Non-enzymatic glycation in corneas from normal and diabetic donors and its effects on epithelial cell attachment in vitro.
Diabetic keratopathy manifests as persistent and recurrent erosions and delayed wound healing. To investigate the role of non-enzymatic glycation of proteins in the pathogenesis of diabetic keratopathy, we studied the presence of advanced glycation end products in corneas normal and diabetic donors, and the ability of human comeal epithelial cells to attach to non-enzymatically glycated extracellular matrix proteins. Corneas from normal donors and donors with diabetes were sectioned and immunostaining was performed using a primary antibody that detects N(epsilon)-(carboxymethyl) lysine. Collagen I and fibronectin-coated tissue culture plates were non-enzymatically glycated by incubating with 500-mM glucose-6-phosphate for three weeks at 37 degrees C. To determine attachment corneal epithelial cells were allowed to adhere to glycated plates (1 to 4 hours, 37 degrees C). Non-adherent cells were removed by gentle washing and the number of attached cells was quantitated using Calcein-AM. Corneas from donors with diabetes showed more-intense immunostaining for N(epsilon)-(carboxymethyl) lysine than normal donors of similar ages. Non-enzymatic glycation of collagen I and fibronectin significantly reduced the ability of corneal epithelial cells to adhere to these extracellular matrix proteins. Our data suggest that non-enzymatically glycated proteins may interfere with attachment and hence migration of epithelial cells across the corneal surface, and therefore may contribute to some of the clinical manifestations of diabetic keratopathy. Diabetes leads to an accelerated aging process resulting in a cornea that may be much older than the chronological age of the patient. From a clinical perspective, particular care should be taken when considering the use of contact lenses and following corneal injury in these patients.


Antihyperglycemic and antioxidant effect of hydroethanolic extract of Butea monosperma bark in diabetic mice.
The antihyperglycemic, antihyperlipidemic and antioxidative properties of hydroethanolic extract of Butea monosperma bark were investigated in alloxan-induced diabetic mice. Alloxan administration resulted in higher blood glucose level and reduced hepatic glycogen content as compared to normal animals. Besides, serum lipid profile parameters such as total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol were also found to be significantly elevated, whereas the level of high density lipoprotein (HDL) cholesterol was markedly reduced in diabetic animals. Oxidative damage in the tissues of diabetic mice was evidenced by a marked increase in the level of thiobarbituric acid reactive substances (TBARS), distinct decrease in reduced glutathione (GSH) content and declined activity of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). The daily treatment of diabetic animals with crude extract of B. monosperma bark (300 mg kg(-1)) for 45 days significantly lowered blood glucose level and elevated hepatic glycogen content, bringing the values close to those observed in normal control and glibenclamide-treated diabetic mice. Furthermore, the level of various lipid profile parameters was also reversed towards normal. TBARS and GSH also restored towards normal and the declined activity of antioxidant enzymes in diabetic animals was also normalized in crude extract administered mice, thus indicating the antioxidant efficacy of the drug in diabetes-induced oxidative damage. Significant antihyperglycemic and antioxidant potential of the crude extract of B. monosperma bark indicated that it may find use in the management of diabetes and resultant oxidative stress.


CD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis.
Dendritic cells (DCs) are critical for immune homeostasis. To target DCs, we generated a mouse line with Flip deficiency in cells that express cre under the CD11c promoter (CD11c-Flip-KO). CD11c-Flip-KO mice spontaneously develop erosive, inflammatory arthritis, resembling rheumatoid arthritis, which is dramatically reduced when these mice are crossed with Rag(-/-) mice. The CD8α(+) DC subset is significantly reduced, along with alterations in NK cells and macrophages. Autoreactive CD4(+) T cells and autoantibodies specific for joint tissue are present, and arthritis severity correlates with the number of autoreactive CD4(+) T cells and plasmablasts in the joint-draining lymph nodes. Reduced T regulatory cells (Tregs) inversely correlate with arthritis severity, and the transfer of Tregs ameliorates arthritis. This KO line identifies a model that will permit in depth interrogation of the pathogenesis of rheumatoid arthritis, including the role of CD8α(+) DCs and other cells of the immune system.


Endocrine therapy with or without whole breast irradiation in low-risk breast cancer patients after breast-conserving surgery: 10-year results of the Austrian Breast and Colorectal Cancer Study Group 8A trial.
To investigate long-term results of patients with hormonal receptor-positive breast cancer treated with breast-conserving surgery (BCS) and consecutive endocrine therapy (ET) with or without whole breast irradiation (WBI). Within the 8 A trial of the Austrian Breast and Colorectal Cancer Study Group, a total of 869 patients received ET after BCS which was randomly followed by WBI (n = 439, group 1) or observation (n = 430, group 2). WBI was applied up to a mean total dosage of 50 Gy (+/- 10 Gy boost) in conventional fractionation. After a median follow-up of 9.89 years, 10 in-breast recurrences (IBRs) were observed in group 1 and 31 in group 2, resulting in a 10-year local recurrence-free survival (LRFS) of 97.5% and 92.4%, respectively (p = 0.004). This translated into significantly higher rates for disease-free survival (DFS): 94.5% group 1 vs 88.4% group 2, p = 0.0156. For distant metastases-free survival (DMFS) and overall survival (OS), respective 10-year rates amounted 96.7% and 86.6% for group 1 versus 96.4% and 87.6%, for group 2 (ns). WBI (hazard ratio [HR]: 0.27, p < 0.01) and tumour grading (HR: 3.76, p = 0.03) were found as significant predictors for IBR in multiple cox regression analysis. After a median follow-up of 10 years, WBI resulted in a better local control and DFS compared with ET alone. The omission of WBI and tumour grading, respectively, were the only negative predictors for LRFS.


IL-4 Inhibits IL-1β-Induced Depressive-Like Behavior and Central Neurotransmitter Alterations.
It has been known that activation of the central innate immune system or exposure to stress can disrupt balance of anti-/proinflammatory cytokines. The aim of the present study was to investigate the role of pro- and anti-inflammatory cytokines in the modulation of depressive-like behaviors, the hormonal and neurotransmitter systems in rats. We investigated whether centrally administered IL-1β is associated with activation of CNS inflammatory pathways and behavioral changes and whether treatment with IL-4 could modulate IL-1β-induced depressive-like behaviors and central neurotransmitter systems. Infusion of IL-4 significantly decreased IL-1β-induced anhedonic responses and increased social exploration and total activity. Treatment with IL-4 markedly blocked IL-1β-induced increase in PGE2 and CORT levels. Also, IL-4 reduced IL-1β-induced 5-HT levels by inhibiting tryptophan hydroxylase (TPH) mRNA and activating serotonin transporter (SERT) in the hippocampus, and levels of NE were increased by activating tyrosine hydroxylase (TH) mRNA expression. These results demonstrate that IL-4 may locally contribute to the regulation of noradrenergic and serotonergic neurotransmission and may inhibit IL-1β-induced behavioral and immunological changes. The present results suggest that IL-4 modulates IL-1β-induced depressive behavior by inhibiting IL-1β-induced central glial activation and neurotransmitter alterations. IL-4 reduced central and systemic mediatory inflammatory activation, as well as reversing the IL-1β-induced alterations in neurotransmitter levels. The present findings contribute a biochemical pathway regulated by IL-4 that may have therapeutic utility for treatment of IL-1β-induced depressive behavior and neuroinflammation which warrants further study.


Intraoperative radiotherapy in locally advanced recurrent colorectal cancer.
In an effort to promote local control and improve quality of life in patients with recurrent colorectal cancer, a multimodality approach has been used. Twenty-seven patients were treated with moderate doses of pre/postoperative radiotherapy with/without simultaneous systemic chemotherapy, surgical re-resection and IORT electron boost over areas at high risk for local recurrence. The 2-year actuarial disease-free and local relapse-free survival for the entire group were 14% and 26%, respectively. The most important factor predicting a favorable outcome was the radicality of surgical procedure. The determinate local control rate and the actuarial 2-year local relapse-free, and disease-free survival for patients undergoing complete resections were 50%, 56%, and 34%, respectively, whereas for patients undergoing partial resections these figures were 16%, 13%, and 6%. The radicality of surgical procedure was influenced by both tumoral size and previous treatment with irradiation. Complete resection rate was higher in patients with tumors less than 5 cm vs. more than 5 cm (40% vs. 22%), and in patients without previous radiotherapy versus those with previous radiotherapy (40% vs. 28%). Distant metastasis rate was high (41%). The most significant toxicities attributable to the whole treatment protocol were enteritis (37%), hydronephrosis (30%), and pelvic neuropathy (52%). Currently, our policy is to recommend IORT in patients with "favorable factors" such as: absence of previous pelvic radiotherapy, single previous surgical procedure, and complete resections.


Temporal variations in road traffic fatalities in South Africa.
The annual road traffic fatality (RTF) burden of 43 deaths per 100000 inhabitants in South Africa (SA) is disproportionately high in comparison to the world average of 22 per 100000 population. Recent research revealed strong geographical variations across district councils in the country, as well as a substantial peak in mortality occurring during December. In this study, the factors that explain temporal variations in RTFs in SA are examined. Using weekly data from the period 2002-2006 for the country's nine provinces, non-linear auto-regression exogenous (NARX) regression models were fitted to explain variations in RTFs and to assess the degree to which the variations between the provinces were associated with the temporal variations in risk factors. Results suggest that a proportion of the variations in weekly RTFs could be explained by factors other than the size of the province population, with both temporal and between-province residual variance remaining after accounting for the modelled risks. Policies directed at reducing the effects of the modifiable risks identified in our study will be important in reducing RTFs in SA.


Staging of Laryngeal and Hypopharyngeal Cancer: Computed Tomography versus Histopathology.
Computed tomography (CT) imaging is the choice of investigation for evaluation of extent of tumor under the mucosa, locally and regionally. This study was undertaken to assess the accuracy of preoperative CT imaging in the staging of carcinoma of the larynx and hypopharynx. In this retrospective study, all cases who were clinically (c) staged T3-T4 and who underwent surgery were evaluated. The sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), and accuracy (Ac) of a preoperative CT scan to detect cartilaginous penetration and spread outside the larynx was evaluated. Clinical T-stage by CT imaging was compared with postoperative histopathological T-stage. There were 22 (96%) male patients and one (4%) female patient. Patients were aged from 48 to 64 years (mean, 56 years). Twenty (87%) patients had laryngeal carcinoma, whereas three (13%) had hypopharyngeal carcinoma. Four (17%) patients had T3 tumors and 19 (83%) had T4a lesions. Preoperative imaging over-staged one of five pathological (p) T3 cases and three out of three pT2 cases, and was accurate in the remaining 19 cases. In a comparison of the results of imaging with histopathological T-classification, T-staging was found to be 82.6% accurate. CT is a precise and non-invasive imaging method with high sensitivity but relatively lower specificity because of increased false positives. CT imaging may be useful to guide the choice of surgical procedure, which can heavily impact a patients' quality of life.


Relationship between lifestyle and health factors and severe lower urinary tract symptoms (LUTS) in 106,435 middle-aged and older Australian men: population-based study.
Despite growing interest in prevention of lower urinary tract symptoms (LUTS) through better understanding of modifiable risk factors, large-scale population-based evidence is limited. To describe risk factors associated with severe LUTS in the 45 and Up Study, a large cohort study. A cross-sectional analysis of questionnaire data from 106,435 men aged ≥ 45 years, living in New South Wales, Australia. LUTS were measured by a modified version of the International Prostate Symptom Score (m-IPSS). The strength of association between severe LUTS and socio-demographic, lifestyle and health-related factors was estimated, using logistic regression to calculate odds ratios, adjusted for a range of confounding factors. Overall, 18.3% reported moderate, and 3.6% severe, LUTS. Severe LUTS were more common among men reporting previous prostate cancer (7.6%), total prostatectomy (4.9%) or having part of the prostate removed (8.2%). After excluding men with prostate cancer or prostate surgery, the prevalence of moderate-severe LUTS in the cohort (n = 95,089) ranged from 10.6% to 35.4% for ages 45-49 to ≥ 80; the age-related increase was steeper for storage than voiding symptoms. The adjusted odds of severe LUTS decreased with increasing education (tertiary qualification versus no school certificate, odds ratio (OR = 0.78 (0.68-0.89))) and increasing physical activity (high versus low, OR = 0.83 (0.76-0.91)). Odds were elevated among current smokers versus never-smokers (OR = 1.64 (1.43-1.88)), obese versus healthy-weight men (OR = 1.27 (1.14-1.41)) and for comorbid conditions (e.g., heart disease versus no heart disease, OR = 1.36 (1.24-1.49)), and particularly for severe versus no physical functional limitation (OR = 5.17 (4.51-5.93)). LUTS was associated with a number of factors, including modifiable risk factors, suggesting potential targets for prevention.


From deafness genes to hearing mechanisms: harmony and counterpoint.
The study of hereditary hearing impairments provides a unique opportunity to deal with two objectives simultaneously: (i) identification of the causative genes and the underlying pathogenic process in each form of deafness; and (ii) elucidation of the molecular and cellular mechanisms of hearing. This review highlights the breakthroughs achieved during the past 12 years, with respect to their medical impacts and advances in basic scientific knowledge. To date, this research relies extensively on mouse models to study human forms of deafness. But, can mouse models sustain genetic approaches to study the physiology and pathophysiology of the auditory system and to develop and test drugs?


Symmetric and antisymmetric solitons in finite lattices.
We propose a simple model for the realization of symmetrically and antisymmetrically shape-preserving nonlinear waves with nonvanishing intensities at infinity. A finite lattice embedded into a defocusing saturable medium can support various families of novel solitons, including out-of-phase and in-phase solitons with symmetric and antisymmetric profiles. Although the lattice is finite, the existence and stability of solitons depend strongly on the band-gap structure of the corresponding infinite lattice. Saturable nonlinearity enhances the pedestal height and renormalized energy flow of solitons evidently. In particular, increasing the lattice site number or saturation degree of nonlinearity can considerably suppresses the instability of solitons. In addition, we find two branches of in-phase solitons in finite lattices and one branch of them can be dynamically stable. Our findings may provide a helpful hint for linking the solitons supported by infinite and finite lattices.


Fidelity variants of RNA dependent RNA polymerases uncover an indirect, mutagenic activity of amiloride compounds.
In a screen for RNA mutagen resistance, we isolated a high fidelity RNA dependent RNA polymerase (RdRp) variant of Coxsackie virus B3 (CVB3). Curiously, this variant A372V is also resistant to amiloride. We hypothesize that amiloride has a previously undescribed mutagenic activity. Indeed, amiloride compounds increase the mutation frequencies of CVB3 and poliovirus and high fidelity variants of both viruses are more resistant to this effect. We hypothesize that this mutagenic activity is mediated through alterations in intracellular ions such as Mg²+ and Mn²+, which in turn increase virus mutation frequency by affecting RdRp fidelity. Furthermore, we show that another amiloride-resistant RdRp variant, S299T, is completely resistant to this mutagenic activity and unaffected by changes in ion concentrations. We show that RdRp variants resist the mutagenic activity of amiloride via two different mechanisms: 1) increased fidelity that generates virus populations presenting lower basal mutation frequencies or 2) resisting changes in divalent cation concentrations that affect polymerase fidelity. Our results uncover a new antiviral approach based on mutagenesis.


A neural-based vocoder implementation for evaluating cochlear implant coding strategies.
Most simulations of cochlear implant (CI) coding strategies rely on standard vocoders that are based on purely signal processing techniques. However, these models neither account for various biophysical phenomena, such as neural stochasticity and refractoriness, nor for effects of electrical stimulation, such as spectral smearing as a function of stimulus intensity. In this paper, a neural model that accounts for stochastic firing, parasitic spread of excitation across neuron populations, and neuronal refractoriness, was developed and augmented as a preprocessing stage for a standard 22-channel noise-band vocoder. This model was used to subjectively and objectively assess consonant discrimination in commercial and experimental coding strategies. Stimuli consisting of consonant-vowel (CV) and vowel-consonant-vowel (VCV) tokens were processed by either the Advanced Combination Encoder (ACE) or the Excitability Controlled Coding (ECC) strategies, and later resynthesized to audio using the aforementioned vocoder model. Baseline performance was measured using unprocessed versions of the speech tokens. Behavioural responses were collected from seven normal hearing (NH) volunteers, while EEG data were recorded from five NH participants. Psychophysical results indicate that while there may be a difference in consonant perception between the two tested coding strategies, mismatch negativity (MMN) waveforms do not show any marked trends in CV or VCV contrast discrimination.


A complex phenotype of peripheral neuropathy, myopathy, hoarseness, and hearing loss is linked to an autosomal dominant mutation in MYH14.
Both peripheral neuropathy and distal myopathy are well-established inherited neuromuscular disorders characterized by progressive weakness and atrophy of the distal limb muscles. A complex phenotype of peripheral neuropathy, myopathy, hoarseness, and hearing loss was diagnosed in a large autosomal dominant Korean family. A high density single nucleotide polymorphism (SNP)-based linkage study mapped the underlying gene to a region on chromosome 19q13.3. The maximum multipoint LOD score was 3.794. Sequencing of 34 positional candidate genes in the segregating haplotype revealed a novel c.2822G>T (p.Arg941Leu) mutation in the gene MYH14, which encodes the nonmuscle myosin heavy chain 14. Clinically we observed a sequential pattern of the onset of muscle weakness starting from the anterior to the posterior leg muscle compartments followed by involvement of intrinsic hand and proximal muscles. The hearing loss and hoarseness followed the onset of distal muscle weakness. Histopathologic and electrodiagnostic studies revealed both chronic neuropathic and myopathic features in the affected patients. Although mutations in MYH14 have been shown to cause nonsyndromic autosomal dominant hearing loss (DFNA4), the peripheral neuropathy, myopathy, and hoarseness have not been associated with MYH14. Therefore, we suggest that the identified mutation in MYH14 significantly expands the phenotypic spectrum of this gene.


Supporting HIV prevention and reproductive goals in an HIV-endemic setting: taking safer conception services from policy to practice in South Africa.
Safer conception care encompasses HIV care, treatment and prevention for persons living with HIV and their partners who desire children. In 2012, South Africa endorsed a progressive safer conception policy supporting HIV-affected persons to safely meet reproductive goals. However, aside from select research-supported clinics, widespread implementation has not occurred. Using South Africa as a case study, we identify key obstacles to policy implementation and offer recommendations to catalyse expansion of these services throughout South Africa and further afield. Four key implementation barriers were identified by combining authors' safer conception service delivery experiences with available literature. First, strategic implementation frameworks stipulating where, and by whom, safer conception services should be provided are needed. Integrating safer conception services into universal test-and-treat (UTT) and elimination-of-mother-to-child-transmission (eMTCT) priority programmes would support HIV testing, ART initiation and management, viral suppression and early antenatal/eMTCT care engagement goals, reducing horizontal and vertical transmissions. Embedding measurable safer conception targets into these priority programmes would ensure accountability for implementation progress. Second, facing an organizational clinic culture that often undermines clients' reproductive rights, healthcare providers' (HCP) positive experiences with eMTCT and enthusiasm for UTT provide opportunities to shift facility-level and individual attitudes in favour of safer conception provision. Third, safer conception guidelines have not been incorporated into HCP training. Combining safer conception with "test-and-treat" training would efficiently ensure that providers are better equipped to discuss clients' reproductive goals and support safer conception practices. Lastly, HIV-affected couples remain largely unaware of safer conception strategies. HIV-affected populations need to be mobilized to engage with safer conception options alongside other HIV-related healthcare services. Key barriers to widespread safer conception service provision in South Africa include poor translation of policy into practical and measurable implementation plans, inadequate training and limited community engagement. South Africa should leverage the momentum and accountability associated with high priority UTT and eMTCT programmes to reinvigorate implementation efforts by incorporating safer conception into implementation and monitoring frameworks and associated HCP training and community engagement activities. South Africa's experiences should be used to inform policy development and implementation processes in other HIV high-burden countries.


Pituitary gland recovery following fully endoscopic transsphenoidal surgery for nonfunctioning pituitary adenoma: results of a prospective multicenter study.
Recovery from preexisting hypopituitarism after transsphenoidal surgery for pituitary adenoma is an important outcome to investigate. Furthermore, pituitary function has not been thoroughly evaluated after fully endoscopic surgery, and benchmark outcomes have not been clearly established. Here, the authors characterize pituitary gland outcomes with a focus on gland recovery following endoscopic transsphenoidal removal of clinically nonfunctioning adenomas. This multicenter prospective study was conducted at 6 US pituitary centers among adult patients with nonfunctioning pituitary macroadenomas who had undergone endoscopic endonasal pituitary surgery. Pituitary gland function was evaluated 6 months after surgery. The 177 enrolled patients underwent fully endoscopic transsphenoidal surgery; 169 (95.5%) of them were available for follow-up. Ninety-five (56.2%) of the 169 patients had had a preoperative deficiency in at least one hormone axis, and 20/95 (21.1%) experienced recovery in at least one axis at the 6-month follow-up. Patients with adrenal insufficiency were more likely to recover (10/34 [29.4%]) than were those with hypothyroidism (8/72 [11.1%]) or male hypogonadism (5/50 [10.0%]). At the 6-month follow-up, 14/145 (9.7%) patients had developed at least one new deficiency. The study did not identify any predictors of gland recovery (p ≥ 0.20). Permanent diabetes insipidus was observed in 4/166 (2.4%) patients. Predictors of new gland dysfunction included a larger tumor size (p = 0.009) and Knosp grade 3 and 4 (p = 0.051). Fully endoscopic pituitary surgery resulted in improvement of pituitary gland function in a substantial minority of patients. The deficiency from which patients were most likely to recover was adrenal insufficiency. Overall rates of postoperative permanent diabetes insipidus were low. This study provides multicenter benchmark neuroendocrine clinical outcome data for the endoscopic technique.


Adaptation of the critical incident technique to requirements engineering in public health.
The introduction of modern information systems in public health provides new possibilities for improvements in public health services and hence also of population's health. However, development of information systems that truly supports public health practices requires that technical, cognitive, and social issues be taken into consideration. In requirements engineering for public health, a notable problem is that of capturing all aspects of the future user's voices, i.e., the viewpoints of different public health practitioners. Failing to capture these voices will result in inefficient or even useless systems. The aim of this paper is to report a requirements-engineering instrument to describe problems in the daily work of public health professionals. The issues of concern thus captured can be used as the basis for formulating the requirements of information systems for public health professionals.


[Information cards and enlightened assent. Proposition of twelve informant cards for plastic and aesthetic surgery].
Obligation to deliver full information and obtaining enlightened assent are now, for the whole french practitioner, a necessary preliminary to each operation. Henceforth, in case of suit, the practitioner must prove the reality and the quality of preoperative information. The National Medical French Council (CNOM) called scientific societies attention to propose to their members some index standard cards, corresponding to main medical and surgical records. The National Agency for Accreditation and Evaluation in Health (Anaes) defined the main characteristics of these documents. The authors propose twelve information cards corresponding to the most currently operations of plastic and aesthetic surgery. They will being clear and simple, with a large agreement, strictly informative and yearly up to date. They have the label and therefore the scientific guaranty of French Society of Plastic Reconstructive and Aesthetic Surgery.


Severe myoclonic epilepsy in infancy: evolution of electroencephalographic and clinical features.
Since 1987, we have diagnosed 10 patients, 4 males and 6 females, aged 2-11 years at the last evaluation, who all met the following criteria of severe myoclonic epilepsy in infancy (SMEI): generalized or unilateral long-lasting febrile clonic seizures in the first year of life; the subsequent appearance of myoclonic seizures and other types of seizure (partial seizures, atypical absences and convulsive status epilepticus); and neuropsychological deterioration for a certain period. Family histories of epilepsy and febrile seizures could be traced in 1 and 3 cases, respectively. None of them had previous personal history of brain insult. Electroencephalographic (EEGic) recordings in febrile seizure stage were normal; and continuous prophylaxis with phenobarbital failed to prevent the recurrence of febrile seizures. EEG studies in myoclonic stage showed generalized spike-and-waves, polyspike-and-waves, focal abnormalities and/or photosensitivity. The seizures were highly resistant to antiepileptic drugs. Our experiences suggested that comedication of valproic acid, clonazepam and carbamazepine may be most effective in treatment of the diverse seizures including myoclonic seizures, myoclonic-tonic-clonic seizures, atypical absences and partial seizures. Myoclonic seizures and atypical absences diminished in parallel to a clear-cut decrease in generalized abnormalities on EEG in 4 cases aged more than 7 years. However, the partial seizures, secondarily generalized seizures and status epilepticus were still present. Further investigations should aim to identify the underlying etiology and to search more effective treatment.


Exercise for intermittent claudication.
Exercise programmes are a relatively inexpensive, low-risk option compared with other, more invasive therapies for treatment of leg pain on walking (intermittent claudication (IC)). This is the fourth update of a review first published in 1998. Our goal was to determine whether an exercise programme was effective in alleviating symptoms and increasing walking treadmill distances and walking times in people with intermittent claudication. Secondary objectives were to determine whether exercise was effective in preventing deterioration of underlying disease, reducing cardiovascular events, and improving quality of life. For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched 15 November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10) via the Cochrane Register of Studies Online, along with trials registries. Randomised controlled trials of an exercise regimen versus control or versus medical therapy for people with IC due to peripheral arterial disease (PAD). We included any exercise programme or regimen used for treatment of IC, such as walking, skipping, and running. Inclusion of trials was not affected by duration, frequency, or intensity of the exercise programme. Outcome measures collected included treadmill walking distance (time to onset of pain or pain-free walking distance and maximum walking time or maximum walking distance), ankle brachial index (ABI), quality of life, morbidity, or amputation; if none of these was reported, we did not include the trial in this review. For this update (2017), RAL and AH selected trials and extracted data independently. We assessed study quality by using the Cochrane 'Risk of bias' tool. We analysed continuous data by determining mean differences (MDs) and 95% confidence intervals (CIs), and dichotomous data by determining risk ratios (RRs) and 95% CIs. We pooled data using a fixed-effect model unless we identified significant heterogeneity, in which case we used a random-effects model. We used the GRADE approach to assess the overall quality of evidence supporting the outcomes assessed in this review. We included two new studies in this update and identified additional publications for previously included studies, bringing the total number of studies meeting the inclusion criteria to 32, and involving a total of 1835 participants with stable leg pain. The follow-up period ranged from two weeks to two years. Types of exercise varied from strength training to polestriding and upper or lower limb exercises; supervised sessions were generally held at least twice a week. Most trials used a treadmill walking test for one of the primary outcome measures. The methodological quality of included trials was moderate, mainly owing to absence of relevant information. Most trials were small and included 20 to 49 participants. Twenty-seven trials compared exercise versus usual care or placebo, and the five remaining trials compared exercise versus medication (pentoxifylline, iloprost, antiplatelet agents, and vitamin E) or pneumatic calf compression; we generally excluded people with various medical conditions or other pre-existing limitations to their exercise capacity.Meta-analysis from nine studies with 391 participants showed overall improvement in pain-free walking distance in the exercise group compared with the no exercise group (MD 82.11 m, 95% CI 71.73 to 92.48, P < 0.00001, high-quality evidence). Data also showed benefit from exercise in improved maximum walking distance (MD 120.36 m, 95% CI 50.79 to 189.92, P < 0.0007, high-quality evidence), as revealed by pooling data from 10 studies with 500 participants. Improvements were seen for up to two years.Exercise did not improve the ABI (MD 0.04, 95% CI 0.00 to 0.08, 13 trials, 570 participants, moderate-quality evidence). Limited data were available for the outcomes of mortality and amputation; trials provided no evidence of an effect of exercise, when compared with placebo or usual care, on mortality (RR 0.92, 95% CI 0.39 to 2.17, 5 trials, 540 participants, moderate-quality evidence) or amputation (RR 0.20, 95% CI 0.01 to 4.15, 1 trial, 177 participants, low-quality evidence).Researchers measured quality of life using Short Form (SF)-36 at three and six months. At three months, the domains 'physical function', 'vitality', and 'role physical' improved with exercise; however this was a limited finding, as it was reported by only two trials. At six months, meta-analysis showed improvement in 'physical summary score' (MD 2.15, 95% CI 1.26 to 3.04, P = 0.02, 5 trials, 429 participants, moderate-quality evidence) and in 'mental summary score' (MD 3.76, 95% CI 2.70 to 4.82, P < 0.01, 4 trials, 343 participants, moderate-quality evidence) secondary to exercise. Two trials reported the remaining domains of the SF-36. Data showed improvements secondary to exercise in 'physical function' and 'general health'. The other domains - 'role physical', 'bodily pain', 'vitality', 'social', 'role emotional', and 'mental health' - did not show improvement at six months.Evidence was generally limited in trials comparing exercise versus antiplatelet therapy, pentoxifylline, iloprost, vitamin E, and pneumatic foot and calf compression owing to small numbers of trials and participants.Review authors used GRADE to assess the evidence presented in this review and determined that quality was moderate to high. Although results showed significant heterogeneity between trials, populations and outcomes were comparable overall, with findings relevant to the claudicant population. Results were pooled for large sample sizes - over 300 participants for most outcomes - using reproducible methods. High-quality evidence shows that exercise programmes provided important benefit compared with placebo or usual care in improving both pain-free and maximum walking distance in people with leg pain from IC who were considered to be fit for exercise intervention. Exercise did not improve ABI, and we found no evidence of an effect of exercise on amputation or mortality. Exercise may improve quality of life when compared with placebo or usual care. As time has progressed, the trials undertaken have begun to include exercise versus exercise or other modalities; therefore we can include fewer of the new trials in this update.


GrapeTree: visualization of core genomic relationships among 100,000 bacterial pathogens.
Current methods struggle to reconstruct and visualize the genomic relationships of large numbers of bacterial genomes. GrapeTree facilitates the analyses of large numbers of allelic profiles by a static "GrapeTree Layout" algorithm that supports interactive visualizations of large trees within a web browser window. GrapeTree also implements a novel minimum spanning tree algorithm (MSTree V2) to reconstruct genetic relationships despite high levels of missing data. GrapeTree is a stand-alone package for investigating phylogenetic trees plus associated metadata and is also integrated into EnteroBase to facilitate cutting edge navigation of genomic relationships among bacterial pathogens.


IDegLira Versus Insulin Glargine U100: A Long-term Cost-effectiveness Analysis in the US Setting.
Treatment with IDegLira has the potential to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) without the weight gain and with a lower risk of hypoglycemia than with other therapies. The aim of the present analysis was to evaluate the long-term cost-effectiveness of IDegLira versus insulin glargine U100 with re-education and up-titration of the dose for treatment of patients with T2DM failing to achieve glycemic control on basal insulin in the US setting. Data were obtained from the DUAL V randomized controlled trial in which adults with T2DM failing to achieve glycemic targets with insulin glargine U100 were randomly allocated to receive either IDegLira or insulin glargine U100. Long-term projections of clinical outcomes and direct costs were made using the IMS CORE Diabetes Model. Costs were accounted from a healthcare payer perspective. Future costs and clinical benefits were discounted at 3% annually. IDegLira was associated with improved discounted life expectancy (13.99 [standard deviation 0.19] versus 13.82 [standard deviation 0.20] years) and quality-adjusted life expectancy (9.14 [standard deviation 0.12] versus 8.87 [standard deviation 0.13] quality-adjusted life years [QALYs]) compared to insulin glargine U100. IDegLira was associated with increased direct costs of $16,970, yielding an incremental cost-effectiveness ratio (ICER) of $63,678 per QALY gained versus insulin glargine U100. Sensitivity analyses identified that the key driver of cost-effectiveness was the greater reduction in glycated hemoglobin with IDegLira compared with insulin glargine U100. Based on head-to-head clinical trial data, the present analysis suggests that IDegLira is likely to improve long-term clinical outcomes for patients with T2DM not achieving glycemic control on basal insulin compared to re-education and up-titration of the dose of insulin glargine U100, with these improvements coming at an increased cost from a healthcare payer perspective. An ICER within the range described as high care value was calculated, suggesting IDegLira is a cost-effective treatment option in the US. Novo Nordisk A/S and Novo Nordisk Inc.


Optic Nerve Lipidomics Reveal Impaired Glucosylsphingosine Lipids Pathway in Glaucoma.
To determine major differences in lipid profile between human control and glaucomatous optic nerve. To assess major enzymes in lipid pathway if aberration is revealed for a lipid class by profiling. Optic nerve (ON) samples were obtained from human cadaveric donors [control (n = 11) and primary open-angle glaucoma (POAG; n = 12)]; the lipids were extracted using Bligh and Dyer methods. Control and glaucoma donors were all Caucasians age 72.3 ± 5.9 and 70.3 ± 10.5 (inclusive of both sexes), respectively. Lipids were extracted after weighing the tissue; the protein amounts in the corresponding aqueous phase of organic solvent extraction were recorded. High-resolution mass spectrometry was performed using a Q-exactive mass spectrometer coupled with an EASY-nLC 1000 liquid chromatograph instrument. Bioinformatics and statistical analysis were performed using LipidSearch v.4.1 and MetaboAnalyst 4.0/STATA 14.2. Protein amounts were determined using Bradford's method. Western blot, ELISA, and immunohistochemistry utilized established protocols and were performed for protein quantification and localization, respectively. Additional donor tissues were utilized for Western blot, ELISA, and immunohistochemistry. Principal component analysis (PCA) placed control and glaucomatous ONs in two distinct groups based on analysis of lipid profiles. Total lipid, total phospholipids, total ceramide, and total sphingolipids were similar (without significant difference) between control and glaucoma. However, we found a significant increase in glucosylsphingosine in glaucoma compared to control samples. We found similar levels of glucocerebrosidase (GBA), ceramide glucosyltransferase (UGCG), decreased nonlysosomal glucocerebrosidase (GBA2), and increased lysosomal and nonlysosomal acylsphingosine amidohydrolase (ASAH1 and ASAH2) levels in glaucomatous ON compared to control. We found significant differences in glucosylsphingosine lipids, consistent with decreased GBA and GBA2 and increased ASAH1 and ASAH2 immunoreactivity in glaucoma, suggesting the potential impairment of sphingolipid enzymatic pathways in lysosomal and nonlysosomal cellular compartments.


Visilant: Visual Support for the Exploration and Analytical Process Tracking in Criminal Investigations.
The daily routine of criminal investigators consists of a thorough analysis of highly complex and heterogeneous data of crime cases. Such data can consist of case descriptions, testimonies, criminal networks, spatial and temporal information, and virtually any other data that is relevant for the case. Criminal investigators work under heavy time pressure to analyze the data for relationships, propose and verify several hypotheses, and derive conclusions, while the data can be incomplete or inconsistent and is changed and updated throughout the investigation, as new findings are added to the case. Based on a four-year intense collaboration with criminalists, we present a conceptual design for a visual tool supporting the investigation workflow and Visilant, a web-based tool for the exploration and analysis of criminal data guided by the proposed design. Visilant aims to support namely the exploratory part of the investigation pipeline, from case overview, through exploration and hypothesis generation, to the case presentation. Visilant tracks the reasoning process and as the data is changing, it informs investigators which hypotheses are affected by the data change and should be revised. The tool was evaluated by senior criminology experts within two sessions and their feedback is summarized in the paper. Additional supplementary material contains the technical details and exemplary case study.


A seven item scale for the assessment of disabilities after child and adolescent injuries.
To develop a scale to assess physical disabilities after child or adolescent injuries. The three main hospitals of Jerusalem. Telephone interviews pertaining to the injury's effect on the functioning of children 4-17 years old (n = 281) were carried out six months after an injury. Disabilities were recalled by the parents for the period immediately after the injury (short term) and at the time of interview (long term). Of 25 questions derived from the International Classification of Impairments, Disabilities and Handicaps, seven were selected: limitations in walking, running, getting up/lying down, moving in bed, going to the toilet, bathing/keeping personal hygiene, and dressing. Construct validity was tested using the usual, sport, school, and leisure time activities as the gold standard. The prevalence of short term disabilities ranged from 23.8% to 37.7% and of long term disabilities from 0.4% to 11.8%. Cronbach's alpha was 0.91 for the short term scale and over 0.90 for the different categories of the sociodemographic variables. It decreased to 0.66 for the long term scale. Sensitivity of the short term scale ranged from 77% to 89%, but was lower for the long term scale. Specificity varied from 72% to 84% and increased to 88% to 90%, six months after the injury. This scale could be used to study disability after injury among children and adolescents in different cultures. It is a simple method that does not require expert personnel and has relatively high validity and internal reliability.


Photosynthetic induction responses of two rainforest tree species in relation to light environment.
Photosynthetic induction of in situ saplings of two Costa Rican rainforest tree species wre compared in relation to their light environment, using infrared gas analysis and hemispherical photography. The species studied were Dipteryx panamensis, a climax species found in bright microsites, and Cecropia obtusifolia, a pioneer species. In the morning, when leaves were most responsive, induction time necessary to reach 90% of the lightsaturated rate of photosynthesis was on average 16 min for Dipteryx and 10 min for Cecropia. However, induction times for both species increased in the afternoon resulting in shorter daily average induction times for Dipteryx than for Cecropia. Dipteryx also maintained higher levels of induction for a longer period under low light conditions than did Cecropia. The two species differed in the way they adjusted to light availability. Dipteryx saplings growing in shady sites had faster rates of induction than saplings growing in bright sites, with no difference in light-saturated photosynthetic rate. In contrast, Cecropia saplings growing in bright sites had higher light-saturated photosynthetic rates than saplings growing in shady sites, with no difference in rates of induction. Dipteryx appears to exploit temporal variation in light availability by refining the quickness of the induction response to the light environment, while Cecropia adjusts its scale of exploitation by realizing a higher lightsaturated photosynthetic rate in sites of higher light.


Enhancement of the fluorescence and stability of o-phthalaldehyde-derived isoindoles of amino acids using hydroxypropyl-beta-cyclodextrin.
Addition of hydroxypropyl-beta-cyclodextrin to o-phthalaldehyde (OPA)-amino acid-thiol reaction mixtures is shown to cause significant enhancement of the fluorescence of the isoindole product for a wide range of amino acids, with the largest effects observed in the cases of glycine and lysine. The largest enhancement observed was a factor of 2.67 in the case of the derivative of glycine. This fluorescence enhancement is the result of the formation of a 1:1 host:guest inclusion complex between the isoindole and the cyclodextrin. Relatively small association constants of 44 and 130 M(-1) were obtained for the inclusion of the derivatives of glycine and lysine, respectively. Inclusion of the isoindole derivative into hydroxypropyl-beta-cyclodextrin was also found to result in a significant stabilization of the isoindole derivatives, contrary to what has been previously reported for inclusion into beta-cyclodextrin. For example, the lifetime of the lysine derivative was found to increase from 42 to 222 min, a factor of 5.3. These results have potential applications in fluorescence-based HPLC and high-performance capillary electrophoresis amino acid analysis methods using OPA derivation. Addition of hydroxypropyl-beta-cyclodextrin to the reaction mixture results in an increase in both the fluorescence and the stability of the isoindole product, providing potentially significant improvements to the method.


Thalamic stroke. Presentation and prognosis of infarcts and hemorrhages.
Thalamic strokes in 62 patients selected from the Stroke Data Bank were studied to determine differences among 18 infarctions (INF), 23 localized hemorrhages (ICH), and 21 hematomas with ventricular extension (IVH). Stupor or coma at onset occurred more frequently in the IVH (62%) than in the INF (6%) or ICH (13%) groups and was reflected in significantly lower median Glasgow Coma Scores in the IVH group (7) than in the INF (15) and ICH (14) groups. Although ocular movements were more frequently abnormal in the IVH group compared with the ICH and INF groups, no significant differences were found in the frequency of motor or sensory deficits. Among the 62 strokes, 32 had restricted lesions of the posterolateral (n = 9), anterior (n = 3), paramedian (n = 7), and dorsal (n = 13) portions of the thalamus. Differences in consciousness and in motor, sensory, and oculomotor deficits were found among the topographic subgroups. Stroke-related deaths occurred in 52% of IVH cases, 13% of ICH cases, and no cases of INF. Median lesion volume as detected with computed tomography was greater in hemorrhages (INF, 2 cm3; ICH, 10 cm3; IVH, 16 cm3), with mortality related to increasing hematoma size. Coma, Glasgow Coma Score lower than 9, weakness score greater than 15 of a possible 30, abnormal ocular movements, and fixed pupils were also associated with stroke-related mortality. We conclude that the initial neurologic syndrome does not discriminate infarcts from intrathalamic hemorrhages. Ventricular extension, however, causes significantly more severe deficits and higher mortality.


Observations at mercury encounter by the plasma science experiment on mariner 10.
A fully developed bow shock and magnetosheath were observed near Mercury, providing unambiguous evidence for a strong interaction between Mercury and the solar wind. Inside the sheath there is a distinct region analogous to the magnetosphere or magnetotail of Earth, populated by electrons with lower density and higher temperature than the electrons observed in the solar wind or magnetosheath. At the time of encounter, conditions were such that a perpendicular shock was observed on the inbound leg and a parallel shock was observed on the outbound leg of the trajectory, and energetic plasma electron events were detected upstream from the outbound shock crossing. The interaction is most likely not atmospheric, but the data clearly indicate that the obstacle to solar wind flow is magnetic, either intrinsic or induced. The particle fluxes and energy spectra showed large variations while the spacecraft was inside the magnetosphere, and these variations could be either spatial or temporal.


The NIN Transcription Factor Coordinates Diverse Nodulation Programs in Different Tissues of the Medicago truncatula Root.
Biological nitrogen fixation in legumes occurs in nodules that are initiated in the root cortex following Nod factor recognition at the root surface, and this requires coordination of diverse developmental programs in these different tissues. We show that while early Nod factor signaling associated with calcium oscillations is limited to the root surface, the resultant activation of Nodule Inception (NIN) in the root epidermis is sufficient to promote cytokinin signaling and nodule organogenesis in the inner root cortex. NIN or a product of its action must be associated with the transmission of a signal between the root surface and the cortical cells where nodule organogenesis is initiated. NIN appears to have distinct functions in the root epidermis and the root cortex. In the epidermis, NIN restricts the extent of Early Nodulin 11 (ENOD11) expression and does so through competitive inhibition of ERF Required for Nodulation (ERN1). In contrast, NIN is sufficient to promote the expression of the cytokinin receptor Cytokinin Response 1 (CRE1), which is restricted to the root cortex. Our work in Medicago truncatula highlights the complexity of NIN action and places NIN as a central player in the coordination of the symbiotic developmental programs occurring in differing tissues of the root that combined are necessary for a nitrogen-fixing symbiosis.


[Bronchial injury due to double-lumen endobronchial tube].
A 68-years-old and 148 cm tall female with lung cancer was operated on a left lower lobectomy via posterolateral thoracotomy. A 35 Fr double-lumen endobronchial tube was smoothly inserted and the tip was placed in the left main bronchus whose position was confirmed by fiberoptic bronchoscope. After lobectomy and lymph node dissection were completed, 1-lung ventilation was terminated, the left chest cavity was filled with saline, and an air-leak test was performed. Immediately after the initiation of bilateral lung ventilation, massive air-leak was observed in the left hilar region and the saline in the chest regurgitated into the airway, and she fell into critical ventilatory insufficiency. After sucking the saline in the chest, thorough observation revealed a 3 cm-long rupture of the membranous portion of the left main bronchus. The rupture was manually occluded and ventilatory insufficiency was avoided, then the tip of the endobronchial tube was re-inserted into the right main bronchus and right single lung ventilation was initiated. The rupture was closed by a 4-0 polydioxanone (PDS) running suture with no coverage. The patient was extubated immediately after the operation. Ten days later, she had a tiny bronchial fistula, and it was cured by chest drainage only, and she discharged home on the 48th postoperative day.


Getting Back to Normal: A Grounded Theory Study of Function in Post-hospitalized Older Adults.
The literature on transitions after hospitalization is based on a medicalized model focusing primarily on medication management and readmission, but little is known about the process older adults engage in to maintain their normal life posthealth event or how older adults define what the transition is. This grounded theory study aimed to describe how older adults understand and define a transition process, what actions they take based on their understanding, and what consequences they experience as they transition. Adults aged 65 and older discharged from a large Midwestern teaching hospital (N = 14) were interviewed using in-depth one-on-one interviews. Data were analyzed using open, axial, and selective coding. All participants described the process of transition as moving from a state of normal function to loss, and then working back to a normal state. A conceptual model was developed to illustrate the complexity of movement related to how older adults understand and manage the transition. All participants described starting out being normal until they experienced a major health event (acute or chronic illness). Losing normal involved experiencing a lower level of function both inside and outside the home. Working back to normal was accomplished by two different pathways: those "working to regain" focused on getting back to the level they were at prior to the major health event, whereas those "working to maintain" often involved redefining a new normal. The consequences of the two pathways were quite different, with those working to maintain describing several negative consequences. This study provides a detailed understanding of how older adults transition and the complexity of that transition. Findings provide a foundation for broadening our understanding of function beyond typical activities of daily living and reveal a more complex transition process that can span months to years.


Tracing Genomic Divergence of Vibrio Bacteria in the Harveyi Clade.
The mechanism of bacterial speciation remains a topic of tremendous interest. To understand the ecological and evolutionary mechanisms of speciation in Vibrio bacteria, we analyzed the genomic dissimilarities between three closely related species in the so-called Harveyi clade of the genus Vibrio, V. campbellii, V. jasicida, and V. hyugaensis The analysis focused on strains isolated from diverse geographic locations over a long period of time. The results of phylogenetic analyses and calculations of average nucleotide identity (ANI) supported the classification of V. jasicida and V. hyugaensis into two species. These analyses also identified two well-supported clades in V. campbellii; however, strains from both clades were classified as members of the same species. Comparative analyses of the complete genome sequences of representative strains from the three species identified higher syntenic coverage between genomes of V. jasicida and V. hyugaensis than that between the genomes from the two V. campbellii clades. The results from comparative analyses of gene content between bacteria from the three species did not support the hypothesis that gene gain and/or loss contributed to their speciation. We also did not find support for the hypothesis that ecological diversification toward associations with marine animals contributed to the speciation of V. jasicida and V. hyugaensis Overall, based on the results obtained in this study, we propose that speciation in Harveyi clade species is a result of stochastic diversification of local populations, which was influenced by multiple evolutionary processes, followed by extinction events.IMPORTANCE To investigate the mechanisms underlying speciation in the genus Vibrio, we provided a well-assembled reference of genomes and performed systematic genomic comparisons among three evolutionarily closely related species. We resolved taxonomic ambiguities and identified genomic features separating the three species. Based on the study results, we propose a hypothesis explaining how species in the Harveyi clade of Vibrio bacteria diversified.


Comparative efficacy of a once-daily controlled-release formulation of glipizide and immediate-release glipizide in patients with NIDDM.
To compare the efficacy and safety of controlled-release glipizide (glipizide-GITS [gastrointestinal therapeutic system]) and immediate-release glipizide in patients with non-insulin-dependent diabetes mellitus (NIDDM). In a multicenter, open-label, randomized, two-way crossover study, 132 patients with NIDDM received daily doses of 5, 20, or 40 mg of either glipizide-GITS or immediate-release glipizide for 8 weeks followed by 8 weeks of the alternate formulation. Plasma glucose, serum insulin, C-peptide, and plasma glipizide levels were measured at fasting and post-Sustacal challenge at the end of 1 and 8 weeks of each treatment phase. HbA1c was measured at the end of weeks 7 and 8 of each treatment phase. Both formulations of glipizide yielded similar mean HbA1c values. However, mean fasting plasma glucose (FPG) levels were significantly lower with glipizide-GITS treatment than with immediate-release glipizide at the end of week 1 (11.0 vs. 11.6 mmol/l; P < 0.01) and at the end of the 8-week treatment phase (10.9 vs. 11.7 mmol/l; P < 0.001). Fasting insulin and C-peptide levels were lower after 5 mg glipizide-GITS vs. immediate-release glipizide. Glucose responses to Sustacal were similar after both formulations of glipizide; however, serum insulin (P < 0.01) and C-peptide responses (P < 0.05) were lower with glipizide-GITS than with immediate-release glipizide treatment at the end of the 8-week treatment phase. Mean plasma glipizide concentrations were stable by the end of week 1, and the concentrations increased proportionately with dose. Once-daily Glipizide-GITS provided effective mean glipizide concentrations (> 50 ng/ml) 24 h after dosing, even at the lowest (5 mg) dose level. Both formulations were well tolerated. Glipizide-GITS was significantly more effective than immediate-release glipizide in reducing FPG levels. Both formulations reduced postprandial plasma glucose levels equally; however, glipizide-GITS exerted its control in the presence of lower plasma glipizide concentrations in addition to significantly lower insulin and C-peptide levels. This suggests that glipizide-GITS improves insulin sensitivity.


Health risk assessment of inorganic arsenic intake of Cambodia residents through groundwater drinking pathway.
In order to compare the magnitudes and health impacts of arsenic and other toxic trace elements in well water, groundwater and hair samples were collected from three areas with different arsenic exposure scenarios in the Mekong River basin of Cambodia. Ampil commune in Kampong Cham province was selected as an uncontaminated area, Khsarch Andaet commune in Kratie province was selected as a moderately contaminated area, and Kampong Kong commune in Kandal Province was selected as an extremely contaminated area. Results of ICP-MS analyses of the groundwater samples revealed that As, Mn, Fe and Ba concentrations were significantly different among the three study areas (Kruskal-Wallis test, p < 0.0001). Out of 46 observed wells in the Kandal province study area, 100% detected As > 50 μg L(-1) and Fe > 300 μg L(-1); 52.17% had Mn > 400 μg L(-1) and 73.91% found Ba > 700 μg L(-1). In the Kratie province study area (n = 12), 25% of wells showed elevated arsenic levels above 10 μg L(-1) and 25% had Mn > 400 μg L(-1), whereas samples from Kampong Cham province study area (n = 18) were relatively clean, with As < 10 μg L(-1). A health risk assessment model derived from the USEPA was applied to calculate individual risks resulting from drinking groundwater. Computational results indicated that residents from Kandal Province study area (n = 297) confronted significantly higher non-carcinogenic and carcinogenic risks than those in Kratie (n = 89) and Kampong Cham (n = 184) province study areas (Kruskal-Wallis test, p < 0.0001). 98.65% of respondents from the Kandal province study area were at risk for the potential non-cancer effect and an average cancer risk index was found to be 5 in 1000 exposure. The calculations also indicated that, in the Kratie province study area, 13.48% of respondents were affected by non-cancer health risks and 33.71% were threatened by cancer, whereas none of respondents in the Kampong Cham province study area appeared to have non-carcinogenic effect. Positively significant correlations of the arsenic content in scalp hair (As(h)) with both arsenic levels in groundwater (As(w)) (r(s) (304) = 0.757, p < 0.0001) and individual average daily doses (ADD) of arsenic (r(s) (304) = 0.763, p < 0.0001) undoubtedly indicated that arsenic accumulation in the bodies of Cambodia residents in the Mekong River basin was mainly through a groundwater drinking pathway. To the best of our knowledge, this is the first comprehensive report comparing individual health risk assessments of arsenic exposure through a groundwater drinking pathway to enriched arsenic levels from groundwater in the Mekong River basin, Cambodia. This study indicates that elevated arsenic concentrations in groundwater may lead to thousands of cases of arsenicosis in the near future if mitigating actions are not taken.


Epizootiology of the parasitic dinoflagellate Hematodinium sp. in the American blue crab Callinectes sapidus.
Hematodinium sp. is a parasitic dinoflagellate that infects and kills blue crabs Callinectes sapidus. Periodic outbreaks of dinoflagellate infections with subsequent high host mortalities prompted a study of the epizootiology and distribution of the crab pathogen. Hemolymph samples from over 13000 crabs were assessed for infections over 8 yr. Moderate to high prevalences were found at several locations along the Atlantic and Gulf coasts of the United States. In the coastal bays of Maryland and Virginia, prevalence followed a seasonal pattern, with a sharp peak in late autumn. Infections were significantly more prevalent in crabs measuring less than 30 mm carapace width; host sex did not influence prevalence. Prevalences were highest in crabs collected from salinities of 26 to 30%o; no infected crabs were found in salinities below 11%o. Intensity of infection did not vary among crab sizes, molt stages, or sexes. Naturally and experimentally infected crabs died over 35 and 55 d in captivity, with a mean time to death of approximately 13 and 42 d, respectively. Several other crustaceans, including gammaridean amphipods, xanthid (mud) crabs, and the green crab Carcinus maenus, were found with Hematodinium-like infections. Considering its widespread distribution and high pathogenicity, we suggest that Hematodinium sp. represents a significant threat to blue crab populations in high salinity estuaries along the Atlantic and Gulf coasts of the USA.


Quantitative Trait Loci for Light Sensitivity, Body Weight, Body Size, and Morphological Eye Parameters in the Bumblebee, Bombus terrestris.
Bumblebees such as Bombus terrestris are essential pollinators in natural and managed ecosystems. In addition, this species is intensively used in agriculture for its pollination services, for instance in tomato and pepper greenhouses. Here we performed a quantitative trait loci (QTL) analysis on B. terrestris using 136 microsatellite DNA markers to identify genes linked with 20 traits including light sensitivity, body size and mass, and eye and hind leg measures. By composite interval mapping (IM), we found 83 and 34 suggestive QTLs for 19 of the 20 traits at the linkage group wide significance levels of p = 0.05 and 0.01, respectively. Furthermore, we also found five significant QTLs at the genome wide significant level of p = 0.05. Individual QTLs accounted for 7.5-53.3% of the phenotypic variation. For 15 traits, at least one QTL was confirmed with multiple QTL model mapping. Multivariate principal components analysis confirmed 11 univariate suggestive QTLs but revealed three suggestive QTLs not identified by the individual traits. We also identified several candidate genes linked with light sensitivity, in particular the Phosrestin-1-like gene is a primary candidate for its phototransduction function. In conclusion, we believe that the suggestive and significant QTLs, and markers identified here, can be of use in marker-assisted breeding to improve selection towards light sensitive bumblebees, and thus also the pollination service of bumblebees.


Number of cues influences the cost of remembering to remember.
A current focus in the prospective memory literature is the extent to which a prospective memory task (remembering to perform a future action) interferes with ongoing activities (defined in this study as lexical decision latencies). In the present study, participants had to detect one, two, three, four, five, or six prospective memory cues. Results showed no significant increase in lexical decision latencies with one or two targets; however, significant costs emerged with three or more targets. Furthermore, task interference showed a linear increase in task costs for word trial performance but not for nonword trial performance. Practical and theoretical implications of these findings are discussed.


A dramatic pH-dependent alteration in ANP receptor density: a note for using cultured cells.
Culture media tend to become acidic when rapidly growing cells are cultured under batch conditions using a CO2/HCO3- buffer system. The effects of this inherent lowering of pH on cellular makeup of cultured cells, which have long been ignored, were examined by monitoring the pH and number of the atrial natriuretic peptide (ANP) receptors expressed on the cultured bovine endothelial cells. The Eagle's minimum essential medium was adjusted to three different pH values of 7.0, 7.4, and 7.7 and used for 48-h batch cultures. After this 48-h incubation, the pH values of the media were found to be 7.0, 7.1, and 7.4, respectively. These pH shifts had unexpectedly strong influences on the ANP receptor levels without affecting the affinity. Cells maintained in the slightly higher pH medium had a trace amount of the receptor (< 10 sites/cell), while those in the lower pH environment exhibited a large number of binding sites (40,000 sites/cell). Similar situations might occur in other cellular components and in other types of cells, and therefore, such possibilities should be kept in mind when cultured cell systems are used.


MiPanda: A Resource for Analyzing and Visualizing Next-Generation Sequencing Transcriptomics Data.
The Michigan Portal for the Analysis of NGS data portal (http://mipanda.org) is an open-access online resource that provides the scientific community with access to the results of a large-scale computational analysis of thousands of high-throughput RNA sequencing (RNA-seq) samples. The portal provides access to gene expression profiles, enabling users to interrogate expression of genes across myriad normal and cancer tissues and cell lines. From these data, tissue- and cancer-specific expression patterns can be identified. Gene-gene coexpression profiles can also be interrogated. The current portal contains data for over 20,000 RNA-seq samples and will be continually updated.


Surrogacy relationships: a critical interpretative review.
Based on a critical interpretative review of existing qualitative research investigating accounts of 'lived experience' of surrogates and intended parents from a relational perspective, this article proposes a typology of surrogacy arrangements. The review is based on the analysis of 39 articles, which belong to a range of different disciplines (mostly sociology, social psychology, anthropology, ethnology, and gender studies). The number of interviews in each study range from as few as seven to over one hundred. Countries covered include Australia, Canada, Greece, India, Iran, Israel, Italy, Mexico, Norway, Russia, Sweden, UK, Ukraine, and the USA. Most studies focus only on surrogacy practices in one country (although often with intended parents from other countries), and some include several countries (e.g. interviewees from several countries or fieldwork in different field-sites). The proposed typology goes beyond the division between altruistic versus commercial, and traditional versus gestational surrogacy, in order to inform further research and to contribute to bioethical and policy debates on surrogacy in a transnational context. Four types of relations are identifiable: open, restricted, structured, and enmeshed. The criteria which influence these relationships are: the frequency and character of contact pre- and post-birth; expectations of both parties; the type of exchange involved in surrogacy arrangements; and cultural, legal, and economic contexts. The theoretical contribution of the article is to further the development of a relational justice approach to surrogacy.


Does the femoral cam lesion regrow after osteoplasty for femoroacetabular impingement? Two-year follow-up.
There are currently no studies that have examined the recurrence of the cam lesion after femoral neck osteoplasty for femoroacetabular impingement. Although patient-reported outcome (PRO) scores at midterm follow-up have shown continued success, the maintenance of a normalized alpha angle has not been shown radiographically. To assess the radiographic recurrence of cam deformity at 2-year follow-up after adequate decompression during the index hip arthroscopic procedure and correlate the findings with PRO scores. The hypothesis was that there would be no recurrence or regrowth of the cam deformity at the 2-year postoperative time point after adequate cam decompression during hip arthroscopic surgery. Case series; Level of evidence, 4. Between March 2009 and January 2011, data were prospectively collected on all patients undergoing hip arthroscopic surgery with femoral neck osteoplasty. Minimum follow-up was 2 years, with radiographic images for review. A total of 47 patients met the inclusion criteria. The mean age of the participants at the start of the study was 37.18 years (range, 31.70-47.43 years). There were 28 men (59.57%) and 19 women (40.43%). The mean follow-up duration was 28.32 months (range, 24-41 months). The mean preoperative alpha angle (Dunn view) was 70° (range, 60°-97°), compared with 42.79° (range, 32°-50°) at 2 weeks postoperatively (P < .0001). The mean 2-year alpha angle was 42.72° (range, 32°-54°), which was not significantly different compared with the mean 2-week alpha angle (P = .93). Additionally, the mean femoral offset measurement was 3.7 mm (range, 0-9.9 mm) preoperatively and 7.8 mm (range, 0.3-13.9 mm) 2 weeks postoperatively (P < .0001). The mean 2-year postoperative femoral offset measurement was 8.0 mm (range, 2.4-12.8 mm), which was not significantly different compared with the mean 2-week femoral offset measurement (P = .63). All PRO scores were significantly improved at 3 months compared with preoperative scores and, except for visual analog scale score, continued to show improvement at 2-year follow-up. There was no recurrence of cam deformity at 2 years after femoral neck osteoplasty for femoroacetabular impingement. PRO scores were improved at the 3-month and 2-year postoperative time points.


Eel parasite diversity and intermediate host abundance in the River Rhine, Germany.
European eels (Anguilla anguilla) from 2 sampling sites on the Rhine river (near Karlsruhe and near Worms) were investigated with respect to their parasite communities. Nine different metazoan species were found to live in and on the eels. The highest number of species was recorded from the intestine, which contained up to 6 different helminths. Among these, acanthocephalans were the most prevalent worms with the eel-specific parasite Paratenuisentis ambiguus as the dominant species of the intestinal component communities at both sites. Comparing the intestinal parasites from eels caught near Karlsruhe with those from Worms, the acanthocephalans showed a significantly lower abundance at Worms. A significantly lower mean number of intestinal helminth species as well as a significantly lower Brillouin's Index was found at Worms compared with Karlsruhe. This difference could be related to the abundance of the respective intermediate crustacean hosts. At the sampling site Worms the amphipod Corophium curvispinum was the dominant crustacean. Additionally, only the isopod Jaera istri and the amphipod Dikerogammarus villosus were found. All these crustacean species have only recently colonized the Rhine river system via the Main-Danube canal, built in the early 1990s. They are not known to act as intermediate hosts for any of the acanthocephalans found in the eels. The site near Karlsruhe exhibited a higher crustacean diversity, including Asellus aquaticus and different species of the genus Gammarus, which are all known intermediate hosts for the acanthocephalans found. Therefore, changes of eel parasite diversity can be correlated with the appearance of invading crustacean species (neozoans).


Effect of low-fat, fermented milk enriched with plant sterols on serum lipid profile and oxidative stress in moderate hypercholesterolemia.
Plant sterol (PS)-enriched foods have been shown to reduce plasma LDL-cholesterol concentrations. In most studies, however, PSs were incorporated into food products of high fat content. We examined the effect of daily consumption of PS-supplemented low-fat fermented milk (FM) on the plasma lipid profile and on systemic oxidative stress in hypercholesterolemic subjects. Hypercholesterolemic subjects (LDL-cholesterol concentrations >or=130 and <or= 190 mg/dL; n = 194) consumed 2 low-fat portions of FM in the same meal daily for 6 wk. Subjects were randomly assigned to 2 groups: low-fat FM enriched with 0.8 g PS ester per portion or control FM. Plasma concentrations of lipids, oxidized LDL, beta-carotene, beta-sitosterol, campesterol, and high-sensitivity C-reactive protein were measured during the trial. Plasma LDL-cholesterol concentrations were reduced by 9.5% and 7.8% after 3 and 6 wk, respectively, in the 1.6-g/d PS group compared with the control group, whereas plasma triacylglycerol and HDL-cholesterol concentrations were not significantly affected. In addition, there were no significant changes in serum beta-carotene on normalization to LDL cholesterol during the study period in both groups, whereas plasma concentrations of oxidized LDL were reduced significantly in the PS group compared with the control group (-1.73 compared with 1.40 U/L, respectively; P < 0.05). Plasma sitosterol concentrations were increased by 35% (P < 0.001 compared with control); however, campesterol concentrations did not change during the study period. Daily consumption of 1.6 g PS in low-fat FM efficiently lowers LDL cholesterol in subjects with moderate hypercholesterolemia without deleterious effects on biomarkers of oxidative stress.


A web-based laboratory information system to improve quality of care of tuberculosis patients in Peru: functional requirements, implementation and usage statistics.
Multi-drug resistant tuberculosis patients in resource-poor settings experience large delays in starting appropriate treatment and may not be monitored appropriately due to an overburdened laboratory system, delays in communication of results, and missing or error-prone laboratory data. The objective of this paper is to describe an electronic laboratory information system implemented to alleviate these problems and its expanding use by the Peruvian public sector, as well as examine the broader issues of implementing such systems in resource-poor settings. A web-based laboratory information system "e-Chasqui" has been designed and implemented in Peru to improve the timeliness and quality of laboratory data. It was deployed in the national TB laboratory, two regional laboratories and twelve pilot health centres. Using needs assessment and workflow analysis tools, e-Chasqui was designed to provide for improved patient care, increased quality control, and more efficient laboratory monitoring and reporting. Since its full implementation in March 2006, 29,944 smear microscopy, 31,797 culture and 7,675 drug susceptibility test results have been entered. Over 99% of these results have been viewed online by the health centres. High user satisfaction and heavy use have led to the expansion of e-Chasqui to additional institutions. In total, e-Chasqui will serve a network of institutions providing medical care for over 3.1 million people. The cost to maintain this system is approximately US$0.53 per sample or 1% of the National Peruvian TB program's 2006 budget. Electronic laboratory information systems have a large potential to improve patient care and public health monitoring in resource-poor settings. Some of the challenges faced in these settings, such as lack of trained personnel, limited transportation, and large coverage areas, are obstacles that a well-designed system can overcome. e-Chasqui has the potential to provide a national TB laboratory network in Peru. Furthermore, the core functionality of e-Chasqui as been implemented in the open source medical record system OpenMRS http://www.openmrs.org for other countries to use.


How dolphins see the world: a comparison with chimpanzees and humans.
Bottlenose dolphins use auditory (or echoic) information to recognise their environments, and many studies have described their echolocation perception abilities. However, relatively few systematic studies have examined their visual perception. We tested dolphins on a visual-matching task using two-dimensional geometric forms including various features. Based on error patterns, we used multidimensional scaling to analyse perceptual similarities among stimuli. In addition to dolphins, we conducted comparable tests with terrestrial species: chimpanzees were tested on a computer-controlled matching task and humans were tested on a rating task. The overall perceptual similarities among stimuli in dolphins were similar to those in the two species of primates. These results clearly indicate that the visual world is perceived similarly by the three species of mammals, even though each has adapted to a different environment and has differing degrees of dependence on vision.


Interferon-based therapy decreases risks of hepatocellular carcinoma and complications of cirrhosis in chronic hepatitis C patients.
Interferon-based therapy (IBT) has been the standard of care for hepatitis C virus (HCV) infection. However, conflicting results exist regarding the effects of IBT on risk of developing hepatocellular carcinoma (HCC) and cirrhosis-associated complications, and most included highly selected patients. This 8-year cohort study was based on the Longitudinal Health Insurance Database 2000 (LHID 2000) consisting of 1,000,000 beneficiaries randomly selected from all Taiwan National Health Insurance enrollees in 2000 (>23.7 million). Patients with newly detected HCV infections (n=11,264) were classified based on treatment and clinical outcomes. IBTs were defined as regimens that included interferon- alfa, pegylated interferon- alfa -2a, or pegylated interferon- alfa -2b for at least 3 months. The Cox proportional hazards models were used to estimate the hazard ratio (HR) and associated confidence interval (CI) of HCC and cirrhosis-associated complications for IBT. The 8-year incidence rate for HCC was 3.9% among patients who received IBT and 5.6% among those who did not. The HCC-free survival rate was significantly higher among patients receiving IBT during the 8-year period than their counterpart (adjusted HR, 0.50; 95% CI, 0.31-0.81; P= .004). Similarly, the event-free survival rates for esophageal variceal bleeding (adjusted HR, 0.45; 95% CI, 0.22-0.91; P= .026), hepatic encephalopathy (adjusted HR, 0.38; 95% CI, 0.21-0.69; P= .001), ascites (adjusted HR, 0.28; 95% CI, 0.14-0.57; P<.001), and cirrhosis (adjusted HR, 0.63; 95% CI, 0.44-0.91; P= .013) were significantly higher among patients who received IBT than those who did not, after adjustment for associated factors. Treatment with interferon may reduce the 8-year risk of HCC and cirrhosis-associated complications in patients with chronic HCV infection.


Interfacial Behavior of n-decyl-beta-D-maltopyranoside on hydrophobic interfaces and the effect of small amounts of surface-active impurities.
The effect of small amounts of surface-active impurities on the interfacial properties of n-decyl-beta-D-maltopyranoside was investigated using various methods. The n-Decyl-beta-D-maltopyranoside was used both as received from Sigma (<98% by GC) and after being purified with the surfactant-purifying apparatus developed by Lunkenheimer, which removes impurities that are more surface active than the major component. Surface tension measurements demonstrate that the surface elasticity of the surfactant-loaded liquid-vapor interface increased after purification. Measurements of interactions across single foam films revealed that the purified solution formed considerably less charged and less stable films compared with the as-received sample. These results are consistent with the lower foam stability for the purified sample as determined by simple shaking experiments. The lower film stability for the purified solution was attributed to the lower double-layer force. The forces acting between spherical silanated glass surfaces across surfactant solutions were determined with the MASIF (measurement and analysis of surface interaction forces) technique. On approach, the same interactions were experienced in solutions of the as-received and purified surfactant. On the other hand, the adhesion force was lower after purification. Both for the as-received and the purified sample it was observed that the adhesion increased with increasing contact time up to a certain limit. This was explained in terms of partial pressure-induced desorption of surfactants from the disordered silane layers. Wetting experiments also indicated that the surfactants were difficult to remove completely from this surface.


A combination of chitooligosaccharide and lipochitooligosaccharide recognition promotes arbuscular mycorrhizal associations in Medicago truncatula.
Plants associate with beneficial arbuscular mycorrhizal fungi facilitating nutrient acquisition. Arbuscular mycorrhizal fungi produce chitooligosaccharides (COs) and lipo-chitooligosaccharides (LCOs), that promote symbiosis signalling with resultant oscillations in nuclear-associated calcium. The activation of symbiosis signalling must be balanced with activation of immunity signalling, which in fungal interactions is promoted by COs resulting from the chitinaceous fungal cell wall. Here we demonstrate that COs ranging from CO4-CO8 can induce symbiosis signalling in Medicago truncatula. CO perception is a function of the receptor-like kinases MtCERK1 and LYR4, that activate both immunity and symbiosis signalling. A combination of LCOs and COs act synergistically to enhance symbiosis signalling and suppress immunity signalling and receptors involved in both CO and LCO perception are necessary for mycorrhizal establishment. We conclude that LCOs, when present in a mix with COs, drive a symbiotic outcome and this mix of signals is essential for arbuscular mycorrhizal establishment.


Self-reported load carriage injuries of military soldiers.
The aim of this study was to investigate whether occupational load carriage constitutes a significant source of injury to military soldiers. An online survey was sent to soldiers serving in specific Australian Army Corps known to experience the greatest occupational exposure to load carriage. Of the 338 respondents, 34% sustained at least one load carriage injury. Fifty-two per cent of those injured during initial training reported sustaining an additional load carriage injury. The majority of injuries (61%) were to the lower limbs with bones and joints the most frequently injured body structures (39%). Endurance marching (continuous marching as part of a physical training session) was the activity accounting for most (38%) injuries. Occupational load carriage is associated with military soldier injuries and, once injured, soldiers are at a high risk of future load carriage injury. The bodily sites and nature of self-reported injuries in this study are akin to those of formally reported injuries and those of other militaries.


Human immunodeficiency virus type 2 (HIV-2) env gene analysis: prediction of glycoprotein epitopes important for heterotypic neutralization and evidence for three genotype clusters within the HIV-2a subtype.
The env gene sequences of ten tissue-culture-adapted human immunodeficiency virus type 2 (HIV-2) isolates from West African patients were determined. Alignment and comparison of the gene sequences and putative translation products with database sequences revealed 11-29% diversity at the nucleotide level and 15-31% variation at the protein level. From analysis of glycoproteins of HIV-2 strains sensitive and resistant to neutralization by HIV-1 antisera, five regions were identified as putative targets for cross-neutralizing antibody. The HIV-2 equivalent of the HIV-1 V3 loop was not included in this number. However, three of the HIV-2 peptides aligned with regions identified as targets for broad neutralization of HIV-1 strains. These were the V2 and CD4-binding domains of gp120 and the Kennedy domain in gp41. Phylogenetic analysis of the env gene sequences, together with HIV-2 env gene sequences published in the Los Alamos database, support the identification of two distinct HIV-2 subtypes, HIV-2a and HIV-2b. The new sequences are located within the HIV-2a subtype and allow prediction of at least three genotypes, designated I-III. Some correlation of genotype with geographical origin of isolates was noted. Genotype I viruses originate from Guinea Bissau and group II viruses mainly originate from The Gambia. One isolate from Guinea Bissau, HIV-2CAM4, appears phylogenetically older than other viruses in the HIV-2a subtype. The possible implications of this in the light of epidemiological findings in Guinea Bissau are discussed.


Predictors of repeated sick leave in the workplace because of mental disorders.
Mental disorders create a considerable burden to society. Previous studies have shown that productivity loss constitutes the largest proportion of the total societal burden. For depression and anxiety disorders, in particular, more than half of the associated productivity loss occurs in the workplace. Many previous studies have clarified the risk factors for the relapse/recurrence of mental disorders in health care settings. However, the risk factors for repeated sick leave among mental disorders prevalent in the workplace have not yet been adequately evaluated. The objective of this study was to investigate which variables could predict repeated sick leave for workers with a history of sick leave because of mental disorders. Data regarding 194 subjects employed at a manufacturing company were obtained. Mental disorders were defined as disorders listed in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The duration between the return to work (RTW) and the repeated sick leave was regarded as a dependent variable. The subjects' age at the RTW, sex, age at the time of employment, job tenure, diagnosis, number of previous sick leave days, duration of most recent sick leave, and employee rank were examined as explanatory variables. Univariate analyses using a log-rank test and a multivariate analysis using the Cox proportional hazard model were conducted. The results of the univariate analyses showed that the number of previous sick-leave episodes was a significant predictor of repeated sick leave. A multivariate analysis revealed that age at RTW and the number of previous sick-leave episodes were significant variables. Age and the number of previous sick-leave episodes appeared to be predictors of repeated sick leave. Therefore, effective intervention to prevent repeated sick leave for those with high risk is quite crucial. Analyses including various work-related factors with subjects from multiple companies should be conducted in future studies.


Adenovirus vector and mRNA vaccines: Mechanisms regulating their immunogenicity.
Replication-incompetent adenovirus (Ad) vector and mRNA-lipid nanoparticle (LNP) constructs represent two modular vaccine platforms that have attracted substantial interest over the past two decades. Due to the COVID-19 pandemic and the rapid development of multiple successful vaccines based on these technologies, there is now clear real-world evidence of the utility and efficacy of these platforms. Considerable optimization and refinement efforts underpin the successful application of these technologies. Despite this, our understanding of the specific pathways and processes engaged by these vaccines to stimulate the immune response remains incomplete. This review will synthesize our current knowledge of the specific mechanisms by which CD8+ T cell and antibody responses are induced by each of these vaccine platforms, and how this can be impacted by specific vaccine construction techniques. Key gaps in our knowledge are also highlighted, which can hopefully focus future studies.


A systematic review of nicardipine vs labetalol for the management of hypertensive crises.
Hypertensive emergencies are acute elevations in blood pressure (BP) that occur in the presence of progressive end-organ damage. Hypertensive urgencies, defined as elevated BP without acute end-organ damage, can often be treated with oral agents, whereas hypertensive emergencies are best treated with intravenous titratable agents. However, a lack of head-to-head studies has made it difficult to establish which intravenous drug is most effective in treating hypertensive crises. This systematic review presents a synthesis of published studies that compare the antihypertensive agents nicardipine and labetalol in patients experiencing acute hypertensive crises. A MEDLINE search was conducted using the term "labetalol AND nicardipine AND hypertension." Conference abstracts were searched manually. Ultimately, 10 studies were included, encompassing patients with hypertensive crises across an array of indications and practice environments (stroke, the emergency department, critical care, surgery, pediatrics, and pregnancy). The results of this systematic review show comparable efficacy and safety for nicardipine and labetalol, although nicardipine appears to provide more predictable and consistent BP control than labetalol.


Translating resuscitation guidelines into practice: health care provider attitudes, preferences and beliefs regarding pediatric fluid resuscitation performance.
Children who require fluid resuscitation for the treatment of shock present to tertiary and non-tertiary medical settings. While timely fluid therapy improves survival odds, guidelines are poorly translated into clinical practice. The objective of this study was to characterize the attitudes, preferences and beliefs of health care providers working in acute care settings regarding pediatric fluid resuscitation performance. A single-centre survey study was conducted at McMaster Children's Hospital from January to May, 2012. The sampling frame (n = 115) included nursing staff, physician staff and subspecialty trainees working in Pediatric Emergency Medicine (PEM) or Pediatric Critical Care Medicine (PCCM). A self-administered questionnaire was developed and assessed for face validity prior to distribution. Eligible participants were invited at 0, 2, and 4 weeks to complete a web-based version of the survey. A follow-up survey administration phase was conducted to improve the response rate. Response rate was 72.2% (83/115), with 83% (68/82) self-identifying as nursing staff and 61% (50/82) as PCCM providers. Resuscitation experience, frequency of shock management, and years in specialty, were similar between PCCM and PEM responders. Physicians and nurses had differing opinions regarding the most effective method to achieve rapid fluid resuscitation in young children presenting in shock (p<0.001). Disagreement also existed regarding the age and size of patients in whom rapid infuser devices, such as the Level-1 Rapid Infuser, should be used (p<0.001). Providers endorsed a number of potential concerns related to the use of rapid infuser devices in children, and only 14% of physicians and 55% of nursing staff felt that they had received adequate training in the use of such devices (p = 0.005). There is a lack of consensus among health care providers regarding how pediatric fluid resuscitation guidelines should be operationalized, supporting a need for further work to define best practices.


SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport.
The epithelial Na+ channel (ENaC) constitutes the rate-limiting step for Na+ transport across tight epithelia and is the principal target of hormonal regulation, particularly by insulin and mineralocorticoids. Recently, the serine-threonine kinase (SGK) was identified as a rapidly mineralocorticoid-responsive gene, the product of which stimulates ENaC-mediated Na+ transport. Like its close relative, protein kinase B (also called Akt), SGK's kinase activity is dependent on phosphatidylinositol 3-kinase (PI3K), a key mediator of insulin signaling. In our study we show that PI3K is required for SGK-dependent stimulation of ENaC-mediated Na+ transport as well as for the production of the phosphorylated form of SGK. In A6 kidney cells, mineralocorticoid induction of the phosphorylated form of SGK preceded the increase in Na+ transport, and specific inhibition of PI3K inhibited both phosphorylation of SGK and mineralocorticoid-induced Na+ transport. Insulin both augmented SGK phosphorylation and synergized with mineralocorticoids in stimulating Na+ transport. In a Xenopus laevis oocyte coexpression assay, SGK-stimulated ENaC activity was also markedly reduced by PI3K inhibition. Finally, in vitro-translated SGK specifically interacted with the ENaC subunits expressed in Escherichia coli as glutathione S-transferase fusion proteins. These data suggest that SGK is a PI3K-dependent integrator of insulin and mineralocorticoid actions that interacts with ENaC subunits to control Na+ entry into kidney collecting duct cells.


Local edge-preserving multiscale decomposition for high dynamic range image tone mapping.
A novel filter is proposed for edge-preserving decomposition of an image. It is different from previous filters in its locally adaptive property. The filtered image contains local means everywhere and preserves local salient edges. Comparisons are made between our filtered result and the results of three other methods. A detailed analysis is also made on the behavior of the filter. A multiscale decomposition with this filter is proposed for manipulating a high dynamic range image, which has three detail layers and one base layer. The multiscale decomposition with the filter addresses three assumptions: 1) the base layer preserves local means everywhere; 2) every scale's salient edges are relatively large gradients in a local window; and 3) all of the nonzero gradient information belongs to the detail layer. An effective function is also proposed for compressing the detail layers. The reproduced image gives a good visualization. Experimental results on real images demonstrate that our algorithm is especially effective at preserving or enhancing local details.


A host-parasite model yielding heterogeneous parasite loads.
Many models of parasitic infections lead to an approximately Poisson distribution of parasites among hosts, in stark contrast to the highly over-dispersed distributions that are usually encountered in practice. In this paper, a model is analyzed which, while assuming all individuals to be alike, can still lead to a very heterogeneous distribution of parasites among the host population. The model can be viewed as a very simple mean field interacting particle system, with the particles corresponding to the individual hosts, which behaves like an associated deterministic system when the number of hosts is large. The deterministic system describes the evolution over time of the proportions of the population with different parasite loads and its equilibria are interpreted as typical distributions of parasites among hosts. Despite its simplicity, the model is complicated enough mathematically to leave a number of open problems.