Evaluation of SOVAT: an OLAP-GIS decision support system for community health assessment data analysis.
Data analysis in community health assessment (CHA) involves the collection, integration, and analysis of large numerical and spatial data sets in order to identify health priorities. Geographic Information Systems (GIS) enable for management and analysis using spatial data, but have limitations in performing analysis of numerical data because of its traditional database architecture.On-Line Analytical Processing (OLAP) is a multidimensional datawarehouse designed to facilitate querying of large numerical data. Coupling the spatial capabilities of GIS with the numerical analysis of OLAP, might enhance CHA data analysis. OLAP-GIS systems have been developed by university researchers and corporations, yet their potential for CHA data analysis is not well understood. To evaluate the potential of an OLAP-GIS decision support system for CHA problem solving, we compared OLAP-GIS to the standard information technology (IT) currently used by many public health professionals. SOVAT, an OLAP-GIS decision support system developed at the University of Pittsburgh, was compared against current IT for data analysis for CHA. For this study, current IT was considered the combined use of SPSS and GIS ("SPSS-GIS"). Graduate students, researchers, and faculty in the health sciences at the University of Pittsburgh were recruited. Each round consisted of: an instructional video of the system being evaluated, two practice tasks, five assessment tasks, and one post-study questionnaire. Objective and subjective measurement included: task completion time, success in answering the tasks, and system satisfaction. Thirteen individuals participated. Inferential statistics were analyzed using linear mixed model analysis. SOVAT was statistically significant (alpha = .01) from SPSS-GIS for satisfaction and time (p < .002). Descriptive results indicated that participants had greater success in answering the tasks when using SOVAT as compared to SPSS-GIS. Using SOVAT, tasks were completed more efficiently, with a higher rate of success, and with greater satisfaction, than the combined use of SPSS and GIS. The results from this study indicate a potential for OLAP-GIS decision support systems as a valuable tool for CHA data analysis.


Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
Zinc inhibits NMDA receptor function through both voltage-dependent and voltage-independent mechanisms. In this report we have investigated the role that the NR1 subunit plays in voltage-independent Zn2+ inhibition. Our data show that inclusion of exon 5 into the NR1 subunit increases the IC50 for voltage-independent Zn2+ inhibition from 3-fold to 10-fold when full length exon 22 is also spliced into the mature NR1 transcript and the NMDA receptor complex contains the NR2A or NR2B subunits; exon 5 has little effect on Zn2+ inhibition of receptors that contain NR2C and NR2D. Mutagenesis within exon 5 indicates that the same residues that control proton inhibition, including Lys211, also control the effects of exon 5 on Zn2+ inhibition. Amino acid exchanges within the NR1 subunit but outside exon 5 (E181Q, E339Q, E342Q, N616R, N616Q, D669N, D669E, C744A, and C798A) that are known to decrease the pH sensitivity also decrease the Zn2+ sensitivity, and concentrations of spermine that relieve tonic proton inhibition also relieve Zn2+ inhibition. In summary, our results define the subunit composition of Zn2+-sensitive NMDA receptors and provide evidence for structural convergence of three allosteric regulators of receptor function: protons, polyamines, and Zn2+.


Muscular adaptations in low- versus high-load resistance training: A meta-analysis.
There has been much debate as to optimal loading strategies for maximising the adaptive response to resistance exercise. The purpose of this paper therefore was to conduct a meta-analysis of randomised controlled trials to compare the effects of low-load (≤60% 1 repetition maximum [RM]) versus high-load (≥65% 1 RM) training in enhancing post-exercise muscular adaptations. The strength analysis comprised 251 subjects and 32 effect sizes (ESs), nested within 20 treatment groups and 9 studies. The hypertrophy analysis comprised 191 subjects and 34 ESs, nested with 17 treatment groups and 8 studies. There was a trend for strength outcomes to be greater with high loads compared to low loads (difference = 1.07 ± 0.60; CI: -0.18, 2.32; p = 0.09). The mean ES for low loads was 1.23 ± 0.43 (CI: 0.32, 2.13). The mean ES for high loads was 2.30 ± 0.43 (CI: 1.41, 3.19). There was a trend for hypertrophy outcomes to be greater with high loads compared to low loads (difference = 0.43 ± 0.24; CI: -0.05, 0.92; p = 0.076). The mean ES for low loads was 0.39 ± 0.17 (CI: 0.05, 0.73). The mean ES for high loads was 0.82 ± 0.17 (CI: 0.49, 1.16). In conclusion, training with loads ≤50% 1 RM was found to promote substantial increases in muscle strength and hypertrophy in untrained individuals, but a trend was noted for superiority of heavy loading with respect to these outcome measures with null findings likely attributed to a relatively small number of studies on the topic.


Inactivation as a new regulatory mechanism for neuronal Kv7 channels.
Voltage-gated K(+) channels of the Kv7 (KCNQ) family have important physiological functions in both excitable and nonexcitable tissue. The family encompasses five genes encoding the channel subunits Kv7.1-5. Kv7.1 is found in epithelial and cardiac tissue. Kv7.2-5 channels are predominantly neuronal channels and are important for controlling excitability. Kv7.1 channels have been considered the only Kv7 channels to undergo inactivation upon depolarization. However, here we demonstrate that inactivation is also an intrinsic property of Kv7.4 and Kv7.5 channels, which inactivate to a larger extent than Kv7.1 channels at all potentials. We demonstrate that at least 30% of these channels are inactivated at physiologically relevant potentials. The onset of inactivation is voltage dependent and occurs on the order of seconds. Both time- and voltage-dependent recovery from inactivation was investigated for Kv7.4 channels. A time constant of 1.47 +/- 0.21 s and a voltage constant of 54.9 +/- 3.4 mV were determined. It was further demonstrated that heteromeric Kv7.3/Kv7.4 channels had inactivation properties different from homomeric Kv7.4 channels. Finally, the Kv7 channel activator BMS-204352 was in contrast to retigabine found to abolish inactivation of Kv7.4. In conclusion, this work demonstrates that inactivation is a key regulatory mechanism of Kv7.4 and Kv7.5 channels.


Epistasis and its implications for personal genetics.
The widespread availability of high-throughput genotyping technology has opened the door to the era of personal genetics, which brings to consumers the promise of using genetic variations to predict individual susceptibility to common diseases. Despite easy access to commercial personal genetics services, our knowledge of the genetic architecture of common diseases is still very limited and has not yet fulfilled the promise of accurately predicting most people at risk. This is partly because of the complexity of the mapping relationship between genotype and phenotype that is a consequence of epistasis (gene-gene interaction) and other phenomena such as gene-environment interaction and locus heterogeneity. Unfortunately, these aspects of genetic architecture have not been addressed in most of the genetic association studies that provide the knowledge base for interpreting large-scale genetic association results. We provide here an introductory review of how epistasis can affect human health and disease and how it can be detected in population-based studies. We provide some thoughts on the implications of epistasis for personal genetics and some recommendations for improving personal genetics in light of this complexity.


CPT-Symmetric Universe.
We propose that the state of the Universe does not spontaneously violate CPT. Instead, the Universe after the big bang is the CPT image of the Universe before it, both classically and quantum mechanically. The pre- and postbang epochs comprise a universe-antiuniverse pair, emerging from nothing directly into a hot, radiation-dominated era. CPT symmetry selects a unique QFT vacuum state on such a spacetime, providing a new interpretation of the cosmological baryon asymmetry, as well as a remarkably economical explanation for the cosmological dark matter. Requiring only the standard three-generation model of particle physics (with right-handed neutrinos), a Z_{2} symmetry suffices to render one of the right-handed neutrinos stable. We calculate its abundance from first principles: matching the observed dark matter density requires its mass to be 4.8×10^{8} GeV. Several other testable predictions follow: (i) the three light neutrinos are Majorana particles and allow neutrinoless double β decay; (ii) the lightest neutrino is massless; and (iii) there are no primordial long-wavelength gravitational waves. We mention connections to the strong CP problem and the arrow of time.


A Systematic Review of Surgical Randomized Controlled Trials: Part I. Risk of Bias and Outcomes: Common Pitfalls Plastic Surgeons Can Overcome.
The authors investigated the methodological validity of plastic surgery randomized controlled trials that compared surgical interventions. An electronic search identified randomized controlled trials published between 2000 and 2013. Reviewers, independently and in duplicate, assessed manuscripts and performed data extraction. Methodological safeguards (randomization, allocation concealment, blinding, and incomplete outcome data) were examined using the Cochrane risk of bias tool. Regression analysis was used to identify trial characteristics associated with risk of bias. Of 1664 potentially eligible studies, 173 randomized controlled trials were included. Proper randomization and allocation concealment methods were described in 61 of 173 (35 percent) and 21 of 173 (12 percent), respectively. Outcome assessors were blinded in 58 of 173 (34 percent) trials, and patients were blinded in 45 of 173 (26 percent). Follow-up rates were high, with 99 of 173 (57 percent) randomized controlled trials appearing to have complete follow-up. An intention-to-treat analysis was used in 19 of 173 (11 percent) trials. One-third (58 of 173, 34 percent) did not state their primary outcomes. The most common type of primary outcome used was a symptom/quality of life, class III, outcome (73 of 173, 42 percent). Multinomial regression demonstrated trials reporting an a priori sample size as more likely to have a low risk of bias (p = 0.001). This article highlights methodological safeguards that plastic surgeons should consider when interpreting results of a surgical randomized controlled trial. Allocation concealment, outcome assessor blinding, and patient blinding were identified as areas of concern. Valid and reliable outcome measures are being used in plastic surgery. This analysis provides strong rationale for continued focus on the performance and reporting of clinical trials within our specialty.


[Udder health on dairy farms. 2. Mastitis prevention programs].
Herd-specific mastitis control programmes are based on the continuous monitoring of primary parameters, of which the bulk milk somatic cell count and the distribution of pathogens responsible for clinical and subclinical mastitis are the most important ones. When a mastitis control programme is started, the herd situation should be analysed. Sampling milk from cows with clinical and subclinical mastitis is essential. During the last 5 years, a number of programmes related to udder health and milk quality have been started in the Netherlands. These programmes are: 1) 'Chain Quality Milk', 2) a herd-specific Mastitis Planner, 3) a sampling programme for subclinical mastitis, and 4) a combined analysis of milk recording data, and subclinical and clinical mastitis data. Using these four programmes, farmers, veterinary practitioners, and other advisors can design a herd-specific programme to improve udder health. Although there have been many studies on mastitis and important progress has been made, some important aspects have often not been studied. Suggestions for further research are made.


Aetiology and antifungal susceptibility of yeast bloodstream infections in a Hungarian university hospital between 1996 and 2000.
The purpose of this study was to evaluate the aetiology and susceptibility of different Candida species originating from blood cultures received from different clinical wards of the University Hospital in Szeged, Hungary, from 1996 to 2000. A total of 145 episodes of fungaemia occurred in 68 patients. In 73.5% of the patients the infections were due to Candida albicans, 7.3% to C. parapsilosis, 5.9% to C krusei, 4.4% to C. tropicalis and 3% each to C. glabrata, other Candida spp. and Cryptococcus neoformans. There were no appreciable differences in the distribution of yeast species during the 5-year period: C. albicans remained the predominant species causing bloodstream infections in this hospital, similar to the results of other studies (Norway, SENTRY Program in USA, Canada and South America). Most of the Candida isolates (39.3%) were from blood cultures of patients hospitalised in surgical wards, 28.3% were from adult intensive care units (ICUs), 13.8% from paediatric ICUs, 11% from haematology and 7.6% from cardiology departments. MICs for amphotericin B, fluconazole and itraconazole were determined for 83% of the isolates. All isolates were susceptible to amphotericin B. The percentage of yeast isolates with decreased susceptibility or resistance to fluconazole was smaller (15.7%) than that for itraconazole (24%).


Reaching hard-to-reach individuals: Nonselective versus targeted outbreak response vaccination for measles.
Current mass vaccination campaigns in measles outbreak response are nonselective with respect to the immune status of individuals. However, the heterogeneity in immunity, due to previous vaccination coverage or infection, may lead to potential bias of such campaigns toward those with previous high access to vaccination and may result in a lower-than-expected effective impact. During the 2010 measles outbreak in Malawi, only 3 of the 8 districts where vaccination occurred achieved a measureable effective campaign impact (i.e., a reduction in measles cases in the targeted age groups greater than that observed in nonvaccinated districts). Simulation models suggest that selective campaigns targeting hard-to-reach individuals are of greater benefit, particularly in highly vaccinated populations, even for low target coverage and with late implementation. However, the choice between targeted and nonselective campaigns should be context specific, achieving a reasonable balance of feasibility, cost, and expected impact. In addition, it is critical to develop operational strategies to identify and target hard-to-reach individuals.


The DST and TRH test in bulimia nervosa.
Abnormal neuroendocrine responses have been found in depression and eating disorders. It remains unclear whether these reflect an underlying shared biology or epiphenomena. To evaluate this further, we conducted the 1 mg DST and the TSH response to 500 micrograms i.v. TRH in normal-weight bulimics and controls. Bulimics (n = 18) demonstrated significantly more DST non-suppression (45%) than controls (18%; n = 20). In the bulimic group, non-suppressors were significantly thinner than suppressors, but did not differ from them on any measure of depression. Bulimics (n = 19) and controls (n = 12) responded similarly without blunting on the TSH response to TRH. These data suggest that DST non-suppression may be related to non-specific variables such as weight. Bulimics do not demonstrate TSH blunting as found in some depressed patients. These tests do not support evidence for a biological link between these disorders.


Associations between variation in CHRNA5-CHRNA3-CHRNB4, body mass index and blood pressure in the Northern Finland Birth Cohort 1966.
The CHRNA5-CHRNA3-CHRNB4 gene cluster on 15q25 has consistently been associated with smoking quantity, nicotine dependence and lung cancer. Recent research also points towards its involvement in cardiovascular homeostasis, but studies in large human samples are lacking, especially on the role of the gene cluster in blood pressure regulation. We studied the associations between 18 single nucleotide polymorphisms (SNPs) in CHRNA5-CHRNA3-CHRNB4 and systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI) in 5402 young adults from the Northern Finland Birth Cohort 1966. We observed some evidence for associations between two SNPs and SBP and between six SNPs and BMI; the evidence for associations with DBP was weaker. The associations with the three phenotypes were driven by different loci with low linkage disequilibrium with each other. The associations appeared more pronounced in smokers, such that the smoking-increasing alleles would predict lower SBP and BMI. Each additional copy of the rs1948 G-allele and the rs950776 A-allele reduced SBP on average by -1.21 (95% CI -2.01, -0.40) mmHg in smokers. The variants associated with BMI included rs2036534, rs6495309, rs1996371, rs6495314, rs4887077 and rs11638372 and had an average effect size of -0.38 (-0.68, -0.08) kg/m(2) per an additional copy of the risk allele in smokers. Formal assessments of interactions provided weaker support for these findings, especially after adjustment for multiple testing. Variation at 15q25 appears to interact with smoking status in influencing SBP and BMI. The genetic loci associated with SBP were in low linkage disequilibrium with those associated with BMI suggesting that the gene cluster might regulate SBP through biological mechanisms that partly differ from those regulating BMI. Further studies in larger samples are needed for more precise evaluation of the possible interactions, and to understand the mechanisms behind.


Post-induction, stimulus-specific regulation of tumor necrosis factor mRNA expression.
The tumor necrosis factor (TNF) gene is activated by multiple extracellular signals in a stimulus- and cell type-specific fashion. Based on the presence of kappaB-like DNA motifs in the region upstream of the TNF gene, some have proposed a direct role for NF-kappaB in lipopolysaccharide (LPS)-induced TNF gene transcription in cells of the monocyte/macrophage lineage. However, we have previously demonstrated a general and critical role for a minimal TNF promoter region bearing only one of the kappaB-like motifs, kappa3, which is bound by nuclear factor of activated T cell proteins in lymphocytes and fibroblasts in response to multiple stimuli and Ets proteins in LPS-stimulated macrophages. Here, in an effort to resolve these contrasting findings, we used a combination of site-directed mutagenesis of the TNF promoter, quantitative DNase I footprinting, and analysis of endogenous TNF mRNA production in response to multiple stimuli under conditions that inhibit NF-kappaB activation (using the proteasome inhibitor lactacystin and using cells lacking either functional NF-kappaB essential modulator, which is the IkappaB kinase regulatory subunit, or the Nemo gene itself). We find that TNF mRNA production in response to ionophore is NF-kappaB-independent, but inhibition of NF-kappaB activation attenuates virus- and LPS-induced TNF mRNA levels after initial induction. We conclude that induction of TNF gene transcription by virus or LPS does not depend upon NF-kappaB binding to the proximal promoter; rather, a stimulus-specific post-induction mechanism involving NF-kappaB, yet to be characterized, is involved in the maintenance of maximal TNF mRNA levels.


Drivers of Cervical Deformity Have a Strong Influence on Achieving Optimal Radiographic and Clinical Outcomes at 1 Year After Cervical Deformity Surgery.
The primary driver (PD) of cervical malalignment is important in characterizing cervical deformity (CD) and should be included in fusion to achieve alignment and quality-of-life goals. This study aims to define how PDs improve understanding of the mechanisms of CD and assesses the impact of driver region on realignment/outcomes. Inclusion: radiographic CD, age >18 years, 1 year follow-up. PD apex was classified by spinal region: cervical, cervicothoracic junction (CTJ), thoracic, or spinopelvic by a panel of spine deformity surgeons. Primary analysis evaluated PD groups meeting alignment goals (by Ames modifiers cervical sagittal vertical axis/T1 slope minus cervical lordosis/chin-brow vergical angle/modified Japanese Orthopaedics Association questionnaire) and health-related quality of life (HRQL) goals (EuroQol-5 Dimensions questionnaire/Neck Disability Index/modified Japanese Orthopaedics Association questionnaire) using t tests. Secondary analysis grouped interventions by fusion constructs including the primary or secondary apex based on lowest instrumented vertebra: cervical, lowest instrumented vertebra (LIV) ≤C7; CTJ, LIV ≤T3; and thoracic, LIV ≤T12. A total of 73 patients (mean age, 61.8 years; 59% female) were evaluated with the following PDs of their sagittal cervical deformity: cervical, 49.3%; CTJ, 31.5%; thoracic, 13.7%; and spinopelvic, 2.7%. Cervical drivers (n = 36) showed the greatest 1-year postoperative cervical and global alignment changes (improvement in T1S, CL, C0-C2, C1 slope). Thoracic drivers were more likely to have persistent severe T1 slope minus cervical lordosis modifier grade at 1 year (0, 20.0%; +, 0.0%; ++, 80.0%). Cervical deformity modifiers tended to improve in cervical patients whose construct included the PD apex (included, 26%; not, 0%; P = 0.068). Thoracic and cervicothoracic PD apex patients did not improve in HRQL goals when PD apex was not treated. CD structural drivers have an important effect on treatment and 1-year postoperative outcomes. Cervical or thoracic drivers not included in the construct result in residual deformity and inferior HRQL goals. These factors should be considered when discussing treatment plans for patients with CD.


Primary anorectal melanoma: A case report with extended follow-up.
Anorectal melanoma is a rare and aggressive disease. The mainstay of treatment is usually surgical with curative or palliative intent, since radio- and chemotherapy do not really improve the outcome. The poor prognosis is attributable to delay in diagnosis and its inherent biologic aggressiveness. We present a case of anorectal melanoma in a 68-year-old man who underwent solely abdominoperineal amputation and was doing well 30 months after surgery, without any evidence of recurrent disease. Treatment of anorectal melanoma should be by the least morbid means possible. Surgical procedure that can achieve a complete local excision and respect the functional aspects and quality of life of the patient remains the best therapeutic approach. No systemic regimen for metastatic anorectal melanoma is considered standard of care.


Properties of the stromal cell in giant cell tumor of bone.
The histiogenesis and mechanisms of bone destruction in giant cell tumor (GCT) of bone are not well understood. We asked whether the spindle-like stromal cells of GCT of bone exhibit osteoblastic properties, and whether the stromal cells produce active matrix-degrading proteases in vitro. We performed immunohistochemistry on 17 paraffin-embedded archival specimens with a pathologic diagnosis of GCT with monoclonal antibodies for the osteoblastic lineage markers osteopontin, osteonectin, and osteocalcin. The average staining grade for the 17 specimens was highest for osteonectin, followed by osteopontin, and osteocalcin. Primary cell cultures of GCT stromal cells were prepared from two fresh tumor specimens. Western blots were used on the cell lysates and media to detect osteocalcin precursor and the matrix-degrading proteases MMP-2 and MMP-9. We found the stromal cells in culture produce osteocalcin precursor, indicating osteoblastic lineage. The cells also express both the active and inactive isoforms of MMP-2 and MMP-9. Gelatinase assays confirmed the activity of the proteases in vitro. The spindle like stromal cells of GCT have characteristics of osteoblast progenitors and produce active matrix-degrading proteases. These cells may therefore play a central role in bone destruction.


Melatonin and renal protection: novel perspectives from animal experiments and human studies (review).
Chronic kidney disease (CKD) is a serious public health problem. Current therapies are designed to slow down progression of the disease and avoid the necessity of dialysis or kidney transplantation. CKD is characterized by chronic inflammation and progressive cell death resulting in fibrotic rebuilding of renal tissue. Melatonin, the primary product of the pineal gland, has been shown to have pluripotent protective effects in many organs and tissues. It exerts anti-hypertensive, anti-inflammatory, anti-apoptotic, and antiremodelling actions. A principal mechanism of these numerous melatonin benefits resides in its extraordinary high efficacy as an antioxidant and scavenger protecting cells both extracellularly and in all subcellular structures. In addition to these receptor-independent actions, the effects of melatonin via specific MT-receptors may be beneficial. In several animal models of CKD, involving experimental hypertension, diabetes mellitus and various models of nephrotoxicity, melatonin reduced the oxidative burden, attenuated the chronic inflammation and limited apoptosis. These effects were associated with the reduction of proteinuria, damage of parenchymal cells and fibrosis. In humans, melatonin's chronobiological action attenuates sleep disturbances in hemodialyzed patients suffering from a relative melatonin deficiency. Moreover, melatonin reduces the oxidative burden and improves iron metabolism in hemodialyzed patients. In conclusion, the pleiotropic physiological actions of melatonin induce beneficial effects at numerous pathophysiological levels related to CKD both under experimental and clinical conditions. It is hoped that this review will prompt a large clinical trial to determine the efficacy of this nontoxic indoleamine as a potential treatment for this debilitating disease.


Mortality and Prehospital Blood Pressure in Patients With Major Traumatic Brain Injury: Implications for the Hypotension Threshold.
Current prehospital traumatic brain injury guidelines use a systolic blood pressure threshold of less than 90 mm Hg for treating hypotension for individuals 10 years and older based on studies showing higher mortality when blood pressure drops below this level. However, the guidelines also acknowledge the weakness of the supporting evidence. To evaluate whether any statistically supportable threshold between systolic pressure and mortality emerges from the data a priori, without assuming that a cut point exists. Observational evaluation of a large prehospital database established as a part of the Excellence in Prehospital Injury Care Traumatic Brain Injury Study. Patients from the preimplementation cohort (January 2007 to March 2014) 10 years and older with moderate or severe traumatic brain injury (Barell Matrix Type 1 classification, International Classification of Diseases, Ninth Revision head region severity score of 3 or greater, and/or Abbreviated Injury Scale head-region severity score of 3 or greater) and a prehospital systolic pressure between 40 and 119 mm Hg were included. The generalized additive model and logistic regression were used to determine the association between systolic pressure and probability of death, adjusting for significant/important confounders. The main outcome measure was in-hospital mortality. Among the 3844 included patients, 2565 (66.7%) were male, and the median (range) age was 35 (10-99) years. The model revealed a monotonically decreasing association between systolic pressure and adjusted probability of death across the entire range (ie, from 40 to 119 mm Hg). Each 10-point increase of systolic pressure was associated with a decrease in the adjusted odds of death of 18.8% (adjusted odds ratio, 0.812; 95% CI, 0.748-0.883). Thus, the adjusted odds of mortality increased as much for a drop from 110 to 100 mm Hg as for a drop from 90 to 80 mm Hg, and so on throughout the range. We found a linear association between lowest prehospital systolic blood pressure and severity-adjusted probability of mortality across an exceptionally wide range. There is no identifiable threshold or inflection point between 40 and 119 mm Hg. Thus, in patients with traumatic brain injury, the concept that 90 mm Hg represents a unique or important physiological cut point may be wrong. Furthermore, clinically meaningful hypotension may not be as low as current guidelines suggest. Randomized trials evaluating treatment levels significantly above 90 mm Hg are needed.


Adrenal steroids regulate postnatal development of the rat dentate gyrus: I. Effects of glucocorticoids on cell death.
The rat dentate gyrus undergoes a period of naturally occurring cell death during the first postnatal week. In the adult rat, removal of circulating adrenal steroids by adrenalectomy is followed by massive death in the granule cell layer, thus raising the possibility that developmental cell death results from low levels of these hormones. Interestingly, the first two postnatal weeks of life in the rat, termed the stress hyporesponsive period, are characterized by very low levels of adrenal steroids. In order to determine whether low levels of adrenal steroids enable developmental cell death to occur in the dentate gyrus, we examined the density of pyknotic and healthy cells in the dentate gyrus of rat pups which received one of the following treatments: (1) injections of the endogenous rat glucocorticoid corticosterone during the first postnatal week, or (2) adrenalectomy at the time when glucocorticoid levels normally rise. Quantitative analysis of the density of pyknotic cells in the granule cell layers revealed significant decreases with corticosterone treatment by the end of the first postnatal week. In these same brains, treatment with corticosterone resulted in a substantial increase in the density of pyknotic cells in the hilus. Adrenalectomy resulted in a significant increase in the density of pyknotic cells in the granule cell layer as well as in the hilus. Despite the dramatic alterations in the density of pyknotic cells with both increases and decreases in glucocorticoid levels, the density of healthy cells remained the same. These observations suggest that glucocorticoids regulate several processes, possibly including neurogenesis and migration, in addition to cell death.


Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukemia. Results of the PETHEMA ALL-93 trial.
The optimal post-remission therapy for adults with high-risk acute lymphoblastic leukemia (ALL) is not well established. This multicenter randomized trial by the Spanish PETHEMA Group was addressed to compare three options of post-remission therapy in adults with high-risk ALL: chemotherapy, allogeneic stem cell transplantation (SCT) and autologous SCT. A total of 222 valid high-risk ALL patients entered the trial. All received a standard five-drug/five-week induction course. Patients in complete remission with an HLA-identical family donor were assigned to allogeneic SCT (n=84) and the remaining were randomized to autologous SCT (n=50) or to delayed intensification followed by maintenance chemotherapy up to 2 years in complete remission (n=48). Overall, 183 patients achieved complete remission (82%). With a median follow-up of 70 months, the median disease-free survival and overall survival were 17 and 23 months, respectively. The 5-year disease-free survival and overall survival were 35% (95% CI, 30%-41%) and 34% (95% CI, 28%-39%), respectively. Patients allocated to the chemotherapy, allogeneic and autologous SCT were comparable in the main pre-treatment ALL characteristics and the rate of response to therapy. Intention-to-treat analysis showed no differences between patients according to whether they had or did not have a donor in disease-free survival (39%, 95% CI 30-48% vs. 33%, 95% CI 23-41%) and overall survival (44%, 95% CI 35-52% vs. 35%, 95% CI 25-44%), as well as for autologous SCT vs. chemotherapy comparisons (disease-free survival: 40%, 95% CI 28-52% vs. 51%, 95% CI 37-67%; overall survival: 43%, 95% CI 29-58% vs. 52%, 95% CI 39-65%). No differences were observed when the analysis was made on the basis of the treatment actually performed. This study failed to prove that, when a family donor is available, allogeneic SCT produces a better outcome than autologous SCT or chemotherapy in adults with high-risk ALL.


Psychedelics, Meditation, and Self-Consciousness.
In recent years, the scientific study of meditation and psychedelic drugs has seen remarkable developments. The increased focus on meditation in cognitive neuroscience has led to a cross-cultural classification of standard meditation styles validated by functional and structural neuroanatomical data. Meanwhile, the renaissance of psychedelic research has shed light on the neurophysiology of altered states of consciousness induced by classical psychedelics, such as psilocybin and LSD, whose effects are mainly mediated by agonism of serotonin receptors. Few attempts have been made at bridging these two domains of inquiry, despite intriguing evidence of overlap between the phenomenology and neurophysiology of meditation practice and psychedelic states. In particular, many contemplative traditions explicitly aim at dissolving the sense of self by eliciting altered states of consciousness through meditation, while classical psychedelics are known to produce significant disruptions of self-consciousness, a phenomenon known as drug-induced ego dissolution. In this article, we discuss available evidence regarding convergences and differences between phenomenological and neurophysiological data on meditation practice and psychedelic drug-induced states, with a particular emphasis on alterations of self-experience. While both meditation and psychedelics may disrupt self-consciousness and underlying neural processes, we emphasize that neither meditation nor psychedelic states can be conceived as simple, uniform categories. Moreover, we suggest that there are important phenomenological differences even between conscious states described as experiences of self-loss. As a result, we propose that self-consciousness may be best construed as a multidimensional construct, and that "self-loss," far from being an unequivocal phenomenon, can take several forms. Indeed, various aspects of self-consciousness, including narrative aspects linked to autobiographical memory, self-related thoughts and mental time travel, and embodied aspects rooted in multisensory processes, may be differently affected by psychedelics and meditation practices. Finally, we consider long-term outcomes of experiences of self-loss induced by meditation and psychedelics on individual traits and prosocial behavior. We call for caution regarding the problematic conflation of temporary states of self-loss with "selflessness" as a behavioral or social trait, although there is preliminary evidence that correlations between short-term experiences of self-loss and long-term trait alterations may exist.


Expanding the genetic code of Escherichia coli.
A unique transfer RNA (tRNA)/aminoacyl-tRNA synthetase pair has been generated that expands the number of genetically encoded amino acids in Escherichia coli. When introduced into E. coli, this pair leads to the in vivo incorporation of the synthetic amino acid O-methyl-l-tyrosine into protein in response to an amber nonsense codon. The fidelity of translation is greater than 99%, as determined by analysis of dihydrofolate reductase containing the unnatural amino acid. This approach should provide a general method for increasing the genetic repertoire of living cells to include a variety of amino acids with novel structural, chemical, and physical properties not found in the common 20 amino acids.


Gene expression biomarkers in the brain of a mouse model for Alzheimer's disease: mining of microarray data by logic classification and feature selection.
The identification of early and stage-specific biomarkers for Alzheimer's disease (AD) is critical, as the development of disease-modification therapies may depend on the discovery and validation of such markers. The identification of early reliable biomarkers depends on the development of new diagnostic algorithms to computationally exploit the information in large biological datasets. To identify potential biomarkers from mRNA expression profile data, we used the Logic Mining method for the unbiased analysis of a large microarray expression dataset from the anti-NGF AD11 transgenic mouse model. The gene expression profile of AD11 brain regions was investigated at different neurodegeneration stages by whole genome microarrays. A new implementation of the Logic Mining method was applied both to early (1-3 months) and late stage (6-15 months) expression data, coupled to standard statistical methods. A small number of "fingerprinting" formulas was isolated, encompassing mRNAs whose expression levels were able to discriminate between diseased and control mice. We selected three differential "signature" genes specific for the early stage (Nudt19, Arl16, Aph1b), five common to both groups (Slc15a2, Agpat5, Sox2ot, 2210015, D19Rik, Wdfy1), and seven specific for late stage (D14Ertd449, Tia1, Txnl4, 1810014B01Rik, Snhg3, Actl6a, Rnf25). We suggest these genes as potential biomarkers for the early and late stage of AD-like neurodegeneration in this model and conclude that Logic Mining is a powerful and reliable approach for large scale expression data analysis. Its application to large expression datasets from brain or peripheral human samples may facilitate the discovery of early and stage-specific AD biomarkers.


Expression profile analysis of new candidate genes for the therapy of primary osteoporosis.
Primary osteoporosis is a progressive bone disease that is characterized by a decrease in bone mass and density which can lead to an increased risk of fracture. Most of present treatments are effective for osteoporosis, but have limitations and side-effects. With the aging of the world population is increasing, the incidence of osteoporosis is rising. Therefore, the purpose of this study was to identify new candidate genes used as the therapeutic targets of primary osteoporosis. In this study, microarray data GSE35958 were downloaded from Gene Expression Omnibus, then the differentially expressed genes (DEGs) were identified by limma package. Gene Ontology (GO) and KEGG pathway enrichment analyses were performed for both up- and down-regulated DEGs using DAVID. In addition, the transcription factor analysis was conducted for DEGs. The protein-protein interaction (PPI) network was constructed by STRING and Cytoscape. Finally, CFinder was used to analyze the PPI sub-network. Totally, 327 up-regulated DEGs and 396 down-regulated DEGs were identified. The DEGs such as EGFR and AKT1 were mainly enriched in the pathway of focal adhesion. EGFR was also involved in cell adhesion based on GO enrichment analysis. Functional analysis of DEGs indicated that 26 transcription factors were screened. Moreover, EGFR, AKT1 and transcription factor CTNNB1 were the key nodes with high degrees according to PPI network and sub-network. The literature suggested that AKT1, EGFR and CTNNB1 were closely related to osteoblastic differentiation and osteoclastogenesis. Some crucial DEGs such as EGFR, AKT1 and CTNNB1 might be connected with primary osteoporosis and could be used as therapeutic targets of osteoporosis.


The Preventive and Curative Effects of Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 on Immobilization Stress-Induced Anxiety/Depression and Colitis in Mice.
The gut dysbiosis by stressors such as immobilization deteriorates psychiatric disorders through microbiota-gut-brain axis activation. To understand whether probiotics could simultaneously alleviate anxiety/depression and colitis, we examined their effects on immobilization stress (IS)-induced anxiety/depression and colitis in mice. The probiotics Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 were isolated from healthy human feces. Mice with anxiety/depression and colitis were prepared by IS treatment. NK33 and NK98 potently suppressed NF-κB activation in lipopolysaccharide (LPS)-induced BV-2 cells. Treatment with NK33 and/or NK98, which were orally gavaged in mice before or after IS treatment, significantly suppressed the occurrence and development of anxiety/depression, infiltration of Iba1⁺ and LPS⁺/CD11b⁺ cells (activated microglia) into the hippocampus, and corticosterone, IL-6, and LPS levels in the blood. Furthermore, they induced hippocampal BDNF expression while NF-κB activation was suppressed. NK33 and/or NK98 treatments suppressed IS-induced colon shortening, myeloperoxidase activity, infiltration of CD11b⁺/CD11c⁺ cells, and IL-6 expression in the colon. Their treatments also suppressed the IS-induced fecal Proteobacteria population and excessive LPS production. They also induced BDNF expression in LPS-induced SH-SY5Y cells in vitro. In conclusion, NK33 and NK98 synergistically alleviated the occurrence and development of anxiety/depression and colitis through the regulation of gut immune responses and microbiota composition.


Molecular assessment of protective effect of Vitex negundo in ISO induced myocardial infarction in rats.
Myocardial infarction (MI) is the one of the major causes of death worldwide, however the molecular mechanisms hidden under this disease conditions remain unknown. This demands serious attention to unravel the molecular mechanisms to identify the therapeutic strategies either to prevent or to control MI. Ayurveda is becoming one of the best alternatives for the modern medicines. On the other hand, Vitex negundo is one of the medicinally important plants used for various diseases and to date, its cardioprotective role is not fully elucidated. In the present study, we made an attempt to understand the cardiac signaling cascade of Akt1 and NF-κB in isoproterenol (ISO)-induced MI, and targeting these signaling molecules by using V. negundo leaf ethanolic extract (VNE). Our findings demonstrate that VNE significantly protects the ISO-induced MI by regulating NF-κB and Akt1experssion in rats.


Low self-esteem is a risk factor for depressive symptoms from young adulthood to old age.
Data from two large longitudinal studies were used to analyze reciprocal relations between self-esteem and depressive symptoms across the adult life span. Study 1 included 1,685 participants aged 18 to 96 years assessed 4 times over a 9-year period. Study 2 included 2,479 participants aged 18 to 88 years assessed 3 times over a 4-year period. In both studies, cross-lagged regression analyses indicated that low self-esteem predicted subsequent depressive symptoms, but depressive symptoms did not predict subsequent levels of self-esteem. This pattern of results replicated across all age groups, for both affective-cognitive and somatic symptoms of depression, and after controlling for content overlap between the self-esteem and depression scales. The results suggest that low self-esteem operates as a risk factor for depressive symptoms at all phases of the adult life span.


First international external quality assessment of molecular detection of Crimean-Congo hemorrhagic fever virus.
Crimean-Congo hemorrhagic fever (CCHF) is a zoonosis caused by a Nairovirus of the family Bunyaviridae. Infection is transmitted to humans mostly by Hyalomma ticks and also by direct contact with the blood or tissues of infected humans or viremic livestock. Clinical features usually include a rapid progression characterized by hemorrhage, myalgia and fever, with a lethality rate up to 30%. CCHF is one of the most widely distributed viral hemorrhagic fevers and has been reported in Africa, the Middle East and Asia, as well as parts of Europe. There is no approved vaccine or specific treatment against CCHF virus (CCHFV) infections. In this context, an accurate diagnosis as well as a reliable surveillance of CCHFV infections is essential. Diagnostic techniques include virus culture, serology and molecular methods, which are now increasingly used. The European Network for the Diagnostics of "Imported" Viral Diseases organized the first international external quality assessment of CCHVF molecular diagnostics in 2011 to assess the efficiency and accurateness of CCHFV molecular methods applied by expert laboratories. A proficiency test panel of 15 samples was distributed to the participants including 10 different CCHFV preparations generated from infected cell cultures, a preparation of plasmid cloned with the nucleoprotein of CCHFV, two CCHFV RNA preparations and two negative controls. Forty-four laboratories worldwide participated in the EQA study and 53 data sets were received. Twenty data sets (38%) met all criteria with optimal performance, 10 (19%) with acceptable performance, while 23 (43%) reported results showing a need for improvement. Differences in performance depended on the method used, the type of strain tested, the concentration of the sample tested and the laboratory performing the test. These results indicate that there is still a need for improving testing conditions and standardizing protocols for the molecular detection of Crimean-Congo hemorrhagic fever virus.


Edit, cut and paste in the nicotinic acetylcholine receptor gene family of Drosophila melanogaster.
Nicotinic acetylcholine receptors (nAChRs) are important for fast synaptic cholinergic transmission. They are targets of drugs/chemicals for human and animal health as well as for pest control. With the advent of genome sequencing, entire nAChR gene families have now been described for vertebrates and invertebrates. Mostly, these are extensive with a large number of distinct subunits, making possible many nAChR subtypes differing in transmitter affinity, channel conductance, ion selectivity, desensitization, modulation and pharmacology. The smallest nAChR gene family to date is that of the fruit fly, Drosophila melanogaster, with only 10 members. This apparently compact family belies its true diversity as 4 of the 10 subunits show alternative splicing. Also, using Drosophila, A-to-I pre-mRNA editing has been demonstrated for the first time in nAChRs. Such is the extent of this variation, that one subunit alone (Dalpha6) can potentially generate far more isoforms than seen in entire gene families from other species. We present here three-dimensional models constructed for insect nAChRs, which show that many variations introduced by alternative splicing and RNA editing may influence receptor function.


A 3,3'-dichlorobenzidine-imprinted polymer gel surface plasmon resonance sensor based on template-responsive shrinkage.
Molecularly imprinted polymer gel film on the gold substrate of a chip was prepared with minute amount of cross-linker for the fabrication of a surface plasmon resonance (SPR) sensor sensitive to 3,3'-dichlorobenzidine. The molecularly imprinted gel film was anchored on a gold chip by a surface-bound photo-radical initiator. The sensing of 3,3'-dichlorobenzidine is based on responsive shrinkage of the imprinted polymer gel film that is triggered by target binding. This change can improve the responsiveness of the imprinted SPR sensor to 3,3'-dichlorobenzidine. The molecularly imprinted polymer gel film was characterized with contact angle measurements, electrochemical impedance spectroscopy, cyclic voltammogram, swelling measurements and atomic force microscopy. The changes of SPR spectroscopy wavenumber shifts revealed that the imprinted gel sensing film can 'memorize' the binding of 3,3'-dichlorobenzidine compared to non-imprinted one. The imprinted gel-SPR sensor showed a linear response in the range of 9.0×10(-12) to 5.0×10(-10) mol L(-1) (R(2)=0.9998) for the detection of 3,3'-dichlorobenzidine, and it also exhibited high selectivity to 3,3'-dichlorobenzidine compared to its structurally related analogues. We calculated the detection limits to be 0.471 ng L(-1) for tap water and 0.772 ng kg(-1) for soil based on a signal to noise ratio of 3. The method showed good recoveries and precision for the samples spiked with 3,3'-dichlorobenzidine. This suggest that the imprinted gel-SPR sensing method can be used as a promising alternative for the detection of 3,3'-dichlorobenzidine.


Cucurbitacin B Induces Hypermethylation of Oncogenes in Breast Cancer Cells.
Breast cancer is a complex disease driven by multiple factors including both genetic and epigenetic alterations. Recent studies revealed that abnormal gene expression induced by epigenetic changes including aberrant promoter methylation plays a critical role in human breast carcinogenesis. Cucurbitacin B has antiproliferative activity against various human breast cancer cells, but the molecular mechanism is not completely understood. In this study, we explore the influence of cucurbitacin B from Trichosanthes cucumerina on the methylation status at the promoter of oncogenes c-Myc, cyclin D1, and survivin in breast cancer cell lines. Growth inhibitory effect of cucurbitacin B on breast cancer cells was assessed by MTT assay and colony formation assay. Methylation status of genomic DNA was determined by methylation-specific PCR. Gene and protein expression levels of all genes studied were analyzed by real-time RT-PCR and western blot. The results indicated that cucurbitacin B could inhibit cell growth in breast cancer cells. The oncogene promoters are usually hypomethylated in cancer cells. Upon cucurbitacin B treatment, upregulation of DNMT1 and obvious heavy methylation in the promoters of c-Myc, cyclin D1, and survivin, which consequently downregulated the expression of all these oncogenes, were observed. Hence, cucurbitacin B proved to be a potential cancer therapeutic agent, in part by inducing hypermethylation and silences the oncogenic activation.


Will endovascular repair replace open surgery for abdominal aortic aneurysm repair?
To evaluate of the impact of endovascular aneurysm repair on the rate of open surgical repair and on the overall treatment of abdominal aortic aneurysms (AAAs). All patients with AAA who were treated during two consecutive 40-month periods were reviewed. During the first period, only open surgical repair was performed; during the subsequent 40 months, endovascular repair and open surgical repair were treatment options. A total of 727 patients with AAA were treated during the entire period. During the initial 40 months, 268 patients were treated with open surgical repair, including 216 infrarenal (81%), 43 complex (16%), and 9 ruptured (3%) aortic aneurysms. During the subsequent 40 months, 459 patients with AAA were treated (71% increase). There was no significant change in the number of patients undergoing open surgical repair and no significant difference in the rate of infrarenal (238 [77%]) and complex (51 [16%]) repairs. A total of 353 patients were referred for endovascular repair. Of these, 190 (54%) were considered candidates for endovascular repair based on computed tomography or arteriographic morphologic criteria. Analyzing a subgroup of 123 patients, the most common primary reasons for ineligibility for endovascular repair were related to morphology of the neck in 80 patients (65%) and of the iliac arteries in 35 patients (28%). A total of 149 patients underwent endovascular repair. Of these, the procedure was successful in 147 (99%), and 2 (1%) patients underwent surgical conversion. The hospital death rate was 0%, and the 30-day death rate was 1%. During a follow-up period of 1 to 39 months (mean 12 +/- 9), 21 secondary procedures to treat endoleak (20) or to maintain graft limb patency (1) were performed in 17 patients (11%). There were no aneurysm ruptures or aneurysm-related deaths. Endovascular repair appears to have augmented treatment options rather than replaced open surgical repair for patients with AAA. Patients who previously were not candidates for repair because of medical comorbidity may now be safely treated with endovascular repair.


Asthma guideline use by pediatricians in private practices and asthma morbidity.
We sought to examine whether pediatric clinicians in private, non-health maintenance organization practices could implement the national asthma guidelines and whether, when implemented, these guidelines would decrease medical services utilization and improve asthma care for children. A trial of a disease management program (Easy Breathing II) involving 20 private pediatric practices in the greater Hartford, Connecticut area was conducted between January 1, 2001, and December 31, 2003. Demographic data on participating practitioners and patients were obtained from questionnaires. Medical services utilization data from claims were obtained from ConnectiCare, a regional managed care organization. Of the 16750 children enrolled in Easy Breathing II, 2458 were enrolled in ConnectiCare and 490 had asthma. Inhaled corticosteroid use increased in the community overall during the study period. After enrollment in Easy Breathing II, with adjustment for age, gender, ethnicity, asthma severity, season, and calendar year, children with persistent asthma experienced an additional 47% increase in inhaled corticosteroid use, a 56% reduction in outpatient visits, and a 91% decrease in emergency department visits for treatment of asthma. Adherence to national asthma guidelines for prescribing inhaled corticosteroids was 95%. Seventeen of the 20 practices are still using Easy Breathing, 5 years after program implementation. Pediatric primary care clinicians in private practice settings can implement an asthma management program patterned after the national asthma guidelines. When implemented, this program is successful in reducing medical services utilization for children with asthma. Just as differences in patterns of medical services utilization exist in private practices, compared with urban clinics, the impact of disease management on medical services utilization differs in private practices, compared with urban clinics.


In osteoporosis, differentiation of mesenchymal stem cells (MSCs) improves bone marrow adipogenesis.
The formation, maintenance, and repair of bone tissue involve close interlinks between two stem cell types housed in the bone marrow: the hematologic stem cell originating osteoclasts and mesenchymal stromal cells (MSCs) generating osteoblasts. In this review, we consider malfunctioning of MSCs as essential for osteoporosis. In osteoporosis, increased bone fragility and susceptibility to fractures result from increased osteoclastogenesis and insufficient osteoblastogenesis. MSCs are the common precursors for both osteoblasts and adipocytes, among other cell types. MSCs' commitment towards either the osteoblast or adipocyte lineages depends on suitable regulatory factors activating lineage-specific transcriptional regulators. In osteoporosis, the reciprocal balance between the two differentiation pathways is altered, facilitating adipose accretion in bone marrow at the expense of osteoblast formation; suggesting that under this condition MSCs activity and their microenvironment may be disturbed. We summarize research on the properties of MSCs isolated from the bone marrow of control and osteoporotic post-menopausal women. Our observations indicate that intrinsic properties of MSCs are disturbed in osteoporosis. Moreover, we found that the regulatory conditions in the bone marrow fluid of control and osteoporotic patients are significantly different. These conclusions should be relevant for the use of MSCs in therapeutic applications.


Moving forward with wellness incentives under the Affordable Care Act: lessons from Germany.
Health care payers in the United States and abroad have used wellness incentives as a tool to improve health and reduce costs. In Germany, public insurers operate many such programs. Participation nearly doubled between 2004 and 2008, reaching one-quarter of the publicly insured population. An evaluation of one large wellness program there found that it reduced costs. However, population-level survey data also suggest that individuals with low incomes or poor health are less likely to enroll. In the United States, the Affordable Care Act raised the maximum allowed size of wellness incentives, which could lead to wide differences in insurance premiums between users and nonusers of programs, and may risk reintroducing a form of medical underwriting. The German experience confirms the cost-saving potential of programs, but also suggests that they should be evaluated rigorously to ensure they do not disadvantage those with health problems or low incomes.


Oregon's Emphasis On Equity Shows Signs Of Early Success For Black And American Indian Medicaid Enrollees.
In 2012 Oregon transformed its Medicaid program, providing coverage through sixteen coordinated care organizations (CCOs). The state identified the elimination of health disparities as a priority for the CCOs, implementing a multipronged approach that included strategic planning, community health workers, and Regional Health Equity Coalitions. We used claims-based measures of utilization, access, and quality to assess baseline disparities and test for changes over time. Prior to the CCO intervention there were significant white-black and white-American Indian/Alaska Native disparities in utilization measures and white-black disparities in quality measures. The CCOs' transformation and implementation of health equity policies was associated with reductions in disparities in primary care visits and white-black differences in access to care, but no change in emergency department use, with higher visit rates persisting among black and American Indian/Alaska Native enrollees, compared to whites. States that encourage payers and systems to prioritize health equity could reduce racial and ethnic disparities for some measures in their Medicaid populations.


Molecular Characterization of Renal Cell Carcinoma: A Potential Three-MicroRNA Prognostic Signature.
Background: Aberrantly expressed miRNAs promote renal cell carcinoma (RCC) growth and metastasis and are potentially useful biomarkers for metastatic disease. However, a consensus clinically significant miRNA signature has not been identified. To identify an miRNA signature for predicting clinical outcome in RCC patients, we used a four-pronged interconnected approach.Methods: Differentially expressed miRNAs were identified and analyzed in 113 specimens (normal kidney: 59; tumor: 54). miRNA profiling was performed in matched normal and tumor specimens from 8 patients and extended to 32 specimens. Seven aberrantly expressed miRNAs were analyzed by qPCR, and their levels were correlated with RCC subtypes and clinical outcome. miRNA signature was confirmed in The Cancer Genome Atlas RCC dataset (n = 241).Results: Discovery phase identified miR-21, miR-142-3p, miR-142-5p, miR-150, and miR-155 as significantly upregulated (2-4-fold) and miR-192 and miR-194 as downregulated (3-60-fold) in RCC; miR-155 distinguished small tumors (<4 cm) from benign oncocytomas. In univariate and multivariate analyses, miRNA combinations (miR-21+194; miR-21+142-5p+194) significantly predicted metastasis and/or disease-specific mortality; miR-21+142-5p+194 (for metastasis): P = 0.0017; OR, 0.53; 95% confidence interval (CI), 0.75-0.33; 86.7% sensitivity; 82% specificity. In the TCGA dataset, combined biomarkers associated with metastasis and overall survival (miR-21+142-5p+194: P < 0.0001; OR, 0.37; 95% CI, 0.58-0.23).Conclusions: The interconnected discovery-validation approach identified a three-miRNA signature as a potential predictor of disease outcome in RCC patients.Impact: With 10% survival at 5 years, metastatic disease presents poor prognosis for RCC patients. The three-miRNA signature discovered and validated may potentially at an early stage detect and predict metastasis, to allow early intervention for improving patient prognosis. Cancer Epidemiol Biomarkers Prev; 27(4); 464-72. ©2018 AACR.


Breast cancer among Danish women occupationally exposed to diesel exhaust and polycyclic aromatic hydrocarbons, 1964-2016.
Objective The aim of this study was to explore the association between occupational exposure to diesel exhaust and polycyclic aromatic hydrocarbons (PAH), respectively, and breast cancer subtypes. Methods The study included 38 375 women <70 years with incident breast cancer, identified in the Danish Cancer Registry, and 5 breast cancer-free controls per case who were randomly selected from the Danish Civil Registration System and matched on year of birth. Full employment history was obtained for all study subjects from a nationwide pension fund, and exposure to diesel exhaust and PAH was assessed using a job exposure matrix. Conditional logistic regression was used for estimation of odds ratios (OR) with adjustment for reproductive factors and socioeconomic status. Results No noteworthy associations were observed for overall breast cancer in women exposed to diesel exhaust. However, diesel exhaust modestly elevated the risk of estrogen receptor negative breast tumors before age 50 [OR 1.26, 95% confidence interval (CI) 1.09-1.46]. Duration- and dose-response relationships were further observed for this subtype in this age group. No notable risk patterns were generally observed for PAH exposure. Conclusion Occupational exposure to diesel exhaust may increase the risk of early-onset estrogen receptor negative breast tumors in women. Future studies exploring this association are warranted.


Food Insecurity in Singapore: The Communicative (Dis)Value of the Lived Experiences of the Poor.
Food insecurity is a form of health disparity that results in adverse health outcomes, particularly among disenfranchised and vulnerable populations. Using the culture-centered approach, this article engages with issues of food insecurity, health, and poverty among the low-income community in Singapore. Through 30 in-depth interviews, the narratives of the food insecure are privileged in articulating their lived experiences of food insecurity and in co-constructing meanings of health informed by their sociocultural context, in a space that typically renders them invisible. Arguing that poverty is communicatively sustained through the erasure of subaltern voices from mainstream discourses and policy platforms, we ask the research question: What are the meanings of food insecurity in the everyday experiences of health among the poor in Singapore? Our findings demonstrate that the meanings of health among the food insecure are constituted in culture and materiality, structurally constrained, and ultimately complexify their negotiations of health and health decision making.


Rat mesothelioma cell proliferation requires p38δ mitogen activated protein kinase and C/EBP-α.
Pleural malignant mesothelioma is a rare but deadly tumour mainly induced by asbestos inhalation. Despite the ban of asbestos in 1990 in 52 countries, mesothelioma cases still increase worldwide. In pleural mesothelioma, p38 mitogen activated protein kinases (MAPK) have been suggested to play a major role in carcinogenesis and aggressiveness of tumours. The aim of this study was to determine the role of the different four p38 MAPK isoforms and their effect on proliferation together with the underlying signalling pathways in a rat pleural mesothelioma cell line. Rat pleural mesothelioma cells were stimulated with platelet-derived growth factor (PDGF)-BB and/or transforming growth factor beta (TGF)-β. MAPK and transcription factor expression and activation was monitored in the cytosol and nucleus by immuno-blotting. Proliferation was determined by manual cell count and siRNAs were used to control MAPK and transcription factor expression and action. Only PDGF-BB, but not TGF-β1 induced proliferation via activated Erk1/2 and p38 MAPK. The p38α and δ isoforms were expressed in the cytosol, and upon activation p38δ translocated into the nucleus, while p38α remained in the cytosol. No other p38 isoform was expressed by rat mesothelioma cells. C/EBP-α was found in both the cytosol and the nucleus, while C/EBP-β was not expressed at all. PDGF-BB induced proliferation was suppressed by down-regulation of either Erk1/2, or p38δ MAPK, or C/EBP-α. Furthermore, TGF-β inhibited PDGF-BB induced proliferation by interruption of p38 MAPK signalling. From this rat model, we conclude that in pleural mesothelioma, p38δ in C/EBP-α mediate proliferation and thus may represent new targets in mesothelioma therapy.


Self-assembling short immunostimulatory duplex RNAs with broad spectrum antiviral activity.
The current COVID-19 pandemic highlights the need for broad-spectrum antiviral therapeutics. Here we describe a new class of self-assembling immunostimulatory short duplex RNAs that potently induce production of type I and type III interferon (IFN-I and IFN-III), in a wide range of human cell types. These RNAs require a minimum of 20 base pairs, lack any sequence or structural characteristics of known immunostimulatory RNAs, and instead require a unique conserved sequence motif (sense strand: 5'-C, antisense strand: 3'-GGG) that mediates end-to-end dimer self-assembly of these RNAs by Hoogsteen G-G base-pairing. The presence of terminal hydroxyl or monophosphate groups, blunt or overhanging ends, or terminal RNA or DNA bases did not affect their ability to induce IFN. Unlike previously described immunostimulatory siRNAs, their activity is independent of TLR7/8, but requires the RIG-I/IRF3 pathway that induces a more restricted antiviral response with a lower proinflammatory signature compared with poly(I:C). Immune stimulation mediated by these duplex RNAs results in broad spectrum inhibition of infections by many respiratory viruses with pandemic potential, including SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A, as well as the common cold virus HCoV-NL63 in both cell lines and human Lung Chips that mimic organ-level lung pathophysiology. These short dsRNAs can be manufactured easily, and thus potentially could be harnessed to produce broad-spectrum antiviral therapeutics at low cost.


Fundamentals of Population Pharmacokinetic Modelling : Modelling and Software.
Population pharmacokinetic modelling is widely used within the field of clinical pharmacology as it helps to define the sources and correlates of pharmacokinetic variability in target patient populations and their impact upon drug disposition. This review focuses on the fundamentals of population pharmacokinetic modelling and provides an overview of the commonly available software programs that perform these functions.This review attempts to define the common, fundamental aspects of population pharmacokinetic modelling through a discussion of the literature describing the techniques and placing them in the appropriate context. An overview of the most commonly available software programs is also provided.Population pharmacokinetic modelling is a powerful approach where sources and correlates of pharmacokinetic variability can be identified in a target patient population receiving a pharmacological agent. There is a need to further standardize and establish the best approaches in modelling so that any model created can be systematically evaluated and the results relied upon. Various nonlinear mixed-effects modelling methods, packaged in a variety of software programs, are available today. When selecting population pharmacokinetic software programs, the consumer needs to consider several factors, including usability (e.g. user interface, native platform, price, input and output specificity, as well as intuitiveness), content (e.g. algorithms and data output) and support (e.g. technical and clinical).


Saudi anti-human cancer plants database (SACPD): A collection of plants with anti-human cancer activities.
Several anticancer drugs have been developed from natural products such as plants. Successful experiments in inhibiting the growth of human cancer cell lines using Saudi plants were published over the last three decades. Up to date, there is no Saudi anticancer plants database as a comprehensive source for the interesting data generated from these experiments. Therefore, there was a need for creating a database to collect, organize, search and retrieve such data. As a result, the current paper describes the generation of the Saudi anti-human cancer plants database (SACPD). The database contains most of the reported information about the naturally growing Saudi anticancer plants. SACPD comprises the scientific and local names of 91 plant species that grow naturally in Saudi Arabia. These species belong to 38 different taxonomic families. In Addition, 18 species that represent16 family of medicinal plants and are intensively sold in the local markets in Saudi Arabia were added to the database. The website provides interesting details, including plant part containing the anticancer bioactive compounds, plants locations and cancer/cell type against which they exhibit their anticancer activity. Our survey revealed that breast, liver and leukemia were the most studied cancer cell lines in Saudi Arabia with percentages of 27%, 19% and 15%, respectively. The current SACPD represents a nucleus around which more development efforts can expand to accommodate all future submissions about new Saudi plant species with anticancer activities. SACPD will provide an excellent starting point for researchers and pharmaceutical companies who are interested in developing new anticancer drugs. SACPD is available online at https://teeqrani1.wixsite.com/sapd.


Switching associations between facial identity and emotional expression: a behavioural and ERP study.
The aim of this study was to determine if, and when, the neural processes involved in switching associations formed with angry and happy faces start to diverge. We measured event-related potentials (ERPs) and behavioural responses while participants performed a reversal learning task with angry and happy faces. In the task, participants were simultaneously presented with two neutral faces and learned to associate one of the faces with an emotional expression (either angry or happy), which was displayed by the face when correctly selected. After three to seven trials, the face that had consistently been displaying an emotional expression when selected would instead remain neutral, signalling the participant to switch their response and select the other face on the subsequent trial. The neural processes involved in switching associations formed with angry and happy faces diverged 375 ms after stimulus onset. Specifically, P3a amplitude was reduced and P3b latency was delayed when participants were cued to switch associations formed with angry expressions compared to happy expressions. This difference was also evident in later behavioural responses, which showed that it was more difficult to switch associations made with angry expressions than happy expressions. These findings may reflect an adaptive mechanism that facilitates the maintenance of our memory of threatening individuals by associating them with their potential threat.


Effect of protein kinase C inhibitors and 2,3-butanedione monoxime on the long-term hypothermic preservation of isolated rat hearts.
1. This study examines the protective effect of staurosporine, chelerythrine, Ro 31-8220 and 2,3-butanedione monoxime in rat hearts during hypothermic storage. 2. Hearts were microperfused at 4 degrees C for 24 or 48 h with a storage buffer that in some cases contained one of these protein kinase C inhibitors either alone or in combination with 2,3-butanedione monoxime. After hypothermic storage, hearts were rewarmed to 37 degrees C with Krebs-Henseleit buffer. Cardiac function was then assessed in either Langendorff mode or working heart mode. 3. Compared with values from fresh non-stored hearts, hypothermic stored hearts showed a significant decrease in both coronary flow and left ventricular developed pressure when the stored hearts were reperfused in Langendorff mode. The decrease in coronary flow and left ventricular developed pressure was more pronounced in hearts stored for 48 h than in those stored for 24 h. 4. Hearts stored for 24 or 48 h, with or without the protein kinase C inhibitors, and then perfused in working mode generated less aortic flow and less cardiac output than fresh unstored hearts. 5. Hearts preserved in solutions containing staurosporine, chelerythrine, Ro 31-8220 or 2,3-butanedione monoxime had significantly higher left ventricular developed pressure values on reperfusion than hearts stored without any such drug. 6. Addition of 2,3-butanedione monoxime to a storage buffer containing either staurosporine, chelerythrine or Ro 31-8220 further improved left ventricular developed pressure, aortic flow and cardiac output values in these stored hearts. The group of hearts stored in a buffer containing 2,3-butanedione monoxime and chelerythrine gave the highest left ventricular developed pressure value seen during reperfusion. 7. The ATP and creatine phosphate concentrations of hearts stored in buffer alone were significantly lower than those of fresh unstored hearts, irrespective of the duration of storage. ATP concentrations were better preserved in hearts stored in a buffer containing 2,3-butanedione monoxime or/and one of the protein kinase C antagonists than those stored without such antagonists. A positive correlation was found between peak cardiac output values and the concentrations of combined high-energy phosphates in various groups of stored and reperfused hearts. 8. The present study showed that inhibition of protein kinase C during long-term hypothermic storage significantly increased high-energy phosphate concentrations and also improved contractile function during reperfusion.


Visualizing the quality of partially accruing data for use in decision making.
Secondary use of clinical health data for near real-time public health surveillance presents challenges surrounding its utility due to data quality issues. Data used for real-time surveillance must be timely, accurate and complete if it is to be useful; if incomplete data are used for surveillance, understanding the structure of the incompleteness is necessary. Such data are commonly aggregated due to privacy concerns. The Distribute project was a near real-time influenza-like-illness (ILI) surveillance system that relied on aggregated secondary clinical health data. The goal of this work is to disseminate the data quality tools developed to gain insight into the data quality problems associated with these data. These tools apply in general to any system where aggregate data are accrued over time and were created through the end-user-as-developer paradigm. Each tool was developed during the exploratory analysis to gain insight into structural aspects of data quality. Our key finding is that data quality of partially accruing data must be studied in the context of accrual lag-the difference between the time an event occurs and the time data for that event are received, i.e. the time at which data become available to the surveillance system. Our visualization methods therefore revolve around visualizing dimensions of data quality affected by accrual lag, in particular the tradeoff between timeliness and completion, and the effects of accrual lag on accuracy. Accounting for accrual lag in partially accruing data is necessary to avoid misleading or biased conclusions about trends in indicator values and data quality.


Assessing positive and negative changes in the aftermath of adversity: psychometric evaluation of the changes in outlook questionnaire.
The Changes in Outlook Questionnaire (CiOQ; S. Joseph, R. Williams, & W. Yule, 1993) is a 26-item self-report measure that was designed to assess positive and negative changes in the aftermath of adversity. This article had 3 aims: 1st, to investigate the factor structure of the CiOQ; 2nd, to test for internal consistency reliability and convergent and discriminant validity; and, 3rd, to investigate the association between positive and negative changes in outlook, posttraumatic stress, and psychological distress. Three studies are reported. Study 1 provides evidence that positive and negative changes are statistically separable and that the 2-factor model is a better fit than the 1-factor model. Studies 2 and 3 provide evidence for internal consistency reliability, convergent and discriminant validity of the CiOQ, and its associations with posttraumatic stress and psychological distress. In conclusion, the CiOQ has much promise for research on responses to stressful and traumatic events.


Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice.
Mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO) exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8-10 week) Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis. Aged (20-24 months) Mttp-IKO mice and WT mice underwent intratracheal injection with P. aeruginosa. Mice were either sacrificed 24 hours post-operatively for mechanistic studies or followed seven days for survival. In contrast to young septic Mttp-IKO mice, aged septic Mttp-IKO mice had a significantly higher mortality than aged septic WT mice (80% vs. 39%, p = 0.005). Aged septic Mttp-IKO mice exhibited increased gut epithelial apoptosis, increased jejunal Bax/Bcl-2 and Bax/Bcl-XL ratios yet simultaneously demonstrated increased crypt proliferation and villus length. Aged septic Mttp-IKO mice also manifested increased pulmonary myeloperoxidase levels, suggesting increased neutrophil infiltration, as well as decreased systemic TNFα compared to aged septic WT mice. Blocking intestinal chylomicron secretion alters mortality following sepsis in an age-dependent manner. Increases in gut apoptosis and pulmonary neutrophil infiltration, and decreased systemic TNFα represent potential mechanisms for why intestine-specific Mttp deletion is beneficial in young septic mice but harmful in aged mice as each of these parameters are altered differently in young and aged septic WT and Mttp-IKO mice.


A new mouse model of ATR-X syndrome carrying a common patient mutation exhibits neurological and morphological defects.
ATRX is a chromatin remodelling ATPase that is involved in transcriptional regulation, DNA damage repair and heterochromatin maintenance. It has been widely studied for its role in ALT-positive cancers, but its role in neurological function remains elusive. Hypomorphic mutations in the X-linked ATRX gene cause a rare form of intellectual disability combined with alpha-thalassemia called ATR-X syndrome in hemizygous males. Clinical features also include facial dysmorphism, microcephaly, short stature, musculoskeletal defects and genital abnormalities. As complete deletion of ATRX in mice results in early embryonic lethality, the field has largely relied on conditional knockout models to assess the role of ATRX in multiple tissues. Given that null alleles are not found in patients, a more patient-relevant model was needed. Here, we have produced and characterized the first patient mutation knock-in model of ATR-X syndrome, carrying the most common causative mutation, R246C. This is one of a cluster of missense mutations located in the chromatin-binding domain and disrupts its function. The knock-in mice recapitulate several aspects of the patient disorder, including craniofacial defects, microcephaly, reduced body size and impaired neurological function. They provide a powerful model for understanding the molecular mechanisms underlying ATR-X syndrome and testing potential therapeutic strategies.


Effect of chronic exercise on fluoride metabolism in fluorosis-susceptible mice exposed to high fluoride.
The present study investigated the effect of chronic exercise on fluoride (F) metabolism in fluorosis-susceptible mice exposed to high-F and explored the relationship between F concentrations in bone and plasma. Thirty male mice were randomised into three groups: Group I (No-F, No-Exercise), Group II (50 ppmF, No-Exercise), Group III (50 ppmF, Exercise). Body weight and physical performance of all mice were measured at baseline and end of experiment. F concentrations of plasma and bone were measured at the end of experiment. Mean plasma F concentration was significantly higher (p < 0.001) in Groups II and III compared with Group I. Mean bone F concentration was also significantly higher (p < 0.01) in Groups II and III compared with Group I. There was a significant correlation (p = 0.01, r = 0.54) between F concentration of plasma and bone. Mean body weight of Group I mice was significantly higher than Group II (p < 0.001) and Group III (p = 0.001) mice at the end of the experiment. This study, which provides the first data on the effect of chronic exercise on F metabolism in fluorosis-susceptible mice, suggests no effect of chronic exercise on F in plasma and bone. However, exposure to high-F resulted in lower body weight and exercise capacity in mice.


Enhanced recovery after surgery (ERAS) and fast-track in video-assisted thoracic surgery (VATS) lobectomy: preoperative optimisation and care-plans.
Main specific interventions for preoperative clinical optimisation of patients undergoing lung cancer surgery include assessment and treatment of comorbidities, minimizing preoperative hospitalization, minimizing preoperative fasting, and optimisation of antibiotic and thrombo-embolic prophylaxis. Preoperative patient optimisation is considered a crucial part of enhanced recovery after thoracic surgery pathways. Potentially, advantages of this fast-track management could be even higher when considering video-assisted thoracic surgery (VATS) major lung resection, because reduced trauma related to minimally invasive techniques is one of the main factors improving postoperative outcome. Literature data and clinical evidences in this setting are reported and discussed.


Pediatric Nurses' Perceptions of Medication Safety and Medication Error: A Mixed Methods Study.
This study aims to outline the current workplace culture of medication practice in a pediatric medical ward. The objective is to explore the perceptions of nurses in a pediatric clinical setting as to why medication administration errors occur. As nurses have a central role in the medication process, it is essential to explore nurses' perceptions of the factors influencing the medication process. Without this understanding, it is difficult to develop effective prevention strategies aimed at reducing medication administration errors. Previous studies were limited to exploring a single and specific aspect of medication safety. The methods used in these studies were limited to survey designs which may lead to incomplete or inadequate information being provided. This study is phase 1 on an action research project. Data collection included a direct observation of nurses during medication preparation and administration, audit based on the medication policy, and guidelines and focus groups with nursing staff. A thematic analysis was undertaken by each author independently to analyze the observation notes and focus group transcripts. Simple descriptive statistics were used to analyze the audit data. The study was conducted in a specialized pediatric medical ward. Four key themes were identified from the combined quantitative and qualitative data: (1) understanding medication errors, (2) the busy-ness of nurses, (3) the physical environment, and (4) compliance with medication policy and practice guidelines. Workload, frequent interruptions to process, poor physical environment design, lack of preparation space, and impractical medication policies are identified as barriers to safe medication practice. Overcoming these barriers requires organizations to review medication process policies and engage nurses more in medication safety research and in designing clinical guidelines for their own practice.


Anti-HLA alloantibody is found in children but does not correlate with a lack of HIV type 1 transmission from infected mothers.
Searching for mechanisms of natural resistance to HIV infection with which to guide HIV vaccine design, we have examined antibody responses to HLA class I antigens in children of HIV-1-infected mothers. Anti-HLA antibodies are known to block HIV infectivity in vitro and can be protective against SIV challenge in macaques immunized with purified class I HLA. It was hypothesized that alloantibody to maternal HLA in children might contribute to the prevention of mother-to-child transmission of HIV-1. In fact, a surprisingly high proportion of the children examined, 22%, were found to have antibody against class I alloantigens. This alloantibody, however, did not correlate with the HIV status of the children and was found in a similar proportion of children of HIV-negative mothers. The HLA specificity of the antibody was not correlated with noninherited maternal HLA alleles and occurred with a higher frequency in older children. This result suggests environmental factors, rather than exposure to maternal cells, are involved in the formation of the alloantibody. The finding that anti-allo-class I HLA antibodies are not associated with a decreased risk of mother-to-child transmission indicates that this humoral immune response is unlikely to be the natural mechanism that accounts for the lack of transmission observed in many births. This result, however, does not preclude the further investigation of cellular alloimmune responses, or the use of alloimmunization as an artificial HIV immunization strategy.


Plain and computed radiography for detecting experimentally induced pneumothorax in cadavers: implications for detection in patients.
Pneumothorax was induced in cadavers to determine the effects of patient positioning and imaging modality (conventional screen-film and computed radiography) on radiographic findings. Chest radiography, with cadavers in the supine frontal, erect frontal, and left lateral decubitus positions, was performed at baseline and after injection of incremental quantities of air into the pleural space. Five radiologists independently interpreted each radiograph. The ability of the radiologists to diagnose pneumothorax varied by cadaver position and depended on volume of air. Overall, the left lateral decubitus view was most sensitive (88%) for diagnosis of pneumothorax, followed by the erect (59%) and supine (37%) views. Receiver operating characteristic curves and multiple repeated measures analysis of variance revealed no statistically significant difference between diagnostic proficiency with conventional screen-film radiography and that with computed radiography. The authors conclude that the lateral decubitus view is superior to the erect and supine views for pneumothorax detection and that conventional and computed radiography perform similarly in pneumothorax detection.


Mortality Patterns of Toxoplasmosis and Its Comorbidities in Tanzania: A 10-Year Retrospective Hospital-Based Survey.
Introduction: Toxoplasmosis is a parasitic zoonosis and an important cause of abortions, mental retardation, encephalitis, blindness, and death worldwide. Few studies have quantified toxoplasmosis mortality and associated medical conditions in Sub-Saharan Africa. This retrospective hospital-based study aimed to determine the mortality patterns of toxoplasmosis and its comorbidities among in-patients in Tanzania. Methods: Data on causes of death were collected using customized paper-based collection tools. Sources of data included death registers, inpatient registers, and International Classification of Diseases report forms. All death events from January 2006 to December 2015 were collected. Data used in this study is a subset of deaths where the underlying cause of death was toxoplasmosis. Data was analyzed by STATA programme version 13. Results: Thirty-seven public hospitals were involved in the study. A total of 188 deaths due to toxoplasmosis were reported during the 10-years period. Toxoplasmosis deaths accounted for 0.08% (188/247,976) of the total deaths recorded. The age-standardized mortality rate per 100,000 population increased from 0.11 in 2006 to 0.79 in 2015. Most deaths due to toxoplasmosis affected the adult age category. Of the 188 deaths, males accounted for 51.1% while females for 48.9% of the deaths. Dar es Salaam, Mbeya, Pwani, Tanga, and Mwanza contributed to over half (59.05%) of all deaths due to Toxoplasmosis. Of the total deaths due to toxoplasmosis, 70.7% were associated with other medical conditions; which included HIV/AIDS (52.6%), HIV/AIDS+Cryptococcal meningitis (18.8%) and HIV+Pneumocystis pneumonia (6.8%). Conclusion: The age-standardized mortality rate due to toxoplasmosis has been increasing substantially between 2006 and 2015. Most deaths due to toxoplasmosis affected the adult age category and were highly associated with HIV/AIDS. Appropriate interventions are needed to alleviate the burden of toxoplasmosis in Tanzania.


Antithrombotic regimens for percutaneous coronary intervention of the left main coronary artery: The EXCEL trial.
We compared the effect of bivalirudin or heparin and use or nonuse of glycoprotein IIb/IIIa inhibitors (GPI) on the outcome of left main coronary artery (LMCA) percutaneous coronary intervention (PCI) in the randomized EXCEL trial. The optimal antithrombotic regimen to support PCI of the LMCA remains controversial because of low representation of this subset in clinical trials. The PCI cohort (n = 928) in EXCEL was divided according to bivalirudin versus heparin antithrombin treatment and compared for the primary composite endpoint of death, myocardial infarction (MI), or stroke at 30 days and 5 years. Bivalirudin was used in 319 patients (34.4%). The composite endpoint at 30 days occurred in 7.2% versus 3.8% bivalirudin and heparin patients, respectively, p = .02; at 5 years, the composite endpoint occurred in 26.3% versus 19.9% bivalirudin and heparin patients, respectively, p = .02. Major bleeding was more frequent in bivalirudin patients (4.1% versus 1.3%, p = .008). There were no differences in stent thrombosis between the groups. Bivalirudin use was an independent predictor of the 30-day composite endpoint (OR 2.88, 95% CI 1.28-6.48, p = .01) but not of the 5-year composite endpoint (OR 1.30, 95% CI 0.84-2.02, p = .23). GPI use was infrequent (n = 67, 7.2%) and was not associated with adverse outcomes. Among patients undergoing LMCA PCI in the EXCEL trial, procedural use of bivalirudin was associated with greater rates of periprocedural MI and the 30-day composite endpoint without reducing bleeding complications. Five-year outcomes were similar. GPIs were used infrequently and were not associated with clinical outcomes.


A second prepilin peptidase gene in Escherichia coli K-12.
Escherichia coli K-12 strains grown at 37 degrees C or 42 degrees C, but not at 30 degrees C, process the precursors of the Neisseria gonorrhoeae type IV pilin PilE and the Klebsiella oxytoca type IV pseudopilin PulG in a manner reminiscent of the prepilin peptidase-dependent processing of these proteins that occurs in these bacteria. Processing of prePulG in Escherichia coli requires a glycine at position -1, as does processing by the cognate prepilin peptidase (PulO), and is unaffected by mutations that inactivate several non-specific proteases. These data suggested that E. coli K-12 has a functional prepilin peptidase, despite the fact that it does not itself appear to express either type IV pilin or pseudopilin genes under the conditions that allow prePilE and prePulG processing. The E. coli K-12 genome contains two genes encoding proteins with significant sequence similarity to prepilin peptidases: gspO at minute 74.5 and pppA (f310c) at minute 67 on the genetic map. We have previously obtained evidence that gspO encodes an active enzyme but is not transcribed. pppA was cloned and shown to code for a functional prepilin peptidase capable of processing typical prepilin peptidase substrates. Inactivation of pppA eliminated the endogenous, thermoinducible prepilin peptidase activity. PppA was able to replace PulO prepilin peptidase in a pullulanase secretion system reconstituted in E. coli when expressed from high-copy-number plasmids but not when present in a single chromosomal copy. The analysis of pppA-lacZ fusions indicated that pppA expression was very low and regulated by the growth temperature at the level of translation, in agreement with the observed temperature dependence of PppA activity. Polymerase chain reaction and Southern hybridization analyses revealed the presence of the pppA gene in 12 out of 15 E. coli isolates.


Quantitative MR imaging assessment of prostate gland deformation before and during MR imaging-guided brachytherapy.
The authors performed this study to document the deformations that occur between pretreatment magnetic resonance (MR) imaging and intraoperative MR imaging during brachytherapy. MR images obtained at 1.5 and 0.5 T in 10 patients with prostate cancer were analyzed for changes in the shape and substructure of the prostate. Three-dimensional models of the prostate were obtained. The authors measured anteroposterior dimension; total gland, peripheral zone, and central gland volumes; transverse dimension; and superoinferior height. Gland deformations were seen at visual inspection of the three-dimensional models. The anteroposterior dimension of the total gland, central gland, and peripheral zone increased from 1.5- to 0.5-T imaging (median dimension, 4.9, 1.5, and 1.8 mm, respectively), and the increase was greatest in the peripheral zone (P < .05, all comparisons). There was a decrease in the transverse dimension from 1.5- to 0.5-T imaging (median, 4.5 mm; P < .005). The total gland volume and the superoinferior height did not show a statistically significant change. There were significant deformations in the shape of the prostate, especially in the peripheral zone, between the two imaging studies. The likely causes of the shape change are differences in rectal filling (endorectal coil used in 1.5-T studies vs obturator in 0.5-T studies) and/or changes in patient position (supine vs lithotomy). These findings suggest that pretreatment images alone may not be reliable for accurate therapy planning. It may be useful to integrate pre-and intraoperative data.


Effect of early intravenous rt-PA on infarct size estimated from serum enzyme activity: results from the TEAHAT Study.
In 319 patients who participated in a double-blind trial to evaluate the effect of early rt-PA administration compared to placebo in suspected acute myocardial infarction, infarct size was assessed from analyses of serum activity of lactate dehydrogenase isoenzyme 1 (LD 1). Treatment was always started less than 3 h after the onset of symptoms, with one-third of the patients' treatment being initiated outside the hospital. The maximum activity of LD 1 was reduced by 32%, from 13.3 mu kat l-1 in placebo to 9.0 mu kat l-1 in rt-PA treated patients (P = 0.001). A reduction in LD-1 activity after rt-PA treatment was restricted to patients with ST-elevation in the initial electrocardiogram, and was more pronounced in patients with previous ischaemic heart disease, above median age, and in those with a shorter delay in initiation of treatment. We conclude that very early intravenous treatment with rt-PA limits indirect signs of infarct size. The effect appears to be restricted to patients with ST-segment elevation in their initial electrocardiogram.


Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.
Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drug's ability to prevent type 2 diabetes in individuals at high risk of developing the condition. 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654. At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome (hazard ratio 0.40, 95% CI 0.35-0.46; p<0.0001); 1330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (1.71, 1.57-1.87; p<0.0001). Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (p=0.01). Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both.