Molecular Characterization and Prospective Evaluation of Pathologic Response and Outcomes with Neoadjuvant Therapy in Metaplastic Triple-Negative Breast Cancer.
Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy in retrospective studies. To better define clinical outcomes and correlates of response, we analyzed the rate of pathologic complete response (pCR) to neoadjuvant therapy, survival outcomes, and genomic and transcriptomic profiles of the pretreatment tumors in a prospective clinical trial (NCT02276443). A total of 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide-based neoadjuvant therapy. Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience a pCR (23% vs. 40%; P = 0.07), had shorter event-free survival (29.4 vs. 32.2 months, P = 0.15), metastasis-free survival (30.3 vs. 32.4 months, P = 0.22); and overall survival (32.6 vs. 34.3 months, P = 0.21). This heterogeneity is mirrored in the molecular profiling. Mutations in PI3KCA (23% vs. 9%, P = 0.07) and its pathway (41% vs. 18%, P = 0.02) were frequently observed and enriched in MpBCs. The gene expression profiles of each histologically defined subtype were distinguishable and characterized by distinctive gene signatures. Among nonmetaplastic (non-Mp) TNBCs, 10% possessed a metaplastic-like gene expression signature and had pCR rates and survival outcomes similar to MpBC. Further investigations will determine if metaplastic-like tumors should be treated more similarly to MpBC in the clinic. The 23% pCR rate in this study suggests that patients with MpBC should be considered for NAT. To improve this rate, a pathway analysis predicted enrichment of histone deacetylase (HDAC) and RTK/MAPK pathways in MpBC, which may serve as new targetable vulnerabilities.


Occupational history of night shift work and Parkinson's disease in Denmark.
We investigated whether working night shifts was associated with the risk of Parkinson's disease (PD). Between January 2008 and December 2010, we recruited 1808 patients with a confirmed diagnosis of idiopathic PD from Denmark and 1876 population controls matched by year of birth and gender. Information on lifelong occupational history, including information on night work, smoking, caffeine and alcohol consumption habits, and family history of PD was collected through structured telephone interviews. Overall, there was no association between a history of night shift work and PD [odds ratio (OR) for any type of night work (ie, either permanent or rotating night work) 1.01, 95% confidence interval (95% CI) 0.86-1.21]. Compared with persons who never worked night shifts, risks of those with longer durations of night work did not appear to differ (OR <10 years=0.95, 95% CI 0.75-1.19, OR 10-19 years= 1.09, 95% CI 0.77-1.53, OR ≥20 years=1.05, 95% CI 0.81-1.37, P for trend=0.23). Associations were similar among men and women. These data suggest that working night shifts is not associated with PD or that low tolerance for night shift work is an early marker of PD. Due to the novel and exploratory nature of these findings, confirmation is needed.


Impact of FDA Actions, DTCA, and Public Information on the Market for Pain Medication.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most important classes of prescription drugs used by primary care physicians to manage pain. The NSAID class of products has a somewhat controversial history, around which a complex regulatory and informational environment has developed. This history includes a boxed warning mandated by the Food and Drug Administration (FDA) for all NSAIDs in 2005. We investigate the impact that various information shocks have had on the use of prescription medications for pain in primary care in the USA. We accomplish this by extracting data on nearly 600,000 patients from a unique nationwide electronic medical record database and estimate the probability of any active prescription for the four types of pain medications as a function of FDA actions, advertising, media coverage, and patient characteristics. We find that even after accounting for multiple sources of information, the FDA label changes and boxed warnings had a significant effect on pain medication prescribing. The boxed warning did not have the same impact on the use of all NSAID inhibitors. We find that the boxed warning reduced the use of NSAID COX-2 inhibitor use, which was the focus of much of the press attention. In contrast, however, the warning actually increased the use of non-COX-2 NSAID inhibitors. Thus, the efficacy of the FDA's black box warning is clearly mixed.


On removing interpolation and resampling artifacts in rigid image registration.
We show that image registration using conventional interpolation and summation approximations of continuous integrals can generally fail because of resampling artifacts. These artifacts negatively affect the accuracy of registration by producing local optima, altering the gradient, shifting the global optimum, and making rigid registration asymmetric. In this paper, after an extensive literature review, we demonstrate the causes of the artifacts by comparing inclusion and avoidance of resampling analytically. We show the sum-of-squared-differences cost function formulated as an integral to be more accurate compared with its traditional sum form in a simple case of image registration. We then discuss aliasing that occurs in rotation, which is due to the fact that an image represented in the Cartesian grid is sampled with different rates in different directions, and propose the use of oscillatory isotropic interpolation kernels, which allow better recovery of true global optima by overcoming this type of aliasing. Through our experiments on brain, fingerprint, and white noise images, we illustrate the superior performance of the integral registration cost function in both the Cartesian and spherical coordinates, and also validate the introduced radial interpolation kernel by demonstrating the improvement in registration.


Glucose-stimulated insulin secretion is coupled to the interaction of actin with the t-SNARE (target membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein) complex.
The actin monomer sequestering agent latrunculin B depolymerized beta-cell cortical actin, which resulted in increased glucose-stimulated insulin secretion in both cultured MIN6 beta-cells and isolated rat islet cells. In perifused islets, latrunculin B treatment increased both first- and second-phase glucose-stimulated insulin secretion without any significant effect on total insulin content. This increase in secretion was independent of calcium regulation because latrunculin B also potentiated calcium-stimulated insulin secretion in permeabilized MIN6 cells. Confocal immunofluorescent microscopy revealed a redistribution of insulin granules to the cell periphery in response to glucose or latrunculin B, which correlated with a reduction in phalloidin staining of cortical actin. Moreover, the t-SNARE [target membrane soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor] proteins Syntaxin 1 and SNAP-25 coimmunoprecipitated polymerized actin from unstimulated MIN6 cells. Glucose stimulation transiently decreased the amount of actin coimmunoprecipitated with Syntaxin 1 and SNAP-25, and latrunculin B treatment fully ablated the coimmunoprecipitation. In contrast, the actin stabilizing agent jasplakinolide increased the amount of actin coimmunoprecipitated with the t-SNARE complex and prevented its dissociation upon glucose stimulation. These data suggest a mechanism whereby glucose modulates beta-cell cortical actin organization and disrupts the interaction of polymerized actin with the plasma membrane t-SNARE complex at a distal regulatory step in the exocytosis of insulin granules.


Possible role of human herpesvirus 6 as a trigger of autoimmune disease.
Human herpesvirus 6 (HHV-6) infection is common and has a worldwide distribution. Recently, HHV-6A and HHV-6B have been reclassified into two distinct species based on different biological features (genetic, antigenic, and cell tropism) and disease associations. A role for HHV-6A/B has been proposed in several autoimmune disorders (AD), including multiple sclerosis (MS), autoimmune connective tissue diseases, and Hashimoto's thyroiditis. The focus of this review is to discuss the above-mentioned AD associated with HHV-6 and the mechanisms proposed for HHV-6A/B-induced autoimmunity. HHV-6A/B could trigger autoimmunity by exposing high amounts of normally sequestered cell antigens, through lysis of infected cells. Another potential trigger is represented by molecular mimicry, with the synthesis of viral proteins that resemble cellular molecules, as a mechanism of immune escape. The virus could also induce aberrant expression of histocompatibility molecules thereby promoting the presentation of autoantigens. CD46-HHV-6A/B interaction is a new attractive mechanism proposed: HHV-6A/B (especially HHV-6A) could participate in neuroinflammation in the context of MS by promoting inflammatory processes through CD46 binding. Although HHV-6A/B has the ability to trigger all the above-mentioned mechanisms, more studies are required to fully elucidate the possible role of HHV-6A/B as a trigger of AD.


Bony manifestation of rickets in a sunny city - a case report from Yazd, Iran.
Rickets is disease that occurs in growing bones in which defective mineralization occurs in both the bone and the cartilage of the epiphyseal growth plate, resulting in the retardation of growth and skeletal deformities. Rickets is more common in areas with less sunlight. However, this case report presents a case of the bony manifestation of rickets with the intake of vitamin D supplements in Yazd, a city in central Iran that has sunshine almost every day. A patient was referred to an out-patient general pediatric clinic for deformities of the legs and growth disturbance, with his height far below the normal range. The changes that were most evident in his X-rays were the bowing of the long bones of the legs and forearms and the cupping of the wrist metaphyseal region. In summary, we present a patient with bony manifestation of rickets despite living in a sunny area and taking vitamin D supplements. Thus, it is important to remember that rickets is still a common disease among children in Iran. More studies of this issue should be conducted, including the identification of abnormal cases and rescheduling vitamin D supplementation programs.


HrpG and HrpV proteins from the Type III secretion system of Erwinia amylovora form a stable heterodimer.
Bacterial type III secretion systems (T3SSs) are specialized multicomponent nanomachines that mediate the transport of proteins either to extracellular locations or directly into eukaryotic host cell cytoplasm. Erwinia amylovora, the main agent of rosaceous plants fireblight disease, employs an Hrp/Hrc1 T3SS to accomplish its pathogenesis. The regulatory network that controls the activation of this T3SS is largely unknown in E. amylovora. However, in Pseudomonas syringae pathovars, the HrpG/HrpV complex has been shown to directly regulate the activity of transcription factor HrpS and consequently the upregulation of the Hrp/Hrc1 T3SS related genes. In this work, we report the successful recombinant production and purification of a stable E. amylovora HrpG/HrpV complex, using pPROpET, a bicistronic expression vector. Furthermore, we present the first solution structure of this complex based on small-angle X-ray scattering data.


Angiotensin-I converting enzyme genotype-dependent benefit from hormone replacement therapy in isometric muscle strength and bone mineral density.
Low bone mineral density (BMD) and muscle weakness are major risk factors for postmenopausal osteoporotic fracture. Hormone replacement therapy (HRT) reverses the menopausal decline in maximum voluntary force of the adductor pollicis and reduces serum angiotensin-I converting enzyme (ACE) levels. The insertion (I) allele of the ACE gene polymorphism is associated with lower ACE activity and improved muscle efficiency in response to physical training. Therefore, we examined whether the presence of the I allele in postmenopausal women would affect the muscle response to HRT. Those taking HRT showed a significant gain in normalized muscle maximum voluntary force slope, the rate of which was strongly influenced by ACE genotype (16.0 +/- 1.53%, 14.3 +/- 2.67%, and 7.76 +/- 4.13%, mean +/- SEM for II, ID, and DD genotype, respectively; P = 0.017 for gene effect, P = 0.004 for I allele effect). There was also a significant ACE gene effect in the response of BMD to HRT in Ward's triangle (P = 0.03) and a significant I allele effect in the spine (P = 0.03), but not in the neck of femur or total hip. These data suggests that low ACE activity associated with the I allele confers an improved muscle and BMD response in postmenopausal women treated with HRT.


The use of medication against attention deficit hyperactivity disorder in Denmark: a drug use study from a national perspective.
The purpose of the study was to characterize the utilization of medication against attention deficit hyperactivity disorder (ADHD) in Denmark between 1995 and 2011 from a national perspective, by using population-based prescription data. National data on drug use in Denmark between 1 January 1995 and 30 September 2011 were extracted from the Registry of Medicinal Product Statistics (RMPS). Drug utilization was characterized using descriptive statistics. A total of 1,085,090 prescriptions issued to 54,020 persons were identified. The incidence rate was stable in the last 3 years of the study period, and a slightly decreasing incidence rate and a stabilizing prevalence were observed towards the end of this period. The therapeutic intensity was 6.7 defined daily dose/person/day, with large regional differences that ranged from 64 to 145 % of the national average. Methylphenidate accounted for 92.6 % of DDDs used. The general practitioner (GP) rarely initiated treatment, although treatment initiation based on the GP's advice increased with older age of the patient. Maintenance treatment was found to be distributed roughly equally between prescriber types. For methylphenidate, 1 % of users accounted for 6.1 % of the drug volume and 50 % of users accounted for 84.4 %. The data therefore do not suggest a high proportion of heavy users. The findings of this analysis are mostly reassuring, with the data indicating a seemingly stagnant incidence and prevalence rate and lacking evidence of heavy users. However, the prescriber profile for incident users and the large regional variances raise concerns. It is therefore vital that the use of ADHD drugs is closely monitored.


A high capacity 3D steganography algorithm.
In this paper, we present a very high-capacity and low-distortion 3D steganography scheme. Our steganography approach is based on a novel multilayered embedding scheme to hide secret messages in the vertices of 3D polygon models. Experimental results show that the cover model distortion is very small as the number of hiding layers ranges from 7 to 13 layers. To the best of our knowledge, this novel approach can provide much higher hiding capacity than other state-of-the-art approaches, while obeying the low distortion and security basic requirements for steganography on 3D models.


Dermal nerve fibre and mast cell density, and proximity of mast cells to nerve fibres in the skin of patients with complex regional pain syndrome.
An interaction between cutaneous nerves and mast cells may contribute to pain in complex regional pain syndrome (CRPS). To explore this, we investigated the density of dermal nerve fibres, and the density and proximity of mast cells to nerve fibres, in skin biopsies obtained from the affected and unaffected limbs of 57 patients with CRPS and 28 site-matched healthy controls. The percentage of the dermis stained by the pan-neuronal marker protein gene-product 9.5 was lower in the affected limb of patients than in controls (0.12 ± 0.01% vs 0.22 ± 0.04%, P < 0.05), indicating a reduction in dermal nerve fibre density. This parameter did not correlate with CRPS duration. However, it was lower in the affected than unaffected limb of patients with warm CRPS. Dermal mast cell numbers were similar in patients and controls, but the percentage of mast cells less than 5 µm from nerve fibres was significantly lower in the affected and unaffected limbs of patients than in controls (16.8 ± 1.7%, 16.5 ± 1.7%, and 31.4 ± 2.3% respectively, P < 0.05). We confirm previous findings of a mild neuropathy in CRPS. Our findings suggest that this either develops very early after injury or precedes CRPS onset. Loss of dermal nerve fibres in CRPS might result in loss of chemotactic signals, thus halting mast cell migration toward surviving nerve fibres. Failure of normal nerve fibre-mast cell interactions could contribute to the pathophysiology of CRPS.


Inhaled hypertonic saline for cystic fibrosis: Reviewing the potential evidence for modulation of neutrophil signalling and function.
Cystic fibrosis (CF) is a multisystem disorder with significantly shortened life expectancy. The major cause of mortality and morbidity is lung disease with increasing pulmonary exacerbations and decline in lung function predicting significantly poorer outcomes. The pathogenesis of lung disease in CF is characterised in part by decreased airway surface liquid volume and subsequent failure of normal mucociliary clearance. This leads to accumulation of viscous mucus in the CF airway, providing an ideal environment for bacterial pathogens to grow and colonise, propagating airway inflammation in CF. The use of nebulised hypertonic saline (HTS) treatments has been shown to improve mucus clearance in CF and impact positively upon exacerbations, quality of life, and lung function. Several mechanisms of HTS likely improve outcome, resulting in clinically relevant enhancement in disease parameters related to increase in mucociliary clearance. There is increasing evidence to suggest that HTS is also beneficial through its anti-inflammatory properties and its ability to reduce bacterial activity and biofilm formation. This review will first describe the use of HTS in treatment of CF focusing on its efficacy and tolerability. The emphasis will then change to the potential benefits of aerosolized HTS for the attenuation of receptor mediated neutrophil functions, including down-regulation of oxidative burst activity, adhesion molecule expression, and the suppression of neutrophil degranulation of proteolytic enzymes.


Rates of infection after spine surgery based on 108,419 procedures: a report from the Scoliosis Research Society Morbidity and Mortality Committee.
Retrospective review of a prospectively collected database. Our objective was to assess the rates of postoperative wound infection associated with spine surgery. Although wound infection after spine surgery remains a common source of morbidity, estimates of its rates of occurrence remain relatively limited. The Scoliosis Research Society prospectively collects morbidity and mortality data from its members, including the occurrence of wound infection. The Scoliosis Research Society morbidity and mortality database was queried for all reported spine surgery cases from 2004 to 2007. Cases were stratified based on factors including diagnosis, adult (≥ 21 years) versus pediatric (<21 years), primary versus revision, use of implants, and whether a minimally invasive approach was used. Superficial, deep, and total infection rates were calculated. RESULTS.: In total, 108,419 cases were identified, with an overall total infection rate of 2.1% (superficial = 0.8%, deep = 1.3%). Based on primary diagnosis, total postoperative wound infection rate for adults ranged from 1.4% for degenerative disease to 4.2% for kyphosis. Postoperative wound infection rates for pediatric patients ranged from 0.9% for degenerative disease to 5.4% for kyphosis. Rate of infection was further stratified based on subtype of degenerative disease, type of scoliosis, and type of kyphosis for both adult and pediatric patients. Factors associated with increased rate of infection included revision surgery (P < 0.001), performance of spinal fusion (P < 0.001), and use of implants (P < 0.001). Compared with a traditional open approach, use of a minimally invasive approach was associated with a lower rate of infection for lumbar discectomy (0.4% vs. 1.1%; P < 0.001) and for transforaminal lumbar interbody fusion (1.3% vs. 2.9%; P = 0.005). Our data suggest that postsurgical infection, even among skilled spine surgeons, is an inherent potential complication. These data provide general benchmarks of infection rates as a basis for ongoing efforts to improve safety of care.


Recent advances in the treatment of tuberculosis.
Tuberculosis (TB) is a global health challenge and one of the leading causes of death worldwide. In the last decade, the TB treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid, and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, and SHINE) and drug-resistant TB (STREAM, NiX-TB, ZeNix, and TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs has also brought hopes of further development of safe and effective regimens. Consequently, international and WHO clinical guidelines have been updated multiple times in the last years to keep pace with these advances. This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant TB, as well as recent trial results and an overview of ongoing clinical trials. A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of TB. Ongoing clinical trials were listed according to the authors' knowledge and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials). This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetics and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research. Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centred access to new treatment options for all people affected by TB.


Major Contribution of Genomic Copy Number Variation in Syndromic Congenital Heart Disease: The Use of MLPA as the First Genetic Test.
Congenital heart disease (CHD) is the most common congenital disorder among live births. When associated with extracardiac abnormalities, it is characterized as a syndromic heart disease (syndromic CHD) and corresponds to 25% of all liveborn infants with a heart defect. The etiology in about 65% of the cases still remains unknown, and in about 35% of the patients, it is associated with genetic factors. In the present study, MLPA and SNP-array techniques were used to investigate a group of 47 patients with syndromic CHD. In total, 16 defects (34%) were identified, of which 12 (25.5%) were classified as pathogenic or probably pathogenic. The most frequent abnormalities were 22q11.2 deletion (22q11.2 deletion syndrome) and 7q11.23 deletion (Williams-Beuren syndrome). We also show that rarer malformations may be associated with syndromic CHD, such as 14q32.33 deletion as well as 17q25.3, 15q11.2 (BP1-BP2), 22q13.31, and 12p13.31 (SLC2A3) duplications. The present study demonstrates that CNVs are important causal factors and should be studied in patients with syndromic CHD. Furthermore, the use of MLPA as a first screening test was appropriate, as this less expensive technology detected 11 of the 12 pathogenic abnormalities (91.6%).


Compressive sensing resonator spectroscopy.
We present a new fast compressive spectroscopic technique based on the resonance spectrometric mechanism. This technique uses an appropriately designed Fabry-Perot resonator and a photo-sensor in order to acquire different multiplexed spectral modulations, from which the original signal is reconstructed using a compressive sensing reconstruction algorithm. We present experimental results that demonstrate the acquisition of hundreds of spectral bands with a compression ratio of about 1:13.


Use of electronic medical records and biomarkers to manage risk and resource efficiencies.
The migration from paper to electronic medical records (EMRs) was motivated by the administrative need to record, retrieve and process increasing amounts of clinical data in the 1980s. In the intervening period, there has been growing recognition of the potential of such records for achieving care efficiencies, informing clinical decision making and real-life research. EMRs can be used to characterise patient groups, management approaches and differential outcomes. Characterisation can also help with identification of potential biomarkers for future risk determination and likely treatment response. The future heralds even greater opportunities through integration of clinical records and a range of technology-based solutions within a more complete electronic health record (EHR). Through application of algorithms based on identified risk predictors and disease determinants, clinical records could also be used to enable risk stratification of patients to optimise targeted interventions, conserving resources to achieve individual patient and system-wide benefit. In this review, we reflect on the evolution of the EMR and EHR and discuss current and emerging opportunities, particularly with respect to biomarkers and targeting of innovative biologic interventions. We also consider some of the critical issues associated with realising the potential of the EHR as a clinical aid and research tool in an age of emerging technologies..


NOTCH1 inhibition in vivo results in mammary tumor regression and reduced mammary tumorsphere-forming activity in vitro.
NOTCH activation has been recently implicated in human breast cancers, associated with a poor prognosis, and tumor-initiating cells are hypothesized to mediate resistance to treatment and disease relapse. To address the role of NOTCH1 in mammary gland development, transformation, and mammary tumor-initiating cell activity, we developed a doxycycline-regulated mouse model of NOTCH1-mediated mammary transformation. Mammary gland development was analyzed by using whole-mount analysis and by flow cytometry in nulliparous transgenic mice maintained in the presence/absence of doxycycline (or intracellular NOTCH1). Mammary tumors were examined histologically and immunophenotyped by staining with antibodies followed by flow cytometry. Tumors were transplanted into mammary fat pads under limiting dilution conditions, and tumor-initiating cell frequency was calculated. Mammary tumor cells were also plated in vitro in a tumorsphere assay in the presence/absence of doxycycline. RNA was isolated from mammary tumor cell lines cultured in the presence/absence of doxycycline and used for gene-expression profiling with Affymetrix mouse arrays. NOTCH1-regulated genes were identified and validated by using quantitative real-time polymerase chain reaction (PCR). Mammary tumor-bearing mice were treated with doxycycline to suppress NOTCH1 expression, and disease recurrence was monitored. Similar to published studies, we show that constitutive expression of human intracellular NOTCH1 in the developing mouse mammary gland inhibits side branching and promotes luminal cell fate. These mice develop mammary adenocarcinomas that express cytokeratin (CK) 8/18. In vivo limiting-dilution analyses revealed that these mammary tumors exhibit functional heterogeneity and harbor a rare (1/2,978) mammary tumor-initiating cell population. With this dox-regulated NOTCH1 mammary tumor model, we demonstrate that NOTCH1 inhibition results in mammary tumor regression in vivo and prevents disease recurrence in four of six tumors tested. Consistent with the in vivo data, NOTCH1 inhibition reduces mammary tumorsphere activity in vitro. We also identify the embryonic stem cell transcription factor Nanog as a novel NOTCH1-regulated gene in tumorspheres and in mouse and human breast cancer cell lines. These data indicate that NOTCH1 inhibition results in mammary tumor regression in vivo and interferes with disease recurrence. We demonstrate that NOTCH1-transformed mouse mammary tumors harbor a rare mammary tumor-initiating population and that NOTCH1 contributes to mammary tumor-initiating activity. This work raises the possibility that NOTCH therapeutics may target mammary tumor-initiating cells in certain human breast cancer subtypes.


Computational Screening of Rhodopsin Mutations Associated with Retinitis Pigmentosa.
Retinitis pigmentosa (RP) refers to a group of debilitating, hereditary disorders that cause severe visual impairment in as many as 1.5 million patients worldwide. Rhodopsin mutations account for >25% of the autosomal dominant form of the disease (ADRP). Forty artificial and ADRP-associated mutations located in the second extracellular loop (EL2) that folds into a twisted β-hairpin were screened through replica exchange molecular dynamics (REMD) simulations using the FACTS implicit solvent model. According to in vitro experiments, ADRP-linked mutants fail to express at the plasma membrane and/or to reconstitute with 11-cis-retinal, indicative of variable defects in protein folding and/or stability. The computational protocol was first probed on the protein G C-terminal β-hairpin, proving the effectiveness of the implicit solvent model in reproducing the free energy landscape of β-hairpin formation. Eight out of the 40 EL2 mutants resulted in misfolding effects on the native β-hairpin structure, consistent with in vitro evidence that they all share severe impairments in folding/expression. Five mutants displayed moderate misfolding attitudes, whereas the remaining 27 mutants, overall characterized by milder effects on rhodopsin expression, did not perturb significantly the conformational behavior of the native β-hairpin but are expected to exert variably disturbing effects on the native interactions of the loop with the chromophore and/or the surrounding receptor domains. Collectively, the results of this study add structural insight to the poorly resolved biochemical behavior of selected class II ADRP mutations, a fundamental step toward an understanding of the atomistic causes of the disease.


Airway Inflammatory Biomarker: Could It Tailor the Right Medications for the Right Asthmatic Patient?
Asthma is a heterogeneous disease, in which asthmatic patients present with different clinical phenotypes, variable endotypes, and different response to asthma medicines. Thus, we are faced with an asthma paradox; asthma is diagnosed subjectively by clinical history and treated with biologically active drugs. To solve this paradox, we need objective airway biomarkers to tailor the proper medications to the proper patient. Biomarkers should have one or more of the following characteristics:1) A biomarker that could differentiate poor symptoms perceivers from over perceivers, 2) A biomarker that could predict disease activity and hence disease outcome, 3) A biomarker that could clarify responders from non-responders asthma phenotypes, and finally 4) A biomarker that could characterize different clinical asthma phenotypes. In conclusion, we have conducted a review of literature trying to apply those four parameters to different airway inflammatory biomarkers. We found that FeNO fulfilled the four proposed clinical parameters of airway inflammatory biomarkers whereas; serum periostin was the single best systemic biomarker of airway luminal and tissue eosinophilia in severe uncontrolled TH2 asthma phenotype. Thus, this may be considered a trial towards tailoring the proper medication to the proper patient. However, application of biomarkers in clinical practice requires easier and cheaper techniques together with standardized methods for sample collection and analysis.


Diagnosing Allergic Bronchopulmonary Aspergillosis: A Review.
Dr. Hinson and his colleagues first described allergic bronchopulmonary aspergillosis (ABPA) in 1952. Later in 1977, Rosenberg proposed a diagnostic criteria for ABPA that even today remains widely acknowledged. Despite these steps taken, there still isn't a standardized diagnostic criteria set for ABPA although many have been proposed by various physicians over the years. ABPA is a condition caused by hypersensitivity to Aspergillus fumigatus antigens. It is seen most commonly in patients with either asthma or cystic fibrosis. In susceptible hosts, repeated inhalation of Aspergillus spores can cause an allergic response. Although a standardized diagnostic criteria is re-quired, there is no single test that establishes the diagnosis oth-er than a demonstration of central bronchiectasis (CB) with nor-mal tapering bronchi, a feature that is still considered pathognomonic of ABPA. Because of lack of standardized diagnostic criteria and screening, even today ABPA is under diagnosed and often times treatment for it is delayed. This can lead to complications in patients like pulmonary fibrosis, bronchiectasis with chronic sputum production, and increasingly severe persistent asthma with loss of lung function. For this alone, it becomes imperative that the diagnostic criteria guidelines need to be reviewed and standardized preferably with the help of larger research studies. In the following review article, we address the epidemiology, pathophysiology, and the current cumulative view regarding the diagnosis of ABPA.


Neurovascular-glymphatic dysfunction and white matter lesions.
Cerebral white matter lesions (WML) represent a spectrum of age-related structural changes that are identified as areas of white matter high signal intensity on brain magnetic resonance imaging (MRI). Preservation of white matter requires proper functioning of both the cerebrovascular and glymphatic systems. The cerebrovascular safeguards adequate cerebral blood flow to supply oxygen, energy, and nutrients through a dynamic process of cerebral autoregulation and neurovascular coupling to keep up with global and regional demands of the brain. The glymphatic system maintains white matter integrity by preserving flow of interstitial fluid, exchanging metabolic waste and eventually its clearance into the venous circulation. Here, we argue that these two systems should not be considered separate entities but as one single physiologically integrated unit to preserve brain health. Due to the process of aging, damage to the neurovascular-glymphatic system accumulates over the life course. It is an insidious process that ultimately leads to the disruption of cerebral autoregulation, to the neurovascular uncoupling, and to the accumulation of metabolic waste products. As cerebral white matter is particularly vulnerable to hypoxic, inflammatory, and metabolic insults, WML are the first recognized pathologies of neurovascular-glymphatic dysfunction. A better understanding of the underlying pathophysiology will provide starting points for developing effective strategies to prevent a wide range of clinical disorders among which there are gait disturbances, functional dependence, cognitive impairment, and dementia.


NTP Toxicology and Carcinogenesis Studies of Phenylephrine Hydrochloride (CAS No. 61-76-7) in F344/N Rats and B6C3F1 Mice (Feed Studies).
Phenylephrine hydrochloride is a sympathomimetic amine recommended for use as a nasal decongestant and as a mydriatic in ophthalmic applications. In 1977, total U.S. human exposure was estimated at 1.9 x 107 g per year. Phenylephrine hydrochloride was nominated for toxicology and carcinogenesis studies because of a lack of previous long-term studies and because two other sympathomimetic agents (soterenol hydrochloride and mesuprine hydrochloride) produced mesovarial leiomyomas in Sprague-Dawley rats. Toxicology and carcinogenesis studies of USP-grade phenylephrine hydrochloride were conducted by administering diets containing the chemical (99% pure) to F344/N rats and B6C3F1 mice of each sex in studies of 14 days, 12 weeks, and 2 years. In the 14-day studies, no toxic effects were seen in rats or mice fed diets containing up to 2,000 ppm phenylephrine hydrochloride. Doses were increased in the 12-week studies, and deaths of male rats and male mice were observed in groups fed diets containing 10,000 or 20,000 ppm; 1/10 male rats in the 5,000-ppm group died. Other than inflammatory eye lesions (considered secondary to the pharmacologic drying action of the chemical), no specific organ toxicity was noted. Body weights decreased as concentrations of phenylephrine hydrochloride in the diet were increased, and feed consumption was lower in dosed rats. Doses of 0, 620, and 1,250 ppm for rats and 0, 1,250, and 2,500 ppm for mice were selected for the 2-year studies because of the decreased body weight gains in animals given higher doses in the 12-week studies. In the 2-year studies, the approximate amount of phenylephrine hydrochloride consumed per day was 24 mg/kg for low dose rats, 50 mg/kg for high dose rats, 133 mg/kg for low dose mice, and 270 mg/kg for high dose mice. Body weight differences in rats appeared to be dose related, and dosed animals were 3%-15% lighter than controls. Body weights of dosed mice averaged 3%-14% lower than those of controls throughout the 2-year studies. Survival of high dose male rats was greater than that of the controls (control, 30/50; low dose, 33/50; high dose, 42/50); differences in survival were not significant for female rats (42/50; 34/50; 36/50), male mice (35/50; 38/50; 43/50), or female mice (37/50; 34/50; 34/50). Few nonneoplastic lesions were related to phenylephrine hydrochloride dosing in rats or mice. Chronic focal inflammation of the liver was observed at increased incidences in dosed rats (male: 2/50; 13/50; 17/50; female:17/50; 28/50; 35/50). Inflammation of the prostate was seen more frequently in dosed than in control males (10/50; 24/50; 24/50). The incidence of focal cellular change in the liver was increased slightly in high dose male mice (0/50; 2/50; 7/50). In male rats, mononuclear cell leukemia (24/50; 9/50; 5/50) and pheochromocytomas of the adrenal gland (14/49; 11/50; 2/50) occurred with negative trends, and the incidences in the high dose group were lower than those in the controls. No increases in neoplasia were seen in dosed male or female rats or mice. Phenylephrine hydrochloride was not mutagenic in four strains of Salmonella typhimurium (TA100, TA1535, TA1537, and TA98) with or without Aroclor 1254-induced liver S9 from male Sprague-Dawley rats or male Syrian hamsters. The results of mutagenicity studies of phenylephrine hydrochloride were equivocal in the mouse lymphoma L5178Y/TK+/- assay in the absence of S9; it was not tested in the presence of S9. Phenylephrine hydrochloride induced sister-chromatid exchanges (SCEs) but not chromosomal aberrations in Chinese hamster ovary cells. The increase in SCEs was seen only in the absence of metabolic activation with S9. An audit of the experimental data was conducted for the 2-year studies of phenylephrine hydrochloride. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year studies, there was no evidence of carcinogenicity of phenylephrine hydrochloride for male B6C3F1 mice given 1,250 or 2,500 ppm in feed. Survival of high dose male rats was greater than of high dose male rats was greater than that of controls, and the incidences of mononuclear cell leukemia and pheochromocytomas were lower in dosed than in control male rats. Inflammation was observed more frequently in the liver and prostate gland of dosed male rats than in controls. Synonyms: benzene methanol,3-hydroxy-a[(methylamino)methyl]hydrochloride (R)-; (-)-meta-hydroxy-a-[(methylamino)methyl]benzyl alcohol hydrochloride; meta-Synephrine hydrochloride; Neo-synephrinereg.


Continuous sorting of microparticles using dielectrophoresis.
Sorting of particles such as cells is a critical process for many biomedical applications, and it is challenging to integrate it into an analytical microdevice. We report an effective and flexible dielectrophoresis (DEP)-based microfluidic device for continuous sorting of multiple particles in a microchannel. The particle sorter is composed of two components-a DEP focusing unit and a Movable DEP Trap (MDT). The trap is formed by an array of microelectrodes at the bottom of the channel and a transparent electrode plate placed at the top. The location of the trap is dependent on the configuration of voltages on the array and therefore is addressable. Flowing particles are first directed and focused into a single particle stream by the focusing unit. The streamed particles are then sorted into different fractions using the movable trap by rapidly switching the applied voltage. The performance of the sorter is demonstrated by successfully sorting microparticles in a continuous flow. The proposed DEP-based microfluidic sorter can be implemented in applications such as sample preparation and cell sorting for subsequent analytical processing, where sorting of particles is needed.


Occurrence of nodulation in the Leguminosae.
Reports of nodulation in the Leguminosae are examined in the light of current views on the taxonomy of the family. In the subfamily Caesalpinioideae, nodulation is largely restricted to the tribe Caesalpinieae and the genus Chamaecrista from the Cassieae. All nodules studied have rhizobia retained within infection threads during the nitrogen fixing period. In the Mimosoideae, nodulation is general, except for 4 groups within the tribe Mimoseae, and a very few species of Acacia. The only tribe from the Papilionoideae which appears not to nodulate is the Dipterygeae, although the monogeneric Euchresteae has not been examined. A number of genera in the Swartzieae do not nodulate. Taking tile family as a whole, nodulation appears to be very uniform - certain sections nodulate, others do not.


Risk of cataract development among children with juvenile idiopathic arthritis-related uveitis treated with topical corticosteroids.
We sought to investigate the risk of cataract development among patients with juvenile idiopathic arthritis (JIA)-associated uveitis treated with topical corticosteroids. Retrospective cohort study. We included 75 patients with JIA-associated uveitis observed from July 1984 through August 2005 at a single academic center. Clinical data on these patients were collected by chart review and were analyzed. Incidence of new-onset cataract. Risk factors for cataract development were assessed with attention paid to the use of topical corticosteroids. Over a median follow-up of 4 years, the incidence of new-onset cataract was 0.04/eye-year (EY; 95% confidence interval [CI], 0.02-0.09). Of the 60 eyes in 40 patients who received topical corticosteroid therapy, there was a dose-dependent increase in the rate of cataract development among eyes receiving topical corticosteroids. The incidence of cataract was 0.01/EY for eyes treated with < or = 3 drops daily and 0.16/EY (P = 0.0006 for log-rank test) for eyes treated with >3 drops daily. Among eyes receiving < or = 2 drops daily, the incidence of cataract was 0/EY (95% CI [1 sided], 0.03/EY). Presence of posterior synechiae, active uveitis, and use of topical corticosteroids at presentation were significantly associated with cataract development after controlling for confounding variables. Use of topical corticosteroids was associated with cataract formation independent of uveitis activity. Using longitudinal data analysis and controlling for duration of uveitis, presence and degree of active uveitis, and concomitant use of other forms of corticosteroids in a time-updated fashion, treatment with < or = 3 drops daily of topical corticosteroid was associated with an 87% lower risk of cataract formation compared with eyes treated with >3 drops daily (relative risk, 0.13; 95% CI, 0.02-0.69; P = 0.02). In our cohort, topical corticosteroid use was associated with an increased risk of cataract formation independent of active uveitis or presence of posterior synechiae. However, chronic use of topical corticosteroids dosed at < or = 3 drops daily seemed to be associated with a lower risk of cataract development relative to eyes receiving higher doses over follow-up in the setting of suppressed uveitis. Proprietary or commercial disclosure may be found after the references.


Parasitic keratitis - An under-reported entity.
Parasitic keratitis (PK) is unique entity among parasitic infections where corneal involvement could result from direct inoculation of the parasite via exogenous environment or spread via endogenous neighboring organs or as a result of immune-mediated damage secondary to a systemic parasitic infection. Most cases of PK are caused by Acanthamoeba spp. and Microsporidia spp. though few other parasitic agents can also lead to corneal involvement. Mimicking as other infectious and non-infectious causes of keratitis, PK often escapes detection. This review summarizes the predominant causes of PK along with the epidemiological, clinical and microbiological details of each. Though several gaps exist in our understanding of the prevalence of PK, the one thing for sure is that PK is on the rise. With advanced diagnostic modalities and enough literature on optimal management of cases of PK, it is now imperative that a strong clinical suspicion of PK is kept when examining a case of corneal pathology and adequate investigations are ordered.


Angiotensin IV elevates oxytocin levels in the rat amygdala and produces anxiolytic-like activity through subsequent oxytocin receptor activation.
The effects of angiotensin (Ang) IV result from binding to a constitutively active metallopeptidase known as the AT(4) receptor (or oxytocinase/insulin-regulated membrane aminopeptidase). While in vitro evidence indicates that Ang IV inhibits the peptidase activity of AT(4) receptors, leading to increases in the concentrations of several peptides, including oxytocin, the consequence of inhibiting AT(4) peptidase activity in vivo remains unresolved. Microdialysis coupled to immunoassay techniques revealed that systemic and intra-amygdala injection of Nle-Ang IV, a metabolically stable derivative of Ang IV, significantly elevated extracellular levels of oxytocin in the rat amygdala. Based on earlier reports describing the anxiolytic-like effects of oxytocin, we investigated whether disrupting AT(4) peptidase activity would yield similar responses. In the mouse four-plate test, acute treatment with either Nle-Ang IV or LVV-hemorphin-7, a related AT(4) receptor ligand, elicited significant increases in the number of punished crossings. These behavioral responses were comparable to the anxiolytic-like effects of oxytocin and to the standard anxiolytic agent, chlordiazepoxide. Cotreatment with either the AT(4) receptor antagonist, divalinal, or the selective oxytocin receptor antagonist, WAY-162720, reversed the anxiolytic-like effects of Nle-Ang IV, while combining ineffective doses of Nle-Ang IV and oxytocin increased the number of punished crossings in this assay. Conversely, Nle-Ang IV and LVV-hemorphin-7 were inactive in the mouse tail suspension test of antidepressant activity. These findings represent the first in vivo demonstration of the peptidase activity of AT(4) receptors, confirm the anxiolytic-like properties of Ang IV, and reveal a unique and previously uncharacterized relationship between AT(4) and oxytocin receptor systems.


A molecular switch controls interspecies prion disease transmission in mice.
Transmissible spongiform encephalopathies are lethal neurodegenerative disorders that present with aggregated forms of the cellular prion protein (PrPC), which are known as PrPSc. Prions from different species vary considerably in their transmissibility to xenogeneic hosts. The variable transmission barriers depend on sequence differences between incoming PrPSc and host PrPC and additionally, on strain-dependent conformational properties of PrPSc. The beta2-alpha2 loop region within PrPC varies substantially between species, with its structure being influenced by the residue types in the 2 amino acid sequence positions 170 (most commonly S or N) and 174 (N or T). In this study, we inoculated prions from 5 different species into transgenic mice expressing either disordered-loop or rigid-loop PrPC variants. Similar beta2-alpha2 loop structures correlated with efficient transmission, whereas dissimilar loops correlated with strong transmission barriers. We then classified literature data on cross-species transmission according to the 170S/N polymorphism. Transmission barriers were generally low between species with the same amino acid residue in position 170 and high between those with different residues. These findings point to a triggering role of the local beta2-alpha2 loop structure for prion transmissibility between different species.


Screening for familial hypercholesterolaemia in primary care: Time for general practice to play its part.
Fifty per cent of first-degree relatives of index cases with familial hypercholesterolemia (FH) inherit the disorder. Despite cascade screening being the most cost-effective method for detecting new cases, only a minority of individuals with FH are currently identified. Primary care is a key target area to increase identification of new index cases and initiate cascade screening, thereby finding close relatives of all probands. Increasing public and health professional awareness about FH is essential. In the United Kingdom and in Australia, most of the population are reviewed by a General Practitioner (GP) at least once over a three-year period, offering opportunities to check for FH as part of routine clinical consultations. Such opportunistic approaches can be supplemented by systematically searching electronic health records with information technology tools that identify high risk patients. GPs can help investigate and implement results of this data retrieval. Current evidence suggests that early detection of FH and cascade testing meet most of the criteria for a worthwhile screening program. Among heterozygous patients the long latent period before the expected onset of coronary artery disease provides an opportunity for initiating effective drug and lifestyle changes. The greatest challenge for primary care is to implement an efficacious model of care that incorporates sustainable identification and management pathways.


Repetitive endocytosis and recycling of the beta 2-adrenergic receptor during agonist-induced steady state redistribution.
The human beta 2-adrenergic receptor (beta 2AR) rapidly internalizes after binding agonist, resulting in a dramatic redistribution of receptors from the plasma membrane and into endocytic vesicles. We sought to determine whether intracellular receptors constitute a static pool or represent a fraction of dynamically internalizing and recycling receptors. Using cells expressing a beta 2AR with an epitope tag at its amino-terminal ectodomain, changes in surface receptor levels were measured by flow cytometry and radioligand binding assays. The addition of a saturating level of a strong agonist (isoproterenol) caused the endocytosis of receptors with first-order kinetics (ke for naive cells, 0.222 min-1). After 10 min, the level of surface receptors remained stable at approximately 20% that of untreated cells, even though endocytosis continued with similar kinetics (ke for pretreated cells, 0.258 min-1), suggesting that internalized receptors were cycling in steady state with surface receptors. This prediction was confirmed directly by showing that internalized beta 2ARs recycled to the cell surface in the continued presence of agonist. The calculated transit times (1/k) in the presence of isoproterenol were 3.9 min for endocytosis and 11.2 min for recycling. The endocytic rate constant and the steady state redistribution to the internal pool were much lower after treatment with the partial agonist albuterol, suggesting a correlation between the efficiency of endocytosis and that of receptor coupling to the downstream signal transduction pathway. These findings indicate that in the presence of agonist, beta 2ARs are in a dynamic steady state between the plasma membrane and endosomes that is regulated principally by agonist efficacy.


Psychopathy and chronotype disposition: the mediating role of depression.
This study examined the relationship between dark triad personality traits and chronotype disposition, whilst incorporating the mediating role of anxiety and/or depression after excluding individuals presenting insomnia and/or physiological sleep-disorder symptoms. Members of the general population (N = 453) completed online measures of dark triad personality traits, chronotype, and anxious and depressive symptoms. Psychopathy and Machiavellianism were independently related to an evening chronotype disposition. However, after accounting for age, sex, anxiety and depression, psychopathy and depression remained the only significant predictors of chronotype. Therefore, whilst psychopathy was the strongest predictor of an evening chronotype preference, this relationship is partially mediated by depression. Individuals presenting an evening disposition may display increased psychopathic traits due to greater emotion dysregulation. This is potentially perpetuated by depressive symptoms stemming from a delayed or blunted affective rhythm. Interacting factors (e.g. reduced light exposure) may also contribute to alterations in the biological rhythm amongst evening-types, resulting in a negative feedback cycle. Targeting chronotype and depressive symptoms amongst individuals presenting psychopathic tendencies could increase the efficacy of existing sleep-based interventions for hostile behaviour.


Development of a light scattering solver applicable to particles of arbitrary shape on the basis of the surface-integral equations method of Müller type. I. Methodology, accuracy of calculation, and electromagnetic current on the particle surface.
We develop a numerical algorithm for calculating the light-scattering properties of small particles of arbitrary shape on the basis of a method involving surface integral equations. The calculation error was estimated by performing a comparison between the proposed method and the exact Mie method with regard to the extinction efficiency factor, and the results show that the error is less than 1% when four or more nodes per wavelength are set on the surface of a spherical particle. The accuracy fluctuates in accordance with the distribution of nodal points on the particle surface with respect to the direction of propagation of the incident light. From our examinations, it is shown that the polar incidence alignment yields higher accuracy than equator incidence when a "latitude-longitude" type of mesh generation is adopted. The electric currents on the particle surface and the phase functions of all scattering directions are shown for particles shaped as spheres or hexagonal columns. It is shown that the phase function for a hexagonal column has four or eight cold spots. The phase function of a randomly oriented hexagonal column shows halolike peaks with size parameters of up to 20. This method can be applied to particles with a size parameter of up to about 20 without using the symmetry characteristic of the particle.


Association of bedding types with management practices and indicators of milk quality on larger Wisconsin dairy farms.
The objective of this study was to identify associations of bedding type and selected management practices with bulk milk quality and productivity of larger Wisconsin dairy farms. Dairy herds (n=325) producing ≥11,340 kg of milk daily were surveyed during a single farm visit. Monthly bulk milk SCC and total bacteria counts were obtained from milk buyers for 255 farms for a 2-yr period. Of farms with the same type of bedding in all pens during the study period, most used inorganic bedding (IB), followed by organic nonmanure bedding (OB) and manure products (MB). Almost all bulk milk total bacterial counts were <10,000 cfu/mL and total bacterial count was not associated with bedding type. Bulk milk somatic cell score (BMSCS) was least for farms using IB, varied seasonally, and was greatest in the summer. The BMSCS was reduced when new bedding was added to stalls at intervals greater than 1 wk and when teats were dried before attaching the milking unit. The BMSCS for farms using OB was reduced when bedding in the backs of stalls was removed and replaced regularly and when fewer cows with nonfunctioning mammary quarters were present. The BMSCS for farms using MB was reduced when the proportion of cows with milk discarded was less. The rolling herd average (RHA) of herds using IB was 761 and 1,153 kg greater than the RHA of herds using OB and MB, respectively. The RHA was 353 kg greater on farms where farmers understood subclinical mastitis and 965 kg greater on farms milking 3 times daily. Each 1% increase of cows with nonfunctioning mammary quarters was associated with a decrease of 57 kg of RHA. The BMSCS, proportions of cows with milk discarded and proportion of cows with nonfunctioning mammary quarters were least for herds using IB and were associated with increased productivity. Large Wisconsin dairy farms that used inorganic bedding had greater productivity and better milk quality compared with herds using other bedding types.


Recreational Diver Behavior and Contacts with Benthic Organisms in the Abrolhos National Marine Park, Brazil.
In the last two decades, coral reefs have become popular among recreational divers, especially inside marine protected areas. However, the impact caused by divers on benthic organisms may be contributing to the degradation of coral reefs. We analyzed the behavior of 142 scuba divers in the Abrolhos National Marine Park, Brazil. We tested the effect of diver profile, reef type, use of additional equipment, timing, and group size on diver behavior and their contacts with benthic organisms. Eighty-eight percent of divers contacted benthic organism at least once, with an average of eight touches and one damage per dive. No significant differences in contacts were verified among gender, group size, or experience level. Artificial reef received a higher rate of contact than pinnacle and fringe reefs. Specialist photographers and sidemount users had the highest rates, while non-users of additional equipment and mini camera users had the lowest contact rates. The majority of contacts were incidental and the highest rates occurred in the beginning of a dive. Our findings highlight the need of management actions, such as the provision of pre-dive briefing including ecological aspects of corals and beginning dives over sand bottoms or places with low coral abundance. Gathering data on diver behavior provides managers with information that can be used for tourism management.


A source of support. An ethics committee helps nurses do the right thing.
In 1984 Archbishop Bergan Mercy Hospital, Omaha, established a nursing bioethics committee to increase its professional nurses' knowledge of applied ethics. The committee's original objectives were to (1) help nurses assume the authority and responsibility to make ethical judgements, (2) influence the development of policies on healthcare standards, (3) serve as a resource to clinicians and managers responsible for delivering high-quality nursing care, (4) develop systemwide support for nurses' participation in ethical decision making, and (5) serve as a source from which nurses could be selected to the hospital's Human Values Committee. The bioethics committee established a formal mechanism to ensure that nurses receive support when they take the initiative in ethical decisions. The nurse and the committee member from his or her department organize a "community of concern" consisting of all persons necessary to address the essential ethical components of the issue at hand.


Improving documentation and coding for acute organ dysfunction biases estimates of changing sepsis severity and burden: a retrospective study.
Claims-based analyses report that the incidence of sepsis-associated organ dysfunction is increasing. We examined whether coding practices for acute organ dysfunction are changing over time and if so, whether this is biasing estimates of rising severe sepsis incidence and severity. We assessed trends from 2005 to 2013 in the annual sensitivity and incidence of discharge ICD-9-CM codes for organ dysfunction (shock, respiratory failure, acute kidney failure, acidosis, hepatitis, coagulopathy, and thrombocytopenia) relative to standardized clinical criteria (use of vasopressors/inotropes, mechanical ventilation for ≥ 2 consecutive days, rise in baseline creatinine, low pH, elevated transaminases or bilirubin, abnormal international normalized ratio or low fibrinogen, and decline in platelets). We studied all adult patients with suspected infection (defined by ≥ 1 blood culture order) at two US academic hospitals. Acute organ dysfunction codes were present in 57,273 of 191,695 (29.9%) hospitalizations with suspected infection, most commonly acute kidney failure (60.2% of cases) and respiratory failure (28.9%). The sensitivity of all organ dysfunction codes except thrombocytopenia increased significantly over time. This was most pronounced for acute kidney failure codes, which increased in sensitivity from 59.3% in 2005 to 87.5% in 2013 relative to a fixed definition for changes in creatinine (p = 0.019 for linear trend). Acute kidney failure codes were increasingly assigned to patients with smaller creatinine changes: the average peak creatinine change associated with a code was 1.99 mg/dL in 2005 versus 1.49 mg/dL in 2013 (p <0.001 for linear decline). The mean number of dysfunctional organs in patients with suspected infection increased from 0.32 to 0.59 using discharge codes versus 0.69 to 0.79 using clinical criteria (p < 0.001 for both trends and comparison of the two trends). The annual incidence of hospitalizations with suspected infection and any dysfunctional organ rose an average of 5.9% per year (95% CI 4.3, 7.4%) using discharge codes versus only 1.1% (95% CI 0.1, 2.0 %) using clinical criteria. Coding for acute organ dysfunction is becoming increasingly sensitive and the clinical threshold to code patients for certain kinds of organ dysfunction is decreasing. This accounts for much of the apparent rise in severe sepsis incidence and severity imputed from claims.


Burden of norovirus in healthcare facilities and strategies for outbreak control.
Norovirus is the most frequently occurring cause of community-acquired acute gastroenteritis in people of all ages. It is also one of the most frequent causes of outbreaks in healthcare settings, affecting both long-term care facilities and acute care hospitals. Whereas norovirus gastroenteritis is typically mild and resolves without medical attention, healthcare-associated infections often affect vulnerable populations, resulting in severe infections and disruption of healthcare services. Globally, most norovirus outbreaks in hospitals and residential care institutions are associated with genogroup II type 4 (GII.4) strains. Recent data demonstrate that excess mortality occurs during outbreak periods in healthcare facilities. Nosocomial outbreaks can result in large economic and societal costs. Current control measures for norovirus are largely based on general infection control principles, and treatment is mainly supportive and non-specific. While neither vaccines nor antiviral agents are currently available, both are being developed with encouraging results.


Low Socioeconomic Status Is Associated with a Greater Neural Response to Both Rewards and Losses.
Low socioeconomic status (SES) has been associated with distinct patterns of reward processing, which appear to have adverse implications for health outcomes, well-being, and human capital. However, most studies in this literature have used complex tasks that engage more than reward processing and/or retrospectively studied childhood SES in samples of adults. To clarify how SES relates to the development of reward processing tendencies, we measured income-to-poverty ratio (IPR) in 172 youth who subsequently underwent functional MRI while completing a passive avoidance task to assess neural responses to reward and loss information. Participants were 12-15 years old (mean = 13.94, SD = .52; 65.7% female) from a sample broadly representative of the Chicago area in terms of SES (IPR range = 0.1-34.53; mean = 3.90; SD = 4.15) and racial makeup (40.1% White 30.8% Black; 29.1% Hispanic). To the extent they had lower IPR, children displayed a trend toward worse behavioral performance on the passive avoidance task. Lower IPR also was associated with a greater response in attention brain regions to reward and loss cues and to reward and loss feedback. Lower IPR also was associated with reduced differentiation between reward and loss feedback in the ventromedial prefrontal and parietal cortex. The current data suggest that both increased salience of reward/loss information and reduced discrimination between reward and loss feedback could be factors linking SES with the development of human capital and health outcomes.


Curare and pancuronium compared: effects on previously undepressed mammalian myoneural junctions.
Curare and pancuronium have multiple effects on previously undepressed rat diaphragm; these include depression of transmitter output and prolongation of the refractory period of prejunctional structures. The effect of curare on motor nerve terminals is greater than that of pancuronium. Both drugs depress postjunctional receptors; but curare, in addition, raises the threshold for the generation of muscle action potentials. In addition, these results raise questions about the validity of statistical methods used to calculate transmitter output.


Human longevity and variation in DNA damage response and repair: study of the contribution of sub-processes using competitive gene-set analysis.
DNA-damage response and repair are crucial to maintain genetic stability, and are consequently considered central to aging and longevity. Here, we investigate whether this pathway overall associates to longevity, and whether specific sub-processes are more strongly associated with longevity than others. Data were applied on 592 SNPs from 77 genes involved in nine sub-processes: DNA-damage response, base excision repair (BER), nucleotide excision repair, mismatch repair, non-homologous end-joining, homologous recombinational repair (HRR), RecQ helicase activities (RECQ), telomere functioning and mitochondrial DNA processes. The study population was 1089 long-lived and 736 middle-aged Danes. A self-contained set-based test of all SNPs displayed association with longevity (P-value=9.9 × 10(-5)), supporting that the overall pathway could affect longevity. Investigation of the nine sub-processes using the competitive gene-set analysis by Wang et al indicated that BER, HRR and RECQ associated stronger with longevity than the respective remaining genes of the pathway (P-values=0.004-0.048). For HRR and RECQ, only one gene contributed to the significance, whereas for BER several genes contributed. These associations did, however, generally not pass correction for multiple testing. Still, these findings indicate that, of the entire pathway, variation in BER might influence longevity the most. These modest sized P-values were not replicated in a German sample. This might, though, be due to differences in genotyping procedures and investigated SNPs, potentially inducing differences in the coverage of gene regions. Specifically, five genes were not covered at all in the German data. Therefore, investigations in additional study populations are needed before final conclusion can be drawn.


Cardiac Sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia-reperfusion.
Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion (I/R) injury. We previously found the essential roles of endothelial nitric oxide synthase in the development of CR-induced cardioprotection and Sirt1 activation during CR (Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury.Am J Physiol Heart Circ Physiol 308: H894-H903, 2015). However, the exact mechanism by which Sirt1 in cardiomyocytes mediates the cardioprotective effect of CR remains undetermined. We subjected cardiomyocyte-specific Sirt1 knockout (CM-Sirt1(-/-)) mice and the corresponding control mice to either 3-mo ad libitum feeding or CR (-40%). Isolated perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. The recovery of left ventricle function after I/R was improved, and total lactate dehydrogenase release into the perfusate during reperfusion was attenuated in the control mice treated with CR, but a similar cardioprotective effect of CR was not observed in the CM-Sirt1(-/-)mice. The expression levels of cardiac complement component 3 (C3) at baseline and the accumulation of C3 and its fragments in the ischemia-reperfused myocardium were attenuated by CR in the control mice, but not in the CM-Sirt1(-/-)mice. Resveratrol treatment also attenuated the expression levels of C3 protein in cultured neonatal rat ventricular cardiomyocytes. Moreover, the degree of myocardial I/R injury in conventional C3 knockout (C3(-/-)) mice treated with CR was similar to that in the ad libitum-fed C3(-/-)mice, although the expression levels of Sirt1 were enhanced by CR. These results demonstrate that cardiac Sirt1 plays an essential role in CR-induced cardioprotection against I/R injury by suppressing cardiac C3 expression. This is the first report suggesting that cardiac Sirt1 regulates the local complement system during CR.


Results From Malaysia's 2016 Report Card on Physical Activity for Children and Adolescents.
The 2016 Malaysia Active Healthy Kids Report Card aims to collect, assess, and grade current and comprehensive data on physical activity (PA) and associated factors in Malaysian children and adolescents aged 5 to 17 years. This report card was developed following the Active Healthy Kids Canada Report Card protocol. The Research Working Group identified the core matrices, assessed the key data sources, and evaluated the evidence gathered for grade assignments. A grade was assigned to each indicator by comparing the best available evidence against relevant benchmark using a standardized grading scheme. Overall Physical Activity, Active Transportation, and Sedentary Behavior were assigned the D grade. The lowest grade of F was assigned to Diet, while School and Government Strategies and Investments were graded higher with a B. Five indicators were assigned INC (incomplete) due to a lack of representative data. The report card demonstrates that Malaysian children and adolescents are engaging in low levels of PA and active commuting, high levels of screen time, and have extremely low compliance with dietary recommendations. More efforts are needed to address the root causes of physical inactivity while increasing the opportunities for children and adolescents to be more physically active.


Electroencephalography in children with and without sensory processing disorders during auditory perception.
We sought to determine whether children with sensory processing disorder (SPD) differ from typically developing children on a neurophysiological measure, the P300 component of event-related potentials produced in response to brief auditory stimulation. We used electroencephalographic measures (i.e., N200 and P300 components) to examine auditory processing in 20 children with SPD and 71 typically developing children, ages 5-10 yr. Children with SPD demonstrated significantly smaller P300 amplitudes and shorter N200 latencies than typically developing children. Brain activity correctly distinguished children with SPD from typically developing children with 77% accuracy. We also found a significant relationship between the neurophysiological measures and functional performance on sensory and motor tasks. This study presents empirical evidence that children with SPD display unique brain processing mechanisms compared with typical children and, therefore, provide further evidence for the neural deviations associated with SPD.


Estimating material elasticity by spherical indentation load-relaxation tests on viscoelastic samples of finite thickness.
A two-step viscoelastic spherical indentation method is proposed to compensate for 1) material relaxation and 2) sample thickness. In the first step, the indenter is moved at a constant speed and the reaction force is measured. In the second step, the indenter is held at a constant position and the relaxation response of the material is measured. Then the relaxation response is fit with a multi-exponential function which corresponds to a three-branch general Maxwell model. The relaxation modulus is derived by correcting the finite ramp time introduced in the first step. The proposed model takes into account the sample thickness, which is important for applications in which the sample thickness is less than ten times the indenter radius. The model is validated numerically by finite element simulations. Experiments are carried out on a 10% gelatin phantom and a chicken breast sample with the proposed method. The results for both the gelatin phantom and the chicken breast sample agree with the results obtained from a surface wave method. Both the finite element simulations and experimental results show improved elasticity estimations by incorporating the sample thickness into the model. The measured shear elasticities of the 10% gelatin sample are 6.79 and 6.93 kPa by the proposed finite indentation method at sample thickness of 40 and 20 mm, respectively. The elasticity of the same sample is estimated to be 6.53 kPa by the surface wave method. For the chicken breast sample, the shear elasticity is measured to be 4.51 and 5.17 kPa by the proposed indentation method at sample thickness of 40 and 20 mm, respectively. Its elasticity is measured by the surface wave method to be 4.14 kPa.


Anxiolytics, adrenergic agents, and naltrexone.
To review extant data on the efficacy and safety of anxiolytic medications (benzodiazepines, buspirone, and other serotonin 1A agonists), adrenergic agents (beta-blockers and alpha 2-adrenergic agonists clonidine and guanfacine), and the opiate antagonist naltrexone that have been used to treat various psychopathologies in children and adolescents. To identify critical gaps in our current knowledge about these agents and needs for further research. All available controlled trials of these medications in children and adolescents published in English through 1997 were reviewed. In addition, selected uncontrolled studies are included. The major finding, that there are virtually no controlled data that support the efficacy of most of these drugs for the treatment of psychiatric disorders in children and adolescents, is both surprising and unfortunate. For some drugs, e.g., buspirone and guanfacine, this is because no controlled studies have been carried out in children and/or adolescents. For other drugs, e.g., clonidine and naltrexone, most of the placebo-controlled studies have failed to demonstrate efficacy. The strongest recommendations for controlled studies of safety and efficacy in children and adolescents can be given for the following drugs: benzodiazepines for acute anxiety; buspirone (and newer serotonin 1A agonists as they become available) for anxiety and depression; beta-blockers for aggressive dyscontrol; guanfacine for attention-deficit/hyperactivity disorder; and naltrexone for hyperactivity, inattention, and aggression in autistic disorder.


Diagnostic accuracy assessment of Sensititre and agar disk diffusion for determining antimicrobial resistance profiles of bovine clinical mastitis pathogens.
Determining the accuracy and precision of a measuring instrument is pertinent in antimicrobial susceptibility testing. This study was conducted to predict the diagnostic accuracy of the Sensititre MIC mastitis panel (Sensititre) and agar disk diffusion (ADD) method with reference to the manual broth microdilution test method for antimicrobial resistance profiling of Escherichia coli (n = 156), Staphylococcus aureus (n = 154), streptococcal (n = 116), and enterococcal (n = 31) bovine clinical mastitis isolates. The activities of ampicillin, ceftiofur, cephalothin, erythromycin, oxacillin, penicillin, the penicillin-novobiocin combination, pirlimycin, and tetracycline were tested against the isolates. Diagnostic accuracy was determined by estimating the area under the receiver operating characteristic curve; intertest essential and categorical agreements were determined as well. Sensititre and the ADD method demonstrated moderate to highly accurate (71 to 99%) and moderate to perfect (71 to 100%) predictive accuracies for 74 and 76% of the isolate-antimicrobial MIC combinations, respectively. However, the diagnostic accuracy was low for S. aureus-ceftiofur/oxacillin combinations and other streptococcus-ampicillin combinations by either testing method. Essential agreement between Sensititre automatic MIC readings and MIC readings obtained by the broth microdilution test method was 87%. Essential agreement between Sensititre automatic and manual MIC reading methods was 97%. Furthermore, the ADD test method and Sensititre MIC method exhibited 92 and 91% categorical agreement (sensitive, intermediate, resistant) of results, respectively, compared with the reference method. However, both methods demonstrated lower agreement for E. coli-ampicillin/cephalothin combinations than for Gram-positive isolates. In conclusion, the Sensititre and ADD methods had moderate to high diagnostic accuracy and very good essential and categorical agreement for most udder pathogen-antimicrobial combinations and can be readily employed in veterinary diagnostic laboratories.


Lymphocyte-specific protein 1: a specific marker of human leucocytes.
While both murine and human homologues of the LSP1 gene (lymphocyte-specific gene 1) and its protein products have been identified, studies on human LSP1 have been limited. The present report describes a detailed immunocytochemical study of the distribution and localization of human LSP1 in both normal and neoplastic cells and tissues. The specificity of the monoclonal anti-LSP1 reagent was confirmed by expression cloning and transfection studies. The intracellular 60 000 MW LSP1 protein was found to be present in peripheral blood B cells, monocytes and granulocytes but absent in a subpopulation of circulating T cells (10-15% of CD3-positive T cells). The presence of LSP1 protein in medullary thymocytes, but only in scattered cortical thymocytes, provided additional evidence for heterogeneity of expression in T cells. Novel observations also included the presence of LSP1 in plasma cells, dendritic cells and Langerhans' cells. The leucocyte-restricted distribution of LSP1 protein means that it may play an important role in haematopathology. LSP1 protein was detected in a wide range of leukaemias and lymphomas, particularly of B-cell origin, and in tumour cells in classical Hodgkin's disease. Of interest was the indication of a reciprocal relationship in the expression of LSP1 and ALK (anaplastic lymphoma kinase) proteins in patients with anaplastic large cell lymphoma. As the anti-LSP1 reagent used in the present study recognizes a formalin-resistant epitope it should be of considerable value in the diagnosis of routinely fixed material.


The continual presence of C3d but not IgG glomerular capillary deposition in stage I idiopathic membranous nephropathy in patients receiving corticosteroid treatment.
Pathologic diagnosis of stage I idiopathic membranous nephropathy (MN-I) requires electron microscopy or immunohistochemistry that shows a glomerular capillary staining pattern of IgG and C3. However, it is not uncommon that renal biopsy did not obtain sufficient material for electron microscopy and that IgG and C3 staining in glomeruli largely lost at biopsy due to corticosteroid treatment. Since C3d is one of the final degradation products of C3 that is more stable in vivo, we determine if C3d staining could be used as a novel immunohistochemical marker for MN-I. 74 MN-I patients with electron microscopy proven MN-I were examined by immunoperoxidase staining of C3d. Intensive C3d staining was present in glomerular capillary like the staining pattern of IgG and C3 in MN-I. Importantly, in 40 MN-I patients who underwent corticosteroid treatment at biopsy the intensity and glomerular capillary pattern of C3d staining remained largely intact while the staining for IgG had substantially reduced and the pattern of glomerular capillary staining became unrecognizable. C3d glomerular capillary staining may be a novel marker for pathologic diagnosis of MN-I that is continuously present at biopsy in patient who has received corticosteroid treatment. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2120780075734479.


Inequity in provision of and access to health visiting postnatal depression services.
This paper is a report of a study of equity in the provision of a public health nursing postnatal depression service. Postnatal depression is a global public health concern. Health visitors are nurses involved in the early detection and treatment of postnatal depression. However, research has revealed that all women are not assessed for postnatal depression particularly women in minority ethnic groups. A case study was conducted involving 21 observations of health visitors visiting postnatal women, interviews with 20 health visitors, 6 managers, 12 English women, 9 Bangladeshi women and 3 other personnel. Data were collected between 2003 and 2005 and analysis was completed in 2008. The organization had a policy to create equitable postnatal depression services, but practitioners were not clear whether it was to be implemented, and it did not address the needs of a diverse population. All health visitors received specialized training and were consequently expected to assess and treat all women. The training based on the policy had not equipped health visitors with knowledge and skills to assess and treat women in minority ethnic groups. While a policy was in place, equity in care was not achieved. An analysis of women's needs is recommended prior to policy development and policy implementation should be planned. To achieve equity, training should include knowledge and skills for cultural competency. Research is needed to illuminate the characteristics of equitable nursing services.


Gender, inequality and Depo-Provera: Constraints on reproductive choice in Nicaragua.
This article examines the sociocultural determinants of Nicaraguan women's use of Depo-Provera as a means of contraception. The prevalence of Depo-Provera in Nicaragua is high and increasing compared to other Central American countries. Drawing on data from structured interviews with 87 women and from focus groups with 32 women, we show how women's preference for Depo is shaped by both gendered inequalities and socioeconomic constraints. We employ basic statistical tests to analyse correlations between women's marital status and socioeconomic status (SES) with contraceptive use. Our statistical findings show significant associations between use of Depo and both marital status and SES, such that women who are married or in conjugal unions and women with lower SES are more likely to use Depo. To help explain women's use of Depo-Provera in Nicaragua, we situate our findings within the context of gender, culture, and power, reviewing the contested history of Depo-Provera in the developing world and dynamics of gender inequality, which constrain women's contraceptive choices. We conclude with suggestions for reproductive health programming in Nicaragua and beyond, arguing that gender equity and addressing socioeconomic barriers to family planning remain priorities for the achievement of global reproductive health.


Surface tension regularizes the crack singularity of adhesion.
The elastic and adhesive properties of a solid surface can be quantified by indenting it with a rigid sphere. Indentation tests are classically described by the JKR-law when the solid is very stiff, while recent work highlights the importance of surface tension for exceedingly soft materials. Here we show that surface tension plays a crucial role even in stiff solids: Young's wetting angle emerges as a boundary condition and this regularizes the crack-like singularity at the edge of adhesive contacts. We find that the edge region exhibits a universal, self-similar structure that emerges from the balance of surface tension and elasticity. The similarity theory is solved analytically and provides a complete description of adhesive contacts, by which we reconcile global adhesion laws and local contact mechanics.


Functional characterization of the infection-inducible peptide Edin in Drosophila melanogaster.
Drosophila is a well-established model organism for studying innate immunity because of its high resistance against microbial infections and lack of adaptive immunity. In addition, the immune signaling cascades found in Drosophila are evolutionarily conserved. Upon infection, activation of the immune signaling pathways, Toll and Imd, leads to the expression of multiple immune response genes, such as the antimicrobial peptides (AMPs). Previously, we identified an uncharacterized gene edin among the genes, which were strongly induced upon stimulation with Escherichia coli in Drosophila S2 cells. Edin has been associated with resistance against Listeria monocytogenes, but its role in Drosophila immunity remains elusive. In this study, we examined the role of Edin in the immune response of Drosophila both in vitro and in vivo. We report that edin expression is dependent on the Imd-pathway NF-κB transcription factor Relish and that it is expressed upon infection both in vitro and in vivo. Edin encodes a pro-protein, which is further processed in S2 cells. In our experiments, Edin did not bind microbes, nor did it possess antimicrobial activity to tested microbial strains in vitro or in vivo. Furthermore, edin RNAi did not significantly affect the expression of AMPs in vitro or in vivo. However, edin RNAi flies showed modestly impaired resistance to E. faecalis infection. We conclude that Edin has no potent antimicrobial properties but it appears to be important for E. faecalis infection via an uncharacterized mechanism. Further studies are still required to elucidate the exact role of Edin in the Drosophila immune response.


Requirement of the yeast RTH1 5' to 3' exonuclease for the stability of simple repetitive DNA.
Simple repetitive DNA sequences are unstable in human colorectal cancers and a variety of other cancers. Mutations in the DNA mismatch repair genes MSH2, MLH1, and PMS1 result in elevated rates of spontaneous mutation and cause a marked increase in the instability of simple repeats. Compared with the wild type, a null mutation in the yeast RTH1 gene, which encodes a 5' to 3' exonuclease, was shown to increase the rate of instability of simple repetitive DNA by as much as 280 times and to increase the spontaneous mutation rate by 30 times. Epistasis analyses were consistent with the hypothesis that this RTH1-encoded nuclease has a role in the MSH2-MLH-1-PMS1 mismatch repair pathway.


Outcomes After Left Main Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting According to Lesion Site: Results From the EXCEL Trial.
The authors sought to determine the extent to which the site of the left main coronary artery (LM) lesion (distal bifurcation versus ostial/shaft) influences the outcomes of revascularization with percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG). Among 1,905 patients with LM disease and site-assessed SYNTAX scores of <32 randomized in the EXCEL (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, revascularization with PCI and CABG resulted in similar rates of the composite primary endpoint of death, myocardial infarction (MI), or stroke at 3 years. Outcomes from the randomized EXCEL trial were analyzed according to the presence of angiographic core laboratory-determined diameter stenosis ≥50% involving the distal LM bifurcation (n = 1,559; 84.2%) versus disease isolated to the LM ostium or shaft (n = 293; 15.8%). At 3 years, there were no significant differences between PCI and CABG for the primary composite endpoint of death, MI, or stroke for treatment of both distal LM bifurcation disease (15.6% vs. 14.9%, odds ratio [OR]: 1.08, 95% confidence interval [CI]: 0.81 to 1.42; p = 0.61) and isolated LM ostial/shaft disease (12.4% vs. 13.5%, OR: 0.90, 95% CI: 0.45 to 1.81; p = 0.77) (pinteraction = 0.65). However, at 3 years, ischemia-driven revascularization occurred more frequently after PCI than CABG in patients with LM distal bifurcation disease (13.0% vs. 7.2%, OR: 2.00, 95% CI: 1.41 to 2.85; p = 0.0001), but were not significantly different in patients with disease only at the LM ostium or shaft (9.7% vs. 8.4%, OR: 1.18, 95% CI: 0.52 to 2.69; p = 0.68) (pinteraction = 0.25). In the EXCEL trial, PCI and CABG resulted in comparable rates of death, MI, or stroke at 3 years for treatment of LM disease, including those with distal LM bifurcation disease. Repeat revascularization rates during follow-up after PCI compared with CABG were greater for lesions in the distal LM bifurcation but were similar for disease isolated to the LM ostium or shaft.


Motivational state and reward content determine choice behavior under risk in mice.
Risk is a ubiquitous feature of the environment for most organisms, who must often choose between a small and certain reward and a larger but less certain reward. To study choice behavior under risk in a genetically well characterized species, we trained mice (C57BL/6) on a discrete trial, concurrent-choice task in which they must choose between two levers. Pressing one lever (safe choice) is always followed by a small reward. Pressing the other lever (risky choice) is followed by a larger reward, but only on some of the trials. The overall payoff is the same on both levers. When mice were not food deprived, they were indifferent to risk, choosing both levers with equal probability regardless of the level of risk. In contrast, following food or water deprivation, mice earning 10% sucrose solution were risk-averse, though the addition of alcohol to the sucrose solution dose-dependently reduced risk aversion, even before the mice became intoxicated. Our results falsify the budget rule in optimal foraging theory often used to explain behavior under risk. Instead, they suggest that the overall demand or desired amount for a particular reward determines risk preference. Changes in motivational state or reward identity affect risk preference by changing demand. Any manipulation that increases the demand for a reward also increases risk aversion, by selectively increasing the frequency of safe choices without affecting frequency of risky choices.


Evaluation by blue native polyacrylamide electrophoresis colorimetric staining of the effects of physical exercise on the activities of mitochondrial complexes in rat muscle.
Blue native polyacrylamide electrophoresis (BN-PAGE) is a technique developed for the analysis of membrane complexes. Combined with histochemical staining, it permits the analysis and quantification of the activities of mitochondrial oxidative phosphorylation enzymes using whole muscle homogenates, without the need to isolate muscle mitochondria. Mitochondrial complex activities were measured by emerging gels in a solution containing all specific substrates for NADH dehydrogenase and cytochrome c oxidase enzymes (complexes I and IV, respectively) and the colored bands obtained were measured by optique densitometry. The objective of the present study was the application of BN-PAGE colorimetric staining for enzymatic characterization of mitochondrial complexes I and IV in rat muscles with different morphological and biochemical properties. We also investigated these activities at different times after acute exercise of rat soleus muscle. Although having fewer mitochondria than oxidative muscles, white gastrocnemius muscle presented a significantly higher activity (26.7 +/- 9.5) in terms of complex I/V ratio compared to the red gastrocnemius (3.8 +/- 0.65, P < 0.05) and soleus (9.8 +/- 0.9, P < 0.001) muscles. Furthermore, the complex IV/V ratio of white gastrocnemius muscle was always significantly higher when compared to the other muscles. Ninety-five minutes of exhaustive physical exercise induced a decrease in complex I/V and complex IV/V ratios after all resting times (0, 3 and 6 h) compared to control (P < 0.05), probably reflecting the oxidative damage due to increasing free radical production in mitochondria. These results demonstrate the possible and useful application of BN-PAGE-histochemical staining to physical exercise studies.


Increased carotid thickness in subjects with recently-diagnosed diabetes from rural Cameroon.
We have recently shown a high prevalence of diabetes and obesity in rural Cameroon, despite an improved lifestyle. Diabetes in rural Africa remains underdiagnosed and its role in increasing risk of atherosclerosis in these populations is unknown. We investigated the prevalence of carotid atherosclerosis and cardiovascular risk factors in a population of subjects with recently-diagnosed diabetes from rural Cameroon. In a case-control study, carotid intima-media thickness (IMT) was measured in 74 subjects with diabetes (diagnosed <2 years), aged 47-85 and 109 controls comparable for age and sex. Subjects were recruited during a health campaign conducted in April 2009. Blood glucose control (HbA1c, fasting blood glucose) and major cardiovascular risk factors (complete lipid panel, blood pressure) were also measured. Mean carotid IMT was higher in subjects with diabetes than healthy controls at each scanned segment (common, internal carotid and bulb) (P<0.05), except the near wall of the left bulb. Vascular stiffness tended to be higher and pressure-strain elastic modulus of the left carotid was increased in subjects with diabetes than controls (P<0.05), but distensibility was similar between the two groups. At least one plaque >0.9 mm was found in 4%, 45.9% and 20% of diabetic subjects at the common, bulb or internal carotid, respectively. Only 25% of patients had an HbA1c<7%, while over 41.6% presented with marked hyperglycemia (HbA1c>9%). The prevalence of diabetic subjects with abnormal levels of LDL-cholesterol, triglycerides, HDL-cholesterol or blood pressure was 45%, 16.6%, 15% and 65.7%, respectively. Carotid thickness is increased in subjects with diabetes from a rural area of Cameroon, despite the relatively recent diagnosis. These findings and the high rate of uncontrolled diabetes in this population support the increasing concern of diabetes and cardiovascular diseases in African countries and indicate the need for multifaceted health interventions in urban and rural settings.


Review of Food Intake Difficulty Assessment Tools for People with Dementia.
This review aimed to summarise the validity and reliability of feeding difficulties assessment tools for Individual with dementia. PubMed, PsycINFO, MEDLINE, CINAHL and Scopus were searched for feeding difficulty measurements studies published between 1990 and 2019. Sixteen publications were included and identified three tools: Edinburgh Feeding Evaluation in Dementia (EdFED), Feeding Behaviour Inventory (FBI), and Feeding Difficulty Index (FDI). Results showed the EdFED was translated and tested in various languages. The EdFED and FDI demonstrated high content and construct validity. The FBI was not validated. The EdFED had high inter-rater reliability, with Cronbach's alpha ranging from 0.75 to 0.90. The FDI and FBI showed moderate inter-rater reliability. Although the EdFED has been tested and widely used, unlike FDI, which addresses multi-aspects of feeding difficulty. The FDI have higher clinical utility but future research needs to test the psychometric properties of FDI to determine its effectiveness in assessing feeding difficulties.


Prevalence and clinical course in invasive infections with meningococcal endotoxin variants.
Meningococci produce a penta-acylated instead of hexa-acylated lipid A when their lpxL1 gene is inactivated. Meningococcal strains with such lipid A endotoxin variants have been found previously in adult meningitis patients, where they caused less blood coagulopathy because of decreased TLR4 activation. A cohort of 448 isolates from patients with invasive meningococcal disease in the Netherlands were screened for the ability to induce IL-6 in monocytic cell Mono Mac 6 cells. The lpxL1 gene was sequenced of isolates, which show poor capacity to induce IL-6.. Clinical characteristics of patients were retrieved from hospital records. Of 448 patients, 29 (6.5%) were infected with meningococci expressing a lipid A variant strain. Lipid A variation was not associated with a specific serogroup or genotype. Infections with lipid A variants were associated with older age (19.3 vs. 5.9 (median) years, p = 0.007) and higher prevalence of underlying comorbidities (39% vs. 17%; p = 0.004) compared to wild-type strains. Patients infected with lipid A variant strains had less severe infections like meningitis or shock (OR 0.23; 95%CI 0.09-0.58) and were less often admitted to intensive care (OR 0.21; 95%CI 0.07-0.60) compared to wild-type strains, independent of age, underlying comorbidities or strain characteristics. In adults with meningococcal disease lipid A variation is rather common. Infection with penta-acylated lipid A variant meningococci is associated with a less severe disease course.