Cortisol resistance in man.
Primary cortisol resistance in man is a familial disease characterized by increased plasma cortisol concentrations, high urinary free cortisol excretion, a normal circadian pattern of cortisol secretion, resistance to adrenal suppression by dexamethasone and absence of the clinical stigmata of Cushing's syndrome or signs of adrenal insufficiency. In its severe form, hypertension and hypokalemic alkalosis are present, owing to increased secretion of the sodium-retaining corticoids, corticosterone and deoxycorticosterone. In subjects with a less severe resistance to cortisol, there are no clinical abnormalities and the disease is revealed only by detailed examination of several parameters of cortisol metabolism or by glucocorticoid receptor studies. In whole-cell glucocorticoid receptor assays (peripheral mononuclear leukocytes, fibroblasts, or B-lymphocytes transformed with the Epstein-Barr Virus) low receptor affinity for dexamethasone could be demonstrated conclusively only in the severely affected subject. When affected cells are transformed with the Epstein-Barr virus, receptor induction is less than that of normal cells. The decreased affinity of the receptor for its ligand is reflected in an increased rate of loss of specific bound ligand during thermal activation. The molecular weight of the receptor, determined by SDS-PAGE, is similar to that from normal cells (approximately 92,000). Only in the severely affected patient was the proportion of activated receptor remaining in the cytosol of thermally activated intact cells reduced. At saturating concentrations of dexamethasone, nuclear binding appears normal in cells from both the severe and the asymptomatic forms of this condition, providing an explanation for the apparently complete compensation of the target tissue resistance to glucocorticoids by the high plasma cortisol levels. The clinical manifestations of the disorder (hypertension, hypokalemia) can be corrected with high doses of dexamethasone (3mg/day).


[The total proteolytic and collagenolytic activity in the blood cells of patients with systemic scleroderma].
Collagenolytic (CA) and neutral caseinolytic activity (NCA) was studied in extracts from blood cells (neutrophils, mononuclear cells and platelets) of patients suffering from systemic scleroderma (SSD). 23 persons were examined. Of these, 15 had local skin lesions, 8 diffuse lesions. CA, both specific and per 10(6) cells was found to be dramatically decreased (2-4-fold) in all blood cells, whereas NCA was increased in neutrophils and mononuclear cells; in platelets, it remained within normal. The amount of protein in neutrophils and mononuclear cells was lowered 1.2 and 2-fold respectively. In diffuse skin lesions, the amount of protein in cells was lower than in local lesions. It should be noted that in SSD patients examined, the inflammatory process was unmarked. Therefore, the data on substantial changes in proteolytic activity cannot be related to the inflammatory process. A reverse correlation was established between CA in neutrophils and circulating immune complexes as was a reverse correlation between CA in mononuclear cells and blood antinuclear factor. The data presented indicate that proteinases are an important factor of the pathogenesis in SSD. Apparently, SSD is characterized not only by enhanced synthesis of collagen but also by a dramatic reduction of the activity of enzymes that specifically hydrolyze this group of proteins, which leads to a decrease of collagen catabolism and hence, to the development of fibrosis in tissues.


Statistical Shape Modeling Approach to Predict Missing Scapular Bone.
Prediction of complete and premorbid scapular anatomy is an important aspect of successful shoulder arthroplasty surgeries to treat glenohumeral arthritis and which remains elusive in the current literature. We proposed to build a statistical shape model (SSM) of the scapula and use it to build a framework to predict a complete scapular shape from virtually created scapular bone defects. The bone defects were synthetically created to imitate bone loss in the glenoid region and missing bony part in inferior and superior scapular regions. Sixty seven dry scapulae were used to build the SSM while ten external scapular shapes (not used in SSM building) were selected to map scapular shape variability using its anatomical classification. For each external scapula, four virtual bone defects were created in the superior, inferior and glenoid regions by manually removing a part of the original mesh. Using these defective shapes as prior knowledge, original shapes were reconstructed using scapula SSM and Gaussian process regression. Robustness of the scapula SSM was excellent (generality = 0.79 mm, specificity = 1.74 mm, first 15 principal modes of variations accounted for 95% variability). The validity and quality of the reconstruction of complete scapular bone were evaluated using two methods (1) mesh distances in terms of mean and RMS values and (2) four anatomical measures (three angles: glenoid version, glenoid inclination, and critical shoulder angle, and glenoid center location). The prediction error in the angle measures ranged from 1.0° to 2.2°. For mesh distances, highest mean and RMS error was 0.97 mm and 1.30 respectively. DICE similarity coefficient between the original and predicted shapes was excellent (≥ 0.81). This framework provided high reconstruction accuracy and can be effectively embedded in the pre-surgical planning of shoulder arthroplasty or in morphology-based shoulder biomechanics modeling pipelines.


Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension.
Inhibition of cytochrome P-450 (CYP450) enzymes with cobalt chloride (CoCl2) prevented hypertension, organ hypertrophy, and renal injury induced by DOCA and salt (1% NaCl) in uninephrectomized (UNx) rats. Systolic blood pressure (SBP) rose to 193 +/- 6 mmHg by day 21 from control levels of 150 +/- 7 mmHg in response to DOCA-salt treatment, a rise that was prevented by CoCl2 (24 mg. kg-1. 24 h-1). The effects of DOCA-salt treatment, which increased protein excretion to 88.3 +/- 6.9 mg/24 h on day 21 from 9.0 +/- 1.1 mg/24 h on day 3, were prevented by CoCl2. CoCl2 also attenuated the renal and left ventricular hypertrophy and the increase in media-to-lumen ratio in hypertensive rats. DOCA-salt treatment increased excretion of endothelin (ET)-1 from 81 +/- 17 to 277 +/- 104 pg. 100 g body wt-1. 24 h-1 associated with a fourfold increase in 20-hydroxyeicosatetraenoic acid (20-HETE) excretion from 3.0 +/- 1.1 to 12.2 +/- 1.9 ng. 100 g body wt-1. 24 h-1 (days 3 vs. 21). CoCl2 blunted these increases by 58 and 72%, respectively. In aortic rings pulsed with [3H]thymidine, ET-1 increased its incorporation. Dibromododec-11-enoic acid, an inhibitor of 20-HETE synthesis, attenuated ET-1-induced increases in [3H]thymidine incorporation. We distinguished effects of CoCl2 acting via CO generation vs. suppression of CYP450-arachidonic acid metabolism by treating UNx-salt-DOCA rats with 1-aminobenzotriazole (ABT), which suppresses CYP450 enzyme activity, and compared these results to those produced by CoCl2. ABT reduced hypertension, as did CoCl2. Unlike CoCl2, ABT did not prevent organ hypertrophy and proteinuria, suggesting that these effects were partially related to CO formation. Blockade of the ETA receptor with BMS-182874 reduced SBP, organ hypertrophy, and proteinuria, indicating the importance of ET-initiated abnormalities to the progression of lesions in UNx-salt-DOCA.


Trends in time to invasive examination and treatment from 2001 to 2009 in patients admitted first time with non-ST elevation myocardial infarction or unstable angina in Denmark.
To investigate trends in time to invasive examination and treatment for patient with first time diagnosis of non-ST elevation myocardial infarction (NSTEMI) and unstable angina during the period from 2001 to 2009 in Denmark. From 1 January 2001 to 31 December 2009 all first time hospitalisations with NSTEMI and unstable angina were identified in the National Patient Registry (n=65 909). Time from admission to initiation of coronary angiography (CAG), percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) was calculated. We described the development in invasive examination and treatment probability (CAG, PCI and CABG at 3, 7, 10, 30 and 60 days) for the years 2001-2009, taking the competing risk of death into account using Aalen-Johansen estimators and a Fine-Gray model. Nationwide Danish cohort. The proportion of patients receiving a CAG and PCI increased substantially over time while the proportion receiving a CABG decreased for both NSTEMI and unstable angina. For both NSTEMI and unstable angina, a significant increase in invasive examination and treatment probability at 3 days for CAG and PCI were seen especially from 2007 through to 2009. For NSTEMI, the CAG examination probability at 3 days leaped from 20% in 2007 to 32% in 2008 and 39% in 2009, and for PCI the same was true with a leap in treatment probability from 19% to 28% from 2008 to 2009. In Denmark the use of CAG and PCI in treatment of NSTEMI and unstable angina has increased from 2001 to 2009, while the use of CABG has decreased. During the same period, there was a marked increase in invasive examination and treatment probability at 3 days, that is, more patients were treated faster which is in line with the political aim of reducing time to treatment.


Flow-based basophil activation test in immediate drug hypersensitivity. An EAACI task force position paper.
Diagnosing immediate drug hypersensitivity reactions (IDHRs) can pose a significant challenge and there is an urgent need for safe and reliable tests. Evidence has emerged that the basophil activation test (BAT), an in vitro assay that mirrors the in vivo response, can be a complementary test for many drugs. In this position paper, members of Task Force (TF) "Basophil activation test in the evaluation of Drug Hypersensitivity Reactions" from the European Academy of Allergy and Clinical Immunology (EAACI) present the data from a survey about the use and utility of BAT in IDHRs in Europe. The survey results indicate that there is a great interest for using BAT especially for diagnosing IDHRs. However, there are still main needs, mainly in the standardization of the protocols. Subsequently consensus-based recommendations were formulated for: (i) Technical aspects of BAT in IDHRs including type of sample, management of drugs, flow cytometry protocols, interpretation of the results; and (ii) Drug-specific aspects that should be taken into account when performing BAT in relation to betalactams, neuromuscular blocking agents, fluoroquinolones, chlorhexidine, opioids, radio contrast media, chemotherapeutics, biological agents, nonsteroidal anti-inflammatory drugs, COVID vaccine, and excipients. Moreover, aspects in the evaluation of pediatric population have also been considered. All this indicates that BAT offers the clinician and laboratory a complementary tool for a safe diagnostic for IDHRs, although its place in the diagnostic algorithm depends on the drug class and patient population (phenotype, geography, and age). The standardization of BAT is important for generalizing this method beyond the individual laboratory.


Randomized double-blinded comparison of norepinephrine and phenylephrine for maintenance of blood pressure during spinal anesthesia for cesarean delivery.
During spinal anesthesia for cesarean delivery, phenylephrine can cause reflexive decreases in maternal heart rate and cardiac output. Norepinephrine has weak β-adrenergic receptor agonist activity in addition to potent α-adrenergic receptor activity and therefore may be suitable for maintaining blood pressure with less negative effects on heart rate and cardiac output compared with phenylephrine. In a randomized, double-blinded study, 104 healthy patients having cesarean delivery under spinal anesthesia were randomized to have systolic blood pressure maintained with a computer-controlled infusion of norepinephrine 5 μg/ml or phenylephrine 100 μg/ml. The primary outcome compared was cardiac output. Blood pressure heart rate and neonatal outcome were also compared. Normalized cardiac output 5 min after induction was greater in the norepinephrine group versus the phenylephrine group (median 102.7% [interquartile range, 94.3 to 116.7%] versus 93.8% [85.0 to 103.1%], P = 0.004, median difference 9.8%, 95% CI of difference between medians 2.8 to 16.1%). From induction until uterine incision, for norepinephrine versus phenylephrine, systolic blood pressure and stroke volume were similar, heart rate and cardiac output were greater, systemic vascular resistance was lower, and the incidence of bradycardia was smaller. Neonatal outcome was similar between groups. When given by computer-controlled infusion during spinal anesthesia for cesarean delivery, norepinephrine was effective for maintaining blood pressure and was associated with greater heart rate and cardiac output compared with phenylephrine. Further work would be of interest to confirm the safety and efficacy of norepinephrine as a vasopressor in obstetric patients.


[Extravaginal transposition of the urethra in the treatment of post-coital cystitis].
From 2005 to 2013, 106 patients with post-coital cystitis underwent surgery. Of these, vaginal ectopia of urethral meatus was diagnosed in 19 (17.9%), and hypermobility of the distal urethra in 87 (82.1%). 28 (26.4%) women underwent the traditional plasty of distal urethra by O'Donnell method (group 1) and 78 (73.6%) patients underwent surgery using new method of extravaginal transposition of the urethra developed in our clinic (group 2). In group 1, satisfactory results were obtained in 23 (82.1%) patients, poor results--in 5 (17.9%) patients; in group 2, in 77 (98.7%) and 1 (1.3%) patients, respectively (p < 0.05). The disappointing results were attributable to the divergence of seams, reverse bias of urethra and recurrence of the disease. The use of method of extravaginal transposition of the urethra compared with a standard method allows to reduce the trauma of surgery, improve reliability of fixing the urethra, reducing the risk of its restriction and disease recurrence.


Protocol for a home-based integrated physical therapy program to reduce falls and improve mobility in people with Parkinson's disease.
The high incidence of falls associated with Parkinson's disease (PD) increases the risk of injuries and immobility and compromises quality of life. Although falls education and strengthening programs have shown some benefit in healthy older people, the ability of physical therapy interventions in home settings to reduce falls and improve mobility in people with Parkinson's has not been convincingly demonstrated. 180 community living people with PD will be randomly allocated to receive either a home-based integrated rehabilitation program (progressive resistance strength training, movement strategy training and falls education) or a home-based life skills program (control intervention). Both programs comprise one hour of treatment and one hour of structured homework per week over six weeks of home therapy. Blinded assessments occurring before therapy commences, the week after completion of therapy and 12 months following intervention will establish both the immediate and long-term benefits of home-based rehabilitation. The number of falls, number of repeat falls, falls rate and time to first fall will be the primary measures used to quantify outcome. The economic costs associated with injurious falls, and the costs of running the integrated rehabilitation program from a health system perspective will be established. The effects of intervention on motor and global disability and on quality of life will also be examined. This study will provide new evidence on the outcomes and cost effectiveness of home-based movement rehabilitation programs for people living with PD. The trial is registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12608000390381).


The impact of the introduction of a rapid D-dimer assay on the diagnostic evaluation of suspected pulmonary embolism.
Rapid D-dimer assays are being used in the diagnostic evaluation of suspected pulmonary embolism (PE). Although this hypothesis is anticipated to decrease the use of ventilation-perfusion (VQ) scans and other diagnostic tests for PE, it has not been tested in a "real-world" environment. A randomized prospective trial was conducted on 470 of the 5390 enrolled patients aged 60 years and older who had previously undergone any diagnostic tests for PE at an urban teaching hospital. The use of D-dimer as part of the diagnostic evaluation for PE was promulgated in the 2 randomly chosen intervention firms. The remaining 2 firms served as controls. The number of VQ scans, spiral computed tomographic scans, and pulmonary angiograms performed. Secondary outcomes included mortality and thromboembolic or bleeding events during 3 months of follow-up. Of the 470 inpatients who underwent evaluation for PE on a per PE workup basis, fewer VQ scans were performed in the intervention firms (63.8% vs 81.3%; P<.01). However, the number of patients evaluated for PE nearly doubled in the intervention firms (304 vs 166; P<.01), so that more VQ scans were performed in the intervention than in the control firms (194 vs 135; P<.01). Ninety-four patients from the control firms and 160 patients from the intervention firms were diagnosed and treated for venous thromboembolic disease (P<.01). There were no differences in secondary outcomes during the 3-month follow-up. The introduction of a rapid D-dimer assay increased the number of VQ scans performed because the number of patients screened for PE increased. A larger number of patients in the intervention firms were diagnosed as having venous thromboembolic disease (PE and/or deep vein thrombosis). There were no perceived changes in mortality or venous thromboembolic events during the 3-month follow-up.


Fast image recovery using dynamic load balancing in parallel architectures, by means of incomplete projections.
This paper formulates an incomplete projection algorithm that is applied to the image recovery problem. The algorithm allows an easy implementation of dynamic load balancing for parallel architectures. Furthermore, the local computation-communication load ratio can be adjusted, since each processor performs a finite number of iterations of any projection-type technique, and this number can be provided as a parameter of the algorithm. Numerical results compare favorably with those obtained by the extrapolated method of parallel subgradient projections.


Intracellular chloride accumulation and subcellular elemental distribution during atrial fibrillation.
Ion channel remodeling occurs during atrial fibrillation (AF); however, the extent of alteration in the subcellular distribution of elements (Na, K, Cl, Ca, Mg, P) is unknown. Electron probe microanalysis was used to determine the total (free+bound) in vivo subcellular concentration of these elements during AF. The left atrial appendage (LAA) was snap-frozen in situ after pacing (640 bpm) for 3 minutes (n=5 dogs), 30 minutes (n=3), or 48 hours (n=5). Dogs in sinus rhythm (n=3) served as controls. Whole-cell, cytosolic, and mitochondrial elemental concentrations were measured in cryosections. LAA effective refractory period (ERP) was measured before and after pacing. LAA ERP decreased significantly after 48 hours (116+/-3 to 88+/-10 ms, P=0.02). Whole-cell Cl increased by 9.0 mmol/L and 17 mmol/L after 3 and 30 minutes of pacing, respectively (P<0.0001), without a concomitant increase in Na. However, at 48 hours, whole-cell Na was reduced by 51% (P<0.01). Cytosolic Ca increased by 1.1 mmol/kg dry wt after 3 minutes (P<0.005), but mitochondrial Ca remained low and unchanged. Cell size measured in transverse cryosections increased after 3 minutes of pacing (75+/-5 to 109+/-11 microm2, P=0.007) but returned to baseline by 30 minutes (66+/-5 microm2). Intracellular Cl accumulation induced by rapid pacing is a novel finding and may play a role in AF pathogenesis by causing resting membrane depolarization and ERP reduction. There was no evidence of cellular or mitochondrial Ca overload despite the development of electrical remodeling and transient increase in cytoplasmic Ca.


Biomaterials in Craniomaxillofacial Reconstruction: Past, Present, and Future.
Deformity and tissue loss involving the craniomaxillofacial region occurs frequently as a result of trauma, oncologic resection, or a congenital malformation. In order to maximize the patient's quality of life, reconstruction of the craniomaxillofacial skeleton must seek to restore aesthetics as well as function. Advances in diagnostic technology, surgical technique, instrumentation, and innovative biomaterials used have transformed the way reconstructive surgeons approach their patients' needs. From the advent of alloplastic reconstruction, surgeons have sought the ideal material for use in craniomaxillofacial surgery. Substances such as metals, ceramics, glasses, and more recently resorbable polymers and bioactive materials have all been utilized.While autologous bone has remained widely-favored and the gold standard, synthetic alternatives remain a necessity when autologous reconstruction is not readily available. Today, alloplastic material, autografting via microvascular tissue transfer, hormone and growth factor-induced bone formation, and computer-aided design and manufacturing of biocompatible implants represent only a fraction of a wide range of options used in the reconstruction of the craniomaxillofacial skeleton. We present a brief review of the materials used in the repair of deformities of the craniomaxillofacial skeleton as well as a look into the potential future direction of the field.


Improving older drivers' hazard perception ability.
One reason that older drivers may have elevated crash risk is because they anticipate hazardous situations less well than middle-aged drivers. Hazard perception ability has been found to be amenable to training in young drivers. This article reports an experiment in which video-based hazard perception training was given to drivers who were between the ages of 65 and 94 years. Trained participants were significantly faster at anticipating traffic hazards compared with an untrained control group, and this benefit was present even after the authors controlled for pretraining ability. If future research shows these effects to be robust, the implications for driver training and safety are significant.


Extracorporeal shock wave therapy improves the walking ability of patients with peripheral artery disease and intermittent claudication.
Despite the recent advances in bypass surgery and catheter interventional therapy for peripheral artery disease (PAD), the long-term outcome of revascularization therapy for infrapopliteal lesions remains unsatisfactory. We have previously demonstrated that low-energy extracorporeal shock wave (SW) therapy effectively induces neovascularization through upregulation of angiogenic factors and improves myocardial ischemia in pigs and humans and in hindlimb ischemia in rabbits. In this study, we thus examined whether our SW therapy also improves the walking ability of patients with PAD and intermittent claudication. We treated 12 patients (19 limbs) in Fontaine II stage (males/females, 10/2; 60-86 years old) with low-energy SW therapy to their ischemic calf muscle 3 times/week for 3 consecutive weeks. After 24 weeks, the pain and distance subscale scores of the walking impairment questionnaire were significantly improved (33±25 vs. 64±26, 27±16 vs. 64±23, respectively, both P<0.01). Maximum walking distance was also significantly improved at 4 weeks (151±37% from baseline, P<0.01) and was maintained at 24 weeks (180±74% from baseline, P<0.01). Moreover, the recovery time of the tissue oxygenation index in the calf muscle during a treadmill test, which reflects local O<inf>2</inf> supply, was significantly shortened (295±222s vs. 146±137s, P<0.01). Importantly, no adverse effects were noted. Non-invasive SW therapy improves the walking ability of PAD patients.


Between-sexes differences in lumbopelvic muscle mechanical properties of non-climacteric adults: a cross-sectional design.
The lumbopelvic muscle mechanical properties (MMPs) are clinically relevant, but their dependence on sex remains unknown. Therefore, this study aimed to identify if lumbopelvic MMPs depend on the sex in a young adult population. Thirty-five healthy nulliparous women and 35 healthy men were analyzed (age range: 18-50). Lumbopelvic MMPs, that is, tone, stiffness, elasticity, relaxation and creep, assessed with MyotonPRO®, and pelvic floor (PF) health questionnaires were compared between-sexes. Intra-group correlations between sociodemographic and clinical data, and MMPs were also determined. The MMPs of PF were different between healthy non-climacteric adults of both sexes, with women showing higher values of tone and stiffness and lower values of elasticity and viscoelastic properties than men (in all cases, p < 0.03). At lumbar level, tone and stiffness were higher for men at both sides (in all cases, p < 0.04), and relaxation was lower at left side (p = 0.02). The MMPs showed few correlations with sociodemographic data within women. However, within males, there were positive correlations for PF stiffness and viscoelastic parameters with age, BMI and function (0.334 < r < 0.591) and, at lumbar level, negative correlations for tone and stiffness ( - 0.385 < r < -0.590) and positive correlations for viscoelastic properties (0.564 < r < 0.719), with BMI. This indicated that between-sexes differences of lumbopelvic MMPs depend on the specific location of assessment in healthy non-obese young individuals. Women show higher tone and stiffness and lower elasticity and viscoelasticity than men, at PF level.


Intellectual property and regulation of molecular pathology tests.
Legal and regulatory issues have assumed heightened importance in molecular pathology. Patents on relationships between human gene variants and clinical phenotypes, as well as on the underlying gene sequences themselves, have been extremely controversial. However, recent Supreme Court decisions appear to have rendered invalid these classes of patents. The Clinical Laboratory Improvement Amendments of 1988 have been the primary basis for laboratory oversight in the United States, whereas the Food and Drug Administration has been responsible for regulating in vitro test kits distributed in interstate commerce. However, the Food and Drug Administration has recently announced its intention to regulate laboratory-developed tests, raising concerns in the laboratory community. This article reviews recent developments impacting the legal status of gene patenting and oversight of molecular pathology testing in the United States.


Structural classification of thioredoxin-like fold proteins.
Protein structure classification is necessary to comprehend the rapidly growing structural data for better understanding of protein evolution and sequence-structure-function relationships. Thioredoxins are important proteins that ubiquitously regulate cellular redox status and various other crucial functions. We define the thioredoxin-like fold using the structure consensus of thioredoxin homologs and consider all circular permutations of the fold. The search for thioredoxin-like fold proteins in the PDB database identified 723 protein domains. These domains are grouped into eleven evolutionary families based on combined sequence, structural, and functional evidence. Analysis of the protein-ligand structure complexes reveals two major active site locations for the thioredoxin-like proteins. Comparison to existing structure classifications reveals that our thioredoxin-like fold group is broader and more inclusive, unifying proteins from five SCOP folds, five CATH topologies and seven DALI domain dictionary globular folding topologies. Considering these structurally similar domains together sheds new light on the relationships between sequence, structure, function and evolution of thioredoxins.


Are somatosensory evoked potentials the best predictor of outcome after severe brain injury? A systematic review.
Many tests have been used to predict outcome following severe brain injury. We compared predictive powers of clinical examination (pupillary responses, motor responses and Glasgow Coma Scale, GCS), electroencephalography (EEG) and computed tomography (CT) to that of somatosensory evoked potentials (SEPs) in a systematic review. Medline (1976-2002) and Embase (1980-2002) were searched, manual review of article reference lists was conducted, and authors were contacted. We selected 25 studies addressing the prediction of outcome after severe brain injury using SEPs and either GCS, EEG, CT, pupillary or motor responses. Outcomes were determined for patients with normal or bilaterally absent SEPs and graded measures of GCS, EEG, CT, pupillary responses or motor responses. For favourable outcome prediction SEPs were superior in sensitivity, specificity and positive and negative predictive values, except for pupillary responses which had superior sensitivity and GCS which had higher specificity. SEPs had superior summary receiver operating characteristic curves, with the exception of motor responses, and superior ratio of odds ratios. For unfavourable outcome prediction SEPs were superior to the other tests in sensitivity, specificity and positive and negative predictive values, except for motor and pupillary responses, GCS and CTs which had superior sensitivity. All SEP summary receiver operating characteristic curves and pooled ratio of odds ratios were superior. Although imperfect, SEPs appear to be the best single overall predictor of outcome. There is sufficient evidence for clinicians to use SEPs in the prediction of outcome after brain injury.


Body composition and bone mineral density in childhood.
Body mass compartments may have different directions of influence on bone accrual. Studies of children are limited by relatively small sample sizes and typically make strong assumptions of linear regression. To evaluate associations of overall body mass, components of overall body mass (fat-free and total fat), and components of total fat mass (truncal and non-truncal fat), measured via dual-energy X-ray absorptiometry (DXA) and anthropometry, with total body less head areal bone mineral density (aBMD) Z-score in mid-childhood. We performed a cross-sectional study among 876 Boston-area children who had DXA measures. We evaluated linearity of associations using generalized additive models. Children were median 7.7 (range 6-10) years of age, and 61% were white. After adjustment for sociodemographics and other compartments of body mass, overall body mass, particularly the fat-free mass component, appeared to have a positive relationship with aBMD Z-score [e.g., 0.25 (95% CI: 0.23, 0.28) per 1-kg fat-free mass]. The relationship between truncal fat and aBMD Z-score appeared non-linear, with a negative association only in children with levels of fat mass in the upper 15th percentile [-0.17 (95% CI: -0.26, -0.07) aBMD Z-score per 1-kg truncal fat mass], while non-truncal fat mass was not associated with aBMD Z-score. Our analyses suggest that central adiposity is associated with lower aBMD Z-score only in children with the highest levels of abdominal fat. This finding raises the possibility of a threshold above which central adipose tissue becomes more metabolically active and thereby adversely impacts bone.


Detection of subcritical stenoses by Doppler spectrum analysis.
Little information is available regarding the sensitivity of carotid Doppler signal spectral analysis in documenting flow disturbances caused by subcritical stenotic lesions. We have studied the effects on spectra of stenoses ranging from 10% to 80% diameter reduction using the infrarenal aorta of the dog. Spectral analysis was able to reliably detect stenoses as small as 20% by comparison of the peak systolic frequency at the site of stenosis with that proximal to it; a peak frequency ratio of about 1.5 was typical for this degree of stenosis. This ratio continued to increase in the nearly linear fashion with increasing stenosis, reaching approximately 2.1 for a 50% stenosis. For greater degree of stenosis, turbulent flow patterns and significant spectral broadening were noted a gradual decrease in the peak frequency ratio. Spectra of Doppler signals recorded at sites 1 cm or more distal to the stenosis site were not significantly different from proximal spectra until the stenosis exceeded a 45% diameter reduction and the peak frequency ratio 1.3. At these distal sites this ratio increased with increasing stenosis to a maximum of 1.64 for a 65% stenosis, beyond which the flow was characterized by severe turbulence and a decreasing ratio. Doppler signal spectrum analysis appears to be a potentially quantitative noninvasive technique that has the sensitivity necessary to detect subcritical carotid arterial stenoses and be applicable to the clinical setting.


Alert threshold algorithms and malaria epidemic detection.
We describe a method for comparing the ability of different alert threshold algorithms to detect malaria epidemics and use it with a dataset consisting of weekly malaria cases collected from health facilities in 10 districts of Ethiopia from 1990 to 2000. Four types of alert threshold algorithms are compared: weekly percentile, weekly mean with standard deviation (simple, moving average, and log-transformed case numbers), slide positivity proportion, and slope of weekly cases on log scale. To compare dissimilar alert types on a single scale, a curve was plotted for each type of alert, which showed potentially prevented cases versus number of alerts triggered over 10 years. Simple weekly percentile cutoffs appear to be as good as more complex algorithms for detecting malaria epidemics in Ethiopia. The comparative method developed here may be useful for testing other proposed alert thresholds and for application in other populations.


Serum choline activates mutant acetylcholine receptors that cause slow channel congenital myasthenic syndromes.
We have found that mutant acetylcholine receptor channels (AChRs) that cause slow-channel congenital myasthenic syndromes are activated by serum and that the high frequency of openings in serum is reduced by treatment with choline oxidase. Thus, slow-channel congenital myasthenic syndrome AChRs at the neuromuscular junction are likely to be activated both by steady exposure to serum choline and by transient exposure to synaptically released transmitter. Single-channel kinetic analyses indicate that the increased response to choline is caused by a reduced intrinsic stability of the closed channel. The results suggest that a mutation that destabilizes the inactive conformation of the AChR, together with the sustained exposure of endplates to serum choline, results in continuous channel activity that contributes to the pathophysiology of the disease.


Self-reportance of temporomandibular disorders in adult patients attending general dental practice in Sweden from 2011 to 2013.
The study aim was to evaluate the prevalence of self-reported temporomandibular disorders (TMD) and acceptance or nonacceptance of such disorders in adult patients attending all public dental health services in the County of Sörmland, Sweden, during a 3-year period, 2011-2013. Two questions were asked about TMD and the voluntary mouth-opening capacity was measured. The results were registered in a score 0-3. The registration was completed with a question about each patient's acceptance or nonacceptance of their condition. More than 73,000 registrations of the TMD condition were performed in general dental clinics from 2011 to 2013. The mean prevalence of a TMD score of 1-3 was 5% and was consistent over these years. Seventy percent of these patients were women. The peak prevalence of TMD was registered in patients aged 30-45 years (38%), and the frequency declined in older age groups. Reduced voluntary mouth-opening capacity (≤35 mm) was found in less than 2% of the participants. About one-fifth of the patients with a TMD-score of 1-3 did not accept their condition and wanted professional care. The frequency of nonacceptance of the condition increased with the severity of symptom score: 15%, 27%, and 49% for scores 1, 2, and 3, respectively. This study shows that the prevalence of self-reported TMD in adult patients was consistent from 2011 to 2013 and should be considered as a public health issue in Sweden. Patients with more severe TMD pain symptoms wanted care more frequent. The annual clinical calibrations should be continued to achieve an acceptable level of registration.


Need for integration of gender equity in family planning services.
The family planning programme of India has shown many significant changes since its inception five decades back. The programme has made the contraceptives easily accessible and affordable to the people. Devices with very low failure rate are provided free of cost to those who need it. Despite these significant improvements in service delivery related to family planning the programme cannot be said to achieve success at all levels. There are many issues with the family planning services available through the public health facilities in India. Failure to adopt the latest technology is one of these. But the most serious drawback of the programme is that it has never been able to bridge the gap between the two genders related to contraceptives. The programme gave emphasis to women-centric contraceptive and thus women were seen as their clients. The choice to adopt a contraceptive though is 'cafeteria approach' in family planning lexicon; it is the choice of the husband that is ultimately practiced. There is not enough dialogue between husband and wife and husband and health worker to discuss the use of one contraceptive over another. The male gender needs to be taken in confidence while promoting the family planning practice. The integration of gender equity is to be done carefully so as not to make dominant gender more powerful. Only when there is equity between genders while using family planning services the programme will achieve success.


Reversible pinocytosis in polymorphonuclear leukocytes.
Since pinocytosis has only been recently recognized in polymorphonuclear leukocytes (PMNs), little is known about the fate of pinosomes. Here we report that pinosomes can fuse with the cytoplasmic granules of PMNs. We also find that at least for a short period of time after formation, pinosomes can fuse with the plasma membrane and release their contents to the outside. We present a morphological description and biochemical data on the kinetic parameters of a steady state pool of reversible pinosomes in PMNs. In addition, we have developed conditions under which pinosomes continue to form and fuse with the plasma membrane but fail to fuse with the cytoplasmic granules, i.e., only "reversible" pinocytosis occurs. This inhibition of fusion with the granules is not due to an inability of the pinosomes to move from the surface since under these conditions pinosomes labeled with an electron-dense marker can be seen in the cell interior.


Physical-geometric optics method for large size faceted particles.
A new physical-geometric optics method is developed to compute the single-scattering properties of faceted particles. It incorporates a general absorption vector to accurately account for inhomogeneous wave effects, and subsequently yields the relevant analytical formulas effective and computationally efficient for absorptive scattering particles. A bundle of rays incident on a certain facet can be traced as a single beam. For a beam incident on multiple facets, a systematic beam-splitting technique based on computer graphics is used to split the original beam into several sub-beams so that each sub-beam is incident only on an individual facet. The new beam-splitting technique significantly reduces the computational burden. The present physical-geometric optics method can be generalized to arbitrary faceted particles with either convex or concave shapes and with a homogeneous or an inhomogeneous (e.g., a particle with a core) composition. The single-scattering properties of irregular convex homogeneous and inhomogeneous hexahedra are simulated and compared to their counterparts from two other methods including a numerically rigorous method.


Scar endometriosis in the abdominal wall: a predictable condition for experienced surgeons.
Endometriosis in surgical scars develops in 0.1% of those women who undergo Caesarean section or other obstetric surgery. Herein we analyse and discuss the clinico-pathological characteristics of 15 patients with scar endometriosis in the abdominal wall. Fifteen cases of scar endometriosis in the abdominal wall that were treated surgically in our department between 2003 and 2009 were examined retrospectively. Age, parity, complaint, medical or surgical history, pre/postoperative hormonotherapy, size of the mass, surgical procedure, follow-up and disease recurrence were analysed. This retrospective study included 15 patients presenting with 17 postoperative abdominal wall masses. The mean age of the patients was 32.1 +/- 6.0 years (range, 23-48). Eleven of the patients had a painful mass that became bigger before menstruation, two had palpable masses only, and two were hospitalised because of a mass with persistent pain. The locations of the masses were as follows: eight were close to the right side and three were close to the left side; two were in the middle of the Pfanenstiel incision and two were in trocar tracts. The patients' surgical histories included Caesarean section in thirteen, bilateral laparoscopic ovarian cyst excision in one, and laparoscopic appendectomy in one. If a patient presents with incision pain and a palpable mass after gynaecologic surgery, an incisional endometrioma should be considered. Surgical excision and hormone therapy are effective treatment approaches in these patients.


Effect of point mutations on Herbaspirillum seropedicae NifA activity.
NifA is the transcriptional activator of the nif genes in Proteobacteria. It is usually regulated by nitrogen and oxygen, allowing biological nitrogen fixation to occur under appropriate conditions. NifA proteins have a typical three-domain structure, including a regulatory N-terminal GAF domain, which is involved in control by fixed nitrogen and not strictly required for activity, a catalytic AAA+ central domain, which catalyzes open complex formation, and a C-terminal domain involved in DNA-binding. In Herbaspirillum seropedicae, a β-proteobacterium capable of colonizing Graminae of agricultural importance, NifA regulation by ammonium involves its N-terminal GAF domain and the signal transduction protein GlnK. When the GAF domain is removed, the protein can still activate nif genes transcription; however, ammonium regulation is lost. In this work, we generated eight constructs resulting in point mutations in H. seropedicae NifA and analyzed their effect on nifH transcription in Escherichia coli and H. seropedicae. Mutations K22V, T160E, M161V, L172R, and A215D resulted in inactive proteins. Mutations Q216I and S220I produced partially active proteins with activity control similar to wild-type NifA. However, mutation G25E, located in the GAF domain, resulted in an active protein that did not require GlnK for activity and was partially sensitive to ammonium. This suggested that G25E may affect the negative interaction between the N-terminal GAF domain and the catalytic central domain under high ammonium concentrations, thus rendering the protein constitutively active, or that G25E could lead to a conformational change comparable with that when GlnK interacts with the GAF domain.


Clinical utility of the erythrocyte sedimentation rate.
The erythrocyte sedimentation rate (ESR) determination is a commonly performed laboratory test with a time-honored role. However, the usefulness of this test has decreased as new methods of evaluating disease have been developed. The test remains helpful in the specific diagnosis of a few conditions, including temporal arteritis, polymyalgia rheumatica and, possibly, rheumatoid arthritis. It is useful in monitoring these conditions and may predict relapse in patients with Hodgkin's disease. Use of the ESR as a screening test to identify patients who have serious disease is not supported by the literature. Some studies suggest that the test may be useful as a "sickness index" in the elderly or as a screening tool for a few specific infections in certain settings. An extreme elevation of the ESR is strongly associated with serious underlying disease, most often infection, collagen vascular disease or metastatic malignancy. When an increased rate is encountered with no obvious clinical explanation, the physician should repeat the test after an appropriate interval rather than pursue an exhaustive search for occult disease.


Exosomes from β-Cells Promote Differentiation of Induced Pluripotent Stem Cells into Insulin-Producing Cells Through microRNA-Dependent Mechanisms.
Exosomes have emerged as potential tools for the differentiation of induced pluripotent stem cells (iPSCs) into insulin-producing cells (IPCs). Exosomal microRNAs are receiving increasing attention in this process. Here, we aimed at investigating the role of exosomes derived from a murine pancreatic β-cell line and identifying signature exosomal miRNAs on iPSCs differentiation. Exosomes were isolated from MIN6 cells and identified with TEM, NTA and Western blot. PKH67 tracer and transwell assay were used to confirm exosome delivery into iPSCs. qRT-PCR was applied to detect key pancreatic transcription gene expression and exosome-derived miRNA expression. Insulin secretion was determined using FCM and immunofluorescence. The specific exosomal miRNAs were determined via RNA-interference of Ago2. The therapeutic effect of 21 day-exosome-induced IPCs was validated in T1D mice induced by STZ. iPSCs cultured in medium containing exosomes showed sustained higher expression of MAFA, Insulin1, Insulin2, Isl1, Neuroud1, Nkx6.1 and NGN3 compared to control iPSCs. In FCM analysis, approximately 52.7% of the differentiated cells displayed insulin expression at the middle stage. Consistent with the gene expression data, immunofluorescence assays showed that Nkx6.1 and insulin expression in iPSCs were significantly upregulated. Intriguingly, the expression of pancreatic markers and insulin was significantly decreased in iPSCs cultured with siAgo2 exosomes. Transplantation of 21 day-induced IPCs intoT1D mice efficiently enhanced glucose tolerance and partially controlled hyperglycemia. The therapeutic effect was significantly attenuated in T1D mice that received iPSCs cultured with siAgo2 exosomes. Of the seven exosomal microRNAs selected for validation, miR-706, miR-709, miR-466c-5p, and miR-423-5p showed dynamic expression during 21 days in culture. These data indicate that differentiation of exosome-induced iPSCs into functional cells is crucially dependent on the specific miRNAs encased within exosomes, whose functional analysis is likely to provide insight into novel regulatory mechanisms governing iPSCs differentiation into IPCs.


Increased risk of falls and fractures in patients with psychosis and Parkinson disease.
Evaluate whether the risk of falls and fractures differs between patients with Parkinson disease with psychosis (PDP) and patients with Parkinson disease (PD) without psychosis at similar disease stages. Patients with PD without psychosis were identified in the Medicare claims databases (2008-2018) and followed from the first PD diagnosis date during the study period. Patients with a subsequent diagnosis of psychosis were included in the PDP group. Patients with PDP and PD without psychosis were propensity score-matched based on characteristics within blocks of time since cohort entry. The incidence rates (IRs), expressed per 100 person-years, and 95% confidence intervals (CIs) of falls and fractures were evaluated as composite and separate outcomes. Incidence rate ratios (IRRs) were used to compare patients with PDP and PD without psychosis in the matched cohort. 154,306 patients had PD without psychosis and no falls or fractures before cohort entry; the IR for falls and fractures was 11.41 events (95% CI, 11.29-11.53). 12,127 patients (7.8%) had a subsequent PDP diagnosis. PDP patients had a higher prevalence of most comorbidities and risk factors for falls and fractures than those without psychosis. The crude IR for falls and fractures among PDP patients was 29.03 events (95% CI, 28.27-29.81). PD without psychosis and PDP groups had more falls than fractures. After matching, 24,144 PD patients without psychosis (15.6%) and 12,077 PDP patients (99.6%) were retained. Matched PDP patients had a higher incidence of falls and fractures than PD patients without psychosis (IRR = 1.44; 95% CI, 1.39-1.49). The higher increased rate was noted separately for falls (IRR = 1.48; 95% CI, 1.43-1.54) and any fractures (IRR = 1.17; 95% CI, 1.08-1.27) as well as within specific types of fracture, including pelvis and hip fractures. Our findings suggest a modest but consistently higher increased risk of falls and fractures in PDP patients compared with PD patients without psychosis.


[Study on geographic characteristics of malignant tumors in digestive system in Shanxi province].
The mortality of esophageal, stomach and hepatic cancers occupied 70% among all who died from cancers in Shanxi province. Countries which had the highest mortality of the above three kinds of cancers showed significant aggregation. Differences between countries with higher and lower mortality were obvious. The annual mean temperature and rainfall decreased with the raise of latitude in Shanxi province. So was found the mortality of these cancers. Both of them tended to be coincident, and the difference was statistically significant (P < 0.05). These results were not in agreement with reports from foreign countries which need to be further studied.


Actin filaments undergo limited subunit exchange in physiological salt conditions.
The exchange of actin filament subunits for unpolymerized actin or for subunits in other filaments has been quantitated by three experimental techniques: fluorescence energy transfer, incorporation of 35S-labeled actin monomers into unlabeled actin filaments, and exchange of [14C]ATP with filament-bound ADP. In the fluorescence energy transfer experiments, actin labeled with 5-(iodoacetamidoethyl)aminonaphthalene-1-sulfonic acid (IAENS) served as the fluorescent energy donor, and actin labeled with either fluorescein-5-isothiocyanate (FITC) or fluorescein-5-maleimide (FM) served as the energy acceptor. Fluorescent-labeled actins from Dictyostelium amoebae and rabbit skeletal muscle were very similar to their unlabeled counterparts with respect to critical actin concentration for filament assembly, assembly rate, ATP hydrolysis upon assembly, and steady-state ATPase. As evidenced by two different types of fluorescence energy transfer experiments, less than 5% of the actin filament subunits exchanged under a variety of buffer conditions at actin concentrations greater than 0.5 mg/ml. At all actin concentrations limited exchange to a plateau level occurred with a half-time of about 20 min. Nearly identical results were obtained when exchange was quantitated by incorporation of 35S-labeled Dictyostelium actin monomers into unlabeled muscle actin or Dictyostelium actin filaments. Furthermore, the proportion of filament-bound ADP which exchanged with [14C]-ATP was nearly the same as actin subunit exchange measured by fluorescence energy transfer and 35S-labeled actin incorporation. These experiments demonstrate that under approximately physiologic ionic conditions only a small percentage of subunits in highly purified skeletal muscle or Dictyostelium F-actin participate in exchange.


Efficacy of new antiepileptic drugs.
Regarding efficacy of new antiepileptic drugs (AEDs) for seizure control, there are three important clinical questions. How effective are new AEDs when corrected for the efficacy of placebo? And even more important: How do new AEDs fare in terms of seizure remission compared with established agents? And finally: Have patients seizure-free on new AEDs a better chance for lasting remission after withdrawal versus those withdrawing from older agents? The answers raise concerns. Although add-on therapy with marketed new AEDs is more effective than placebo, as expected, the treatment difference for becoming seizure-free is disappointingly small (6%; 95% CI: 4-8%; z = 6.47; p < 0.001). Although many, but not all, new AEDs have comparable efficacy to old standard drugs in well-controlled trials, none of the new AEDs is superior to old drugs in terms of seizure remission. So far, we have no antiepileptogenic treatments that prevent the development of epilepsy or modify its detrimental course. The sobering results suggest the need for novel experimental and clinical strategies for the development of more effective new AEDs that interrupt ictogenesis more effectively and prevent or abort epileptogenesis. Ideally, we need new drugs that block both ictogenesis and epileptogenesis, resulting in complete cure of epilepsy.


Contractile proteins (actin, myosin) and tubulin are revealed within DNA-containing nucleocytoplasm in mature spermatozoa of Libinia emarginata L.
The localization of DNA and the distribution of the cytoskeletal proteins actin, myosin and tubulin in spermatozoa of Libinia emarginata L. were the aims of this study. DAPI, a highly reactive DNA-binding agent, revealed fluorescent staining within nucleocytoplasmic compartments around the acrosome and in the radial processes extending from the central region of the spermatozoa. The sites of DAPI-DNA staining corresponded to the position of the branched chromatin fibers revealed by electron microscopy. Antisera to myosin, actin, and tubulin revealed staining at different nucleocytoplasmic sites and in radial processes of the spermatozoa. Myosin was present at the base of each of three radial extensions, whereas actin appeared throughout the nucleocytoplasmic compartment and in the radial extensions. Actin fluorescence corresponded to the 6 nm thick filaments visualized by electron microscopy forming the core of the radial processes. Although tubulin was observed throughout the cell and within radial processes by immunofluorescence staining, intact microtubules were not revealed by electron microscopy. However, SDS PAGE comparisons between Libinia sperm extracts and dogfish brain showed small amounts of protein that comigrate with alpha and beta tubulin. These results demonstrate the existence of contractile proteins (myosin, actin) and tubulin within the DNA-containing nucleocytoplasmic compartments of Libinia sperm.


Promoting health in the construction industry?
The construction industry has long been regarded as a high-risk industry in relation to health and safety issues. The purpose of this research was to investigate the extent of occupational health and safety provision within the residential development sector of the construction industry in Britain. An additional aim was to gauge the sectors' attitudes toward health promotion. Data were collected using a self-completed questionnaire that was sent to 200 residential developers; a 46% response rate was achieved. The results revealed a high level of knowledge of health and safety legislation; occupational health provision in the sector is low, but a strong appreciation was demonstrated of the value of such services. There was a low level of health promotion policy development in relation to the areas of alcohol, smoking, and skin cancer.


Automated multi-parameter measurement of cardiomyocytes dynamics with digital holographic microscopy.
Compounds tested during drug development may have adverse effects on the heart; therefore all new chemical entities have to undergo extensive preclinical assessment for cardiac liability. Conventional intensity-based imaging techniques are not robust enough to provide detailed information for cell structure and the captured images result in low-contrast, especially to cell with semi-transparent or transparent feature, which would affect the cell analysis. In this paper we show, for the first time, that digital holographic microscopy (DHM) integrated with information processing algorithms automatically provide dynamic quantitative phase profiles of beating cardiomyocytes. We experimentally demonstrate that relevant parameters of cardiomyocytes can be obtained by our automated algorithm based on DHM phase signal analysis and used to characterize the physiological state of resting cardiomyocytes. Our study opens the possibility of automated quantitative analysis of cardiomyocyte dynamics suitable for further drug safety testing and compounds selection as a new paradigm in drug toxicity screens.


Genetic and antigenic characterization of influenza A/H5N1 viruses isolated from patients in Indonesia, 2008-2015.
Since the initial detection in 2003, Indonesia has reported 200 human cases of highly pathogenic avian influenza H5N1 (HPAI H5N1), associated with an exceptionally high case fatality rate (84%) compared to other geographical regions affected by other genetic clades of the virus. However, there is limited information on the genetic diversity of HPAI H5N1 viruses, especially those isolated from humans in Indonesia. In this study, the genetic and antigenic characteristics of 35 HPAI H5N1 viruses isolated from humans were analyzed. Full genome sequences were analyzed for the presence of substitutions in the receptor binding site, and polymerase complex, as markers for virulence or human adaptation, as well as antiviral drug resistance substitutions. Only a few substitutions associated with human adaptation were observed, a remarkably low prevalence of the human adaptive substitution PB2-E627K, which is common during human infection with other H5N1 clades and a known virulence marker for avian influenza viruses during human infections. In addition, the antigenic profile of these Indonesian HPAI H5N1 viruses was determined using serological analysis and antigenic cartography. Antigenic characterization showed two distinct antigenic clusters, as observed previously for avian isolates. These two antigenic clusters were not clearly associated with time of virus isolation. This study provides better insight in genetic diversity of H5N1 viruses during human infection and the presence of human adaptive markers. These findings highlight the importance of evaluating virus genetics for HPAI H5N1 viruses to estimate the risk to human health and the need for increased efforts to monitor the evolution of H5N1 viruses across Indonesia.


Male Circumcision Reduces Penile HPV Incidence and Persistence: A Randomized Controlled Trial in Kenya.
Male circumcision reduces the risk of human immunodeficiency virus infection in men. We assessed the effect of male circumcision on the incidence and natural history of human papillomavirus (HPV) in a randomized clinical trial in Kisumu, Kenya. Sexually active, 18- to 24-year-old men provided penile exfoliated cells for HPV DNA testing every 6 months for 2 years. HPV DNA was detected via GP5+/6+ PCR in glans/coronal sulcus and in shaft samples. HPV incidence and persistence were assessed by intent-to-treat analyses. A total of 2,193 men participated (1,096 randomized to circumcision; 1,097 controls). HPV prevalence was 50% at baseline for both groups and dropped to 23.7% at 24 months in the circumcision group, and 41.0% in control group. Incident infection of any HPV type over 24 months was lower among men in the circumcision group than in the control group [HR = 0.61; 95% confidence interval (CI), 0.52-0.72]. Clearance rate of any HPV infection over 24 months was higher in the circumcision group than in the control group (HR = 1.87; 95% CI, 1.49-2.34). Lower HPV point-prevalence, lower HPV incidence, and higher HPV clearance in the circumcision group were observed in glans but not in shaft samples. Male circumcision reduced the risk of HPV acquisition and reinfection, and increased HPV clearance in the glans. Providing voluntary, safe, and affordable male circumcision should help reduce HPV infections in men, and consequently, HPV-associated disease in their partners.


Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X.
Approximately 60% of families that meet the Amsterdam-I criteria (AC-I) for hereditary nonpolyposis colorectal cancer (HNPCC) have a hereditary abnormality in a DNA mismatch repair (MMR) gene. Cancer incidence in AC-I families with MMR gene mutations is reported to be very high, but cancer incidence for individuals in AC-I families with no evidence of an MMR defect is unknown. To determine if cancer risks in AC-I families with no apparent deficiency in DNA MMR are different from cancer risks in AC-I families with DNA MMR abnormalities. Identification (1997-2001) of 161 AC-I pedigrees from multiple population- and clinic-based sources in North America and Germany, with families grouped into those with (group A) or without (group B) MMR deficiency by tumor testing. A total of 3422 relatives were included in the analyses. Cancer incidence in groups A and B (excluding the 3 affected members used to define each pedigree as AC-I) and computed age- and sex-adjusted standardized incidence ratios (SIRs) using Surveillance, Epidemiology, and End Results data. Group A families from both population- and clinic-based series showed increased incidence of the HNPCC-related cancers. Group B families showed increased incidence only for colorectal cancer (SIR, 2.3; 95% confidence interval, 1.7-3.0) and to a lesser extent than group A (SIR, 6.1; 95% confidence interval, 5.2-7.2) (P<.001). Families who fulfill AC-I criteria but who have no evidence of a DNA MMR defect do not share the same cancer incidence as families with HNPCC-Lynch syndrome (ie, hereditary MMR deficiency). Relatives in such families have a lower incidence of colorectal cancer than those in families with HNPCC-Lynch syndrome, and incidence may not be increased for other cancers. These families should not be described or counseled as having HNPCC-Lynch syndrome. To facilitate distinguishing these entities, the designation of "familial colorectal cancer type X" is suggested to describe this type of familial aggregation of colorectal cancer.


Erectile Dysfunction Among Men Attending Surgical Outpatients Department in a Tertiary Hospital in South-Western Nigeria.
Erectile dysfunction is becoming a public health issue with high incidences reported in community studies. To evaluate the characteristics and outcome of treatment in men with erectile dysfunction in a tertiary center in Ibadan southwestern Nigeria. Data of men with erectile dysfunction was retrieved between July 2004 and June 2014 and analyzed using SPSS version 16 statistical software. Eighty-nine men with erectile dysfunction were managed which constituted 2% of all urological cases seen during the study period. Their median and mean ages were 39 years and 39.6 ± 1.2SD (range 19-76 years). The peak age incidence at 30-44 years was 41.6% and reduced with increasing age after 65 years to 4.5%. The etiologies were psychogenic in 55%, organic in 27%, idiopathic in 17% and 1% was familial. 67.5%, 31.5% and 3.4% were married, single and separated respectively. Seventy percent neither smoked cigarette nor drank alcohol, 21.3% drank alcohol and 9% took both alcohol and smoked cigarette. Seventy seven and half percent of men presented within 5 years of their symptom. The treatments offered were PDE type 5 inhibitors alone or in combination with psychotherapy or modification of medications. The outcome of these treatments ranged from 89% to 91% success rate. The number of men with erectile dysfunction managed in the tertiary hospital is very low though the outcome of treatment is within acceptable range. Increase public enlightenment may encourage increase hospital patronage and access to the available treatments for erectile dysfunction.


[Malaria in Azerbaijan].
Rapid deterioration of the malaria situation set in after 1990, when 22 cases were reported. The number increased to 667 in 1994, 2840 in 1995 and reached 13,135 in 1996. The main reason for the deterioration was a sharp worsening of socioeconomic conditions and the displacement of nearly one million people from war-stricken zones. With international assistance from WHO, ENI (Italy), MSF (Belgium), the Ministry of Health resumed limited malaria control activities: in 1997, 9911 cases were officially reported and 5175 cases in 1998. Approximately half of malaria cases were reported from seven districts: Nachishivan (10.4%), Imishli (14.6%), Fizuli (8.1%), Sabirabad (6.8%), Saatly (6%), Bejlagan (5.6%) and Bilasuvar (4.8%). 1737 malaria cases were detected during 7 months of 1999, 4007 cases were reported during 7 months of 1998.


Smoking and periodontal microorganisms.
Resolution of dysbiosis following treatment for periodontal disease and tobacco dependence has been reported in longitudinal intervention studies. In the present report, we evaluated the biological findings regarding the effect of smoking on the periodontal microbiome. A standardized electronic search was conducted using MEDLINE; overall, 1099 papers were extracted. Studies that addressed the relationship between tobacco and periodontal pathogens were included. Finally, 42 papers were deemed appropriate for the present review. Functional changes in periodontal pathogens exposed to nicotine and cigarette smoke extract support the clinical findings regarding dysbiosis of the subgingival microbiome. Dysbiosis of the periodontal microbiome was presented in smokers regardless of their periodontal condition (healthy, gingivitis, or periodontitis) and remained significant only in smokers even after the resolution of experimentally-induced gingivitis and following reduction of clinical signs of periodontitis with non-surgical periodontal treatment and over 3 months post-therapy. Based on these findings, smoking cessation in periodontitis patients is beneficial for promoting a health-compatible subgingival microbial community. To maximize the benefits of these interventions in dental settings, further studies on periodontal microbiome are needed to elucidate the impact of tobacco intervention on preventing recurrence of periodontal destruction in the susceptible subjects.


Independent intrachromosomal recombination events underlie the pericentric inversions of chimpanzee and gorilla chromosomes homologous to human chromosome 16.
Analyses of chromosomal rearrangements that have occurred during the evolution of the hominoids can reveal much about the mutational mechanisms underlying primate chromosome evolution. We characterized the breakpoints of the pericentric inversion of chimpanzee chromosome 18 (PTR XVI), which is homologous to human chromosome 16 (HSA 16). A conserved 23-kb inverted repeat composed of satellites, LINE and Alu elements was identified near the breakpoints and could have mediated the inversion by bringing the chromosomal arms into close proximity with each other, thereby facilitating intrachromosomal recombination. The exact positions of the breakpoints may then have been determined by local DNA sequence homologies between the inversion breakpoints, including a 22-base pair direct repeat. The similarly located pericentric inversion of gorilla (GGO) chromosome XVI, was studied by FISH and PCR analysis. The p- and q-arm breakpoints of the inversions in PTR XVI and GGO XVI were found to occur at slightly different locations, consistent with their independent origin. Further, FISH studies of the homologous chromosomal regions in macaque and orangutan revealed that the region represented by HSA BAC RP11-696P19, which spans the inversion breakpoint on HSA 16q11-12, was derived from the ancestral primate chromosome homologous to HSA 1. After the divergence of orangutan from the other great apes approximately 12 million years ago (Mya), a duplication of the corresponding region occurred followed by its interchromosomal transposition to the ancestral chromosome 16q. Thus, the most parsimonious interpretation is that the gorilla and chimpanzee homologs exhibit similar but nonidentical derived pericentric inversions, whereas HSA 16 represents the ancestral form among hominoids.


Mithramycin is a gene-selective Sp1 inhibitor that identifies a biological intersection between cancer and neurodegeneration.
Oncogenic transformation of postmitotic neurons triggers cell death, but the identity of genes critical for degeneration remain unclear. The antitumor antibiotic mithramycin prolongs survival of mouse models of Huntington's disease in vivo and inhibits oxidative stress-induced death in cortical neurons in vitro. We had correlated protection by mithramycin with its ability to bind to GC-rich DNA and globally displace Sp1 family transcription factors. To understand how antitumor drugs prevent neurodegeneration, here we use structure-activity relationships of mithramycin analogs to discover that selective DNA-binding inhibition of the drug is necessary for its neuroprotective effect. We identify several genes (Myc, c-Src, Hif1α, and p21(waf1/cip1)) involved in neoplastic transformation, whose altered expression correlates with protective doses of mithramycin or its analogs. Most interestingly, inhibition of one these genes, Myc, is neuroprotective, whereas forced expression of Myc induces Rattus norvegicus neuronal cell death. These results support a model in which cancer cell transformation shares key genetic components with neurodegeneration.


[Method of the tissue expanding in surgical treatment of the upper extremity deformity].
Results of surgical treatment of 14 patients suffering the segments deformity and the joints contracture of the upper extremity, using the tissue expanding method, were analyzed. The latex expanders as well as those, made according to own model were applied for the dermotension commitment. The peculiarities and modes of operation of the upper extremity tissues expanding were determined. Application of the tissues balloon expanding method during elimination of the upper extremities deformity and the joints contracture had permitted to achieve in immediate period the positive functional and cosmetic results in 83% of observations. In the late period good results were noted in 75% of patients and satisfactory--in 25%.


Palliative Care in Heart Failure: An Integrative Review of Nurse Practice.
Introduction: Because it is a chronic disease of progressive evolution, heart failure requires nursing attitudes and practices that are articulated with palliative care, implemented in an interdisciplinary team along with patients and their families. Objective: Identifying nurses' attitudes and practices in palliative care in cardiology. Method: Integrative literature review. The searches were carried out in the following bases: Google Scholar, Virtual Health Library, LILACS, SciELO, Embase, MEDLINE, CINAHL, and Scopus; through the terms Palliative Care AND Cardiology AND Nursing. Results: We identified 1298 studies published in the last five years, 14 of which have been selected for the scope of this review. Nurse attitudes and practices were characterized as: approach to symptom control; promotion of comfort and well-being; integrality of care and family orientation; effective communication among patients, family members and nursing team; timely evaluation for palliative care. Most of the studies included in this review have evidence level 2C (n = 7) and 2B (n = 4). Therefore, the results can be interpreted as reliable. Conclusions: This study makes important contributions to the practice of nurses in palliative care for heart failure. Based on the evidence collected, nurses can develop actions with the nursing team and with the interdisciplinary team related to direct patient and family care, as well as professional training. However, the field lacks studies showing the practices and actions implemented by the nursing team.


Efficient protein production inspired by how spiders make silk.
Membrane proteins are targets of most available pharmaceuticals, but they are difficult to produce recombinantly, like many other aggregation-prone proteins. Spiders can produce silk proteins at huge concentrations by sequestering their aggregation-prone regions in micellar structures, where the very soluble N-terminal domain (NT) forms the shell. We hypothesize that fusion to NT could similarly solubilize non-spidroin proteins, and design a charge-reversed mutant (NT*) that is pH insensitive, stabilized and hypersoluble compared to wild-type NT. NT*-transmembrane protein fusions yield up to eight times more of soluble protein in Escherichia coli than fusions with several conventional tags. NT* enables transmembrane peptide purification to homogeneity without chromatography and manufacture of low-cost synthetic lung surfactant that works in an animal model of respiratory disease. NT* also allows efficient expression and purification of non-transmembrane proteins, which are otherwise refractory to recombinant production, and offers a new tool for reluctant proteins in general.


Sports specialization in young athletes: evidence-based recommendations.
Sports specialization is intense training in 1 sport while excluding others. Sports specialization in early to middle childhood has become increasingly common. While most experts agree that some degree of sports specialization is necessary to achieve elite levels, there is some debate as to whether such intense practice time must begin during early childhood and to the exclusion of other sports to maximize potential for success. There is a concern that sports specialization before adolescence may be deleterious to a young athlete. PubMed and OVID were searched for English-language articles from 1990 to 2011 discussing sports specialization, expert athletes, or elite versus novice athletes, including original research articles, consensus opinions, and position statements. For most sports, there is no evidence that intense training and specialization before puberty are necessary to achieve elite status. Risks of early sports specialization include higher rates of injury, increased psychological stress, and quitting sports at a young age. Sports specialization occurs along a continuum. Survey tools are being developed to identify where athletes fall along the spectrum of specialization. Some degree of sports specialization is necessary to develop elite-level skill development. However, for most sports, such intense training in a single sport to the exclusion of others should be delayed until late adolescence to optimize success while minimizing injury, psychological stress, and burnout.


Use of viber app: a fast, easy and cost effective method of communication in neurosurgery.
Neurosurgeons often have to rely on judgments of junior staffs to decide on patients whom they cannot attend immediately. Viber is a free to use application for image transfer on Internet. We evaluated the use of viber in neurosurgical scenario, to show it is cheap, fast, accessible, reliable and feasible. We conducted a prospective study from March 2013 to July 2013. Residents were taught to take sharp pictures and upload them immediately using viber on Internet. Primary endpoints were discordance between opinion of residents and consultants on viber images and subsequent actual image evaluation and time delay in decision-making. Discordance was considered significant if it changed management decision. During the study period, 120 (mean age: 42 years, 58% males) patients were enrolled. Wi-Fi is freely available in the institute and thus no costs were involved. Decision could be made on images received on viber at an average of 20 min. There was discordance in 56.7% cases between residents' reports and images on viber, which was significant in 88.2% cases. However in 5% cases decision changed after actual images were reviewed. Of all imaging modalities, computed tomography angiographic images were associated with statistically significant discordance (P <0.05). This study suggests that the use of viber app in neurosurgery can be an easy fast reliable and almost free mode of communicating images enabling a quick decision. However this cost-effective method should be used with caution particularly with imaging modalities, which require processing and review on console.


Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei.
Here we report the cloning, expression, and characterization of a cAMP-specific phosphodiesterase (PDE) from Trypanosoma brucei (TbPDE2B). Using a bioinformatic approach, two different expressed sequence tag clones were identified and used to isolate the complete sequence of two identical PDE genes arranged in tandem. Each gene consists of 2,793 bases that predict a protein of 930 aa with a molecular mass of 103.2 kDa. Two GAF (for cGMP binding and stimulated PDEs, Anabaena adenylyl cyclases, and Escherichia coli FhlA) domains, similar to those contained in many signaling molecules including mammalian PDE2, PDE5, PDE6, PDE10, and PDE11, were located N-terminal to a consensus PDE catalytic domain. The catalytic domain is homologous to the catalytic domain of all 11 mammalian PDEs, the Dictyostelium discoideum RegA, and a probable PDE from Caenorhabditis elegans. It is most similar to the T. brucei PDE2A (89% identity). TbPDE2B has substrate specificity for cAMP with a K(m) of 2.4 microM. cGMP is not hydrolyzed by TbPDE2B nor does this cyclic nucleotide modulate cAMP PDE activity. The nonselective PDE inhibitors 3-isobutyl-1-methylxanthine, papaverine and pentoxifyline are poor inhibitors of TbPDE2B. Similarly, PDE inhibitors selective for the mammalian PDE families 2, 3, 5, and 6 (erythro-9-[3-(2-hydroxynonyl)]-adenine, enoximone, zaprinast, and sildenafil) were also unable to inhibit this enzyme. However, dipyridamole was a reasonably good inhibitor of this enzyme with an IC50 of 27 microM. cAMP plays key roles in cell growth and differentiation in this parasite, and PDEs are responsible for the hydrolysis of this important second messenger. Therefore, parasite PDEs, including this one, have the potential to be attractive targets for selective drug design.


Rockets, radiosensitizers, and RRx-001: an origin story part I.
From Adam and Eve, to Darwinism, origin stories attempt to fill in the blanks, connect the dots, and define the turning points that are fundamental to subsequent developments. The purpose of this review is to present the origin story of a one-of-a-kind anticancer agent, RRx-001, which emerged from the aerospace industry as a putative radiosensitizer; not since the dynamite-to-dilator transformation of nitroglycerin in 1878 or the post-World War II explosive-to-elixir conversion of hydralazine, an ingredient in rocket fuel, to an antihypertensive, an antidepressant and an antituberculant, has energetic chemistry been harnessed for therapeutic purposes. This is Part 1 of the radiosensitization story; Parts 2 and 3, which detail the crossover activity of RRx-001 as a chemosensitizer in multiple tumor types and disease states including malaria, hemorrhagic shock and sickle cell anemia, are the subject of future reviews.


[Differences of wheat yield and economic benefits between soybean-wheat and rice-wheat cropping under different nitrogen fertilization patterns in Jianghan Plain, China].
We analyzed winter wheat yield and growth pattern of soybean-wheat and rice-wheat rotation systems in response to different nitrogen fertilization patterns with the aim to provide theoretical basis for narrowing the wheat yield gap between the two rotations in Jianghan Plain. Field experiments were conducted with three treatments, control without nitrogen, traditional nitrogen management (70% nitrogen as basal and 30% nitrogen as topdressing at overwintering), and improved nitrogen management (one third of N was applied at sowing, wintering and jointing, respectively). The growth pattern, grain yield, yield components, fertilizer use-efficiency and economic benefit under the different nitrogen fertilization patterns were examined. Results showed that grain yield was significantly affected by both nitrogen fertilization pattern and crop rotation. Grain yield under improved nitrogen treatment was significantly higher, with the yield gap being 920 kg·hm-2 in soybean-wheat rotation and 2195 kg·hm-2 in rice-wheat rotation. Traditional nitrogen management showed advantage in establishing winter and spring population. Dry matter accumulation was higher under improved nitrogen treatment than traditional treatment with 5%-31% and 14%-28% increases for soybean-wheat and rice-wheat rotations, respectively. The higher yield in the soybean-wheat rotation was due to greater panicle numbers, higher percentage of tiller ears, and dry matter accumulation. The rice-wheat rotation under improved nitrogen showed a significant increase in grain yield compared with soybean-wheat rotation. This result indicated that yield gap between the two crop rotations could be narrowed through suitable nitrogen management. Grain weight after anthesis showed "slow-fast-medium" in soybean-wheat rotation and "medium-fast-slow" in rice-wheat rotation. Nitrogen use efficiency and net benefit of wheat season were higher in rice-wheat system. Overall, the rice-wheat system showed obvious advantages in population structure, dry matter accumulation, grain yield and benefit under improved nitrogen pattern, which was the optimum pattern for both wheat yield and benefit in Jianghan Plain.


Treatment of type II, IIIA, and IIIB open fractures of the tibial shaft: a prospective comparison of unreamed interlocking intramedullary nails and half-pin external fixators.
To compare unreamed intramedullary nailing (IMN) with external fixation (EF) in patients with Type II, IIIA, and IIIB open fractures of the tibial shaft. An inception cohort of consecutive patients with Type II, IIIA, and IIIB tibial fractures incurred between January 1988 and March 1993 were systematically allocated into one of two treatment groups. Patients were treated and followed with a prospectively designed protocol. All patients were skeletally mature and had incurred a fracture of the tibial diaphysis within twenty-four hours of presentation to the tertiary care hospital, a Level I Trauma Center. One hundred seventy-four fractures in 168 patients were stabilized with either IMN (104) or half-pin EF (70). There were 132 men and thirty-six women, with an average age of thirty-three years (range, 14 to 77 years). Except for the selection of the fixation device, open fracture care was similar in the two treatment groups. All patients underwent emergent irrigation and debridement with concomitant skeletal stabilization. Cephalosporin antibiotics were administered perioperatively for twenty-four to forty-eight hours. No wounds were closed primarily. Delayed primary closure, skin grafting, and/or myoplasty were performed between three and ten days after injury. The main outcome measures were final fracture alignment, presence of infection or inflammation, hardware failure, time to union, and the number of operative procedures. The IMN group had significantly fewer incidences of malalignment than did the EF group [8 vs. 31 percent; p = 0.00005; confidence interval (CI) = 0.18, 0.76] and had significantly fewer subsequent procedures (mean of 1.7 vs. mean of 2.7 per fracture; p = 0.001; CI = 0.45, 1.59). IMN resulted in fewer infections/ inflammatory problems than did EF at the injury site (13 vs. 21 percent; p = 0.73; CI = -0.63, 0.45) and significantly fewer at surgical interfaces (i.e., pin sites, nail and interlocking screw insertion sites; 2 vs. 50 percent; p = 0.000; CI = 0.39, 0.60). No significant difference was found in the healing rates for the two implant groups. The more severe Gustilo injury types had longer healing times regardless of the type of fixation. Results suggest that unreamed interlocking intramedullary nails are more efficacious than half-pin external fixators, in particular with regard to maintenance of limb alignment. However, the severity of soft tissue injury rather than the choice of implant appears to be the predominant factor influencing rapidity of bone healing and rate of injury site infection.


Analysis of Sir2p domains required for rDNA and telomeric silencing in Saccharomyces cerevisiae.
Silent information regulator (Sir) 2 is a limiting component of the Sir2/3/4 complex, which represses transcription at subtelomeric and HM loci. Sir2p also acts independently of Sir3p and Sir4p to influence chromatin organization in the rDNA locus. Deleted and mutated forms of Sir2p have been tested for their ability to complement and/or to disrupt silencing. The highly conserved C-terminal domain of Sir2p (aa 199-562) is insufficient to restore repression at either telomeric or rDNA reporters in a sir2Delta background and fails to nucleate silencing when targeted to an appropriate reporter gene. However, its expression in an otherwise wild-type strain disrupts telomeric repression. Similarly, a point mutation (P394L) within this conserved core inactivates the full-length protein but renders it dominant negative for all types of silencing. Deletion of aa 1-198 from Sir2(394L) eliminates its dominant negative effect. Thus we define two distinct functional domains in Sir2p, both essential for telomeric and rDNA repression: the conserved core domain found within aa 199-562 and a second domain that encompasses aa 94-198. Immunolocalization and two-hybrid studies show that aa 94-198 are required for the binding of Sir2p to Sir4p and for the targeting of Sir2p to the nucleolus through another ligand. The globular core domain provides an essential silencing function distinct from that of targeting or Sir complex formation that may reflect its reported mono-ADP-ribosyl transferase activity.


Uncovering the molecular machinery of the human spindle--an integration of wet and dry systems biology.
The mitotic spindle is an essential molecular machine involved in cell division, whose composition has been studied extensively by detailed cellular biology, high-throughput proteomics, and RNA interference experiments. However, because of its dynamic organization and complex regulation it is difficult to obtain a complete description of its molecular composition. We have implemented an integrated computational approach to characterize novel human spindle components and have analysed in detail the individual candidates predicted to be spindle proteins, as well as the network of predicted relations connecting known and putative spindle proteins. The subsequent experimental validation of a number of predicted novel proteins confirmed not only their association with the spindle apparatus but also their role in mitosis. We found that 75% of our tested proteins are localizing to the spindle apparatus compared to a success rate of 35% when expert knowledge alone was used. We compare our results to the previously published MitoCheck study and see that our approach does validate some findings by this consortium. Further, we predict so-called "hidden spindle hub", proteins whose network of interactions is still poorly characterised by experimental means and which are thought to influence the functionality of the mitotic spindle on a large scale. Our analyses suggest that we are still far from knowing the complete repertoire of functionally important components of the human spindle network. Combining integrated bio-computational approaches and single gene experimental follow-ups could be key to exploring the still hidden regions of the human spindle system.


The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival.
The Tec kinases Itk and Rlk are required for efficient positive selection of conventional CD4+ and CD8+ T cells in the thymus. In contrast, recent studies have shown that these Tec kinases are dispensable for the development of CD8+ T cells with characteristics of innate T cells. These findings raise questions about the potential role of Itk and Rlk in NKT cell development, because NKT cells represent a subset of innate T cells. To address this issue, we examined invariant NKT cells in Itk-/- and Itk/Rlk-/- mice. We find, as has been reported previously, that Itk-/- mice have reduced numbers of NKT cells with a predominantly immature phenotype. We further show that this defect is greatly exacerbated in the absence of both Itk and Rlk, leading to a 7-fold reduction in invariant NKT cell numbers in the thymus of Itk/Rlk-/- mice and a more severe block in NKT cell maturation. Splenic Itk-/- and Itk/Rlk-/- NKT cells are also functionally defective, because they produce little to no cytokine following in vivo activation. Tec kinase-deficient NKT cells also show enhanced cell death in the spleen. These defects correlate with greatly diminished expression of CD122, the IL-2R/IL-15R beta-chain, and impaired expression of the T-box transcription factor, T-bet. These data indicate that the Tec kinases Itk and Rlk provide important signals for terminal maturation, efficient cytokine production, and peripheral survival of NKT cells.


Sleep problems in pediatric epilepsy and ADHD: The impact of comorbidity.
Attention-deficit hyperactivity disorder (ADHD) is a frequent comorbidity in pediatric epilepsy. Although sleep problems are commonly reported in both children with primary ADHD and epilepsy, those with epilepsy-ADHD comorbidity have not been well studied. This study aimed to compare sleep problems among three groups of children: 1) children with epilepsy, 2) children with epilepsy and ADHD (epilepsy-ADHD), and 3) children with primary ADHD. 53 children with epilepsy, 35 children with epilepsy-ADHD, and 52 children with primary ADHD completed the Children's Sleep Habits Questionnaire (CSHQ). Neurology clinic charts were reviewed for the epilepsy-related variables. ADHD subtypes were diagnosed according to the DSM-IV. Children with epilepsy-ADHD had the highest CSHQ total scores, while children with primary ADHD had higher scores than those with epilepsy. Besides the total score, epilepsy-ADHD group differed from the primary ADHD and epilepsy groups with higher CSHQ subscores on sleep onset delay and sleep anxiety. The frequency of moderate-severe sleep problems (CSHQ>56) was 62.9% in children with epilepsy-ADHD, while it was 40.4% and 26.4% in children with primary ADHD and epilepsy, respectively. CSHQ total scores were not different between ADHD subtypes in both children with epilepsy-ADHD and those with primary ADHD. None of the epilepsy-related variables were found to be associated with CSHQ scores. Epilepsy-ADHD is associated with a significantly poor sleep quality which is beyond that of primary ADHD and epilepsy.


Colonization with Staphylococcus aureus in Swedish nursing homes: a cross-sectional study.
Screening for bacterial colonization among risk populations could provide better estimates of the volume of the bacteria-related disease reservoir and the level of antimicrobial resistance, than do conventional laboratory reports. Two hundred and one participants at 10 Swedish nursing homes were screened for colonization with Staphylococcus aureus between January and October 2009. Of the 201 participants, 61 (30%) were male. The median age was 86 y. All participants were systematically sampled from the nasal mucosa, the pharyngeal mucosa, the groin, and active skin lesions, if any. Ninety-nine of 199 participants (50%) were colonized with S. aureus. The colonization rate was 34% for the nose, 35% for throat, 10% for groin, and 54% for active skin lesions. An antibiotic-resistant S. aureus isolate was identified in 8.5% of all participants regardless of colonization status. A total of 24 resistant isolates were detected, and 21 of these were resistant to fluoroquinolones. There was no case of colonization with methicillin-resistant S. aureus (MRSA). The presence of resistant isolates was generally low, and the greater part of the resistance was fluoroquinolone-related. To achieve reasonable precision, screening programmes of this kind must include samples from both the nose and throat, and, although low, the prevalence of antimicrobial resistance in Swedish nursing homes still calls for reflection on how to use the fluoroquinolones wisely.


Long-term evaluation of combined antihypertensive therapy with lisinopril and a thiazide diuretic in patients with essential hypertension.
For the treatment of hypertension, the combination of an angiotensin-converting enzyme (ACE) inhibitor and a thiazide diuretic is supported by multiple lines of evidence, because these drugs have synergistic action and are expected to cancel out each other's adverse side effects. However, the long-term outcome of this combination antihypertensive therapy is not entirely clear. In the present multicenter open trial, we investigated the long-term efficacy and safety of combined antihypertensive therapy with an ACE inhibitor, lisinopril, and a thiazide diuretic, trichlormethiazide. A total of 466 patients with essential hypertension were treated with lisinopril alone (monotherapy group, n = 360) or with a combination of lisinopril with trichlormethiazide (combination therapy group, n = 106) for 1 year. The average blood pressure was effectively lowered to below 150/90 mmHg in both the monotherapy and the combination therapy groups throughout the study period. The average maintenance dose of lisinopril was lower when combined with thiazide than when given alone (9.8 vs. 11.5 mg/day, p < 0.001). Dry cough was the major side effect of lisinopril; no severe adverse effects were observed. The incidence of cough was not significantly different between the monotherapy group (13.1%) and the combination therapy group (11.3%). The increase in serum potassium observed in the monotherapy group was reversed by the concurrent use of the thiazide diuretic in the combination therapy group. Fasting blood glucose was significantly reduced in the monotherapy group; the reduction observed in the combination therapy group was not significant. Thus, the present results provide useful information as to the effectiveness and safety of combined antihypertensive therapy with lisinopril and a thiazide in comparison with monotherapy with lisinopril.


Securing a sustainable and fit-for-purpose UK health and care workforce.
Approximately 13% of the total UK workforce is employed in the health and care sector. Despite substantial workforce planning efforts, the effectiveness of this planning has been criticised. Education, training, and workforce plans have typically considered each health-care profession in isolation and have not adequately responded to changing health and care needs. The results are persistent vacancies, poor morale, and low retention. Areas of particular concern highlighted in this Health Policy paper include primary care, mental health, nursing, clinical and non-clinical support, and social care. Responses to workforce shortfalls have included a high reliance on foreign and temporary staff, small-scale changes in skill mix, and enhanced recruitment drives. Impending challenges for the UK health and care workforce include growing multimorbidity, an increasing shortfall in the supply of unpaid carers, and the relative decline of the attractiveness of the National Health Service (NHS) as an employer internationally. We argue that to secure a sustainable and fit-for-purpose health and care workforce, integrated workforce approaches need to be developed alongside reforms to education and training that reflect changes in roles and skill mix, as well as the trend towards multidisciplinary working. Enhancing career development opportunities, promoting staff wellbeing, and tackling discrimination in the NHS are all needed to improve recruitment, retention, and morale of staff. An urgent priority is to offer sufficient aftercare and support to staff who have been exposed to high-risk situations and traumatic experiences during the COVID-19 pandemic. In response to growing calls to recognise and reward health and care staff, growth in pay must at least keep pace with projected rises in average earnings, which in turn will require linking future NHS funding allocations to rises in pay. Through illustrative projections, we show that, to sustain annual growth in the workforce at approximately 2·4%, increases in NHS expenditure of 4% annually in real terms will be required. Above all, a radical long-term strategic vision is needed to ensure that the future NHS workforce is fit for purpose.