Synthetic Mimics of Bacterial Lipid A Trigger Optical Transitions in Liquid Crystal Microdroplets at Ultralow Picogram-per-Milliliter Concentrations.
We report synthetic six-tailed mimics of the bacterial glycolipid Lipid A that trigger changes in the internal ordering of water-dispersed liquid crystal (LC) microdroplets at ultralow (picogram-per-milliliter) concentrations. These molecules represent the first class of synthetic amphiphiles to mimic the ability of Lipid A and bacterial endotoxins to trigger optical responses in LC droplets at these ultralow concentrations. This behavior stands in contrast to all previously reported synthetic surfactants and lipids, which require near-complete monolayer coverage at the LC droplet surface to trigger ordering transitions. Surface-pressure measurements and SAXS experiments reveal these six-tailed synthetic amphiphiles to mimic key aspects of the self-assembly of Lipid A at aqueous interfaces and in solution. These and other results suggest that these amphiphiles trigger orientational transitions at ultralow concentrations through a unique mechanism that is similar to that of Lipid A and involves formation of inverted self-associated nanostructures at topological defects in the LC droplets.


Effect of chronic ethanol feeding on rat hepatocytic glutathione. Compartmentation, efflux, and response to incubation with ethanol.
Hepatocytes from rats that were fed ethanol chronically for 6-8 wk were found to have a modest decrease in cytosolic GSH (24%) and a marked decrease in mitochondrial GSH (65%) as compared with pair-fed controls. Incubation of hepatocytes from ethanol-fed rats for 4 h in modified Fisher's medium revealed a greater absolute and fractional GSH efflux rate than controls with maintenance of constant cellular GSH, indicating increased net GSH synthesis. Inhibition of gamma-glutamyltransferase had no effect on these results, which indicates that no degradation of GSH had occurred during these studies. Enhanced fractional efflux was also noted in the perfused livers from ethanol-fed rats. Incubation of hepatocytes in medium containing up to 50 mM ethanol had no effect on cellular GSH, accumulation of GSH in the medium, or cell viability. Thus, chronic ethanol feeding causes a modest fall in cytosolic and a marked fall in mitochondrial GSH. Fractional GSH efflux and therefore synthesis are increased under basal conditions by chronic ethanol feeding, whereas the cellular concentration of GSH drops to a lower steady state level. Incubation of hepatocytes with ethanol indicates that it has no direct, acute effect on hepatic GSH homeostasis.


Intracranial bacterial infections of oral origin.
Brain abscesses are rare but potentially deadly complications of odontogenic infections. This phenomenon has been described mainly in the form of case reports, as large-scale studies are difficult to perform. We compiled a total of 60 previously published cases of such a complication to investigate the predisposing factors, microbiology, and clinical outcomes of intracranial abscesses of odontogenic origin. A systematic review of the literature using the PubMed database was performed. Men accounted for 82.1% of cases, and the mean age was 42.1 years. Caries with periapical involvement and periodontitis were the two most common intra-oral sources, and wisdom tooth extraction was the most common preceding dental procedure. In 56.4% of cases, there were obvious signs of dental disease prior to development of intracranial infection. Commonly implicated microorganisms included Streptococcus viridans (especially the anginosus group), Actinomyces, Peptostreptococcus, Prevotella, Fusobacterium, Aggregatibacter actinomycetemcomitans and Eikenella corrodens. There was an 8.3% mortality rate. Intracranial abscesses can form anywhere within the brain, and appear unrelated to the side of dental involvement. This suggests that hematogenous spread is the most likely route of dissemination.


Method and phantom to study combined effects of in-plane (x,y) and z-axis resolution for 3D CT imaging.
Increasingly, the advent of multislice CT scanners, volume CT scanners, and total body spiral acquisition modes has led to the use of Multi Planar Reconstruction and 3D datasets. In considering 3D resolution properties of a CT system it is important to note that both the in-plane (x,y) and z-axis (slice thickness) influence the visual-ization and detection of objects within the scanned volume. This study investigates ways to consider both the in-plane resolution and the z-axis resolution in a single phantom wherein analytic or visualized analysis can yield information on these combined effects. A new phantom called the "Wave Phantom" is developed that can be used to sample the 3D resolution properties of a CT image, including in-plane (x,y) and z-axis information. The key development in this Wave Phantom is the incorporation of a z-axis aspect of a more traditional step (bar) resolution gauge phantom. The phantom can be examined visually wherein a cutoff level may be seen; and/or the analytic analysis of the various characteristics of the waveform profile by including amplitude, frequency, and slope (rate of climb) of the peaks, can be extracted from the Wave Pattern using mathematical analysis such as the Fourier transform. The combined effect of changes in in-plane resolution and z-axis (thickness), are shown, as well as the effect of changes in either in-plane resolu-tion, or z-axis thickness. Examples of visual images of the Wave pattern as well as the analytic characteristics of the various harmonics of a periodic Wave pattern resulting from changes in resolution filter and/or slice thickness, and position in the field of view are shown. The Wave Phantom offers a promising way to investigate 3D resolution results from combined effect of in-plane (x-y) and z-axis resolution as contrasted to the use of simple 2D resolution gauges that need to be used with separate measures of z-axis dependency, such as angled ramps. It offers both a visual pattern as well as a pattern amenable to analytic analysis using Fourier Transform methods, and is believed to offer an image quality test closer to the diagnostic task where the 2D image has the hidden third (z) axis effects.


The influence of strength and power on muscle endurance test performance.
The aim of this study was to determine the importance of muscular strength and power on a muscular endurance performance test. Fourteen firefighter recruits performed a progressive resistance test (PRT) followed by a specific maximum repetition test (MRT40) on the bench press exercise with measurements of power, strength, and muscular endurance. Comparisons were then made to examine relationships between the 3 muscular fitness variables. The results, expressed in absolute form and related to body weight, indicate that the performance in the MRT40 is significantly related (p <or= 0.05) to body weight (r = 0.78), 1 repetition maximum (1RM) (r = 0.83), maximal power (Pmax) during the PRT (r = 0.71), Pmax produced with 40 kg in the PRT (r = 0.64), and the average power and force applied during all repetitions in the MRT40 (r = 0.78 and r = -0.64, respectively). The load that expressed the maximal average power during the PRT was 47.6 +/- 9.0% of the 1RM and did not show any significant relationship with 1RM nor performance in MRT40. It was concluded that performance in this specific upper body endurance test depends on several variables, among which maximum strength, body weight, and maximum absolute power are the most important. As the ability to repeatedly apply submaximal force is a requirement of firefighters, and other occupations/sports, the current research suggests that the initial goal of a training program to enhance muscular endurance should be to increase maximum strength to a point that the specific load being lifted during repeated actions is less than 40% of the individuals' 1RM. Subsequent training should then focus on maintaining maximal strength levels and improving local muscular endurance in the specific task.


Protein Phosphatase 1 Inhibitor-1 Mediates the cAMP-Dependent Stimulation of the Renal NaCl Cotransporter.
A number of cAMP-elevating hormones stimulate phosphorylation (and hence activity) of the NaCl cotransporter (NCC) in the distal convoluted tubule (DCT). Evidence suggests that protein phosphatase 1 (PP1) and other protein phosphatases modulate NCC phosphorylation, but little is known about PP1's role and the mechanism regulating its function in the DCT. We used ex vivo mouse kidney preparations to test whether a DCT-enriched inhibitor of PP1, protein phosphatase 1 inhibitor-1 (I1), mediates cAMP's effects on NCC, and conducted yeast two-hybrid and coimmunoprecipitation experiments in NCC-expressing MDCK cells to explore protein interactions. Treating isolated DCTs with forskolin and IBMX increased NCC phosphorylation via a protein kinase A (PKA)-dependent pathway. Ex vivo incubation of mouse kidney slices with isoproterenol, norepinephrine, and parathyroid hormone similarly increased NCC phosphorylation. The cAMP-induced stimulation of NCC phosphorylation strongly correlated with the phosphorylation of I1 at its PKA consensus phosphorylation site (a threonine residue in position 35). We also found an interaction between NCC and the I1-target PP1. Moreover, PP1 dephosphorylated NCC in vitro, and the PP1 inhibitor calyculin A increased NCC phosphorylation. Studies in kidney slices and isolated perfused kidneys of control and I1-KO mice demonstrated that I1 participates in the cAMP-induced stimulation of NCC. Our data suggest a complete signal transduction pathway by which cAMP increases NCC phosphorylation via a PKA-dependent phosphorylation of I1 and subsequent inhibition of PP1. This pathway might be relevant for the physiologic regulation of renal sodium handling by cAMP-elevating hormones, and may contribute to salt-sensitive hypertension in patients with endocrine disorders or sympathetic hyperactivity.


Mineralization and plant uptake of 14C-labeled nonylphenol, nonylphenol tetraethoxylate, and nonylphenol nonylethoxylate in biosolids/soil systems planted with crested wheatgrass.
Microcosm experiments (duration, 150 d) were conducted to evaluate the mineralization and plant uptake of [14C]nonylphenol (NP), [14C]nonylphenol tetraethoxylate (NPE4), and [14C]nonylphenol nonylethoxylate (NPE9) in a soil/biosolids (99.5:0.5 w/w) environment planted with crested wheatgrass (Agropyron cristatum). Three initial nominal concentrations (6, 24, and 47 mg/kg dry wt) each of NP, NPE4, and NPE9 were examined along with unplanted and unplanted poisoned controls. Phenol (22 mg/kg) also was evaluated as a more degradable reference compound. The biosolids were obtained from a municipal treatment plant, and the loamy sand soil was freshly collected. Mineralization ranged from 7% for NP to 53% for phenol, and no enhancement was observed in the planted systems. For NP, NPE4, and NPE9, 14C foliar tissues concentrations were proportional to exposure concentrations but were 10-fold lower than the root concentrations and two- to threefold lower than the soil concentrations. Bioconcentration factors (BCFs) based on 14C measurements ranged from 0.31 (mg compound/kg dry plant/ mg compound/kg dry soil) for systems spiked with NP to 0.52 for systems spiked with NPE9. Results of the NP analysis (initial concentration, 47 mg/ kg) showed a 90% decrease in the soil concentration and an average BCF of 1.0. The lower BCF calculated from the 14C analysis likely resulted from the presence of NP transformation products in the soil that are less available or are translocated by the plants but quantified by the combustion/liquid scintillation counting procedure.


Complexity Matching: Brain Signals Mirror Environment Information Patterns during Music Listening and Reward.
Understanding how the human brain integrates information from the environment with intrinsic brain signals to produce individual perspectives is an essential element of understanding the human mind. Brain signal complexity, measured with multiscale entropy, has been employed as a measure of information processing in the brain, and we propose that it can also be used to measure the information available from a stimulus. We can directly assess the correspondence between brain signal complexity and stimulus complexity as an indication of how well the brain reflects the content of the environment in an analysis that we term "complexity matching." Music is an ideal stimulus because it is a multidimensional signal with a rich temporal evolution and because of its emotion- and reward-inducing potential. When participants focused on acoustic features of music, we found that EEG complexity was lower and more closely resembled the musical complexity compared to an emotional task that asked them to monitor how the music made them feel. Music-derived reward scores on the Barcelona Music Reward Questionnaire correlated with less complexity matching but higher EEG complexity. Compared with perceptual-level processing, emotional and reward responses are associated with additional internal information processes above and beyond those linked to the external stimulus. In other words, the brain adds something when judging the emotional valence of music.


CD16(+) monocyte subsets are increased in large abdominal aortic aneurysms and are differentially related with circulating and cell-associated biochemical and inflammatory biomarkers.
Proinflammatory components are present in abdominal aortic aneurysm (AAA). Circulating monocytes display heterogeneity, and three subsets have been identified, based on the differential expression for CD14 and CD16 receptors: CD14(+)CD16(−), classical, CD14(+)CD16(+), intermediate and CD14(dim)CD16(+), non-classical monocytes. Increased proinflammatory CD16+ monocytes with high expression of CD143 are present in CKD patients. D-dimer is increased in AAA patients, and might contribute to the pro-inflammatory response associated to circulating monocytes. We aimed to investigate the frequency of CD14(+)CD16(+), CD14(dim)CD16(+) monocytes and monocyte CD143 expression in AAA patients, and their relationship with Ddimer, eGFR and other inflammatory parameters. Blood from 74 AAA patients and 30 healthy controls was analyzed to determine the frequency of CD14(+)CD16(+), CD14(dim)CD16(+) monocytes and the monocyte CD143 expression by means of flow-cytometry. AAA patients had expanded CD16+ subsets (CD14(+)CD16(+): 7.66 ± 0.31% vs 5.42 ± 0.27%; CD14(dim)CD16(+): 7.43 ± 0.48% vs 5.54 ± 0.38%, AAA vs controls, mean ± SE, both p < 0.05). CD14(+)CD16(+) cells were associated to D-dimer and age, and to reduced eGFR. CD14(dim)CD16(+) cells were associated to uric acid, surface CD143, and reduced count of total leukocytes and neutrophils. Within AAA patients, the two CD16(+) subsets and the monocyte CD143 expression display different relationships with D-dimer, parameters of renal function and circulating biochemical and inflammatory biomarkers.


IQGAP1 in rectal adenocarcinomas: localization and protein expression before and after radiochemotherapy.
Treatment of rectal adenocarcinoma includes total mesorectal excision, which is preceded by radiochemotherapy (RCT) in cases of advanced disease. The response to RCT varies from total tumor regression to no effect but this heterogeneous response is unexplained. However, both radiation and treatment with 5-fluorouracil may induce treatment resistance through upregulation of the mitogen-activated protein kinase (MAPK) cascade. IQGAP1 is a scaffold protein that appears to be essential to MAPK signaling in cancers. We have therefore studied IQGAP1 protein expression in rectal adenocarcinomas before and after RCT. We demonstrate that cancer cells show increased apical staining for IQGAP1 following RCT. Interestingly, this increase is significantly higher in patients showing poor RCT responses. Our results also suggest that low levels of apical IQGAP1-staining in biopsies may predict the RCT response. Together, these data suggest that both the level and localization of IQGAP1 may influence the treatment response.


Nitrate, the oral microbiome, and cardiovascular health: a systematic literature review of human and animal studies.
Dietary nitrate is an important source of nitric oxide (NO), a molecule critical for cardiovascular health. Nitrate is sequentially reduced to NO through an enterosalivary nitrate-nitrite-NO pathway that involves the oral microbiome. This pathway is considered an important adjunct pathway to the classical l-arginine-NO synthase pathway. The objective of this study was to systematically assess the evidence for dietary nitrate intake and improved cardiovascular health from both human and animal studies. A systematic literature search was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines by using key search terms in Medline and EMBASE databases and defined inclusion and exclusion criteria. Thirty-seven articles on humans and 14 articles on animals were included from 12,541 screened references. Data on the effects of dietary nitrate on blood pressure, endothelial function, ischemic reperfusion injury, arterial stiffness, platelet function, and cerebral blood flow in both human and animal models were identified. Beneficial effects of nitrate on vascular health have predominantly been observed in healthy human populations, whereas effects in populations at risk of cardiovascular disease are less clear. Few studies have investigated the long-term effects of dietary nitrate on cardiovascular disease clinical endpoints. In animal studies, there is evidence that nitrate improves blood pressure and endothelial function, particularly in animal models with reduced NO bioavailability. Nitrate dose seems to be a critical factor because there is evidence of cross-talk between the 2 pathways of NO production. Evidence for a beneficial effect in humans at risk of cardiovascular disease is limited. Furthermore, there is a need to investigate the long-term effects of dietary nitrate on cardiovascular disease clinical endpoints. Further animal studies are required to elucidate the mechanisms behind the observed effects.


Role of erlotinib in first-line and maintenance treatment of advanced non-small-cell lung cancer.
Erlotinib hydrochloride (Tarceva(®)) is a member of a class of small molecule inhibitors that targets the tyrosine kinase domain of the epidermal growth factor receptor (EGFR), with anti-tumor activity in preclinical models. Erlotinib represents a new-generation of agents known as "targeted therapies" designed to act upon cancer cells by interfering with aberrant specific activated pathways needed for tumor growth, angiogenesis and cell survival. Since its approval in November 2004 for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after the failure of at least one prior chemotherapy regimen and with a view to improving patients' outcomes and prevent symptoms, the scientific community has evaluated the potential role of erlotinib in other scenarios such as in maintenance therapy and, in first-line setting for a selected population based on biological markers of response such as mutations of the EGFR. The convenient once-a-day pill administration and the good toxicity profile of erlotinib make it a reasonable candidate for testing in this context. This report provides a review of the role of erlotinib therapy in advanced NSCLC. It summarizes current data and perspectives of erlotinib in upfront treatment and maintenance for advanced NSCLC as well as looking at candidate biomarkers of response to these new targeted-agents.


Low working memory capacity is only spuriously related to poor reading comprehension.
Accounts of comprehension failure, whether in the case of readers with poor skill or when syntactic complexity is high, have overwhelmingly implicated working memory capacity as the key causal factor. However, extant research suggests that this position is not well supported by evidence on the span of active memory during online sentence processing, nor is it well motivated by models that make explicit claims about the memory mechanisms that support language processing. The current study suggests that sensitivity to interference from similar items in memory may provide a better explanation of comprehension failure. Through administration of a comprehensive skill battery, we found that the previously observed association of working memory with comprehension is likely due to the collinearity of working memory with many other reading-related skills, especially IQ. In analyses which removed variance shared with IQ, we found that receptive vocabulary knowledge was the only significant predictor of comprehension performance in our task out of a battery of 24 skill measures. In addition, receptive vocabulary and non-verbal memory for serial order-but not simple verbal memory or working memory-were the only predictors of reading times in the region where interference had its primary affect. We interpret these results in light of a model that emphasizes retrieval interference and the quality of lexical representations as key determinants of successful comprehension.


Primary systemic therapy of breast cancer.
Primary systemic therapy (PST) or neoadjuvant therapy is used in nonmetastatic breast cancer to treat systemic disease earlier, decrease tumor bulk ideally to a complete pathological response (pCR), and reduce the extent of surgery. The multitude of clinical trials using PST in breast cancer patients has not proven the fundamental hypotheses of improved overall survival and disease-free survival that drove the investigation of PST. The other potential advantages of PST, which include increasing the rate of breast-conserving surgery and predicting outcome to a particular chemotherapy regimen, are also not conclusively established. We examined the published literature on PST for breast cancer and predominantly focused our review on data from large, randomized clinical trials comparing primary systemic chemotherapy with adjuvant chemotherapy, different primary systemic chemotherapy regimens, primary systemic chemotherapy with hormonal therapy, and different preoperative hormonal therapies. Although the optimal neoadjuvant chemotherapy regimen has not been established, a combination of four cycles of an anthracycline followed by four cycles of a taxane appears to produce the highest pCR rate (22%-31%). In patients with HER-2-positive breast cancer, concurrent use of neoadjuvant trastuzumab with an anthracycline-taxane combination has produced provocative results that require further confirmatory studies. Preoperative hormonal therapy is associated with low pCR rates and should be reserved for patients who are poor candidates for systemic chemotherapy. The optimal management of patients with residual disease after the administration of maximum neoadjuvant therapy remains to be defined. The surgical approach, including the role of sentinel node biopsy and delivery of radiation therapy after PST in breast cancer patients, is evolving. Ongoing clinical trials will help identify the subset of patients who would most benefit from the use of PST, establish the most effective PST regimen, and determine the optimal multidisciplinary approach in the management of breast cancer.


Paracetamol sales and atopic disease in children and adults: an ecological analysis.
The authors recently observed that frequent paracetamol use was positively associated with asthma and rhinitis in young adults. Therefore, an ecological analysis was performed to measure international associations between paracetamol sales and atopic disease prevalences in children and adults. Published data from the International Study of Asthma and Allergies in Childhood (ISAAC) on the prevalence of four atopic symptoms in 13-14-yr-olds (112 centres) and 67-yr-olds (66 centres) in 1994/1995, and European Community Respiratory Health Survey (ECRHS) data on the prevalence of asthma symptoms, diagnosed asthma and rhinitis (44 centres), prevalence of atopy, mean bronchial responsiveness and mean total immunoglobulin E levels (34 centres) in young adults in 1991/1992, were used. Their associations with national 1994/1995 per capita paracetamol sales were measured using linear regression. Paracetamol sales were high in English-speaking countries, and were positively associated with asthma symptoms, eczema and allergic rhinoconjunctivitis in 13-14-yr-olds, and with wheeze, diagnosed asthma, rhinitis and bronchial responsiveness in adults. The prevalence of wheeze increased by 0.52% in 13-14-yr-olds and by 0.26% in adults (p<0.0005) for each gram increase in per capita paracetamol sales. These ecological findings require cautious interpretation, but raise the possibility that variation in paracetamol usage may explain some of the variation in atopic disease prevalence between countries.


Dynamic cellular uptake of mixed-monolayer protected nanoparticles.
Nanoparticles (NPs) are gaining increasing attention for potential application in medicine; consequently, studying their interaction with cells is of central importance. We found that both ligand arrangement and composition on gold nanoparticles play a crucial role in their cellular internalization. In our previous investigation, we showed that 66-34OT nanoparticles coated with stripe-like domains of hydrophobic (octanethiol, OT, 34%) and hydrophilic (11-mercaptoundecane sulfonate, MUS, 66%) ligands permeated through the cellular lipid bilayer via passive diffusion, in addition to endo-/pino-cytosis. Here, we show an analysis of NP internalization by DC2.4, 3T3, and HeLa cells at two temperatures and multiple time points. We study four NPs that differ in their surface structures and ligand compositions and report on their cellular internalization by intracellular fluorescence quantification. Using confocal laser scanning microscopy we have found that all three cell types internalize the 66-34OT NPs more than particles coated only with MUS, or particles coated with a very similar coating but lacking any detectable ligand shell structure, or 'striped' particles but with a different composition (34-66OT) at multiple data points.


Role of nanobiotechnology in developing personalized medicine for cancer.
Personalized medicine simply means the prescription of specific therapeutics best suited for an individual. Personalization of cancer therapies is based on a better understanding of the disease at the molecular level. Nanotechnology will play an important role in this area. Nanobiotechnology is being used to refine discovery of biomarkers, molecular diagnostics, drug discovery and drug delivery, which are important basic components of personalized medicine and are applicable to management of cancer as well. Examples are given of the application of quantum dots, gold nanoparticles, and molecular imaging in diagnostics and combination with therapeutics -- another important feature of personalized medicine. Personalized medicine is beginning to be recognized and is expected to become a part of medical practice within the next decade. Personalized management of cancer, facilitated by nanobiotechnology, is expected to enable early detection of cancer, more effective and less toxic treatment increasing the chances of cure.


An Enriched Environment Ameliorates Oxidative Stress and Olfactory Dysfunction in Parkinson's Disease with α-Synucleinopathy.
Parkinson's disease (PD) features nonmotor symptoms such as olfactory dysfunction referred to as hyposmia, an initial sign of disease progression. Metabolic dysfunction can contribute to neurodegenerative diseases, and various xenobiotics and endogenous compounds are also involved in the pathogenesis of PD. Although aerobic exercise was found to induce preservation or improvement in olfactory function in PD patients in a recent study, the exact underlying mechanism for this effect is not clear. We aimed to investigate the influence of an enriched environment (EE) on olfactory dysfunction especially via metabolic pathways related to detoxification enzymes. Eight-month-old transgenic (Tg) PD mice that overexpress human A53T α-synuclein (α-syn) were randomly allocated to an EE or standard conditions for 2 mo. The buried food test showed that EE group had significantly improved olfactory function compared to the control group. Reverse transcription polymerase chain reaction (PCR) and real-time quantitative PCR showed that expression of the detoxification enzymes-- cytochrome P450 family 1 subfamily A member 2, paraoxonase 1, alcohol dehydrogenase 1, UDP glucuronosyltransferase family 2 member A1 complex locus, aldehyde oxidase homolog 2, and aldehyde glutathione peroxidase 6--was significantly increased in the olfactory bulb (OB) of the PD control group, but these enzymes were normalized in the EE group. Immunohistochemical staining of the OB showed that oxidative stress and nitrated α-syn were significantly increased in the control group but decreased in the EE group. In conclusion, we suggest that exposure to an EE decreases both oxidative stress and nitrated α-syn, resulting in normalized detoxification enzymes and amelioration of olfactory dysfunction.


Cannabis: From a Plant That Modulates Feeding Behaviors toward Developing Selective Inhibitors of the Peripheral Endocannabinoid System for the Treatment of Obesity and Metabolic Syndrome.
In this review, we discuss the role of the endocannabinoid (eCB) system in regulating energy and metabolic homeostasis. Endocannabinoids, via activating the cannabinoid type-1 receptor (CB1R), are commonly known as mediators of the thrifty phenotype hypothesis due to their activity in the central nervous system, which in turn regulates food intake and underlies the development of metabolic syndrome. Indeed, these findings led to the clinical testing of globally acting CB1R blockers for obesity and various metabolic complications. However, their therapeutic potential was halted due to centrally mediated adverse effects. Recent observations that highlighted the key role of the peripheral eCB system in metabolic regulation led to the preclinical development of various novel compounds that block CB1R only in peripheral organs with very limited brain penetration and without causing behavioral side effects. These unique molecules, which effectively ameliorate obesity, type II diabetes, fatty liver, insulin resistance, and chronic kidney disease in several animal models, are likely to be further developed in the clinic and may revive the therapeutic potential of blocking CB1R once again.


High-density lipoprotein: vascular protective effects, dysfunction, and potential as therapeutic target.
High-density lipoprotein (HDL) is a complex mixture of lipoproteins that is associated with many minor proteins and lipids that influence the function of HDL. Although HDL is a promising marker and potential therapeutic target based on its epidemiological data and the effects of healthy HDL in vitro in endothelial cells and macrophages, as well as based on infusion studies of reconstituted HDL in patients with hypercholesterolemia, it remains still uncertain whether or not HDL cholesterol-raising drugs will improve outcomes. Recent studies suggest that HDL becomes modified in patients with coronary artery disease or acute coronary syndrome because of oxidative processes that result in alterations in its proteome composition (proteome remodelling) leading to HDL dysfunction.


Clinical practice experience with NovoTTF-100A™ system for glioblastoma: The Patient Registry Dataset (PRiDe).
Recurrent glioblastoma multiforme (GBM) is a highly aggressive cancer with poor prognosis, and an overall survival of 6 to 7 months with optimal therapies. The NovoTTF-100A™ System is a novel antimitotic cancer therapy recently approved for the treatment of recurrent GBM, based on phase III (EF-11) trial results. The Patient Registry Dataset (PRiDe) is a post-marketing registry of all recurrent GBM patients who received NovoTTF Therapy in a real-world, clinical practice setting in the United States between 2011 and 2013. Data were collected from all adult patients with recurrent GBM who began commercial NovoTTF Therapy in the United States between October 2011 and November 2013. All patients provided written consent before treatment was started. Overall survival (OS) curves were constructed for PRiDe using the Kaplan-Meier method. Median OS in PRiDe was compared for patients stratified by average daily compliance (≥75% v<75% per day) and other prognostic variables. Adverse events were also evaluated. Data from 457 recurrent GBM patients who received NovoTTF Therapy in 91 US cancer centers were analyzed. More patients in PRiDe than the EF-11 trial received NovoTTF Therapy for first recurrence (33% v 9%) and had received prior bevacizumab therapy (55.1% v 19%). Median OS was significantly longer with NovoTTF Therapy in clinical practice (PRiDe data set) than in the EF-11 trial (9.6 v 6.6 months; HR, 0.66; 95% CI, 0.05 to 0.86, P = .0003). One- and 2-year OS rates were more than double for NovoTTF Therapy patients in PRiDe than in the EF-11 trial (1-year: 44% v 20%; 2-year: 30% v 9%). First and second versus third and subsequent recurrences, high Karnofsky performance status (KPS), and no prior bevacizumab use were favorable prognostic factors. No unexpected adverse events were detected in PRiDe. As in the EF-11 trial, the most frequent adverse events were mild to moderate skin reactions associated with application of the NovoTTF Therapy transducer arrays. Results from PRiDe, together with those previously reported in the EF-11 trial, indicate that NovoTTF Therapy offers clinical benefit to patients with recurrent GBM. NovoTTF Therapy has high patient tolerability and favorable safety profile in the real-world, clinical practice setting.


Transoral robotic lingual tonsillectomy in adults: preliminary results.
Hypertrophy of lingual tonsils can be safely and effectively managed by transoral robotic surgery via a minimally invasive approach. The operating costs can be relatively high although the advantages to patients seem to justify the procedure. Transoral robotic surgery can represent the definitive treatment in hypertrophy of the lingual tonsils. The purpose of this work was to assess the feasibility, safety, and outcomes of transoral robotic surgery for lingual tonsillar hypertrophy in adults with obstructive sleep apnea. Retrospective medical records of six patients who underwent tongue base resection using the da Vinci Surgical Robotic System from September, 2012 through December, 2013 in a tertiary care hospital were evaluated. Demographic data, preoperative and postoperative polysomnography and Epworth Sleepiness Scale (ESS) scores, robot docking time, operative and postoperative aspects including surgical time, amount of bleeding, and early and late complications were collected and analyzed. All patients successfully underwent lingual tonsillectomy using the da Vinci Surgical system. Transnasal endotracheal entubation was performed in all patients and they were all extubated before leaving the operation room. No tracheotomies were performed perioperatively for airway management. The patients were discharged on the fifth postoperative day. Operative time, estimated blood loss, and postoperative complication profiles were within the expected and acceptable limits for lingual tonsillectomy. There was a statistically significant decrease in apnea hypopnea index (AHI) (mean AHI from 27.5 to 6.3) and ESS scores (from 14.1 to 7.1).


Improved High-Density Myoelectric Pattern Recognition Control Against Electrode Shift Using Data Augmentation and Dilated Convolutional Neural Network.
the objective of this work is to develop a robust method for myoelectric control towards alleviating the interference of electrode shift. M ethods: In the proposed method, a preprocessing approach was first performed to convert high-density surface electromyogram (HD-sEMG) signals into a series of images, and the electrode shift appeared as pixel shift in these images. Next, a data augmentation approach was applied to the training data from just one position (no shift), so as to simulate HD-sEMG images derived from fictitious shift positions. The dilated convolutional neural network (DCNN) was subsequently adopted for classification. Compared to common convolutional neural network, DCNN always contained a larger receptive field that was supposed to be adept at mining wider spatial contextual information in images. This property was further confirmed to facilitate the classification of myoelectric patterns using HD-sEMG. The performance of the proposed method was evaluated with HD-sEMG data recorded by a 10×10 electrode array placed over forearm extensors of ten subjects during their performance of six wrist and finger extension tasks. Under a variety of actual electrode shift conditions, the proposed method achieved a mean classification accuracy of 95.34%, and it outperformed other common methods. This work demonstrated feasibility and usability of combining data augmentation and DCNN in predicting myoelectric patterns in the context of electrode shifts. The proposed method is a practical solution for robust myoelectric control against electrode array shifts.


Stereotactic ablative radiotherapy for reirradiation of locally recurrent lung tumors.
Patients with thoracic tumors that recur after irradiation currently have limited therapeutic options. Retreatment using stereotactic ablative radiotherapy (SABR) is appealing for these patients because of its high conformity but has not been studied extensively. Here we report our experience with SABR for lung tumors in previously irradiated regions. We conducted a retrospective study of patients with primary lung cancer or metastatic lung tumors treated with SABR. We identified 17 such tumors in 15 patients and compared their outcomes with those of a cohort of 135 previously unirradiated lung tumors treated with SABR during the same time period. Twelve-month local control (LC) for retreated tumors was 65.5%, compared with 92.1% for tumors receiving SABR as initial treatment. Twelve-month LC was significantly worse for reirradiated tumors in which the time interval between treatments was 16 months or less (46.7%), compared with those with longer intertreatment intervals (87.5%). SABR reirradiation did not lead to significant increases in treatment-related toxicity. SABR for locally recurrent lung tumors arising in previously irradiated fields seems to be feasible and safe for appropriately selected patients. LC of retreated lesions was significantly lower, likely owing to the lower doses used for retreatment. Shorter time to retreatment was associated with increased risk of local failure, suggesting that these tumors may be particularly radioresistant. Our findings suggest that dose escalation may improve LC while maintaining acceptable levels of toxicity for these patients.


Voxel-wise mapping of cervical cord damage in multiple sclerosis patients with different clinical phenotypes.
To apply voxel-based methods to map the regional distribution of atrophy and T2 hyperintense lesions in the cervical cord of multiple sclerosis (MS) patients with different clinical phenotypes. Brain and cervical cord 3D T1-weighted and T2-weighted scans were acquired from 31 healthy controls (HC) and 77 MS patients (15 clinically isolated syndromes (CIS), 15 relapsing-remitting (RR), 19 benign (B), 15 primary progressive (PP) and 13 secondary progressive (SP) MS). Hyperintense cord lesions were outlined on T2-weighted scans. The T2- and 3D T1-weighted cord images were then analysed using an active surface method which created output images reformatted in planes perpendicular to the estimated cord centre line. These unfolded cervical cord images were co-registered into a common space; then smoothed binary cord masks and lesion masks underwent spatial statistic analysis (SPM8). No cord atrophy was found in CIS patients versus HC, while PPMS had significant cord atrophy. Clusters of cord atrophy were found in BMS versus RRMS, and in SPMS versus RRMS, BMS and PPMS patients, mainly involving the posterior and lateral cord segments. Cord lesion probability maps showed a significantly greater likelihood of abnormalities in RRMS, PPMS and SPMS than in CIS and BMS patients. The spatial distributions of cord atrophy and cord lesions were not correlated. In progressive MS, regional cord atrophy was correlated with clinical disability and impairment in the pyramidal system. Voxel-based assessment of cervical cord damage is feasible and may contribute to a better characterisation of the clinical heterogeneity of MS patients.


Functional mapping-guided resection of low-grade gliomas in eloquent areas of the brain: improvement of long-term survival. Clinical article.
Low-grade gliomas (LGGs) frequently infiltrate highly functional or "eloquent" brain areas. Given the lack of long-term survival data, the prognostic significance of eloquent brain tumor location and the role of functional mapping during resective surgery in presumed eloquent brain regions are unknown. We performed a retrospective analysis of 281 cases involving adults who underwent resection of a supratentorial LGG at a brain tumor referral center. Preoperative MR images were evaluated blindly for involvement of eloquent brain areas, including the sensorimotor and language cortices, and specific subcortical structures. For high-risk tumors located in presumed eloquent brain areas, long-term survival estimates were evaluated for patients who underwent intraoperative functional mapping with electrocortical stimulation and for those who did not. One hundred and seventy-four patients (62%) had high-risk LGGs that were located in presumed eloquent areas. Adjusting for other known prognostic factors, patients with tumors in areas presumed to be eloquent had worse overall and progression-free survival (OS, hazard ratio [HR] 6.1, 95% CI 2.6-14.1; PFS, HR 1.9, 95% CI 1.2-2.9; Cox proportional hazards). Confirmation of tumor overlapping functional areas during intraoperative mapping was strongly associated with shorter survival (OS, HR 9.6, 95% CI 3.6-25.9). In contrast, when mapping revealed that tumor spared true eloquent areas, patients had significantly longer survival, nearly comparable to patients with tumors that clearly involved only noneloquent areas, as demonstrated by preoperative imaging (OS, HR 2.9, 95% CI 1.0-8.5). Presumed eloquent location of LGGs is an important but modifiable risk factor predicting disease progression and death. Delineation of true functional and nonfunctional areas by intraoperative mapping in high-risk patients to maximize tumor resection can dramatically improve long-term survival.


Contractions, a risk for premature rupture of fetal membranes: a new protocol with cyclic biaxial tension.
This study aims at investigating the effect of repeated mechanical loading on the rupture and deformation properties of fetal membranes. Ten membranes delivered by cesarean sections were tested using a custom-built inflation device which provides a multi-axial stress state. For each membrane, a group of samples was first cyclically stretched by application of pressure ranging between 10 and 40 mmHg. After cycles, samples were subjected to inflation up to rupture. Differences between mechanical parameters from cycled and uncycled samples were analyzed. Ten cycles at 40% of mean critical membrane tension--representative of mean physiologic contractions--did not affect strength and stiffness of fetal membranes but reduced the work to rupture, thus indicating that contractions might increase the risk of premature rupture of the membrane. Cyclic testing demonstrated a large hysteresis loop and irreversible deformation on the first cycle, followed by rapid stabilization on subsequent cycles. In 80% of tests, amnion ruptured first and at the periphery of the sample, under uniaxial strain state. Chorion ruptured at higher deformation levels in the middle, under biaxial strain state.


Canadian Public Health Laboratory Network laboratory guidelines for the use of point-of-care tests for the diagnosis of syphilis in Canada.
Syphilis point-of-care tests (POCT) are widely available in developing countries enabling early diagnosis, treatment and support. The majority of commercially available tests use treponemal antigens and the presence of antibodies does not distinguish between current and past infection, which may lead to unnecessary antibiotic use and stigmatization of having a current STI. In hard-to-reach populations, the benefits may outweigh the risks. Available studies show reasonable performance of POCT with median sensitivity of 86%, specificity of 99% and positive predictive values >80% when prevalence was >0.3%. Although no syphilis POCT are approved in Canada at this time, a single study in an outreach setting in Alberta showed limited benefit due to a high prevalence of previous infection but more studies are needed. Newer dual tests employing treponemal and nontreponemal antigens look promising.


Localized nodular synovitis of the knee: MR imaging appearance and clinical correlates in 21 patients.
Localized nodular synovitis of the knee and pigmented villonodular synovitis are similar histologically. The purpose of this study was to evaluate the MR imaging appearance and clinical findings of localized nodular synovitis of the knee and to differentiate this condition from pigmented villonodular synovitis. A retrospective review of MR imaging of the knee was performed in 21 patients with histologically confirmed localized nodular synovitis. Surgical excision of the lesion was performed in all patients. The MR imaging appearances of the lesions were defined, and the clinical and surgical findings were reviewed. All lesions presented as a solitary intraarticular mass. The mass originated from the synovial lining in different locations including the infrapatellar fat pad (n = 14), suprapatellar pouch (n = 5), and posterior aspect of the intercondylar notch (n = 2). A small (2.0-3.5 cm; mean diameter, 2.7 cm) ovoid mass (n = 13) was more common than a large (5.0-9.0 cm; mean diameter, 6.5 cm) polylobulated mass (n = 8). At surgery, a long pedicle attached the mass to the adjacent synovium in two patients, but this was observed on MR imaging in only one patient. The lesions showed intermediate (n = 15) or hyperintense (n = 6) signal intensity on T1-weighted images and heterogeneously high (n = 13) or low (n = 8) signal intensity with variable circular foci of low signal intensity on T2-weighted images. On T2-weighted images, linear regions of high signal intensity within the mass were seen in seven lesions. Prominent enhancement of the lesion with IV contrast administration was shown in all patients who were given contrast material (n = 10). Knee pain, joint swelling, and a palpable mass were the most frequent clinical manifestations. An acutely painful knee was noted in one patient who presented with torsion of an infrapatellar pedicle. Five patients complained of locking of the knee, but at physical examination, restricted terminal knee extension was noted in nine patients. Localized nodular synovitis of the knee predominantly involves the infrapatellar fat pad. It may produce symptoms related to mechanical derangement of the knee. Although there is no typical MR appearance for this lesion, many features help to differentiate it from pigmented villonodular synovitis.


Alternative to homo-oligomerisation: the creation of local symmetry in proteins by internal amplification.
The biologically active state of many proteins requires their prior homo-oligomerisation. Such complexes are typically symmetrical, a feature that has been proposed to increase their stability and facilitate the evolution of allosteric regulation. We wished to examine the possibility that similar structures and properties could arise from genetic amplifications leading to internal symmetrical repeats. For this, we identified internal structural repeats in a nonredundant Protein Data Bank subset. While testing if repeats in proteins tend to be symmetrical, we found that about half of the large internal repeats are symmetrical, most frequently around a rotation axis of 180 degrees . These repeats were most likely created by genetic amplification processes because they show significant sequence similarity. Symmetrical repeats tend to have a fixed number of copies corresponding to their rotational symmetry order, that is, two for 180 degrees rotation axis, whereas asymmetrical repeats are in longer proteins and show copy number variability. When possible, we confirmed that proteins with symmetrical repeats folding as an n-mer have homologues lacking the repeat with a higher oligomerisation number corresponding to the rotation symmetry order of the repeat. Phylogenetic analyses of these protein families suggest that typically, but not always, symmetrical repeats arise in one single event from proteins that are homo-oligomers. These results suggest that oligomerisation and amplification of internal sequences can interplay in evolutionary terms because they result in functional analogues when the latter exhibit rotational symmetry.


Gene expression in nontumoral liver tissue and recurrence-free survival in hepatitis C virus-positive hepatocellular carcinoma.
The goal of this study was to understand gene expression signatures of hepatocellular carcinoma (HCC) recurrence in subjects with hepatitis C virus (HCV) infection. Recurrence-free survival (RFS) following curative resection of HCC in subjects with HCV is highly variable. Traditional clinico-pathological endpoints are recognized as weak predictors of RFS. It has been suggested that gene expression profiling of HCC and nontumoral liver tissue may improve prediction of RFS, aid in understanding of the underlying liver disease, and guide individualized patient management. Frozen samples of the tumors and nontumoral liver were obtained from 47 subjects with HCV-associated HCC. Additional nontumoral liver samples were obtained from HCV-free subjects with metastatic liver tumors. Gene expression profiling data was used to determine the molecular signature of HCV-associated HCC and to develop a predictor of RFS. The molecular profile of the HCV-associated HCC confirmed central roles for MYC and TGFbeta1 in liver tumor development. Gene expression in tumors was found to have poor predictive power with regards to RFS, but analysis of nontumoral tissues yielded a strong predictor for RFS in late-recurring (>1 year) subjects. Importantly, nontumoral tissue-derived gene expression predictor of RFS was highly significant in both univariable and multivariable Cox proportional hazard model analyses. Microarray analysis of the nontumoral tissues from subjects with HCV-associated HCC delivers novel molecular signatures of RFS, especially among the late-recurrence subjects. The gene expression predictor may hold important insights into the pathobiology of HCC recurrence and de novo tumor formation in cirrhotic patients.


Technology-assisted weight loss interventions in primary care: a systematic review.
The US Preventive Services Task Force recommends screening for and treating obesity. However, there are many barriers to successfully treating obesity in primary care (PC). Technology-assisted weight loss interventions offer novel ways of improving treatment, but trials are overwhelmingly conducted outside of PC and may not translate well into this setting. We conducted a systematic review of technology-assisted weight loss interventions specifically tested in PC settings. We searched the literature from January 2000 to March 2014. (1) Randomized controlled trial; (2) trials that utilized the Internet, personal computer, and/or mobile device; and (3) occurred in an ambulatory PC setting. We applied the Cochrane Effective Practice and Organization of Care (EPOC) and Delphi criteria to assess bias and the Pragmatic-Explanatory Continuum Indicator Summary (PRECIS) criteria to assess pragmatism (whether trials occurred in the real world versus under ideal circumstances). Given heterogeneity, results were not pooled quantitatively. Sixteen trials met inclusion criteria. Twelve (75 %) interventions achieved weight loss (range: 0.08 kg - 5.4 kg) compared to controls, while 5-45 % of patients lost at least 5 % of baseline weight. Trial duration and attrition ranged from 3-36 months and 6-80 %, respectively. Ten (63 %) studies reported results after at least 1 year of follow-up. Interventions used various forms of personnel, technology modalities, and behavior change elements; trials most frequently utilized medical doctors (MDs) (44 %), web-based applications (63 %), and self-monitoring (81 %), respectively. Interventions that included clinician-guiding software or feedback from personnel appeared to promote more weight loss than fully automated interventions. Only two (13 %) studies used publically available technologies. Many studies had fair pragmatism scores (mean: 2.8/4), despite occurring in primary care. Compared to usual care, technology-assisted interventions in the PC setting help patients achieve weight loss, offering evidence-based options to PC providers. However, best practices remain undetermined. Despite occurring in PC, studies often fall short in utilizing pragmatic methodology and rarely provide publically available technology. Longitudinal, pragmatic, interdisciplinary, and open-source interventions are needed.


Intracellular kinetics of iron in reticulocytes: evidence for endosome involvement in iron targeting to mitochondria.
In erythroid cells the vast majority of iron (Fe) released from endosomes must cross both the outer and the inner mitochondrial membranes to reach ferrochelatase that inserts Fe into protoporphyrin IX. In the present study, we developed a method whereby a cohort of 59Fe-transferrin (Tf)-laden endosomal vesicles were generated, from which we could evaluate the transfer of 59Fe into mitochondria. Iron chelators, dipyridyl or salicylaldehyde isonicotinoyl hydrazone (SIH), were able to bind the 59Fe when they were present during a 37 degrees C incubation; however, addition of these agents only during lysis at 4 degrees C chelated virtually no 59Fe. Bafilomycin A1 (which prevents endosome acidification) and succinylacetone (an inhibitor of 5-aminolevulinate dehydratase) prevented endosomal 59Fe incorporation into heme. Importantly, both the myosin light chain kinase inhibitor wortmannin and the calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7), caused significant inhibition of 59Fe incorporation from 59Fe-Tf-labeled endosomes into heme, suggesting that myosin is required for Tf-vesicle movement. Our results reaffirm the astonishing efficiency of Tf-derived Fe utilization in hemoglobin (Hb)-producing cells and demonstrate that very little of this Fe is present in a chelatable pool. Collectively, these results are congruent with our hypothesis that a transient endosome-mitochondrion interaction mediates iron transfer between these organelles.


The incidence of diabetes among 0-34 year olds in Sweden: new data and better methods.
We reassessed the validity of previously reported incidence rates for type 1 diabetes in 0-34 year olds in Sweden. We estimated new incidence rates through three nationwide registers. We used capture-recapture methods to assess ascertainment in the Diabetes Incidence Study in Sweden (DISS) and estimated incidence rates in the 20-34 year age group for 2007-2009. We examined whether incidence rates in patients aged 34 and younger could be estimated through the Prescribed Drug Register (PDR) via a proxy for diagnosis of type 1 diabetes; men with at least one and women with at least three prescriptions for insulin were included if they had not been given oral glucose-lowering drugs. We scrutinised the proxy by comparing incidence rates in patients aged 14 and younger with the Swedish Childhood Diabetes Register (SCDR), which has 95-99% ascertainment, and by assessing diabetes type among 18-34 year olds in the National Diabetes Register (NDR). Incidence rates were two to three times higher than previously reported. The absolute number of cases (2007-2009, age 20-34) was 435 in the DISS, 923 in the NDR, 1,217 in the PDR, 1,431 in all three and 1,617 per the capture-recapture method. Ascertainment in the DISS was ~29% for 2007-2009. The proxy diagnosis in the PDR was highly reliable, while the capture-recapture method presumably generated an overestimate. The incidence of type 1 diabetes in patients aged 34 and younger was two to three times higher than previously reported. The PDR can be used to reliably assess incidence rates in this age group.


Inflammatory cytokines in chronic heart failure: interleukin-8 is associated with adverse outcome. Results from CORONA.
We investigated the ability of prototypical inflammatory cytokines to predict clinical outcomes in a large population of patients with chronic systolic heart failure (HF). Serum levels of tumour necrosis factor-α (TNF-α), soluble TNF receptors type I and II (sTNF-RI and sTNF-RII), and the chemokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) were analysed in 1464 patients with chronic ischaemic systolic HF in the CORONA study, aged ≥ 60 years, in NYHA class II-IV, and related to the primary endpoint (n = 320), as well as any coronary event (n = 255), all-cause mortality (n = 329), cardiovascular (CV) mortality (n = 268), and the composite endpoint hospitalization from worsening heart failure (WHF) or CV mortality (n = 547). TNF-α, sTNF-RI, sTNF-RII, and IL-8, but not MCP-1, were independent predictors of all endpoints except the coronary endpoint in multivariable models including conventional clinical variables. After further adjustment for estimated glomerular filtration rate, the ApoB/ApoA-1 ratio, NT-proBNP, and high-sensitivity C-reactive protein, only IL-8 remained a significant predictor of all endpoints (except the coronary endpoint), while sTNF- RI remained independently associated with CV mortality. Adding IL-8 to the full model led to a significant improvement in net reclassification for all-cause mortality and CV hospitalization, but only a borderline significant improvement for the primary endpoint, CV mortality, and the composite endpoint WHF hospitalization or CV mortality. Our study supports a relationship between IL-8 and outcomes in patients with chronic HF. However, the clinical usefulness of IL-8 as a biomarker in an unselected HF population is at present unclear.


Law enforcement duties and sudden cardiac death among police officers in United States: case distribution study.
To assess the association between risk of sudden cardiac death and stressful law enforcement duties compared with routine/non-emergency duties. Case distribution study (case series with survey information on referent exposures). United States law enforcement. Summaries of deaths of over 4500 US police officers provided by the National Law Enforcement Officers Memorial Fund and the Officer Down Memorial Page from 1984 to 2010. Observed and expected sudden cardiac death counts and relative risks for sudden cardiac death events during specific strenuous duties versus routine/non-emergency activities. Independent estimates of the proportion of time that police officers spend across various law enforcement duties obtained from surveys of police chiefs and front line officers. Impact of varying exposure assessments, covariates, and missing cases in sensitivity and stability analyses. 441 sudden cardiac deaths were observed during the study period. Sudden cardiac death was associated with restraints/altercations (25%, n=108), physical training (20%, n=88), pursuits of suspects (12%, n=53), medical/rescue operations (8%, n=34), routine duties (23%, n=101), and other activities (11%, n=57). Compared with routine/non-emergency activities, the risk of sudden cardiac death was 34-69 times higher during restraints/altercations, 32-51 times higher during pursuits, 20-23 times higher during physical training, and 6-9 times higher during medical/rescue operations. Results were robust to all sensitivity and stability analyses. Stressful law enforcement duties are associated with a risk of sudden cardiac death that is markedly higher than the risk during routine/non-emergency duties. Restraints/altercations and pursuits are associated with the greatest risk. Our findings have public health implications and suggest that primary and secondary cardiovascular prevention efforts are needed among law enforcement officers.


Impact of COVID-19 on the Health of the General and More Vulnerable Population and Its Determinants: Health Care and Social Survey-ESSOC, Study Protocol.
This manuscript describes the rationale and protocol of a real-world data (RWD) study entitled Health Care and Social Survey (ESSOC, Encuesta Sanitaria y Social). The study's objective is to determine the magnitude, characteristics, and evolution of the COVID-19 impact on overall health as well as the socioeconomic, psychosocial, behavioural, occupational, environmental, and clinical determinants of both the general and more vulnerable population. The study integrates observational data collected through a survey using a probabilistic, overlapping panel design, and data from clinical, epidemiological, demographic, and environmental registries. The data will be analysed using advanced statistical, sampling, and machine learning techniques. The study is based on several measurements obtained from three random samples of the Andalusian (Spain) population: general population aged 16 years and over, residents in disadvantaged areas, and people over the age of 55. Given the current characteristics of this pandemic and its future repercussions, this project will generate relevant information on a regular basis, commencing from the beginning of the State of Alarm. It will also establish institutional alliances of great social value, explore and apply powerful and novel methodologies, and produce large, integrated, high-quality and open-access databases. The information described here will be vital for health systems in order to design tailor-made interventions aimed at improving the health care, health, and quality of life of the populations most affected by the COVID-19 pandemic.


Patient stratification in myelodysplastic syndromes: how a puzzle may become a map.
Heterogeneity is the disease-defining epithet of myelodysplastic syndromes (MDS), a clonal disorder of hematopoietic stem and progenitor cells. During the last decade, significant progress has been made to better understand the diversity of clinical, molecular, cellular, and immunological factors that are bound to the prognosis and outcomes of patients with MDS. Despite the rapid generation of all of this biological information, how to implement it has fallen short. Redefining clinical tools to use this new information remains a challenge. The holistic integration of novel, high-impact individual risk parameters such as patient-reported outcomes or mutational and immunological data into conventional risk stratification systems may further refine patient subgroups, improve predictive power for survival, and provide a next-generation classification and prognosis system for patients with MDS. Dichotomic treatment strategies in patients with MDS according to their patient and disease profiles highlight the importance of precise risk stratification, which may be complemented by the definition of granular cohorts of patients with myeloid neoplasms and a druggable target (ie, IDH1/2 mutations) across conventional blast thresholds.


Co-prescription trends in a large cohort of subjects predict substantial drug-drug interactions.
Pharmaceutical prescribing and drug-drug interaction data underlie recommendations on drug combinations that should be avoided or closely monitored by prescribers. Because the number of patients taking multiple medications is increasing, a comprehensive view of prescribing patterns in patients is important to better assess real world pharmaceutical response and evaluate the potential for multi-drug interactions. We obtained self-reported prescription data from NHANES surveys between 1999 and 2010, and confirm the previously reported finding of increasing drug use in the elderly. We studied co-prescription drug trends by focusing on the 2009-2010 survey, which contains prescription data on 690 drugs used by 10,537 subjects. We found that medication profiles were unique for individuals aged 65 years or more, with ≥98 unique drug regimens encountered per 100 subjects taking 3 or more medications. When drugs were viewed by therapeutic class, it was found that the most commonly prescribed drugs were not the most commonly co-prescribed drugs for any of the 16 drug classes investigated. We cross-referenced these medication lists with drug interaction data from Drugs.com to evaluate the potential for drug interactions. The number of drug alerts rose proportionally with the number of co-prescribed medications, rising from 3.3 alerts for individuals prescribed 5 medications to 11.7 alerts for individuals prescribed 10 medications. We found 22% of elderly subjects taking both a substrate and inhibitor of a given cytochrome P450 enzyme, and 4% taking multiple inhibitors of the same enzyme simultaneously. By examining drug pairs prescribed in 0.1% of the population or more, we found low agreement between co-prescription rate and co-discussion in the literature. These data show that prescribing trends in treatment could drive a large extent of individual variability in drug response, and that current pairwise approaches to assessing drug-drug interactions may be inadequate for predicting real world outcomes.


Neuroimaging findings in hyperargininemia.
In hyperarginenemia, there is a defect in argininase enzyme, which is a catalyzer of urea cycle. Though the pathogenesis of neuronal damage in hyperargininemia is not clear, high serum and cerebrospinal fluid arginine levels can be directly related with neuronal damage. In this study, our aim was to assess brain magnetic resonance images and magnetic resonance spectroscopy (MRS) patterns of two siblings with hyperarginenemia. We acquired single voxel MRS from the white matter to show the myelination pattern and to figure out any abnormal peak of metabolite stored due to enzymatic defect. We observed mild cerebral and cerebellar atrophy and infarct at bilateral posterior putamen and insular cortex localization on conventional images and elevated choline/creatine ratios and abnormal peak at 3.8 ppm, most likely representing arginine deposition. To the best of our knowledge, this is the first article revealing the brain MRS pattern of hyperargininemia. We reported the clinical and imaging findings of patients and discuss the correlation.


A disjointed effort: paediatric musculoskeletal examination.
Musculoskeletal (MSK) symptoms are a frequent cause of emergency department attendance for children, and while most often indicative of benign or self-limiting disease, such symptoms can occasionally be the first presentation of serious illness such as leukaemia or juvenile idiopathic arthritis. MSK examination, however, is often not included as part of the routine paediatric examination. The authors aimed to evaluate how often and how thoroughly MSK examination was performed during admissions to the paediatric ward and to compare it with the examination of other symptoms in relation to the presenting complaint and eventual diagnosis. Medical records for 100 consecutive patients were reviewed. A poster campaign to increase awareness was then commenced along with oral and written presentations to staff regarding MSK examination. A further 100 consecutive patients were then reviewed. Only 9% of children in the initial group had routine MSK examination, rising to 32% in the second group. Where performed, MSK examination was often incomplete. Frequent errors included only examining the reported site of injury and only examining a single limb or single joint when limpness/stiffness was the presenting complaint. Non-limb joints were very rarely examined. MSK examination is not performed routinely during paediatric admissions in contrast to the examination of other symptoms regardless of the presenting complaint. This may need to be addressed by local audit and increased undergraduate teaching.


The conserved N-terminus of human rhinovirus capsid protein VP4 contains membrane pore-forming activity and is a target for neutralizing antibodies.
Human rhinovirus is the causative agent of the common cold and belongs to the non-enveloped picornavirus family. A trigger such as receptor binding or low pH initiates conformational changes in the capsid that allow the virus to attach to membranes and form a pore for the translocation of viral RNA into the cytoplasm. We previously showed that recombinant capsid protein VP4 was able to form membrane pores. In this study, we show the N-terminus but not C-terminus of VP4 formed pores with properties similar to full-length VP4 and consistent with the size required for transfer of RNA. Sera against the N-terminus but not C-terminus of VP4 were shown to neutralize virus infectivity. Together, this suggests that the N-terminus of VP4 is responsible for membrane activity. This study contributes to an improved understanding of the mechanisms for involvement of VP4 in entry and its potential as an antiviral target.


Evaluation of patient satisfaction of an outpatient colonoscopy service in an asian tertiary care hospital.
Aim. To evaluate patient satisfaction towards an outpatient colonoscopy service and analyze areas of dissatisfaction for potential improvement. Method. Consecutive patients attending the outpatient diagnostic colonoscopy service in University of Malaya Medical Centre between 1st February and 31th July 2010 were interviewed using a questionnaire modified from the modified Group Health Association of America-9 (mGHAA-9) questionnaire. Favorable/unfavorable responses to each question, contribution of each question to unfavorable responses, and effect of waiting times on favorable/unfavorable response rates were analyzed. Results. Interview was carried out on 426 patients (52.1% men). Mean age ± standard deviation was 61.3 ± 12.9 years old. Mean waiting times for colonoscopy appointment and on colonoscopy day were 3.8 ± 2.7 months and 1.1 ± 0.8 hours, respectively. The main factors that contributed to unfavorable responses were bowel preparation followed by waiting times for colonoscopy appointment and on colonoscopy day (32.3%, 27.5%, and 19.6%, resp.). Favorable responses diminished to undesirable levels when waiting times for colonoscopy appointment and on colonoscopy day exceeded 1 month and 1 hour, respectively. Conclusion. Bowel preparation and waiting times were main factors for patient dissatisfaction. Waiting times for colonoscopy appointment and on colonoscopy day should not exceed 1 month and 1 hour, respectively, to maintain acceptable levels of patient satisfaction.


Neurodegeneration in systemic lupus erythematosus: layer by layer retinal study using optical coherence tomography.
Systemic lupus erythematosus (SLE) is a chronic, autoimmune and multisystemic disease. Recent studies with functional and structural magnetic resonance imaging and cognitive tests report an unexpectedly high frequency of central nervous system involvement, even in patients with asymptomatic SLE. The purpose of this study was to identify early signs of retinal neurodegeneration by comparing the thickness of the peripapillary retinal nerve fiber layer (pRNFL) and all macular layers between patients with SLE without ophthalmologic manifestations and healthy controls. The effect of disease duration and systemic comorbidities was also studied. Cross-sectional study, in which all participants underwent a complete ophthalmologic evaluation including retinal segmentation analysis with spectral domain-optical coherence tomography. Patients with SLE also received a detailed autoimmune disease specialist evaluation to assess the disease activity state and systemic involvement. For pRNFL thickness, the global and six peripapillary sectors were determined. Each macular layer thickness was determined in the nine Early Treatment Diabetic Retinopathy Study (ETDRS) subfields. A multiple linear regression analysis was performed to control for the effect of potential demographic, ophthalmic and systemic confounders. A second multivariable analysis, including patients with SLE only, was performed to assess the effect of disease-specific variables on the outcome measures. Sixty-eight eyes of 68 patients with SLE and 50 eyes of 50 healthy controls were considered. The pRNFL was significantly thinner in the SLE group globally (p = 0.026) and in the temporal superior (p = 0.007) and temporal (p = 0.037) sectors. In patients with SLE, chronic medication for hypercholesterolemia, hypertension and anticoagulants were associated with a significant thinning of the pRNFL. Patients with SLE presented significant thinning in the photoreceptor layer in five ETDRS areas (p < 0.05). Shorter disease duration was associated with greater photoreceptor thinning in all ETDRS subfields. Neuropsychiatric SLE, higher disease activity and cardiovascular risk factors were associated with a thinner photoreceptor layer. No differences were observed in overall retinal thickness or the remaining macular layers. Patients with SLE present early signs of retinal neurodegeneration, as evidenced by a reduction in the photoreceptor layer and pRNFL. These signs are more pronounced in patients with higher cardiovascular risk burden or neuropsychiatric involvement.


A family cluster of streptococcal toxic shock syndrome in children: clinical implication and epidemiological investigation.
Most invasive group A streptococcal (GAS) disease occurs sporadically. Reports of family clusters of these infections are scanty, and most invasive disease occurs in adults. We describe a family cluster of streptococcal toxic shock syndrome (STSS) involving 3 children and present the results of an epidemiologic investigation. During a 16-day period, 3 children in a family developed STSS with an interval of 7 and 9 days, respectively, between the onset of disease. Cases 2 and 3 had GAS isolated from blood culture. Case 2 was fatal. Pharyngeal culture survey of the family members and schoolchildren was conducted. Antibiogram, serotyping, detection of exotoxin genes, and random amplified polymorphic DNA patterns of the disease strains and survey strains were examined. One of 15 family members sampled-the sister of the index case-and 7 (5.6%) of 125 schoolchildren sampled had GAS isolated from pharyngeal cultures. Of the 10 strains examined, 2 isolates from the patients, 1 from the sister of index case, and 2 from the classmates of case 2 (the fatal case) had an identical pattern of both genotype and phenotype. We describe a family cluster of STSS involving 3 children caused by a single clone and provide additional data regarding invasive GAS infection subsequent to household contact. Additional studies should be conducted in conjunction with surveillance to define better the magnitude of risk in household contacts and to identify settings in which subsequent infections may occur.


Anterior cervical discectomy and fusion performed using structural allograft or polyetheretherketone: pseudarthrosis and revision surgery rates with minimum 2-year follow-up.
Both structural allograft and PEEK have been used for anterior cervical discectomy and fusion (ACDF). There are reports that PEEK has a higher pseudarthrosis rate than structural allograft. The authors compared pseudarthrosis, revision, subsidence, and loss of lordosis rates in patients with PEEK and structural allograft. The authors performed a retrospective review of patients who were treated with ACDF at their hospital between 2005 and 2017. Inclusion criteria were adult patients with either PEEK or structural allograft, anterior plate fixation, and a minimum 2-year follow-up. Exclusion criteria were hybrid PEEK and allograft cases, additional posterior surgery, adjacent corpectomies, infection, tumor, stand-alone or integrated screw and cage devices, bone morphogenetic protein use, or lack of a minimum 2-year follow-up. Demographic variables, number of treated levels, interbody type (PEEK cage vs structural allograft), graft packing material, pseudarthrosis rates, revision surgery rates, subsidence, and cervical lordosis changes were collected. These data were analyzed by Pearson's chi-square test (or Fisher's exact test, according to the sample size and expected value) and Student t-test. A total of 168 patients (264 levels total, mean follow-up time 39.5 ± 24.0 months) were analyzed. Sixty-one patients had PEEK, and 107 patients had structural allograft. Pseudarthrosis rates for 1-level fusions were 5.4% (PEEK) and 3.4% (allograft) (p > 0.05); 2-level fusions were 7.1% (PEEK) and 8.1% (allograft) (p > 0.05); and ≥ 3-level fusions were 10% (PEEK) and 11.1% (allograft) (p > 0.05). There was no statistical difference in the subsidence magnitude between PEEK and allograft in 1-, 2-, and ≥ 3-level ACDF (p > 0.05). Postoperative lordosis loss was not different between cohorts for 1- and 2-level surgeries. In 1- and 2-level ACDF with plating involving the same number of fusion levels, there was no statistically significant difference in the pseudarthrosis rate, revision surgery rate, subsidence, and lordosis loss between PEEK cages and structural allograft.


Alternatives for unsuccessful living donor kidney exchange pairs.
Living donor kidney exchange has become an efficient solution for recipients with incompatible donors. Here we describe the fate of all patients that were enrolled in our program during 2004-2010. Data on registration, computerized matching, cross matching, and transplantations within or outside the program were collected. Between January 2004 and December 2010, 422 pairs were registered. To create new combinations a match procedure was run 28 times with a median input of 14 (7-22) new pairs and a median of 55 (16-92) participating pairs. Matches were found for 127/185 (69%) cross match-incompatible pairs and 91/237 (38%) ABO-incompatible pairs. 141 of the 218 matched pairs successfully donated and received kidneys in exchange. There were 77 transplants cancelled for medical or psychological reasons, and an alternative solution was found for 26 of these. So in total 167 (141 + 26) patients received a transplant. Of the remaining 51 cancelled transplants, 26 pairs dropped out, 22 patients found an alternative transplantation outside the program and 3 are still waiting. For the 204 unmatched couples, 46 are still in the program while 34 others dropped out, and 124 found an alternative living kidney donor. After 7 years, 39% of participants received a kidney within the exchange program, 35% were transplanted outside the program, 14% of the pairs were delisted and 12% are still waiting. Among the 146 patients who received a kidney outside the program, 47 were transplanted with a deceased donor kidney, 21 found another donor, 37 received an ABO-incompatible transplant and 41 were transplanted in a domino-paired procedure triggered by an non-directed donor. In the 7 years of our Living Donor Kidney Exchange Program 313/422 (74%) of the participating patients were transplanted. Approximately half of them (167/313, 53%) received a kidney through the exchange program, while 47 (15%) received a deceased donor kidney and 99 (32%) were transplanted through other living donation programs. The exchange program proved to be highly successful not only in its direct results but also indirectly by triggering alternative solutions.


High-Level Macrolide Resistance Due to the Mega Element [mef(E)/mel] in Streptococcus pneumoniae.
Transferable genetic elements conferring macrolide resistance in Streptococcus pneumoniae can encode the efflux pump and ribosomal protection protein, mef(E)/mel, in an operon of the macrolide efflux genetic assembly (Mega) element- or induce ribosomal methylation through a methyltransferase encoded by erm(B). During the past 30 years, strains that contain Mega or erm(B) or both elements on Tn2010 and other Tn916-like composite mobile genetic elements have emerged and expanded globally. In this study, we identify and define pneumococcal isolates with unusually high-level macrolide resistance (MICs > 16 μg/ml) due to the presence of the Mega element [mef(E)/mel] alone. High-level resistance due to mef(E)/mel was associated with at least two specific genomic insertions of the Mega element, designated Mega-2.IVa and Mega-2.IVc. Genome analyses revealed that these strains do not possess erm(B) or known ribosomal mutations. Deletion of mef(E)/mel in these isolates eliminated macrolide resistance. We also found that Mef(E) and Mel of Tn2010-containing pneumococci were functional but the high-level of macrolide resistance was due to Erm(B). Using in vitro competition experiments in the presence of macrolides, high-level macrolide-resistant S. pneumoniae conferred by either Mega-2.IVa or erm(B), had a growth fitness advantage over the lower-level, mef(E)/mel-mediated macrolide-resistant S. pneumoniae phenotypes. These data indicate the ability of S. pneumoniae to generate high-level macrolide resistance by macrolide efflux/ribosomal protection [Mef(E)/Mel] and that high-level resistance regardless of mechanism provides a fitness advantage in the presence of macrolides.


Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion.
We tested the hypothesis that the reversibility of insulin resistance and diabetes observed after biliopancreatic diversion (BPD) is related to changes in circadian rhythms of gastrointestinal hormones. Ten morbidly obese participants, five with normal glucose tolerance (NGT) and five with type 2 diabetes, were studied before and within 2 weeks after BPD. Within-day variations in glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) levels were assessed using a single cosinor model. Insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp. Basal GLP1 relative amplitude (amplitude/mesor x 100) was 25.82-4.06% in NGT; it increased to 41.38-4.32% after BPD but was unchanged in diabetic patients. GLP1 and GIP mesor were shifted in time after surgery in diabetic patients but not in NGT participants. After BPD, the GLP1 AUC significantly increased from 775 +/- 94 to 846 +/- 161 pmol l(-1) min in NGT, whereas GIP AUC decreased significantly from 1,373 +/- 565 to 513 +/- 186 pmol l(-1) min in diabetic patients. Two-way ANOVA showed a strong influence of BPD on both GIP (p = 0.010) and GLP1 AUCs (p = 0.033), which was potentiated by the presence of diabetes, particularly for GIP (BPD x diabetes, p = 0.003). Insulin sensitivity was markedly improved (p < 0.01) in NGT (from 9.14 +/- 3.63 to 36.04 +/- 8.55 micromol [kg fat-free mass](-1) min(-1)) and diabetic patients (from 9.49 +/- 3.56 to 38.57 +/- 4.62 micromol [kg fat-free mass](-1) min(-1)). An incretin circadian rhythm was shown for the first time in morbid obesity. The effect of BPD on the 24 h pattern of incretin differed between NGT and diabetic patients. GLP1 secretion impairment was reversed in NGT and could not be overcome by surgery in diabetes. On the other hand, GIP secretion was blunted after the operation only in diabetic patients, suggesting a role in insulin resistance and diabetes.


Effects of daily activities on ambulatory blood pressure during menstrual cycle in normotensive women.
The purpose of this study was to determine whether (1) there is a menstrual phase effect on blood pressure (BP) and heart rate (HR), and (2) the effects of physical effort, posture, or moods on BP and HR is mediated by the menstrual phase. Twelve normotensive women, aged between 28 and 50, with normal menstrual cycles were studied. BP was measured at 30- to 60-min intervals during a 24-hr period using an ambulatory BP monitor on Days 1, 8, 15, and 22 of the menstrual cycle. Participants were asked to report their posture, physical effort, and mood ("annoyed," "tense," and "happy") on 5-point Likert-type scales each time the ambulatory BP monitor took measurements. Systolic BP (SBP) was lower on Day 8 of the cycle. Diastolic BP (DBP) and HR were lower on Days 1 and 8. Daytime SBP was affected by the time of the day and posture, but not by moods, whereas daytime DBP was affected by posture and levels of tenseness. The level of physical effort only affected HR, not BP. The average daytime physical and emotional variables had little influence over the average daytime BP. In 12 normotensive women with a normal menstrual cycle, SBP was lower during the follicular phase and DBP and HR were lower during the follicular phase and menstruation even after controlling the effects of other factors. Physical activity or moods had only momentary effects on BP or HR. A cross-validation statistical method used is suggested to study how individuals are affected by various factors. With the use of this method, the inclusion of menstrual phase in the model improved the prediction of SBP for 5 out of the 12 women studied.


Medical and social aspects of sexual assault of males: a survey of 100 victims.
Sexual assault of males is an infrequently reported and a poorly understood phenomenon. Details of 100 victims who sought assistance from a nationwide agency set up specifically to provide help for such individuals are reported here. Twenty eight victims were aged 16 years or over at the time of assault. The assailants were known by 72 of the victims and were perceived by the victim to have a heterosexual orientation in 72% of these cases. Attacks were often multiple and in 33 cases involved disruption of skin or mucous membranes. Twenty victims received threats about the possibility of transmission of the human immunodeficiency virus and 17 victims sought medical advice following the assault, most commonly from their general practitioner. It is suggested that greater opportunities for medical and psychological support should be given to male victims of sexual assault.


20-Hydroxyeicosatetraenoic acid contributes to the inhibition of K+ channel activity and vasoconstrictor response to angiotensin II in rat renal microvessels.
The present study examined whether 20-hydroxyeicosatetraenoic acid (HETE) contributes to the vasoconstrictor effect of angiotensin II (ANG II) in renal microvessels by preventing activation of the large conductance Ca(2+)-activated K(+) channel (KCa) in vascular smooth muscle (VSM) cells. ANG II increased the production of 20-HETE in rat renal microvessels. This response was attenuated by the 20-HETE synthesis inhibitors, 17-ODYA and HET0016, a phospholipase A2 inhibitor AACOF3, and the AT1 receptor blocker, Losartan, but not by the AT2 receptor blocker, PD123319. ANG II (10(-11) to 10(-6) M) dose-dependently decreased the diameter of renal microvessels by 41 ± 5%. This effect was blocked by 17-ODYA. ANG II (10(-7) M) did not alter KCa channel activity recorded from cell-attached patches on renal VSM cells under control conditions. However, it did reduce the NPo of the KCa channel by 93.4 ± 3.1% after the channels were activated by increasing intracellular calcium levels with ionomycin. The inhibitory effect of ANG II on KCa channel activity in the presence of ionomycin was attenuated by 17-ODYA, AACOF3, and the phospholipase C (PLC) inhibitor U-73122. ANG II induced a peak followed by a steady-state increase in intracellular calcium concentration in renal VSM cells. 17-ODYA (10(-5) M) had no effect on the peak response, but it blocked the steady-state increase. These results indicate that ANG II stimulates the formation of 20-HETE in rat renal microvessels via the AT1 receptor activation and that 20-HETE contributes to the vasoconstrictor response to ANG II by blocking activation of KCa channel and facilitating calcium entry.


Faraday rotation of a system of thin layers containing a thick layer.
An expression for the Faraday rotation produced by a system of thin layers containing a single thick layer is derived for the situation in which the thin layers exhibit fully developed interference fringes, and the fringes caused by the thick layer are completely suppressed. All layers are assumed to be homogeneous and isotropic. The suppression of the fringes produced by the thick layer is assumed to arise from the presence of a frequency distribution in the incident radiation. Restrictions are imposed in order that the result should not depend on the exact details of the frequency distribution.


Optical feedback stabilized laser tuned by single-sideband modulation.
We report a subkilohertz-linewidth distributed-feedback diode laser that is optical-feedback locked to a highly stable V-shaped cavity with drift rates below 20 Hz/s. This source is continuously tunable over 1 THz around 1590 nm by selecting a cavity mode and using an innovative single-sideband modulation scheme, which allows for frequency shifting over up to 40 GHz with millihertz accuracy. This robust setup achieves high performance without advanced vibration isolation and will be a powerful tool for metrological applications, in particular a redetermination of the Boltzmann constant by molecular spectroscopy.


Effects of a Collaborative Intervention Process on Parent-Therapist Interaction: A Randomized Controlled Trial.
Aim: To determine whether a collaborative intervention process facilitates parent-therapist interactions. Methods: Participants were 18 children with physical disabilities, their mothers, and 16 physical therapists. Therapists randomized to the experimental group were instructed in strategies for collaboration (working together) with parents in goal setting, planning, and implementing interventions. Family-therapist dyads participated in 6 weekly sessions. Four sessions were videotaped and combined (1st and 2nd for goal-setting/planning, 3rd and 5th for implementation) to code behaviors using Response Class Matrix. Multivariate analysis of variance was used to compare therapist and parent behaviors between groups. Results: Therapists in the experimental group demonstrated a higher frequency of "seeking information" (p < 0.01), "giving information" (p < 0.05), "positive behavior" (p < 0.01) and lower frequency of "child-related behavior" (p < 0.001) than therapists in the comparison group during goal-setting/planning and implementation. Parents in the experimental group demonstrated a higher frequency of "giving information" than parents in the comparison group (p < 0.01) during goal-setting/planning and implementation. Conclusion: Parents and therapists in the experimental group interacted more with each other, whereas those in the comparison group focused more on the child. The collaborative strategies appear to have increased parent participation in the intervention process, which has been a challenge for physical and occupational therapists.


Basonuclin in murine corneal and lens epithelia correlates with cellular maturation and proliferative ability.
Basonuclin is a zinc finger protein with highly restricted tissue distribution. It has been found in abundance only in keratinocytes of stratified epithelia and the germ cells of the testis and ovary. We studied the expression pattern of basonuclin in relation to cellular proliferation and differentiation in murine corneal and lens epithelia, two self-renewing tissues in the eye which contain cells that proliferate throughout life. Mouse corneal and lens epithelial cells at various stages of development were labeled with BrdU for 90 min to detect cells in S phase and to establish proliferative rates. Whole eyes of mouse or rat were processed for frozen sections and cellular basonuclin was detected by either a rabbit antimouse- or a rabbit anti-human-basonuclin antibody. Basonuclin was expressed in virtually all cells in the basal layer of corneal epithelium and in the pre-equatorial lens epithelium, the respective proliferative compartments of adult corneal and lens epithelia. Basonuclin expression in corneal epithelium began at post-natal life day 4, first in a few cells and then spread to virtually all basal cells at day 20. Basonuclin was consistently absent in limbal epithelium. Lens basonuclin, which was detected earlier than that of the cornea, was confined to the pre-equatorial epithelium and was absent in equatorial cells that expressed p57KIP2, an early differentiation marker for these cells. An important distinction between corneal and lens basonuclin is that the former is predominantly nuclear whereas the latter cytoplasmic.


Interaction dynamics of X-waves in waveguide arrays.
The interaction dynamics of X-waves in an AlGaAs waveguide array is theoretically considered. The nonlinear discrete diffraction dynamics of a waveguide arraymediates the generation of spatio-temporal X-waves from pulsed initial conditions. The interactions between co-propagating and counter-propagating X-waves are studied. For the co-propagating case, the initial phase relation between the X-waves determine the attractive or repulsive behavior of the X-wave interaction. For the counter-propagating case, the collisions between X-waves generate a nonlinear phase-shift. These dynamics show that X-waves interact in a manner similar to solitons.


Relative abundance and prevalence of selected Borrelia infections in Ixodes scapularis and Amblyomma americanum (Acari: Ixodidae) from publicly owned lands in Monmouth County, New Jersey.
To evaluate their potential importance in the transmission of ixodid tick-borne borrelioses in Monmouth County, NJ, we collected host-seeking Ixodes scapularis Say and Amblyomma americanum (L.) (Acari: Ixodidae) adults and nymphs to determine relative encounter frequencies and the infection prevalence of selected Borrelia spp. in their respective tick vectors. We also reviewed records of all ticks submitted for identification by the public in Monmouth County during 2001-2005. Relative abundance of the two species varied markedly among sites. Adult encounter frequencies for the two species were similar; however, A. americanum nymphs were encountered 3 times more frequently than I. scapularis nymphs. Of 435 ticks submitted by the public, 50.1 and 38.9% were I. scapularis and A. americanum, respectively. However, during May through August, the peak Lyme disease transmission season in New Jersey, significantly more submitted ticks were A. americanum (55.9%), compared with I. scapularis (34.1%). Polymerase chain reaction analysis of 94 1. scapularis and 103 A. americanum adults yielded infection prevalences of 31.9% for B. burgdorferi and 5.8% for B. lonestari, respectively. Although the infection prevalence of B. burgdorferi in I. scapularis was considerably higher than the infection prevalence of B. lonestari in A. americanum, the higher encounter frequencies for A. americanum compared with I. scapularis observed in this and other studies may result in increased risk of acquiring exposure to A. americanum-transmitted pathogens. The potential public health implications of these results are discussed.


Rgs13 constrains early B cell responses and limits germinal center sizes.
Germinal centers (GCs) are microanatomic structures that develop in secondary lymphoid organs in response to antigenic stimulation. Within GCs B cells clonally expand and their immunoglobulin genes undergo class switch recombination and somatic hypermutation. Transcriptional profiling has identified a number of genes that are prominently expressed in GC B cells. Among them is Rgs13, which encodes an RGS protein with a dual function. Its canonical function is to accelerate the intrinsic GTPase activity of heterotrimeric G-protein α subunits at the plasma membrane, thereby limiting heterotrimeric G-protein signaling. A unique, non-canonical function of RGS13 occurs following translocation to the nucleus, where it represses CREB transcriptional activity. The functional role of RGS13 in GC B cells is unknown. To create a surrogate marker for Rgs13 expression and a loss of function mutation, we inserted a GFP coding region into the Rgs13 genomic locus. Following immunization GFP expression rapidly increased in activated B cells, persisted in GC B cells, but declined in newly generated memory B and plasma cells. Intravital microscopy of the inguinal lymph node (LN) of immunized mice revealed the rapid appearance of GFP(+) cells at LN interfollicular regions and along the T/B cell borders, and eventually within GCs. Analysis of WT, knock-in, and mixed chimeric mice indicated that RGS13 constrains extra-follicular plasma cell generation, GC size, and GC B cell numbers. Analysis of select cell cycle and GC specific genes disclosed an aberrant gene expression profile in the Rgs13 deficient GC B cells. These results indicate that RGS13, likely acting at cell membranes and in nuclei, helps coordinate key decision points during the expansion and differentiation of naive B cells.


One-step generation of modular CAR-T cells with AAV-Cpf1.
Immune-cell engineering opens new capabilities for fundamental immunology research and immunotherapy. We developed a system for efficient generation of chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) with considerably enhanced features by streamlined genome engineering. By leveraging trans-activating CRISPR (clustered regularly interspaced short palindromic repeats) RNA (tracrRNA)-independent CRISPR-Cpf1 systems with adeno-associated virus (AAV), we were able to build a stable CAR-T cell with homology-directed-repair knock-in and immune-checkpoint knockout (KIKO CAR-T cell) at high efficiency in one step. The modularity of the AAV-Cpf1 KIKO system enables flexible and highly efficient generation of double knock-in of two different CARs in the same T cell. Compared with Cas9-based methods, the AAV-Cpf1 system generates double-knock-in CAR-T cells more efficiently. CD22-specific AAV-Cpf1 KIKO CAR-T cells have potency comparable to that of Cas9 CAR-T cells in cytokine production and cancer cell killing, while expressing lower levels of exhaustion markers. This versatile system opens new capabilities of T-cell engineering with simplicity and precision.