Scan tracking coordinates for improved centering of Stratus OCT scan pattern.
To describe and evaluate a technique to optimize scan centering during the Stratus optical coherence tomography (OCT) image acquisition process using currently available scan tracking coordinates. Observational clinical study. Twelve eyes of six normal subjects were examined using the Fast retinal nerve fiber layer (RNFL) thickness and the Fast Optic Disc acquisition protocols. At visit 1, 3 consecutive measurements (trials) were taken by 2 different operators with the scan subjectively centered on the optic disc for the Fast RNFL thickness protocol and Fast Optic Disc protocol. At visit 2, 3 consecutive measurements were taken by positioning the scan using scan tracking coordinates. The scan coordinates were recorded twice by each operator and the limits of agreement and Bland-Altman plots were used to estimate agreement. The within subjects standard deviation (Sw) and the coefficient of variation (CV) were calculated for RNFL and optic disc parameters for each operator separately and differences by scan positioning method were evaluated using a 3-way (trial x operator x visit) analysis of variance for repeated measures. The Sw and CV for the RNFL thickness parameters were generally higher when the scan was subjectively centered on the disc compared to when using the newly described coordinate system (eg, for operator 2, temporal sector Sw was 1.60+/-0.78 and 4.09+/-0.99 and CV was 2.2% and 5.7% with and without coordinate use, respectively). For the Fast RNFL protocol, the use of scan tracking coordinates resulted in significantly less variability than subjective placement of the scan circle using the landmark feature (currently recommended technique) in the temporal sectors only. No significant difference was found for any of the optic disc parameters. Bland-Altman plots showed good agreement within each operator for calculating scan coordinates suggesting this technique is reproducible. Reproducibility of RNFL thickness measurements generally improves with the use of scan tracking coordinates, particularly in the temporal sector. However, small changes in the position of the scan do not significantly affect the reproducibility of optic disc parameters.


Do we know how much the evidence-based intervention cost?
In this department, Dr Newhouse highlights hot topics in nursing outcomes, research, and evidence-based practice relevant to the nurse administrator. The goal is to discuss the practical implications for nurse leaders in diverse healthcare settings. Content includes evidence-based projects and decision making, locating measurement tools for quality improvement and safety projects, using outcome measures to evaluate quality, practice implications of administrative research, and exemplars of projects that demonstrate innovative approaches to organizational problems. In this article, the author discusses the importance of measuring evidence-based practice intervention costs, introduces common approaches to measuring cost, and interviews a healthcare economist, Dr Kevin Frick.


Dystroglycan organizes axon guidance cue localization and axonal pathfinding.
Precise patterning of axon guidance cue distribution is critical for nervous system development. Using a murine forward genetic screen for novel determinants of axon guidance, we identified B3gnt1 and ISPD as required for the glycosylation of dystroglycan in vivo. Analysis of B3gnt1, ISPD, and dystroglycan mutant mice revealed a critical role for glycosylated dystroglycan in the development of several longitudinal axon tracts. Remarkably, the axonal guidance defects observed in B3gnt1, ISPD, and dystroglycan mutants resemble several of the axon guidance defects found in mice lacking the axon guidance cue Slit and its receptor Robo. This similarity is explained by our observations that dystroglycan binds directly to Slit and is required for proper Slit localization within the basement membrane and floor plate in vivo. These findings establish a novel role for glycosylated dystroglycan as a key determinant of axon guidance cue distribution and function in the mammalian nervous system.


Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9.
Leukaemias and other cancers possess a rare population of cells capable of the limitless self-renewal necessary for cancer initiation and maintenance. Eradication of these cancer stem cells is probably a critical part of any successful anti-cancer therapy, and may explain why conventional cancer therapies are often effective in reducing tumour burden, but are only rarely curative. Given that both normal and cancer stem cells are capable of self-renewal, the extent to which cancer stem cells resemble normal tissue stem cells is a critical issue if targeted therapies are to be developed. However, it remains unclear whether cancer stem cells must be phenotypically similar to normal tissue stem cells or whether they can retain the identity of committed progenitors. Here we show that leukaemia stem cells (LSC) can maintain the global identity of the progenitor from which they arose while activating a limited stem-cell- or self-renewal-associated programme. We isolated LSC from leukaemias initiated in committed granulocyte macrophage progenitors through introduction of the MLL-AF9 fusion protein encoded by the t(9;11)(p22;q23). The LSC were capable of transferring leukaemia to secondary recipient mice when only four cells were transferred, and possessed an immunophenotype and global gene expression profile very similar to that of normal granulocyte macrophage progenitors. However, a subset of genes highly expressed in normal haematopoietic stem cells was re-activated in LSC. LSC can thus be generated from committed progenitors without widespread reprogramming of gene expression, and a leukaemia self-renewal-associated signature is activated in the process. Our findings define progression from normal progenitor to cancer stem cell, and suggest that targeting a self-renewal programme expressed in an abnormal context may be possible.


Inhibition of fast axonal transport by pathogenic SOD1 involves activation of p38 MAP kinase.
Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.


Nadir prostate-specific antigen (PSA) level and time to PSA nadir following primary androgen deprivation therapy as independent prognostic factors in a Japanese large-scale prospective cohort study (J-CaP).
The aim of this study was to investigate whether nadir prostate-specific antigen (PSA) level and time to PSA nadir (TTN) are independent prognostic factors equivalent to the pretreatment factors in the data of the Japan Study Group of Prostate Cancer registry, which is a large, multicenter, population-based database of patients undergoing primary androgen deprivation therapy (PADT). A total of 10,958 patients treated with PADT were enrolled into the present study. Univariate and multivariate Cox proportional hazards regression analysis and Kaplan-Meier analysis were used to evaluate the associations of PSA nadir level and TTN with progression-free survival (PFS) and overall survival (OS), adjusting for the pretreatment factors adopted in the Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score. Of the 10,958 patients, 3,451 (31.5%) had lymph node and/or distant metastases. The median PSA level was 27.0 ng/ml before treatment, and the nadir PSA level in 6,983 patients (63.7%) reached below 0.2 ng/ml. Disease progression occurred in 4,736 cases, and 2,163 patients died during a mean follow-up period of 3.86 years. Nadir PSA level and TTN were independent prognostic factors, similar to the pretreatment factors adopted in the J-CAPRA score. The probabilities of PFS and OS showed significant differences among the groups categorized by the combination of nadir PSA level and TTN in all J-CAPRA risk stratifications. The present study demonstrated that nadir PSA level and TTN are strong predictors in patients undergoing PADT in a large-scale prospective cohort study.


Human soleus single muscle fiber function with exercise or nutrition countermeasures during 60 days of bed rest.
The soleus muscle has been consistently shown to atrophy more than other leg muscles during unloading and is difficult to protect using various exercise countermeasure paradigms. However, the efficacy of aerobic exercise, a known stimulus for oxidative adaptations, has not been tested in combination with resistance exercise (RE), a known hypertrophic stimulus. We hypothesized that a concurrent exercise program (AE + RE) would preserve soleus fiber myosin heavy chain (MHC) I size and function during 60 days of bed rest. A secondary objective was to test the hypothesis that a leucine-enriched high protein diet would partially protect soleus single fiber characteristics. Soleus muscle biopsies were obtained before and after bed rest from a control (BR; n = 7), nutrition (BRN; n = 8), and exercise (BRE; n = 6) group. Single muscle fiber diameter (Dia), peak force (Po), contractile velocity, and power were studied. BR decreased (P < 0.05) MHC I Dia (-14%), Po (-38%), and power (-39%) with no change in contractile velocity. Changes in MHC I size (-13%) and contractile function (approximately 30%) from BRN were similar to BR. BRE decreased (P < 0.05) MHC I Dia (-13%) and Po (-23%), while contractile velocity increased (P < 0.05) 26% and maintained power. These soleus muscle data show 1) the AE + RE exercise program maintained MHC I power but not size and strength, and 2) the nutrition countermeasure did not benefit single fiber size and contractile function. The divergent response in size and functional MHC I soleus properties with the concurrent exercise program was a unique finding further highlighting the challenges of protecting the unloaded soleus.


Permeation selectivity by competition in a delayed rectifier potassium channel.
Permeation selectivity was studied in two human potassium channels, Kv2.1 and Kv1.5, expressed in a mouse cell line. With normal concentrations of potassium and sodium, both channels were highly selective for potassium. On removal of potassium, Kv2.1 displayed a large sodium conductance that was inhibited by low concentrations of potassium. The channel showed a competition mechanism of selectivity similar to that of calcium channels. In contrast, Kv1.5 displayed a negligible sodium conductance on removal of potassium. The observation that structurally similar potassium channels show different abilities to conduct sodium provides a basis for understanding the structural determinants of potassium channel selectivity.


The challenge to reach nutritional adequacy for vitamin A: β-carotene bioavailability and conversion--evidence in humans.
β-Carotene is an important dietary source of vitamin A for humans. However, the bioavailability and vitamin A equivalency of β-carotene are highly variable and can be affected by food- and diet-related factors, including the food matrix, food-processing techniques, size of the dose of β-carotene, and the amounts of dietary fat, fiber, vitamin A, and other carotenoids in the diet as well as by characteristics of the target population, such as vitamin A status, nutrient deficiencies, gut integrity, and genetic polymorphisms associated with β-carotene metabolism. The absorption of β-carotene from plant sources ranges from 5% to 65% in humans. Vitamin A equivalency ratios for β-carotene to vitamin A from plant sources range from 3.8:1 to 28:1, by weight. Vitamin A equivalency ratios for β-carotene from biofortified Golden Rice or biofortified maize are 3.8:1 and 6.5:1, respectively, and are lower than ratios for vegetables that have more complex food matrices (10:1 to 28:1). The vitamin A equivalency of β-carotene is likely to be context-specific and dependent on specific food- and diet-related factors and the health, nutritional, and genetic characteristics of human populations. Although the vitamin A equivalency of β-carotene is highly variable, the provision of vegetable and fruit sources of β-carotene has significantly increased vitamin A status in women and children in community settings in developing countries; these results support the inclusion of dietary interventions with plant sources of β-carotene as a strategy for increasing vitamin A status in populations at risk of deficiency.


Anterior Resection for Rectal Cancer and Visceral Blood Flow: An Explorative Study.
Impaired blood perfusion may be implicated in anastomotic leakage after anterior resection for rectal cancer. We investigated whether high ligation of the inferior mesenteric artery or total mesorectal excision compromises visceral blood flow in the colonic limb and the rectal stump, respectively. A prospective cohort study was conducted in a university hospital setting. We used Laser Doppler flowmetry to evaluate the impact of level of tie on colonic limb perfusion and the extent of the mesorectal excision on the rectal blood flow. In the rectum, different quadrants were also assessed. The Mann-Whitney U test was used to compare mean blood flow ratios between groups. Some 23 patients were recruited in a convenience sample during a period in 2012-2013. The mean blood flow ratio was not decreased after high tie compared to low tie surgery (1.71 vs 1.19; p = 0.28). Total mesorectal excision reduced the mean blood flow ratio in the rectum, as compared with partial mesorectal excision (0.76 vs 1.28; p = 0.14). This was especially pronounced in the posterior aspect of the rectum (0.66 vs 1.68; p = 0.02). High tie ligation did not seem to decrease colonic limb perfusion, while total mesorectal excision may decrease rectal blood flow. The posterior quadrant of the rectum might be particularly vulnerable to the dissection involved in total mesorectal excision.


The involvement of occipital and inferior frontal cortex in the phonological learning of Chinese characters.
Neural changes related to the learning of the pronunciation of Chinese characters in English speakers were examined using fMRI. We examined the item-specific learning effects for trained characters and the generalization of phonetic knowledge to novel transfer characters that shared a phonetic radical (part of a character that gives a clue to the whole character's pronunciation) with trained characters. Behavioral results showed that shared phonetic information improved performance for transfer characters. Neuroimaging results for trained characters over learning found increased activation in the right lingual gyrus, and greater activation enhancement in the left inferior frontal gyrus (Brodmann's area 44) was correlated with higher accuracy improvement. Moreover, greater activation for transfer characters in these two regions at the late stage of training was correlated with better knowledge of the phonetic radical in a delayed recall test. The current study suggests that the right lingual gyrus and the left inferior frontal gyrus are crucial for the learning of Chinese characters and the generalization of that knowledge to novel characters. Left inferior frontal gyrus is likely involved in phonological segmentation, whereas right lingual gyrus may subserve processing visual-orthographic information.


Dysbiosis in Parkinson's disease might be triggered by certain antibiotics.
Parkinson's disease (PD) is a neurodegenerative amyloid disorder with debilitating motor symptoms due to the loss of dopamine-synthesizing, basal ganglia-projecting neurons in the substantia nigra. An interesting feature of the disease is that most of PD patients have gastrointestinal problems and bacterial dysbiosis, years before the full expression of motor symptoms. We hypothesized that antibiotic consumption might be a contributing factor of gut microbiome dysbiosis in PD, favoring curli-producing Enterobacteria. Curli is a bacterial α-synuclein (αSyn) which is deposited first in the enteric nervous system and amyloid deposits are propagated in a prion like manner to the central nervous system. In addition, antibiotics result in a low-grade systemic inflammation, which also contributes to damage of neurons in enteric- and central nervous system. To support our hypothesis, by comparing PD prevalence change with antibiotic consumption data in EU countries, we found significant positive correlation between use narrow spectrum penicillin + penicillinase resistant penicillin and increased prevalence of the disease.


Effects of Head and Neck Positions on Blood Flow in the Vertebral, Internal Carotid, and Intracranial Arteries: A Systematic Review.
Manual therapy interventions targeting the neck include various positions and movements of the craniocervical region. The hemodynamic changes in various spinal positions potentially have clinical relevance. To investigate the effects of craniocervical positions and movements on hemodynamic parameters (blood flow velocity and/or volume) of cervical and craniocervical arteries. A search of 4 databases (PubMed, Embase, CINAHL, and Index to Chiropractic Literature) and, subsequently, a hand search of reference lists were conducted. Full-text experimental and quasi-experimental studies on the influence of cervical positions on blood flow of the vertebral, internal carotid, and basilar arteries were eligible for this review. Two independent reviewers selected and extracted the data using the double-screening method. Of the 1453 identified studies, 31 were included and comprised 2254 participants. Most studies mentioned no significant hemodynamic changes during maximal rotation (n = 16). A significant decrease in hemodynamics was identified for the vertebral artery, with a hemodynamic decrease in the position of maximum rotation (n = 8) and combined movement of maximum extension and maximum rotation (n = 4). A similar pattern of decreased hemodynamics was also identified for the internal carotid and intracranial arteries. Three studies focused on high-velocity thrust positioning and movement. None of the studies reported hemodynamic changes. The synthesized data suggest that in the majority of people, most positions and movements of the craniocervical region do not affect blood flow. The findings of this systematic review suggest that craniocervical positioning may not alter blood flow as much as previously expected. Therapy, level 2a. J Orthop Sports Phys Ther 2019;49(10):688-697. Epub 5 Jul 2019. doi:10.2519/jospt.2019.8578.


Haemolytic effects of hypo-osmotic salt solutions on human erythrocytes.
While it is well known that hypotonic solutions of sodium chloride induce hemolysis, the effects of other salt solutions on human erythrocytes have not been well documented. The study is to compare the effects of other salt solutions on human red cells. Iso-osmotic and hypo-osmotic solutions of various salts were prepared after taking into account their molecular weight and osmotic pressure. Five healthy volunteers between the age of 22-30 years were randomly selected and ten blood samples were collected from them. The study was conducted from January 2009 to February 2009. Blood was collected from subjects by venepuncture into heparinised tubes. 20 fl of blood was pipetted into 1 ml of each solution and incubated for one hour at 37°C in a water bath. The solutions were centrifuged and the colour of the supernatant was read in a spectrophotometer. Supernatant from blood added to distilled water was considered 100% hemolysed. Iso-osmotic salt solutions were free of hemolysis. Among chloride salts, sodium chloride showed the least hemolysis and potassium chloride and nickel chloride resulted into greater hemolysis. Among potassium salts, potassium bromate caused highest amount of hemolysis whereas potassium sulphate showed the least. The significant differences in hemolytic pattern in hypo-osmotic salts solutions suggest that the hypo-osmotic stress causes morphological changes in red cells that alter their permeability to various ions leading to hemolysis. This probably occurs through opening of volume sensitive channels.


Walking to school: distribution by age, sex and socio-economic status.
The aims of this study were to examine route to school, distance and mode of transport for primary school-aged children in Brisbane, and to quantify the exposure to risk of pedestrian injury by the sociodemographic characteristics of the children. This study was part of a longitudinal cohort study of 871 Brisbane families with children aged 4-12 years that aimed to quantify the relationship between socio-economic status and childhood injury. Mode of transport to school and socio-demographic characteristics of children were obtained from a questionnaire completed at baseline by each child's primary carer. Route to school and distance travelled were recorded at the baseline interview on scaled geographical maps. Being driven by car was the predominant mode of transport to school (75%) and from school (72%), with the prevalence decreasing with the age of the child. The mean distance travelled to school was 3.8 kilometres (km), with 50% of children travelling between 1.25 km and 4.5 km. For children who walked to school, exposure to pedestrian injury risk was similar by gender, increased with age and was inversely related to household income and the primary carer's education level. The majority of children aged 5-12 live close to school but only a small minority of students walk the distance. Walking to school was least common in children from higher socio-economic backgrounds.


Wide-field prime focus corrector for the Anglo-Australian telescope.
A wide-field (2°) prime focus corrector has been designed and built for the Anglo-Australian Telescope. The corrector incorporates an atmospheric dispersion compensator for the spectral range 365-1014 nm. A four-element lens system is the basis of the corrector, and it provides a satisfactory state of correction over a full field of 2°. The design of the lens system is described. The choice of layout is related directly to the intrinsic properties of each component.


Evaluating performance of electronic healthcare records and spontaneous reporting data in drug safety signal detection.
Electronic reporting and processing of suspected adverse drug reactions (ADRs) is increasing and has facilitated automated screening procedures. It is crucial for healthcare professionals to understand the nature and proper use of data available in pharmacovigilance practice. To (a) compare performance of EU-ADR [electronic healthcare record (EHR) exemplar] and FAERS [spontaneous reporting system (SRS) exemplar] databases in detecting signals using "positive" and "negative" drug-event reference sets; and (b) evaluate the impact of timing bias on sensitivity thresholds by comparing all data to data restricted to the time before a warning/regulatory action. Ten events with known positive and negative reference sets were selected. Signals were identified when respective statistics exceeded defined thresholds. Main outcome measure Performance metrics, including sensitivity, specificity, positive predictive value and accuracy were calculated. In addition, the effect of regulatory action on the performance of signal detection in each data source was evaluated. The sensitivity for detecting signals in EHR data varied depending on the nature of the adverse events and increased substantially if the analyses were restricted to the period preceding the first regulatory action. Across all events, using data from all years, a sensitivity of 45-73 % was observed for EU-ADR and 77 % for FAERS. The specificity was high and similar for EU-ADR (82-96 %) and FAERS (98 %). EU-ADR data showed range of PPV (78-91 %) and accuracy (78-72 %) and FAERS data yielded a PPV of 97 % with 88 % accuracy. Using all cumulative data, signal detection in SRS data achieved higher specificity and sensitivity than EHR data. However, when data were restricted to time prior to a regulatory action, performance characteristics changed in a manner consistent with both the type of data and nature of the ADR. Further research focusing on prospective validation of is necessary to learn more about the performance and utility of these databases in modern pharmacovigilance practice.


Overt iron deficiency in sickle cell disease.
Overt iron deficiency was diagnosed in four patients with sickle cell disease. Three patients had homozygous SS and one had hemoglobin SC disease. The cause in each case was proved or suspected blood loss. Iron repletion was accompanied by increases in the blood hemoglobin and hematocrit levels, erythrocyte mean corpuscular volume, and mean corpuscular hemoglobin concentration (MCHC) and by change in the RBC morphologic characteristics from hypochromic microcytic to normochromic normocytic. The diagnosis of iron deficiency was confirmed by the finding of a low serum ferritin level, a high serum total iron-binding capacity, or both. Two patients who had had no painful crises while they were iron deficient began having crises again, and another patient had painful crises for the first time after the blood values improved. Whether a lowered MCHC is beneficial to patients with sickle cell diseases is an important but unanswered question.


Single port laparoscopic right hemicolectomy for ileocolic intussusception.
A 36-year-old male was admitted with right lower abdominal pain and diarrhea for more than 3 mo. Colonoscopy and a barium enema study revealed a submucosal tumor over the cecum, but computed tomography showed an ileal lipoma. There was no definitive diagnosis preoperatively, but ileocolic intussusception was noted during surgery. Single port laparoscopic radical right hemicolectomy was performed because intra-operative reduction failed. The histological diagnosis of the resected tumor was lipoma. Single port laparoscopic surgery has recently been proven to be safe and feasible. There are advantages compared with conventional laparoscopic surgery, such as smaller incision wounds, fewer port site complications, and easier conversion. However, there are some drawbacks which need to be overcome, such as difficulties in triangulation and instrument clashing. If there are no contraindications to laparoscopy, single port laparoscopic surgery can be performed safely and should be considered for diagnosis and treatment of intussusception in adults. Here, we report the first case of ileocolic intussusception successfully treated by single port laparoscopic surgery.


Oil wives and intermittent husbands.
An investigation was conducted in the Aberdeen area on wives of oil men working either off-shore or on-shore. No differences were found in measures of general health; but 'off-shore wives' were shown to experience mood and behavioural changes, linked to the pattern of swiftly recurring partings and reunions. While a majority of such wives appeared to tolerate or even thrive on their style of life, 10% had reactions sufficiently pronounced to deserve the label of Intermittent Husband Syndrome or 'caseness'. Many others would have benefited from more effective preventive and support services.


Procedural justice and the mental health court judge's role in reducing recidivism.
Based on qualitative observation and quantitative data from eight mental health courts (MHCs), this article argues that observed reductions in recidivism from participation in MHC are caused in part by the role of the judge in conveying elements of procedural justice. Specifically, the judge provides: (1) a heightened level of interpersonal treatment of participants that accords them dignity, respect, and voice; (2) accountability for participants and service providers alike; and (3) transparency for decisions reached through an open negotiation process. Procedural justice theory predicts that participants will thereby be more likely to see legal decisions as legitimate and incorporate the court's values and goals as their own. Preliminary qualitative and quantitative data are presented from interviews of a sample of participants in the Superior Court of the District of Columbia's Mental Health Diversion Court (DCMHDC) that support these hypotheses. DCMHDC participants hold strongly positive views about the procedural justice they receive from their court experience and of the judge's role in providing justice.


Testis developmental phenotypes in neurotropin receptor trkA and trkC null mutations: role in formation of seminiferous cords and germ cell survival.
The objective of the present study was to determine if the neurotropin receptors trkC and trkA are involved in embryonic testis development. These receptors bind neurotropin 3 and nerve growth factor, respectively. The hypothesis tested was that the absence of trkC or trkA receptors will have detrimental effects on testis development and morphology. The trkA and trkC homozygote knockout (KO) mice generally die either at or shortly after birth. Therefore, heterozygote mice were mated to obtain homozygote gene KO mice at Embryonic Day (E) 13, E14, E17, and E19 of gestation, with E0 being the plug date. Gonads from approximately 80 embryos were collected and fixed, and each embryo was genotyped. To determine gonadal characteristics for each genotype, the number of germ cells, number of seminiferous cords, seminiferous cord area, and interstitial area were calculated at each developmental age. Germ cell numbers varied in trkA gene KO mice from those of wild-type mice at each age evaluated. In trkC gene KO mice, differences were detected in germ cell numbers when compared to wild-type mice at E17 and E19. At E19, germ cell numbers were reduced in both trkA and trkC gene KO mice when compared to wild-type animals. Apoptosis was evaluated in testes of wild-type, trkC gene KO, and trkA gene KO mice to determine if the alteration in germ cell numbers at each developmental age was influenced by different patterns of germ cell survival or apoptosis. No differences were found in germ cell apoptosis during embryonic testis development. Interestingly, trkA gene KO mice that survived to Postnatal Day 19 had a 10-fold increase in germ cell apoptosis when compared to germ cells in wild-type mice. Evaluation of other morphological testis parameters demonstrated that trkC KO testes had reduced interstitial area at E13, reduced number of seminiferous cords at E14, and reduced seminiferous cord area at E19. The trkA gene KO testes had a reduction in the number of seminiferous cords at E14. Histology of both trkA and trkC gene KO testes demonstrated that these gonads appear to be developmentally delayed when compared to their wild-type testis counterparts at E13 during testis development. The current study demonstrates that both trkA and trkC neurotropin receptors influence germ cell numbers during testis development and events such as seminiferous cord formation.


Development of a novel 3D culture system for screening features of a complex implantable device for CNS repair.
Tubular scaffolds which incorporate a variety of micro- and nanotopographies have a wide application potential in tissue engineering especially for the repair of spinal cord injury (SCI). We aim to produce metabolically active differentiated tissues within such tubes, as it is crucially important to evaluate the biological performance of the three-dimensional (3D) scaffold and optimize the bioprocesses for tissue culture. Because of the complex 3D configuration and the presence of various topographies, it is rarely possible to observe and analyze cells within such scaffolds in situ. Thus, we aim to develop scaled down mini-chambers as simplified in vitro simulation systems, to bridge the gap between two-dimensional (2D) cell cultures on structured substrates and three-dimensional (3D) tissue culture. The mini-chambers were manipulated to systematically simulate and evaluate the influences of gravity, topography, fluid flow, and scaffold dimension on three exemplary cell models that play a role in CNS repair (i.e., cortical astrocytes, fibroblasts, and myelinating cultures) within a tubular scaffold created by rolling up a microstructured membrane. Since we use CNS myelinating cultures, we can confirm that the scaffold does not affect neural cell differentiation. It was found that heterogeneous cell distribution within the tubular constructs was caused by a combination of gravity, fluid flow, topography, and scaffold configuration, while cell survival was influenced by scaffold length, porosity, and thickness. This research demonstrates that the mini-chambers represent a viable, novel, scale down approach for the evaluation of complex 3D scaffolds as well as providing a microbioprocessing strategy for tissue engineering and the potential repair of SCI.


Construction of a novel cell-based assay for the evaluation of anti-EGFR drug efficacy against EGFR mutation.
Epidermal growth factor receptor (EGFR) overexpression and EGFR-mediated signaling pathway dysregulation have been observed in tumors from patients with various cancers, especially non-small cell lung cancer. Thus, several anti-EGFR drugs have been developed for cancer therapy. For patients with known EGFR activating mutations (EGFR exon 19 in-frame deletions and exon 21 L858R substitution), treatment with an EGFR tyrosine kinase inhibitor (EGFR TKI; gefitinib, erlotinib or afatinib) represents standard first-line therapy. However, the clinical efficacy of these TKIs is ultimately limited by the development of acquired drug resistance such as by mutation of the gatekeeper T790 residue (T790M). To overcome this acquired drug resistance and develop novel anti-EGFR drugs, a cell-based assay system for EGFR TKI resistance mutant-selective inhibitors is required. We constructed a novel cell-based assay for the evaluation of EGFR TKI efficacy against EGFR mutation. To this end, we established non-tumorigenic immortalized breast epithelial cells that proliferate dependent on EGF (MCF 10A cells), which stably overexpress mutant EGFR. We found that the cells expressing EGFR containing the T790M mutation showed higher resistance against gefitinib, erlotinib and afatinib compared with cells expressing wild-type EGFR. In contrast, L858R mutant-expressing cells exhibited higher TKI sensitivity. The effect of T790M-selective inhibitors (osimertinib and rociletinib) on T790M mutant-expressing cells was significantly higher than gefitinib and erlotinib. Finally, when compared with commercially available isogenic MCF 10A cell lines carrying introduced mutations in EGFR, our EGFR mutant-overexpressing cells exhibited obviously higher responsiveness to EGFR TKIs depending on the underlying mutations because of the higher levels of EGFR phosphorylation in the EGFR mutant-overexpressing cells than in the isogenic cell lines. In conclusion, we successfully developed a novel cell-based assay for evaluating the efficacy of anti-EGFR drugs against EGFR mutation.


Advanced reproductive age and fertility.
To improve awareness of the natural age-related decline in female and male fertility with respect to natural fertility and assisted reproductive technologies (ART) and provide recommendations for their management, and to review investigations in the assessment of ovarian aging. This guideline reviews options for the assessment of ovarian reserve and fertility treatments using ART with women of advanced reproductive age presenting with infertility. The outcomes measured are the predictive value of ovarian reserve testing and pregnancy rates with natural and assisted fertility. Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in June 2010, using appropriate key words (ovarian aging, ovarian reserve, advanced maternal age, advanced paternal age, ART). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated into the guideline to December 2010. The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table). Primary and specialist health care providers and women will be better informed about ovarian aging and the age-related decline in natural fertility and about options for assisted reproductive technology. 1. Women in their 20s and 30s should be counselled about the age-related risk of infertility when other reproductive health issues, such as sexual health or contraception, are addressed as part of their primary well-woman care. Reproductive-age women should be aware that natural fertility and assisted reproductive technology success (except with egg donation) is significantly lower for women in their late 30s and 40s. (II-2A) 2. Because of the decline in fertility and the increased time to conception that occurs after the age of 35, women > 35 years of age should be referred for infertility work-up after 6 months of trying to conceive. (III-B) 3. Ovarian reserve testing may be considered for women ≥ 35 years of age or for women < 35 years of age with risk factors for decreased ovarian reserve, such as a single ovary, previous ovarian surgery, poor response to follicle-stimulating hormone, previous exposure to chemotherapy or radiation, or unexplained infertility. (III-B) 4. Ovarian reserve testing prior to assisted reproductive technology treatment may be used for counselling but has a poor predictive value for non-pregnancy and should be used to exclude women from treatment only if levels are significantly abnormal. (II-2A) 5. Pregnancy rates for controlled ovarian hyperstimulation are low for women > 40 years of age. Women > 40 years should consider IVF if they do not conceive within 1 to 2 cycles of controlled ovarian hyperstimulation. (II-2B) 6. The only effective treatment for ovarian aging is oocyte donation. A woman with decreased ovarian reserve should be offered oocyte donation as an option, as pregnancy rates associated with this treatment are significantly higher than those associated with controlled ovarian hyperstimulation or in vitro fertilization with a woman's own eggs. (II-2B) 7. Women should be informed that the risk of spontaneous pregnancy loss and chromosomal abnormalities increases with age. Women should be counselled about and offered appropriate prenatal screening once pregnancy is established. (II-2A) 8. Pre-conception counselling regarding the risks of pregnancy with advanced maternal age, promotion of optimal health and weight, and screening for concurrent medical conditions such as hypertension and diabetes should be considered for women > age 40. (III-B) 9. Advanced paternal age appears to be associated with an increased risk of spontaneous abortion and increased frequency of some autosomal dominant conditions, autism spectrum disorders, and schizophrenia. Men > age 40 and their partners should be counselled about these potential risks when they are seeking pregnancy, although the risks remain small. (II-2C).


Neuroendocrine modulation sustains the C. elegans forward motor state.
Neuromodulators shape neural circuit dynamics. Combining electron microscopy, genetics, transcriptome profiling, calcium imaging, and optogenetics, we discovered a peptidergic neuron that modulates C. elegans motor circuit dynamics. The Six/SO-family homeobox transcription factor UNC-39 governs lineage-specific neurogenesis to give rise to a neuron RID. RID bears the anatomic hallmarks of a specialized endocrine neuron: it harbors near-exclusive dense core vesicles that cluster periodically along the axon, and expresses multiple neuropeptides, including the FMRF-amide-related FLP-14. RID activity increases during forward movement. Ablating RID reduces the sustainability of forward movement, a phenotype partially recapitulated by removing FLP-14. Optogenetic depolarization of RID prolongs forward movement, an effect reduced in the absence of FLP-14. Together, these results establish the role of a neuroendocrine cell RID in sustaining a specific behavioral state in C. elegans.


Reaction of H + HONO in solid para-hydrogen: infrared spectrum of ˙ONH(OH).
Hydrogenation reactions in the N/O chemical network are important for an understanding of the mechanism of formation of organic molecules in dark interstellar clouds, but many reactions remain unknown. We present the results of the reaction H + HONO in solid para-hydrogen (p-H2) at 3.3 K investigated with infrared spectra. Two methods that produced hydrogen atoms were the irradiation of HONO molecules in p-H2 at 365 nm to produce OH radicals that reacted readily with nearby H2 to produce mobile H atoms, and irradiation of Cl2 molecules (co-deposited with HONO) in p-H2 at 405 nm to produce Cl atoms that reacted, upon IR irradiation of the p-H2 matrix, readily with nearby H2 to produce mobile H atoms. In both experiments, we assigned IR lines at 3549.6 (ν1), 1465.0 (ν3), 1372.2 (ν4), 898.5/895.6 (ν6), and 630.9 (ν7) cm-1 to hydroxy(oxido)-λ5-azanyl radical [˙ONH(OH)], the primary product of HONO hydrogenation. Two weak lines at 3603.4 and 991.0 cm-1 are tentatively assigned to the dihydroxy-λ5-azanyl radical, ˙N(OH)2. The assignments were derived according to the consideration of possible reactions and comparison of observed vibrational wavenumbers and their IR intensities with values predicted quantum-chemically with the B3LYP/aug-cc-pVTZ method. The agreement between observed and calculated D/H- and 15N/14N-isotopic ratios further supports these assignments. The role of this reaction in the N/O chemical network in dark interstellar clouds is discussed.


Firefighters and flame retardant activism.
In the past decade, exposure to flame retardant chemicals has become a pressing health concern and widely discussed topic of public safety for firefighters in the United States. Working through local, state, and national unions and independent health and advocacy organizations, firefighters have made important contributions to efforts to restrict the use of certain flame retardants. Firefighters are key members in advocacy coalitions dedicated to developing new environmental health regulations and reforming flammability standards to reflect the best available fire science. Their involvement has been motivated by substantiated health concerns and critiques of deceptive lobbying practices by the chemical industry. Drawing on observations and interviews with firefighters, fire safety experts, and other involved stakeholders, this article describes why firefighters are increasingly concerned about their exposure to flame retardant chemicals in consumer products, and analyzes their involvement in state and national environmental health coalitions.


Comparison of lumbar endoscopic unilateral laminotomy bilateral decompression and minimally invasive surgery transforaminal lumbar interbody fusion for one-level lumbar spinal stenosis.
The aim of the present study is to compare the clinical outcomes and postoperative complications of lumbar endoscopic unilateral laminotomy bilateral decompression (LE-ULBD) and minimally invasive surgery transforaminal lumbar interbody fusion (MIS-TLIF) to treat one-level lumbar spinal stenosis (LSS) without degenerative spondylolisthesis or deformity. A retrospective analysis of 112 consecutive patients of one-level LSS undergoing either LE-ULBD or MIS-TLIF was performed. Patient demographics, operation time, estimated blood loss, time to ambulation, length of hospitalization, intraoperative and postoperative complications were recorded. The visual analog scale (VAS) score for leg and back pain, the Oswestry Disability Index (ODI) score, and the Macnab criteria were used to evaluate the clinical outcomes. The healthcare cost was also recorded. The operation time, estimated blood loss, time to ambulation and length of hospitalization of LE-ULBD group were shorter than MIS-TLIF group. The postoperative mean VAS and ODI scores decreased significantly in both groups. According to the modified Macnab criteria, the outcomes rated as excellent/good rate were 90.6 and 93.8% in the two groups. The mean VAS scores, ODI scores and outcomes of the modified Macnab criteria of both groups were of no significant difference. The healthcare cost of LE-ULBD group was lower than MIS-TLIF group. Two cases of intraoperative epineurium injury were observed in the LE-ULBD group. One case of cauda equina injury was observed in the LE-ULBD group. No nerve injury, dural injury or cauda equina syndrome was observed in MIS-TLIF group. However, one case with transient urinary retention, one case with pleural effusion, one case with incision infection and one case with implant dislodgement were observed in MIS-TLIF group. Both LE-ULBD and MIS-TLIF are safe and effective to treat one-level LSS without degenerative spondylolisthesis or deformity. LE-ULBD is a more minimally invasive option and of less economic burden compared with MIS-TLIF. Decompression plus instrumented fusion may be not necessary for one-level LSS without degenerative spondylolisthesis or deformity.


Further observations on the effect of synthetic thyrotropin-releasing hormone in man.
Synthetic thyrotrophin-releasing hormone (TRH) given intravenously in doses of 50 mug or more causes a significant rise in serum thyroid-stimulating hormone (TSH) levels but has no effect on serum growth hormone, plasma luteinizing hormone, or plasma 11-hydroxycorticosteroids under carefully controlled basal conditions.The peak TSH response to intravenous TRH occurs at 20 minutes. The mild and transient side effects, which occur only after intravenous TRH, include nausea, a flushing sensation, a desire to micturate, a peculiar taste, and tightness in the chest. There is considerable variability in response to a given dose of TRH in the same subject on different occasions and in different subjects. Oral administration of TRH in doses of 1 mg and above causes a rise in serum TSH, maximal at two hours, a consistent response being obtained at doses of 20 mg and above. A rise in serum protein-bound iodine (P.B.I.) follows that of TSH, a consistent response being observed at 40-mg doses of TRH orally. Measurements of serum TSH after intravenous administration of TRH or of serum TSH or serum P.B.I. after oral TRH should prove useful tests of pituitary TSH reserve.


Assessment of Bioabsorbable Hydroxyapatite for Secondary Bone Grafting in Unilateral Alveolar Clefts.
To evaluate the utility and efficacy of bioabsorbable hydroxyapatite and collagen complex (HA/Col) for secondary bone grafting in unilateral alveolar clefts. Between 2015 and 2016, 21 patients with unilateral cleft lips and alveolar clefts were enrolled. In group I, a cancellous iliac bone graft was placed at the alveolar cleft (6 males, 5 females). In group II, a bioabsorbable HA/Col was placed at the alveolar cleft (4 males, 7 females). The groups did not differ in age, cleft volume, or surgical duration. There was a significant difference in intraoperative blood loss between the 2 groups (6.7 ± 1.89 mL in group II vs 38.8 ± 9.73 mL in group I [P < .01]). The use of patient-controlled intravenous analgesia was also significantly lower in group II than in group I (2.2 ± 1.9 times vs 12.2 ± 4.4 times [P < .01]). Only 1 female in group II who had maxillary sinusitis did not achieve osteosynthesis. With the exception of this patient, the 12-month bone volumes in groups I and II were 0.567 ± 0.066 and 0.596 ± 0.073 mL, respectively, without significant difference (P = .18). Compared with an autogenous bone, bioabsorbable HA/Col significantly reduces postoperative pain. In addition, the use of HA/Col alone produced the same result as an autologous bone and is effective in filling the alveolar cleft.


A Doctor's Testimony: Medical Neutrality and the Visibility of Palestinian Grievances in Jewish-Israeli Publics.
This paper follows the testimony of Izzeldin Abuelaish, a Palestinian physician who bears witness to his experiences working, living, and suffering under Israeli rule. He presents his story as a doctor's story, drawing on his identity as a medical professional to gain credibility and visibility and to challenge the limited legitimacy of Palestinian grievances. In this paper, I explore his testimony as a medical voice that at once recounts the suffering and loss endured by the Palestinian people and also struggles to negotiate the values associated with being a "reliable" witness. Consequently, I ethnographically examine the social life and reception of his story in Jewish-Israeli publics. In comparison with most Palestinian narratives, Abuelaish's testimony achieved an extremely rare degree of visibility and sympathy, a phenomenon that calls out for analysis. I identify the boundaries that typically render Palestinian grievances invisible to Israeli publics and suggest how medicine's self-proclaimed ethos of neutrality served as a channel for crossing them. Finally, I reflect on the political possibilities and limitations of medical witnessing to render suffering visible and arouse compassion toward those construed as a dangerous/enemy Other.


Histamine impairs midbrain dopaminergic development in vivo by activating histamine type 1 receptors.
Histamine (HA) regulates the sleep-wake cycle, synaptic plasticity and memory in adult mammals. Dopaminergic specification in the embryonic ventral midbrain (VM) coincides with increased HA brain levels. To study the effect of HA receptor stimulation on dopamine neuron generation, we administered HA to dopamine progenitors, both in vitro and in vivo. Cultured embryonic day 12 (E12) VM neural stem/progenitor cells expressed transcripts for HA receptors H1R, H2R and H3R. These undifferentiated progenitors increased intracellular calcium upon HA addition. In HA-treated cultures, dopamine neurons significantly decreased after activation of H1R. We performed intrauterine injections in the developing VM to investigate HA effects in vivo. HA administration to E12 rat embryos notably reduced VM Tyrosine Hydroxylase (TH) staining 2 days later, without affecting GABA neurons in the midbrain, or serotonin neurons in the mid-hindbrain boundary. qRT-PCR and Western blot analyses confirmed that several markers important for the generation and maintenance of dopaminergic lineage such as TH, Lmx1a and Lmx1b were significantly diminished. To identify the cell type susceptible to HA action, we injected embryos of different developmental stages, and found that neural progenitors (E10 and E12) were responsive, whereas differentiated dopaminergic neurons (E14 and E16) were not susceptible to HA actions. Proliferation was significantly diminished, whereas neuronal death was not increased in the VM after HA administration. We injected H1R or H2R antagonists to identify the receptor responsible for the detrimental effect of HA on dopaminergic lineage and found that activation of H1R was required. These results reveal a novel action of HA affecting dopaminergic lineage during VM development.


Alcohol and energy drink use among adolescents seeking emergency department care.
Emergency department (ED) visits due to energy drinks rose drastically from 2007 to 2011. Consuming alcohol mixed with energy drinks by young people is particularly concerning. Among youth (aged 14-20 years) in the ED reporting past-year alcohol use, we assessed frequency, reasons, and medical consequences of consuming alcohol and energy drinks in the same beverage or on the same occasion, and relationships with other risk behaviors. The sample included 439 youth (M(age)=18.6 years, SD=1.4; 41% male; 73% Caucasian): those who drank alcohol, but not energy drinks (Non-Users; 41%, n=178), those who drank alcohol and energy drinks on separate occasions (Separate; 23%, n=103), and those who combined alcohol and energy drinks in the same beverage or on the same occasion (Combined; 36%, n=158). Common reasons for combining energy drinks and alcohol were hiding the flavor of alcohol (39%) and liking the taste (36%). Common consequences were feeling jittery (71%) and trouble sleeping (46%). Combined users had the highest rates of risk behaviors (e.g., drug use, sexual risk behaviors, driving after drinking) and alcohol use severity. Multinomial logistic regression indicated that men, those who had sex after substance use, those who had used drugs, and those with higher alcohol severity were more likely to be Combined users than Non-Users. Those with higher alcohol severity were also more likely to be Combined users than Separate users. Combining energy drinks and alcohol is associated with higher rates of other risk behaviors among young drinkers. Future studies are needed to determine longitudinal relationships of energy drink use on substance use problem trajectories.


Novel macrophage receptor for glucose-modified proteins is distinct from previously described scavenger receptors.
A high-affinity macrophage receptor has been identified that recognizes proteins modified by a common in vivo process, long-term nonenzymatic reaction of glucose with proteins (AGE proteins). This receptor for glucose-modified proteins is now shown to be distinct from previously described scavenger receptors, using competition and crosscompetition experiments between AGE-modified protein and a variety of in vitro-modified scavenger receptor ligands, including unmodified BSA, unmodified low-density lipoproteins (LDL), acetyl-LDL, maleyl-BSA, and formaldehyde-treated BSA. Furthermore, the specific pattern of AGE-protein receptor inhibition by the polyanionic compounds polyinosinic acid, polyadenylic acid, polyglutamic acid, polycytidylic acid, fucoidin, and heparin was distinctly different from that of acetyl-LDL. By thus selectively recognizing a time-dependent in vivo protein modification, macrophages may preferentially degrade senescent macromolecules, thereby having an important role in the regulation of extracellular protein turnover.


Cancer stem cells in the mammalian central nervous system.
Malignant tumours intrinsic to the central nervous system (CNS) are among the most difficult of neoplasms to treat effectively. The major biological features of these tumours that preclude successful therapy include their cellular heterogeneity, which renders them highly resistant to both chemotherapy and radiotherapy, and the propensity of the component tumour cells to invade, diffusely, the contiguous nervous tissues. The tumours are classified according to perceived cell of origin, gliomas being the most common generic group. In the 1970s transplacental administration of the potent neurocarcinogen, N-ethyl-N-nitrosourea (ENU), enabled investigation of the sequential development of brain and spinal neoplasms by electron microscopy and immunohistochemistry. The significance of the primitive cells of the subependymal plate in cellular origin and evolution of a variety of glial tumours was thereby established. Since then, the development of new cell culture methods, including the in vitro growth of neurospheres and multicellular tumour spheroids, and new antigenic markers of stem cells and glial/neuronal cell precursor cells, including nestin, Mushashi-1 and CD133, have led to a reappraisal of the histological classification and origins of CNS tumours. Moreover, neural stem cells may also provide new vectors in exciting novel therapeutic strategies for these tumours. In addition to the gliomas, stem cells may have been identified in paediatric tumours including cerebellar medulloblastoma, thought to be of external granule cell neuronal derivation. Interestingly, while the stem cell marker CD133 is expressed in these primitive neuroectodermal tumours (PNETs), the chondroitin sulphate proteoglycan neuronal/glial 2 (NG2), which appears to denote increased proliferative, but reduced migratory activity in adult gliomas, is rarely expressed. This is in contrast to the situation in the histologically similar supratentorial PNETs. A possible functional 'switch' between proliferation and migration in developing neural tumour cells may exist between NG2 and ganglioside GD3. The divergent pathways of differentiation of CNS tumours and the possibility of stem cell origin, for some, if not all, such neoplasms remain a matter for debate and continued research, but the presence of self-renewing neural stem cells in the CNS of both children and adults strongly suggests a role for these cells in tumour initiation and resistance to current therapeutic strategies.


ARGET-ATRP synthesis and characterization of PNIPAAm brushes for quantitative cell detachment studies.
Stimuli responsive (or "smart") polymer brushes represent a non-toxic approach for achieving release of biofouling layers. Thermo-responsive poly(N-isopropylacrylamide) (PNIPAAm) polymer brushes have been shown to modulate bacterial adhesion and release through transition between temperatures above and below the lower critical solution temperature (LCST ~32 °C) of PNIPAAm in water. In this article, we describe a convenient method to synthesize grafted PNIPAAm brushes over large areas for biological studies using a relatively simple and rapid method which allows atom transfer radical polymerization (ATRP) in presence of air using the activator regenerated electron transfer (ARGET) mechanism. PNIPAAm brushes were characterized using X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectroscopy, Fourier transform infrared spectroscopy, ellipsometry, and contact angle measurements. Our studies demonstrate that uniform, high purity PNIPAAm brushes with controlled and high molecular weight can be easily produced over large areas using ARGET-ATRP. We also report the use of a spinning disk apparatus to systematically and quantitatively study the detachment profiles of bacteria from PNIPAAm surfaces under a range (0-400 dyne/cm(2)) of shear stresses.


Male circumcision for HIV prevention: a prospective study of complications in clinical and traditional settings in Bungoma, Kenya.
Male circumcision reduces the risk of HIV acquisition by approximately 60%. Male circumcision services are now being introduced in selected populations in sub-Saharan Africa and further interventions are being planned. A serious concern is whether male circumcision can be provided safely to large numbers of adult males in developing countries. This prospective study was conducted in the Bungoma district, Kenya, where male circumcision is universally practised. Young males intending to undergo traditional or clinical circumcision were identified by a two-stage cluster sampling method. During the July-August 2004 circumcision season, 1007 males were interviewed 30-89 days post- circumcision. Twenty-four men were directly observed during and 3, 8, 30 and 90 days post-circumcision, and 298 men underwent clinical exams 45-89 days post-procedure. Twenty-one traditional and 20 clinical practitioners were interviewed to assess their experience and training. Inventories of health facilities were taken to assess the condition of instruments and supplies necessary for performing safe circumcisions. Of 443 males circumcised traditionally, 156 (35.2%) experienced an adverse event compared with 99 of 559 (17.7%) circumcised clinically (odds ratio: 2.53; 95% confidence interval: 1.89-3.38). Bleeding and infection were the most common adverse effects, with excessive pain, lacerations, torsion and erectile dysfunction also observed. Participants were aged 5 to 21 years and half were sexually active before circumcision. Practitioners lacked knowledge and training. Proper instruments and supplies were lacking at most health facilities. Extensive training and resources will be necessary in sub-Saharan Africa before male circumcision can be aggressively promoted for HIV prevention. Two-thirds of African men are circumcised, most by traditional or unqualified practitioners in informal settings. Safety of circumcision in communities where it is already widely practised must not be ignored.


Ipsiversive rotation in awake rats following chronic electrical stimulation of one caudate nucleus.
Rats were chronically implanted with stimulating electrodes in one caudate nucleus. Under light anaesthesia they received daily electrical stimulation (100-400 microA/HZ) for 30 min on 4 consecutive days. During this period, and for up to 3 subsequent days, tests for possible circling behaviour in response to administration of apomorphine i.p. were performed daily. Turning occurred towards the treated side and was reversible. The possibility is discussed that high levels of dopamine are released into the striatum during electrical stimulation, inducing transient subsensitivity of striatal dopamine receptors.


Templating and supersaturation-driven anti-templating: principles of biomineral architecture.
The structural synergy between biominerals (CaCO(3), hydroxyapatite) and biosubstrates were examined for the first time. The templating effect of substrate and a newly identified supersaturation-driven interfacial structure mismatch effect were identified in the context of a new nucleation model. It follows that the heterogeneous nucleation which corresponds to a good structural match and synergy between biominerals and substrates will promote an ordered, compact, and tough complex biomineral structure, and occur only at low supersaturations, whereas at high supersaturations the heterogeneous nucleation associated with a poor structural match and synergy between biominerals and substrates will become dominant due to supersaturation-driven interfacial structural mismatch. The latter normally results in a disordered and porous structure. A phenomenon, so-called microgravity-driven homogeneous nucleation, was also examined. It turns out that microgravity will suppress convection and consequently promote homogeneous-like nucleation during biomineralization. This could be responsible for microgravity-induced osteoporousis.


Characterization of the Rabbit as an In Vitro and In Vivo Model to Assess the Effects of Fibrinogenolytic Activity of Snake Venom on Coagulation.
Several in vitro investigations have demonstrated that anticoagulant effects of fibrinogenolytic snake venom metalloproteinases have been abrogated in human plasma by modifying fibrinogen with iron (Fe) and carbon monoxide (CO) to prevent catalysis or by directly inhibiting these enzymes with CO. To translate these findings, we chose to assess the rabbit as a model of envenomation with Crotalus atrox venom. It was determined with thrombelastography that 15 times the concentration of venom noted to compromise coagulation in plasma in vitro was required to cause coagulopathy in vivo, likely secondary to venom binding to blood cells and being cleared from the circulation rapidly. Unlike human plasma, rabbit plasma pre-treated with Fe/CO was not protected from fibrinogenolysis by venom. Consequently, the administration of purified human fibrinogen (with or without Fe/CO) would be required before venom administration to rabbits. Of greater interest, venom exposed to CO had complete loss of fibrinogenolytic effect in rabbit plasma and partial loss of activity in whole blood, indicative of unbinding of CO from venom and binding to haemoglobin. Thus, venom exposed to CO could remain partially or completely inhibited in whole blood long enough for clearance from the circulation, allowing rabbits to be a useful model to test the efficacy of regional CO administration to the bite site. Future investigations are planned to test these novel approaches to attenuate venom-mediated coagulopathy in the rabbit.


PPARdelta in humans: genetic and pharmacological evidence for a significant metabolic function.
Abundant data in rodents suggest an important role for peroxisomal proliferators-activated receptor-delta (PPARdelta) in regulating skeletal muscle fatty acid oxidation and this has consequences for lipid and lipoprotein metabolism. Considerably less is known in humans and this review will focus on evidence derived from studies of the PPARD gene and pharmacological use of specific PPARdelta agonists. Genetic association studies of single-nucleotide polymorphisms in the PPARD gene have only provided negative or conflicting evidence for gross phenotypes such as obesity, hyperlipidaemia and type 2 diabetes. This does not exclude more subtle effects in skeletal muscle metabolic function, but studies of this type need replication. A couple of recent studies using the specific PPARdelta agonist GW501516 suggest potent hypolipidaemic actions, presumably caused by enhanced fat oxidation in skeletal muscle. Considering the hypolipidaemic effect in humans by PPARdelta agonists, long-term studies are needed to confirm efficacy and safety.


Regulation of NF-κB activity in astrocytes: effects of flavonoids at dietary-relevant concentrations.
Neuroinflammation plays an important role in the progression of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Sustained activation of nuclear transcription factor κB (NF-κB) is thought to play an important role in the pathogenesis of neurodegenerative disorders. Flavonoids have been shown to possess antioxidant and anti-inflammatory properties and we investigated whether flavonoids, at submicromolar concentrations relevant to their bioavailability from the diet, were able to modulate NF-κB signalling in astrocytes. Using luciferase reporter assays, we found that tumour necrosis factor (TNFα, 150 ng/ml) increased NF-κB-mediated transcription in primary cultures of mouse cortical astrocytes, which was abolished on co-transfection of a dominant-negative IκBα construct. In addition, TNFα increased nuclear localisation of p65 as shown by immunocytochemistry. To investigate potential flavonoid modulation of NF-κB activity, astrocytes were treated with flavonoids from different classes; flavan-3-ols ((-)-epicatechin and (+)-catechin), flavones (luteolin and chrysin), a flavonol (kaempferol) or the flavanones (naringenin and hesperetin) at dietary-relevant concentrations (0.1-1 μM) for 18 h. None of the flavonoids modulated constitutive or TNFα-induced NF-κB activity. Therefore, we conclude that NF-κB signalling in astrocytes is not a major target for flavonoids.


Blood Glucose Levels of Patients With Diabetes in the Immediate Post-Acute Hemodialysis Period: An Exploratory Study.
PROBLEM/PURPOSE: To establish the evidence on which to base a protocol for monitoring capillary blood glucose in hospitalized patients with diabetes mellitus in the immediate post-acute hemodialysis period. Hospitalized, non-critically ill, adult patients (n = 68) with diabetes undergoing acute hemodialysis treatments. Capillary blood glucose was tested 30 minutes prior to the end of the hemodialysis treatment, at the end of the treatment, and 30 minutes and 60 minutes post-treatment. Data were analyzed to determine both within and between patient variability. Glucose levels varied widely before, during, and after hemodialysis, with greatest variability at 60 minutes post-hemodialysis. Levels did not vary based on diabetes type or admitting diagnosis. Possible relationships were identified with length of treatment, insulin administration prior to treatment, and food consumed within an hour after treatment. CONCLUSIONS/NURSING IMPLICATIONS: Testing post-dialysis glucose levels earlier than 60 minutes post-treatment may miss the need for additional medication.


Multilocus sequence analysis of the genus Citrobacter and description of Citrobacter pasteurii sp. nov.
Strains originating from various sources and classified as members of the genus Citrobacter within the family Enterobacteriaceae were characterized by sequencing internal portions of genes rpoB, fusA, pyrG and leuS, 16S rRNA gene sequencing, average nucleotide identity (ANI) of genomic sequences and biochemical tests. Phylogenetic analysis based on the four housekeeping genes showed that the 11 species of the genus Citrobacter with validly published names are well demarcated. Strains CIP 55.13(T) and CIP 55.9 formed a distinct branch associated with Citrobacter youngae. The ANI between CIP 55.9 and CIP 55.13(T) was 99.19%, whereas it was 94.75% between CIP 55.13(T) and strain CIP 105016(T) of the species C. youngae, the most closely related species. Biochemical characteristics consolidated the fact that the two isolates represent a separate species, for which the name Citrobacter pasteurii sp. nov. is proposed. The type strain is CIP 55.13(T) ( =DSM 28879(T) =Na 1a(T)).


Positioning colloids at the surfaces of cholesteric liquid crystal droplets.
We report on the internal configurations of aqueous dispersions of droplets of cholesteric liquid crystals (LCs; 5-50 μm-in-diameter; comprised of 4-cyano-4'-pentylbiphenyl and 4-(1-methylheptyloxycarbonyl)phenyl-4-hexyloxybenzoate) and their influence on the positioning of surface-adsorbed colloids (0.2 or 1 μm-in-diameter polystyrene (PS)). When N = 2D/P was less than 4, where D is the droplet diameter and P is the cholesteric pitch, the droplets adopted a twisted bipolar structure (TBS) and colloids were observed to assume positions at either the poles or equator of the droplets. A statistical analysis of the distribution of locations of the colloids revealed a potential well of depth 2.7 kBT near the equator, a conclusion that was supported by computer simulations performed via the minimization of the Landau-de Gennes free energy (well depth of 7 kBT from simulation). In contrast, for N > 4, a majority of the droplets exhibited a radial spherical structure (RSS) characterized by a pair of closely spaced surface defects (angle of separation with respect to the center of the droplet θ < 5°) connected by a disclination winding to/from the droplet center, which led to the positioning of pairs of colloids with well-defined spacing at these surface defects. The separation of the pairs of surface-adsorbed colloids was colloid size-dependent, ranging from 1.11 ± 0.04 μm for 1 μm-in-diameter colloids to 1.7 ± 0.2 μm for 200 nm-in-diameter colloids. We also observed long-lived metastable configurations in which the two surface point defects were separated by much larger distances (corresponding to populations with angles of θ = 20 ± 10° and 85 ± 10° with respect to the center), and observed these pairs of defects to also position pairs of colloids. A third configuration, the diametrical spherical structure (DSS) was also observed. Consistent with the predictions of computer simulations, we found experimentally that the DSS is indeed composed of disconnected defect rings positioned along the diameter of the droplet. Overall, these results reveal that the rich palette of defects exhibited by confined cholesteric LC systems (equilibrium and metastable) provide the basis of a versatile class of templates that enable the surface positioning of colloids in ways that are not possible with achiral LC droplets.


Head induction in the chick by primitive endoderm of mammalian, but not avian origin.
Different types of endoderm, including primitive, definitive and mesendoderm, play a role in the induction and patterning of the vertebrate head. We have studied the formation of the anterior neural plate in chick embryos using the homeobox gene GANF as a marker. GANF is first expressed after mesendoderm ingression from Hensen's node. We found that, after transplantation, neither the avian hypoblast nor the anterior definitive endoderm is capable of GANF induction, whereas the mesendoderm (young head process, prechordal plate) exhibits a strong inductive potential. GANF induction cannot be separated from the formation of a proper neural plate, which requires an intact lower layer and the presence of the prechordal mesendoderm. It is inhibited by BMP4 and promoted by the presence of the BMP antagonist Noggin. In order to investigate the inductive potential of the mammalian visceral endoderm, we used rabbit embryos which, in contrast to mouse embryos, allow the morphological recognition of the prospective anterior pole in the living, pre-primitive-streak embryo. The anterior visceral endoderm from such rabbit embryos induced neuralization and independent, ectopic GANF expression domains in the area pellucida or the area opaca of chick hosts. Thus, the signals for head induction reside in the anterior visceral endoderm of mammals whereas, in birds and amphibia, they reside in the prechordal mesendoderm, indicating a heterochronic shift of the head inductive capacity during the evolution of mammalia.


Expression of the c-fos gene and of an fos-related gene is stimulated by platelet-derived growth factor.
Complementary DNA clones of genes induced by platelet-derived growth factor (PDGF) in BALB/c-3T3 cells were isolated; one such clone contains a domain having nucleotide sequence homology with the third exon of c-fos. This nucleotide sequence homology is reflected in the predicted amino acid sequences of the gene products. Under low stringency conditions, the mouse v-fos gene cross-hybridizes with the PDGF-inducible complementary DNA clone. However, the messenger RNA transcripts of mouse c-fos and the new fos-related gene can be distinguished by gel electrophoresis and by S1 nuclease analysis. Expression of the authentic c-fos gene is induced by PDGF and superinduced by the combination of PDGF and cycloheximide.


Factors that impact recruitment and retention of veterinarians in emergency practice.
To examine factors that impact emergency veterinarians' decisions in selecting a place of employment and their perceptions of factors important in fostering a work environment conducive to long-term employment. 433 Veterinary Information Network members who reported practicing emergency medicine in the US and were not diplomates of the American College of Veterinary Emergency and Critical Care. An electronic survey distributed via the Veterinary Information Network data collection portal, made available from May 25, 2022, through June 15, 2022. Factors rated as most important in selecting a place of employment included working with a highly trained support staff and collegiality of coworkers. Factor analysis was used to extract factors that can influence emergency medicine practitioners' views of a work environment conducive to long-term employment. The factor found to be most important was leadership. All factors, except for professional growth, were rated as more important by female practitioners when compared to male practitioners. Aspects promoted in emergency medicine veterinarian recruitment efforts should include, in addition to the innate nature of the position, the elements identified as most attractive to current practitioners. By better understanding the impact of gender, children status, and years practicing emergency medicine on the relative importance in creating workplace environments conducive to long term employment, hospitals can be better equipped to meet the needs of both their current employees as well as potential new hires.


Endotoxin and immune activation in chronic heart failure: a prospective cohort study.
Immune activation in patients with chronic heart failure may be secondary to endotoxin (lipopolysaccharide) action. We investigated the hypothesis that altered gut permeability with bacterial translocation and endotoxaemia would be increased in patients with oedema secondary to congestive heart failure. We compared 20 patients who had chronic heart failure with recent-onset peripheral oedema (mean age 64 years [SD 10], New York Heart Association [NYHA] class 3.3 [0.7]), 20 stable non-oedematous patients with chronic heart failure (mean age 63 years [19], NYHA class 2.6 [0.7]), and 14 healthy volunteers (mean age 55 years [16]). Biochemical markers of endotoxaemia, inflammation, and immune activation were measured. Ten patients were studied within 1 week of complete resolution of oedema. Five patients survived longer than 6 months and were restudied again after remaining free of oedema for more than 3 months. Mean endotoxin concentrations were higher in oedematous patients with chronic heart failure than in stable patients with chronic heart failure (0.74 [SD 0.45] vs 0.37 EU/mL [0.23], p=0.0009) and controls (0.46 EU/mL [0.21], p=0.02). Oedematous patients had the highest concentrations of several cytokines. After short-term diuretic treatment, endotoxin concentrations decreased from 0.84 EU/mL [0.49] to 0.45 EU/mL [0.21], p<0.05) but cytokines remained raised. After freedom of oedema for more than 3 months after oedema resolved, endotoxin concentrations remained unchanged from the previous visit (0.49 EU/mL [0.06], p=0.45). Raised concentrations of endotoxin and cytokines are found in patients with chronic heart failure during acute oedematous exacerbation. Intensified diuretic treatment can normalise endotoxin concentrations. Our preliminary findings suggest that endotoxin may trigger immune activation in patients with chronic heart failure during oedematous episodes.


The antibacterial effect of mesenchymThe antibacterial effect of mesenchymal stem cells on graft infections: An experimental studyal stem cells on graft infections: An experimental study.
In this study, we aimed to investigate the antibacterial effects of mesenchymal stem cells, compared to tigecycline, on graft infection related with methicillin-resistant Staphylococcus epidermidis in a rat model. A total of 42 male adult Wistar rats (age >6 months; weight 300 to 350 g) were divided into six groups including seven rats in each. Group 0 did not undergo any procedure; Group 1 was infected, but untreated; Group 2 was infected and treated with tigecycline without graft placement; Group 3 was infected and received mesenchymal stem cells without graft placement; Group 4 was infected and treated with tigecycline after graft placement; Group 5 was infected and treated with mesenchymal stem cells after graft placement. The pockets created were either left empty or implanted with Dacron grafts. Treatment was commenced at 48 h. Specimens were collected on Day 13. Perigraft tissues were evaluated histopathologically and bacterial colony numbers were counted. No bacterial colonization was observed in Group 0, whereas there was a significant colonization in Group 1. Complete eradication was achieved in Group 2 and Group 3 (graft-free groups), and near-complete eradication was achieved in Group 4 and Group 5 (graft-implanted groups). The histopathological findings significantly differed between Group 1-Group 2 and between Group 1-Group 3 (graft-free groups). The histopathological findings were similar between Group 2-Group 3 and between Group 4-Group 5. Our study results suggest that mesenchymal stem cells may be a novel, contemporary alternative to antibiotherapy and may decrease the bio-burden of Staphylococcus at the infected graft areas, and mesenchymal stem cell treatment may be as effective as tigecycline.


Influence of carboxylic acids on the stereospecific nicotinamide adenine dinucleotide-dependent and nicotinamide adenine dinucleotide-independent lactate dehydrogenases of Leuconostoc mesenteroides.
Leuconostoc mesenteroides increased its lactic acid production from glucose threefold when malic acid was added to the culture. This increase resulted also in a reduction of the ratio of d-lactic acid to l-lactic acid (31.5 to 1.23). Addition of malic acid increased 6.5-fold the specific activity of nicotinamide adenine dinucleotide (NAD)-linked l-lactate dehydrogenase and increased 3.2-fold that of NAD-linked d-lactate dehydrogenase. The Michaelis constant (K(m)) for NAD of the NAD-linked l-lactate dehydrogenase increased with the addition of malate, but no change was observed in the K(m) values for the respective d-enzyme. The effect of carboxylic acids on the NAD-linked l-lactate dehydrogenase activities was tested by using partially purified enzyme preparations from cells grown with glucose alone and from cells grown with glucose plus malate. Malate stimulated the l-enzyme and inhibited the d-lactate dehydrogenase. The NAD-linked l-lactate dehydrogenase exhibited the same activity bands on polyacrylamide gel electrophoresis whether the cell-free preparation originated from cells grown on glucose plus malate or on glucose as the sole carbon source. The NAD-linked d-lactate dehydrogenase, however, exhibited a different pattern of electrophoretic mobility, depending upon the source of origin of the cell-free preparation. The results suggest that malate has a stimulatory effect on the synthesis of both enzymes and may result in rearrangement of the protein structure of the d-lactate dehydrogenase. This rearrangement apparently makes the d-enzyme more susceptible to inhibition of catalytic activity. The l-lactate dehydrogenase, however, is stimulated not only in its synthesis but also in its activity. It is proposed that these effects are responsible for the regulation of lactic acid production.


Influence of infection on clinical picture of diabetic foot syndrome.
The aim of our study was to analyse the foot infections in diabetic patients. We analysed foot ulcerations in 124 diabetics who attended outpatient foot clinic, or were hospitalized in the period from 1996 to 2006. Basic neuropathy screening examination was made with cotton wisp, pin-prick, tuning fork, and monofilament. For evaluation of leg ischemia, besides the evaluation of the presence of pedal pulses, the ankle-brachial pressure index was measured. If the infection of foot ulceration was clinically present, bacteriology examinations was performed. In the case of deep wound infection, x-ray examination was made. If bone destruction was present, osteomyelitis was diagnosed by technecium bone scanning and by technecium-labelled leukocyte scan. Deformation and destruction of the bone without infection was appoited as Charcot neuroarthropathy. Foot ulcer infection was found in 58 % diabetic patients, wounds were more often deep (80 %). Infection was not associated with special location of foot ulcer. Two-third of the total infected wounds were associated with leg ischemia and 30.6 % of infected ulcer ended with leg amputation. More foot ulcer infections were found in the diabetics with HbAlc over 8 %. Infection was coupled with diabetic retinopathy (in 63 % patients) (p=0.023), and also with diabetic nephropathy (in 66 % patients) (p=0.012). Bacteriology examination revealed most often Staphylococci (45.8 %), antibiotic therapy was made most often with chinolones. Osteomyelitis was present in 34.7 % of foot ulcer infections. In 14 diabetics (56 %) after antibiotic therapy it was not necessary to perform a leg amputation. HbAlc seems to be a significant predictor of osteomyelitis (p<0.02; OR=1.76). In conclusion, we confirmed that diabetic foot infections, especially on ischemic leg, in diabetics with poor metabolic control and chronic diabetic microvascular complications, are associated with a higher risk of leg amputations. Further, it is possible to cure osteomyelitis successfully without surgery in more than half the cases (Tab. 1, Ref. 24). Full Text in free PDF www.bmj.sk.


Anticancer effect of ursolic acid via mitochondria-dependent pathways.
Ursolic acid is a plant-derived pentacyclic triterpenoid found in various medicinal herbs and fruits. It has generated clinical interest due to its anti-inflammatory, antioxidative, antiapoptotic and anticarcinogenic effects. An increasing amount of evidence supports the anticancer effect of ursolic acid in various cancer cells. One of the hallmarks of malignant transformation is metabolic reprogramming that sustains macromolecule synthesis, bioenergetic demand and tumor cell survival. Mitochondria are important regulators of tumorigenes is as well as a major site of the metabolic reactions that facilitate this reprogramming and adaption to cellular and environmental changes. The current review explored the close association between the anticancer effect of ursolic acid and the activation of mitochondrial-dependent signaling pathways.


High performance set of PseAAC and sequence based descriptors for protein classification.
The study of reliable automatic systems for protein classification is important for several domains, including finding novel drugs and vaccines. The last decade has seen a number of advances in the development of reliable systems for classifying proteins. Of particular interest has been the exploration of new methods for extracting features from a protein that enhance classification for a given problem. Most methods developed to date, however, have been evaluated in only one or two application areas. Methods have not been explored that generalize well across a number of application areas and datasets. The aim of this study is to find a general method, or an ensemble of methods, that works well on different protein classification datasets and problems. Towards this end, we evaluate several feature extraction approaches for representing proteins starting from their amino acid sequence as well as different feature descriptor combinations using an ensemble of classifiers (support vector machines). In our experiments, more than ten different protein descriptors are compared using nine different datasets. We develop our system using a blind testing protocol, where the parameters of the system are optimized using one dataset and then validated using the other datasets (and so on for each dataset). Although different stand-alone classifiers work well on some datasets and not on others, we have discovered that fusion among different methods obtains a good performance across all the tested datasets, especially when using the weighted sum rule. Included in our feature descriptor combinations is the introduction of two new descriptors, one based on wavelets and the other based on amino acid groups. Using our system, both outperform their standard implementations. We also consider as a baseline the simple amino acid composition (AC) and dipeptide composition (2G), since they have been widely used for protein classification. Our proposed method outperforms AC and 2G.


Farm Fresh Foods for Healthy Kids (F3HK): An innovative community supported agriculture intervention to prevent childhood obesity in low-income families and strengthen local agricultural economies.
Childhood obesity persists in the United States and is associated with serious health problems. Higher rates of obesity among children from disadvantaged households may be, in part, attributable to disparities in access to healthy foods such as fruits and vegetables. Community supported agriculture can improve access to and consumption of fresh produce, but the upfront payment structure, logistical barriers, and unfamiliarity with produce items may inhibit participation by low-income families. The aim of this project is to assess the impact of subsidized, or "cost-offset," community supported agriculture participation coupled with tailored nutrition education for low-income families with children. The Farm Fresh Foods for Healthy Kids community-based, randomized intervention trial will build on formative and longitudinal research to examine the impact of cost-offset community supported agriculture on diet and other health behaviors as well as the economic impacts on local economies. The intervention will involve reduced-price community supported agriculture shares which can be paid for on a weekly basis, nine skill-based and seasonally-tailored healthy eating classes, and the provision of basic kitchen tools. Low income families with at least one child aged 2-12 years will be recruited to join existing community supported agriculture programs in New York, North Carolina, Vermont, and Washington. In each program, families will be randomized 1:1 to intervention or delayed intervention groups. Data will be collected at baseline, and in the fall and spring for 3 years. The primary outcomes are children's intake of fruits and vegetables and foods high in sugar and/or (solid) fat, as well as diet quality; secondary outcomes include physical, behavioral, psychosocial, and environmental variables. Cost-effectiveness and economic impact at the farm and community levels also will be assessed. This integrated project will provide important information and contribute to the evidence base regarding the use of local agricultural interventions to improve children's dietary behaviors and weight maintenance. Findings also will inform the development of a toolkit for farmers and education modules related to local food system innovations for undergraduate and graduate students. ClinicalTrials.gov NCT02770196 . Registered 5 April 2016.


Efficacy of an Emotion Self-regulation Program for Promoting Development in Preschool Children.
This work reports the results of an evaluation study to assess the efficacy of the Early HeartSmarts (EHS) program in schools of the Salt Lake City, Utah, School District. The EHS program is designed to guide teachers with methods that support young children (3-6 y old) in learning emotion self-regulation and key age-appropriate socioemotional competencies with the goal of facilitating their emotional, social, and cognitive development. The study was conducted over one school year using a quasiexperimental longitudinal field research design with 3 measurement points (baseline, preintervention, and postintervention) using The Creative Curriculum Assessment (TCCA), a teacher-scored, 50-item instrument measuring students growth in 4 areas of development: social/emotional, physical, cognitive, and language development. Children in 19 preschool classrooms in the Salt Lake City School District were divided into intervention and control group samples (n = 66 and n = 309, respectively; mean age = 3.6 y). The intervention classes were specifically selected to target children of lower socioeconomic and ethnic minority backgrounds. Overall, there is compelling evidence of the efficacy of the EHS program in increasing total psychosocial development and each of the 4 development areas measured by the TCCA: the results of a series of analyses of covariance found a strong, consistent pattern of large, significant differences on the development measures favoring preschool children who received the EHS program over those in the control group.


Anterolateral thoracotomy as an alternative to repeat median sternotomy for replacement of the mitral valve.
Median sternotomy is the most common approach for repeat cardiac surgery despite the potential complications of cardiac injury. Right anterolateral thoracotomy has been recommended as an alternative for patients undergoing mitral valve replacement, but data supporting one approach over the other do not exist. To compare these procedures, the records of 43 patients who had had a previous median sternotomy and who underwent mitral valve replacement were reviewed. No statistically significant differences between patients undergoing repeat median sternotomy (33 patients) and those undergoing right anterolateral thoracotomy (10 patients) were demonstrable when compared for age, gender, New York Heart Association Functional Class, other diseased valves, urgency of operation, indication for operation, type of valve removed, type of valve implanted, length of postoperative hospitalization, length of operation, days of ventilatory support, length of intensive care unit stay, and survival (90% for thoracotomy group; 76% for median sternotomy group; p, NS). Significant differences between the two groups, favoring right anterolateral thoracotomy, were apparent when comparisons were made for length of perfusion (means, 94.8 min, thoracotomy group; 121.4 min, sternotomy group; p = .03), incidence of reexploration (0%, thoracotomy group; 13%, sternotomy group; p = .001), and blood transfusion (means, 5.3 units, thoracotomy group; 11.4 units, sternotomy group; p = .003). Right anterolateral thoracotomy is an effective alternative to repeat median sternotomy for replacement of the mitral valve in patients who have had a previous median sternotomy.


The caudate: a key node in the neuronal network imbalance of insomnia?
Insomnia is prevalent, severe and partially heritable. Unfortunately, its neuronal correlates remain enigmatic, hampering the development of mechanistic models and rational treatments. Consistently reported impairments concern fragmented sleep, hyper-arousal and executive dysfunction. Because fronto-striatal networks could well play a role in sleep, arousal regulation and executive functioning, the present series of studies used an executive task to evaluate fronto-striatal functioning in disturbed sleep. Patients with insomnia showed reduced recruitment of the head of the left caudate nucleus during executive functioning, which was not secondary to altered performance or baseline perfusion. Individual differences in caudate recruitment were associated with hyper-arousal severity. Seed-based functional connectivity analysis suggested that attenuated input from a projecting orbitofrontal area with reduced grey matter density contributes to altered caudate recruitment in patients with insomnia. Attenuated caudate recruitment persisted after successful treatment of insomnia, warranting evaluation as a potential vulnerability trait. A similar selective reduction in caudate recruitment could be elicited in participants without sleep complaints by slow-wave sleep fragmentation, providing a model to facilitate investigation of the causes and consequences of insomnia.


Alternative-based thresholding with application to presurgical fMRI.
Functional magnetic reasonance imaging (fMRI) plays an important role in pre-surgical planning for patients with resectable brain lesions such as tumors. With appropriately designed tasks, the results of fMRI studies can guide resection, thereby preserving vital brain tissue. The mass univariate approach to fMRI data analysis consists of performing a statistical test in each voxel, which is used to classify voxels as either active or inactive-that is, related, or not, to the task of interest. In cognitive neuroscience, the focus is on controlling the rate of false positives while accounting for the severe multiple testing problem of searching the brain for activations. However, stringent control of false positives is accompanied by a risk of false negatives, which can be detrimental, particularly in clinical settings where false negatives may lead to surgical resection of vital brain tissue. Consequently, for clinical applications, we argue for a testing procedure with a stronger focus on preventing false negatives. We present a thresholding procedure that incorporates information on false positives and false negatives. We combine two measures of significance for each voxel: a classical p-value, which reflects evidence against the null hypothesis of no activation, and an alternative p-value, which reflects evidence against activation of a prespecified size. This results in a layered statistical map for the brain. One layer marks voxels exhibiting strong evidence against the traditional null hypothesis, while a second layer marks voxels where activation cannot be confidently excluded. The third layer marks voxels where the presence of activation can be rejected.


MLVA-typing on Streptococcus pneumoniae serotype 1 isolated from meningitis cases in Niger before the introduction of PCV-13 revealed a low genetic diversity.
Serotype 1 was the most prevalent pneumococcal meningitis serotype encountered in Niger over the period 2003-2011 (pre-vaccination era), accounting for 45.3% of infections. Multiple locus VNTR analysis (MLVA) was used to create a genotypic snapshot of a representative subset of the pneumococcal population of serotype 1. MLVA using 16 markers revealed a homogeneous genetic background of pneumococci serotype 1 from Niger, which clustered with few serotype 1 pneumococci from some African countries, while other African countries displayed different clonal complexes. DNA from Niger and from other African countries were different from pneumococci serotype 1 from European countries. MLVA-typing revealed a low genetic diversity among pneumococci serotype 1 from meningitis cases in Niger in the pre-vaccination era.


Sulfate, nitrate and blood pressure - An EPIC interaction between sulfur and nitrogen.
Nitrate (NO3-)-rich foods such as green leafy vegetables are not only part of a healthy diet, but increasingly marketed for primary prevention of cardiovascular disease (CVD) and used as ergogenic aids by competitive athletes. While there is abundant evidence for mild hypotensive effects of nitrate on acute application there is limited data on chronic intake in humans, and results from animal studies suggest no long-term benefit. This is important as nitrate can also promote the formation of nitrosamines. It is therefore classified as 'probably carcinogenic to humans', although a beneficial effect on CVD risk might compensate for an increased cancer risk. Dietary nitrate requires reduction to nitrite (NO2-) by oral commensal bacteria to contribute to the formation of nitric oxide (NO). The extensive crosstalk between NO and hydrogen sulfide (H2S) related metabolites may further affect nitrate's bioactivity. Using nitrate and nitrite concentrations of drinking water - the only dietary source continuously monitored for which detailed data exist - in conjunction with data of >14,000 participants of the EPIC-Norfolk study, we found no inverse associations with blood pressure or CVD risk. Instead, we found a strong interaction with sulfate (SO42-). At low sulfate concentrations, nitrate was inversely associated with BP (-4mmHg in top quintile) whereas this was reversed at higher concentrations (+3mmHg in top quintile). Our findings have a potentially significant impact for pharmacology, physiology and public health, redirecting our attention from the oral microbiome and mouthwash use to interaction with sulfur-containing dietary constituents. These results also indicate that nitrate bioactivation is more complex than hitherto assumed. The modulation of nitrate bioactivity by sulfate may render dietary lifestyle interventions aimed at increasing nitrate intake ineffective and even reverse potential antihypertensive effects, warranting further investigation.