performance of the model was assessed by using the area under the receiver operating characteristic curve (AUC-ROC). A total of 1802 patients with complete data for generating the IER-START was randomly dichotomized into training (n = 1219) and test (n = 583) sets. The AUC-ROC of IER-START was 0.838 (95% confidence interval [CI]): 0.816-0.869) in the training set, and 0.820 (95% CI: 0.786-0.854) in the test set. The IER-START nomogram is the first prognostic model developed and validated in the largest population of stroke patients currently candidates to thrombectomy which reliably calculates the probability of three-month unfavorable outcome.


Combined hyperthermia and radiotherapy for the treatment of cancer.
Radiotherapy is used to treat approximately 50% of all cancer patients, with varying success. Radiation therapy has become an in-tegral part of modern treatment strategies for many types of cancer in recent decades, but is associated with a risk of long-term adverse effects. Of these side effects, car-diac complications are particularly relevant since they not only adversely affect quality of life but can also be potentially life-threat-ening. The dose of ionizing radiation that can be given to the tumor is determined by the sensitivity of the surrounding normal tissues. Strategies to improve radiotherapy therefore aim to increase the effect on the tumor or to decrease the effects on normal tissues, which must be achieved without sensitizing the normal tissues in the first approach and without protecting the tumor in the second approach. Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR), which can be attributed to the fact that heat is a pleiotropic damaging agent, affecting multiple cell components to varying degrees by altering protein structures, thus influencing the DNA damage response. Hyperthermia induces heat shock protein 70 (Hsp70; HSPA1A) synthesis and enhances telomerase activity. HSPA1A expression is associated with radioresistance. Inactivation of HSPA1A and telomerase increases residual DNA DSBs post IR exposure, which correlates with increased cell killing, supporting the role of HSPA1A and telomerase in IR-induced DNA damage repair. Thus, hyperthermia influences several molecular parameters involved in sensitizing tumor cells to radiation and can enhance the potential of targeted radiotherapy. Therapy-inducible vectors are useful for conditional expression of therapeutic genes in gene therapy, which is based on the control of gene expression by conventional treatment modalities. The understanding of the molecular response of cells and tissues to ionizing radiation has lead to a new appreciation of the exploitable genetic alterations in tumors and the development of treatments combining pharmacological interventions with ionizing radiation that more specifically target either tumor or normal tissue, leading to improvements in efficacy.


User-documented food consumption data from publicly available apps: an analysis of opportunities and challenges for nutrition research.
The need for a better understanding of food consumption behaviour within its behavioural context has sparked the interest of nutrition researchers for user-documented food consumption data collected outside the research context using publicly available nutrition apps. The study aims to characterize the scientific, technical, legal and ethical features of this data in order to identify the opportunities and challenges associated with using this data for nutrition research. A search for apps collecting food consumption data was conducted in October 2016 against UK Google Play and iTunes storefronts. 176 apps were selected based on user ratings and English language support. Publicly available information from the app stores and app-related websites was investigated and relevant data extracted and summarized. Our focus was on characteristics related to scientific relevance, data management and legal and ethical governance of user-documented food consumption data. Food diaries are the most common form of data collection, allowing for multiple inputs including generic food items, packaged products, or images. Standards and procedures for compiling food databases used for estimating energy and nutrient intakes remain largely undisclosed. Food consumption data is interlinked with various types of contextual data related to behavioural motivation, physical activity, health, and fitness. While exchange of data between apps is common practise, the majority of apps lack technical documentation regarding data export. There is a similar lack of documentation regarding the implemented terms of use and privacy policies. While users are usually the owners of their data, vendors are granted irrevocable and royalty free licenses to commercially exploit the data. Due to its magnitude, diversity, and interconnectedness, user-documented food consumption data offers promising opportunities for a better understanding of habitual food consumption behaviour and its determinants. Non-standardized or non-documented food data compilation procedures, data exchange protocols and formats, terms of use and privacy statements, however, limit possibilities to integrate, process and share user-documented food consumption data. An ongoing research effort is required, to keep pace with the technical advancements of food consumption apps, their evolving data networks and the legal and ethical regulations related to protecting app users and their personal data.


Vitamin D deficiency and endothelial dysfunction in non-dialysis chronic kidney disease patients.
Cardiovascular (CV) events are common in patients with chronic kidney disease (CKD) but inadequately explained by traditional risk factors. Vitamin D deficiency is highly prevalent in CKD and has been proposed to be a non-traditional risk factor, but its relationship with vascular function is unknown. The aim of this study was to investigate the relationship between vitamin D levels and endothelial function in non-diabetes patients with mild to moderate CKD. Endothelial function was measured non-invasively using brachial artery flow mediated dilation (FMD). 25 hydroxy vitamin D levels were measured using electrochemiluminescence immunoassay. In 50 CKD patients (age 56±11 years, BMI 25±4kg/m(2), 46% females, 14% smokers, 86% hypertensives, 52% with dyslipidaemia) the mean vitamin D level was 53±33nmol/L (21±13ng/L). The mean FMD was 3.8±2.4%. Decreasing 25 hydroxy vitamin D levels were associated with decreasing FMD [r=0.44, p=0.001]. In multivariate analysis the association remained independent after adjustment with traditional risk factors (adjusted beta 0.451; t=3.46; p<0.002). Patients with low vitamin D (≤37.5nmol/L) demonstrated low FMD compared to patients with vitamin D values >37.5nmol/L (4.4±2.5% vs. 2.5±1.6%; p=0.007); however the traditional risk factors were similar between the two groups. This is the first demonstration of an association of vitamin D deficiency with abnormal vascular endothelial function in non-dialysis CKD patients. Further studies with intervention and exploration of the mechanism are needed to establish a cause effect relationship.


[Anaplastic glioma. Neuropathology, molecular diagnostics and current study concepts].
According to the current WHO classification anaplastic gliomas comprise pure astrocytomas and oligodendrogliomas and mixed tumors. This review summarizes findings, discusses problems and defines new questions from the phase III trials on anaplastic gliomas. The molecular subgroup analyses of the NOA-04 trial identified three molecular parameters, which predict longer progression-free and overall survival independent from the mode of therapy, radiotherapy or alkylating chemotherapy-. These are 1p/19q codeletion, methylation of the promoter of the O(6)-methylguanyl methyltransferase (MGMT) gene and hot-spot mutations in the isocitrate dehydrogenase 1 (IDH1) gene. The prognostic relevance of these markers is not lower than that of histopathological subclassification but determination is potentially more robust. Therefore, marker profiles should be included into the next WHO brain tumor classification. The current standard of care for first-line treatment in anaplastic gliomas is radiotherapy or chemotherapy. The next steps, e.g. within the international CATNON trial, are to define the role and optimal sequencing of combined modality treatment focusing on radiotherapy and temozolomide. Inclusion in this trial is already based on the WHO grade and the 1p/19q status and not on the histopathological subtype. Furthermore, anaplastic gliomas are an important group of brain tumors for developing future molecular targeted therapies and should therefore be in the main focus of academic and industrial drug development, which aims at improved efficacy and avoiding long-term side-effects.


Induction of Kruppel-like factor 5 expression by androgens results in increased CXCR4-dependent migration of prostate cancer cells in vitro.
Advanced prostate cancers preferentially metastasize to bone, suggesting that this tissue produces factors that provide a suitable microenvironment for prostate cancer cells. Recently, it has become clear that even in antiandrogen-resistant cancers, the androgen receptor (AR)-signaling axis is required for prostate cancer progression. Therefore, we hypothesized that AR may be involved in the regulation of pathways that are responsible for the homing of prostate cancer cells to select microenvironments. In support of this hypothesis, we have determined that chemokine (C-X-C motif) receptor 4 (CXCR4), the receptor for the chemokine CXCL12, is up-regulated in prostate cancer cells in response to androgens. Given that the levels of CXCL12 are elevated at sites of known prostate cancer metastases such as bone, these results suggest that androgens may influence prostate cancer metastasis. Specifically, we demonstrate that androgens increase the levels of both CXCR4 mRNA and functional protein in LNCaP prostate cancer cells. Importantly, androgens enhanced the migration of LNCaP cells toward a CXCL12 gradient, an effect that could be blocked by the specific CXCR4 antagonist AMD3100. Interestingly, CXCR4 is not directly regulated by androgens but rather is positively up-regulated by Krüppel-like factor 5 (KLF5), a transcription factor that we have shown to be an early, direct target of AR. Further, KLF5 is both required and sufficient for androgen-mediated CXCR4 expression and migration toward CXCL12. Taken together, these findings demonstrate that AR can utilize the CXCL12/CXCR4 axis through induction of KLF5 expression to promote prostate cancer progression and highlight the potential utility of CXCR4 antagonists as prostate cancer therapeutics.


A2B adenosine receptor signaling attenuates acute lung injury by enhancing alveolar fluid clearance in mice.
Although acute lung injury contributes significantly to critical illness, resolution often occurs spontaneously via activation of incompletely understood pathways. We recently found that mechanical ventilation of mice increases the level of pulmonary adenosine, and that mice deficient for extracellular adenosine generation show increased pulmonary edema and inflammation after ventilator-induced lung injury (VILI). Here, we profiled the response to VILI in mice with genetic deletions of each of the 4 adenosine receptors (ARs) and found that deletion of the A2BAR gene was specifically associated with reduced survival time and increased pulmonary albumin leakage after injury. In WT mice, treatment with an A2BAR-selective antagonist resulted in enhanced pulmonary inflammation, edema, and attenuated gas exchange, while an A2BAR agonist attenuated VILI. In bone marrow-chimeric A2BAR mice, although the pulmonary inflammatory response involved A2BAR signaling from bone marrow-derived cells, A2BARs located on the lung tissue attenuated VILI-induced albumin leakage and pulmonary edema. Furthermore, measurement of alveolar fluid clearance (AFC) demonstrated that A2BAR signaling enhanced amiloride-sensitive fluid transport and elevation of pulmonary cAMP levels following VILI, suggesting that A2BAR agonist treatment protects by drying out the lungs. Similar enhancement of pulmonary cAMP and AFC were also observed after beta-adrenergic stimulation, a pathway known to promote AFC. Taken together, these studies reveal a role for A2BAR signaling in attenuating VILI and implicate this receptor as a potential therapeutic target during acute lung injury.


Prostate Cancer Education, Detection, and Follow-Up in a Community-Based Multiethnic Cohort of Medically Underserved Men.
The Prostate Outreach Project (POP) provided free prostate cancer (PCa) education and early detection to medically underserved communities. POP recruited participants in medically underserved communities. PCa education and detection events occurred in POP locations (static) or natural gathering places (mobile) within the community. PCa education was delivered by video and evaluated using a questionnaire. Screening consisted of serum prostate-specific antigen and digital rectal examination. A navigated follow-up strategy was utilized to provide medical care for participants with abnormal screening examinations (ASE). POP recruited 4,420 men, 62.8% (2,667) were African American (AA). Most participants had a high school education and no prior screening. Fifty-four percent (2,159) were uninsured and 41% (1,811) had no access to a physician. PCa knowledge increased following the educational video. Prostate-specific antigen levels were elevated in 9.8% (436), while 6.9% (233) had an abnormal digital rectal examination. Follow-up among 609 men with ASE was successful in 40% (244), despite a navigated approach. Overall, 3.3% (144) cancers were diagnosed among the POP with AA participants exhibiting a significantly higher incidence. Recruitment, education, and PCa testing among a medically underserved cohort was successful. However, failure to follow through on ASE could contribute to maintaining the disparity in PCa outcomes noted among AAs and the medically underserved if not addressed.