Prevention of prescription opioid abuse: the role of the dentist.
Opioids are analgesics that have potential for misuse, abuse or addiction. Up to an estimated 23 percent of prescribed doses are used nonmedically. As prescribers of 12 percent of immediate-release (IR) opioids in the United States, dentists can minimize the potential for misuse or abuse. The authors participated in a two-day meeting in March 2010 cohosted by Tufts Health Care Institute Program on Opioid Risk Management, Boston, and Tufts University School of Dental Medicine, Boston. The purpose of the meeting was to synthesize available opioid abuse literature and data from a 2010 survey regarding West Virginia dentists' analgesic prescribing practices, identify dentists' roles in prescribing opioids that are used nonmedically, highlight practices that dentists can implement and identify research gaps. Dentists can play a role in minimizing opioid abuse through patient education, careful patient assessment and referral for substance abuse treatment when indicated, and using tools such as prescription monitoring programs. Research is needed to determine the optimal number of doses needed to treat dental-related pain. Dentists cannot assume that their prescribing of opioids does not affect the opioid abuse problem in the United States. The authors suggest that dentists, along with other prescribers, take steps to identify problems and minimize prescription opioid abuse through greater prescriber and patient education; use of peer-reviewed recommendations for analgesia; and, when indicated, the tailoring of the appropriate and legitimate prescribing of opioids to adequately treat pain. Practice Implications. The authors encourage dentists to incorporate practical safeguards when prescribing opioids, consistently educate patients about how to secure unused opioids properly, screen patients for substance use disorders and develop a referral network for the treatment of substance use disorders.


Remediating munitions-contaminated soil with zerovalent iron and cationic surfactants.
Soils contaminated from military operations often contain mixtures of HMX (octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine), RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine), and TNT (2,4,6-trinitrotoluene) rather than a single explosive. Differences among explosives in solubility and reactivity make developing a single remediation treatment difficult. When Fe(0) was used to treat a munitions-contaminated soil, we observed high rates of destruction for RDX and TNT (98%) but not HMX. Our objective was to determine if HMX destruction by Fe(0) could be enhanced by increasing HMX solubility by physical (temperature) or chemical (surfactants) means. To determine electron acceptor preference, we treated RDX and HMX with Fe(0) in homogeneous solutions and binary mixtures. Increasing aqueous temperature (20 to 55 degrees C) increased HMX solubility (2 to 22 mg L(-1)) but did not increase destruction by Fe(0) in a contaminated soil slurry that also contained RDX and TNT. Batch experiments using equal molar concentrations of RDX and HMX demonstrated that RDX was preferentially reduced over HMX by Fe(0). By testing various surfactants, we found that the cationic surfactants (HDTMA [hexadecyltrimethylammonium bromide], didecyl, and didodecyl) were most effective in increasing HMX concentration in solution. Didecyl and HDTMA were also found to be highly effective in facilitating the transformation of HMX by Fe(0). Using HDTMA or didecyl solutions (3%, w/v) containing solid-phase HMX, we observed that 100% of the added HMX was transformed by Fe(0) in the didecyl matrix and 60% in the HDTMA matrix. These results indicate that cationic surfactants can increase HMX solubility and facilitate Fe(0)-mediated transformation kinetics but HMX destruction rates will be slowed when RDX is present.


Interstitial lung disease associated with trastuzumab monotherapy: A report of 3 cases.
We herein report 3 cases of female patients with breast cancer who developed interstitial lung disease (ILD) during trastuzumab monotherapy in an adjuvant setting. Prior chemotherapy included 4 cycles of epirubicin and cyclophosphamide in patients 1 and 2, and 4 cycles of docetaxel, cyclophosphamide and trastuzumab in patient 3. Patient 1 presented with a cough and fever after the fourth cycle of trastuzumab. Patient 2 experienced rapid deterioration of oxygen saturation without subjective symptoms within 3 h of the first administration of trastuzumab. Patient 3 was unexpectedly diagnosed with organizing pneumonia in a scheduled computed tomography (CT) scan after the first course of trastuzumab. Based on clinical data, such as decreased PaO2 level, increased serum levels of KL-6 and/or lactate dehydrogenase, and findings on chest CT, these patients were diagnosed with drug-induced ILD. Considering the clinical course, trastuzumab was incriminated as the cause of ILD, particularly in patients 1 and 2. All 3 patients improved due to the timely diagnosis, discontinuation of trastuzumab and immediate administration of corticosteroid therapy. Although ILD is a rare adverse event associated with trastuzumab, it may cause rapid deterioration without preceding symptoms. Close observation and early diagnosis are required to avoid an unfavorable outcome.


Silence of α1-Antitrypsin Inhibits Migration and Proliferation of Triple Negative Breast Cancer Cells.
BACKGROUND α1-antitrypsin (α1-AT) is highly expressed in many tumors. However, to the best of our knowledge, its relationship to triple negative breast cancer (TNBC) has not yet been studied. Thus, in this research we first explored the influence of α1-AT silencing on the abilities of migration and invasion, and then further study its molecular mechanism in TNBC cells. MATERIAL AND METHODS The viability of MDA-MB-231 cells were detected using cell counting kit-8 (CCK-8). The abilities of migration and invasion were examined by Transwell assay. The metastasis-related factors were tested respectively by quantitative real-time PCR (qRT-PCR) and western blot assays. RESULTS Our study results showed that α1-AT level in TNBC tissues was higher than non-triple negative breast cancer (n-TNBC) and adjacent normal breast tissues. The high expression of α1-AT was linked to type of cancer, tumor size, TNM stage and metastasis, but was not correlated with α1-AT expression and age. si-α1-AT suppressed the viability, migration, and invasion of cells. While si-α1-AT upregulated E-cadherin and the tissue inhibitor of metalloproteinases-2 (TIMP-2) levels, it downregulated metastasis associated 1 (MTA1), matrix metallopeptidase 2 (MMP2), phosphorylated-mammalian target of rapamycin (p-mTOR), phosphorylated-protein kinase B (p-Akt), and phosphorylated-phosphatidylinositol 3 kinase (p-PI3K) levels. We also found that the PI3K/Akt/mTOR pathway activator reversed the role of si-α1-AT in metastasis-related factors. CONCLUSIONS α1-AT was highly expressed in TNBC tissues, and its silencing suppressed the abilities of migration and invasion in TNBC cells and downregulated the PI3K/Akt/mTOR pathway. Thus, α1-AT may have a potential therapeutic effect on TNBC.


Dietary conjugated linoleic acid modify gene expression in liver, muscles, and fat tissues of finishing pigs.
The aim of this study was to investigate underlying mechanisms of dietary conjugated linoleic acid (CLA) on lipid metabolism in various tissues of pigs. Sixteen gilts (73 ± 3 kg) were fed a control (containing sunflower oil) or an experimental diet in which 4% of sunflower oil was replaced by CLA, and slaughtered at an average BW of 117 ± 4.9 kg. Transcription of peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS), sterol regulatory element binding protein (SREBP1), acetyl-CoA carboxylase (ACC), lipoprotein lipase (LPL), delta-6-desaturase (D6D), and stearoyl CoA desaturase (SCD) were determined by real-time PCR in longissimus thoracis (LT) and semimembranosus (SM) muscles, LT subcutaneous and SM intermuscular fat, and in the liver. Fatty acid (FA) composition was analyzed using gas chromatography in these tissues, except for SM intermuscular fat. Dietary CLA increased PPARγ in LT muscle (P < 0.05), whereas CLA reduced PPARα transcription in all tissues studied (P < 0.05) with the exception of intermuscular fat. Transcription of genes related to FA synthesis was reduced by CLA in SM muscle and liver (SREBP1, both P < 0.1; ACC, P < 0.01 in SM; and FAS, P < 0.01 in liver), whereas CLA reduced (P < 0.05) LPL and D6D transcriptions in SM muscle and reduced (P < 0.05) SCD in liver but increased (P < 0.05) SCD in LT muscle and intermuscular fat. Saturated FA were increased in all studied tissues (P < 0.01), while monosaturated and polyunsaturated FA were reduced in a tissue-specific way by CLA. It was concluded that dietary CLA affected transcription of genes and fat metabolism in a tissue-specific manner.


Weight-bearing MRI of the Lumbar Spine: Technical Aspects.
Magnetic resonance imaging (MRI) has an established role in the assessment of degenerative musculoskeletal conditions. However, conventional supine MRI findings often correlate poorly with clinical findings. Some patients experience accentuated back pain in the weight-bearing position. Therefore, supine MRI may underestimate the severity of degenerative spine findings. To try and improve the clinical validity of spine imaging, axial loading devices have been used with conventional supine MR imaging to simulate loading of the upright spine. More recently, upright weight-bearing MRI systems (0.25-0.6 T) were introduced, allowing images to be obtained in the standing or seated weight-bearing position and even during upright flexion or extension, rotation, or bending. Some scanners even enable capturing of real-time spinal movement. This review addresses the technical aspects and potential challenges of weight-bearing MRI, both in clinical practice and research.


Foraging ecology of aphidophagous predators against Aphis punicae Passerini.
Foraging behaviour of three aphidophagous predators, viz., Cheilomenes sexmaculata (Fabricius), Scymnus sp. (Coleoptera: Coccinellidae) and Paragus serratus (Fabricius) (Diptera: Syrphidae) on prey Aphis punicae Passerini (Homoptera: Aphididae) was studied in the laboratory at Indian Institute of Horticultural Research, Bangalore (12 degrees 58' N; 77 degrees 35'E) during 2002-03 to understand the predation dynamics. The foraging studies of grubs of C. sexmaculata and Scymnus sp. on A. punicae revealed that the distance travelled to reach the food (aphids) was negatively correlated with the feeding time of prey (r = -0.434 and -0.743, respectively). The time taken for second encounter was positively correlated with feeding time in case of both C. sexmaculata (r = 0.715) and P.serratus (r = 0.641). The time taken for first encounter of prey by Scymnus sp. showed negative correlation with the feeding time (r = -0.9491) and positive correlation with the distance traveled by the predator to reach the food (r = 0.620). The foraging behavioural studies of syrphid, P. serratus on A. punicae showed that the time taken for first encounter of prey was positively correlated with both the feeding time (r = 0.467) and the distance travelled by the syrphid to reach the food (r = 0.485). The time taken for first encounter of prey also showed significant positive correlation with the search time of the prey (r = 0.384).


Excitons in poly(para phenylene vinylene): a quantum-chemical perspective based on high-level ab initio calculations.
Excitonic effects play a fundamental role in the photophysics of organic semiconductors such as poly(para phenylene vinylene) (PPV). The emergence of these effects is examined for PPV oligomers based on high level ab initio excited-state calculations. The computed many-body wavefunctions are subjected to our recently developed exciton analysis protocols to provide a qualitative and quantitative characterization of excitonic effects. The discussion is started by providing high-level benchmark calculations using the algebraic-diagrammatic construction for the polarization propagator in third order of perturbation theory (ADC(3)). These calculations support the general adequacy of the computationally more efficient ADC(2) method in the case of singly excited states but also reveal the existence of low-energy doubly excited states. In a next step, a series of oligomers with chains of two to eight phenyl rings is studied at the ADC(2) level showing that the confinement effects are dominant for small oligomers, while delocalized exciton bands emerge for larger systems. In the case of the largest oligomer, the first twenty singlet and triplet excited states are computed and a detailed analysis in terms of the Wannier and Frenkel models is presented. The presence of different Wannier bands becomes apparent, showing a general trend that exciton sizes are lowered with increasing quasi-momentum within the bands.


Frequency of the virilising effects of attenuated androgens reported by women with hereditary angioedema.
Danazol, a drug extensively used in the management of hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), has various side effects. This study investigated the virilizing actions of this drug in 31 danazol-treated female patients with HAE-C1-INH. We compared our findings with those of healthy controls and with literature data. The patients were interviewed individually about the type and severity of the virilizing effects, as well as about their satisfaction with danazol therapy. The average duration of danazol treatment was 10.31 years [2 to 23] and its mean daily dose was 131.7 mg [33 to 200]. The most common adverse effects were hirsutism (n=14), weight gain (n=13), and menstrual disturbances (n=8). The severity of danazol adverse effects did not differ by duration of treatment or by daily drug dose. The mean level of patient satisfaction with the treatment was high. The comparison of age-matched healthy controls and of HAE-C1-INH patients receiving danazol did not demonstrate a statistically higher incidence of any of the monitored symptoms in the danazol group. Our findings indicate that long-term danazol treatment - using the lowest effective dose - has only a mild virilizing effect.


Highly Multiplexed Targeted Proteomics Acquisition on a TIMS-QTOF.
Targeted proteomics allows the highly sensitive detection of specific peptides and proteins in complex biological samples. Here, we describe a methodology for targeted peptide quantification using a trapped ion mobility quadrupole time-of-flight mass spectrometer (timsTOF Pro). The prm-PASEF method exploits the multiplexing capability provided by the trapped ion mobility separation, allowing more than 200 peptides to be monitored over a 30 min liquid chromatography separation. Compared to conventional parallel reaction monitoring (PRM), precursor ions are accumulated in the trapped ion mobility spectrometry (TIMS) cells and separated according to their shape and charge before eluting into the quadrupole time-of-flight (QTOF) part of the mass spectrometer. The ion mobility trap allows measuring up to six peptides from a single 100 ms ion mobility separation with the current setup. Using these improved mass spectrometric capabilities, we detected and quantified 216 isotope-labeled synthetic peptides (AQUA peptides) spiked in HeLa human cell extract with limits of quantification of 17.2 amol for some peptides. The acquisition method is highly reproducible between injections and enables accurate quantification in biological samples, as demonstrated by quantifying KRas, NRas, and HRas as well as several Ras mutations in lung and colon cancer cell lines on fast 10 min gradient separations.


Molecular detection of equine trypanosomes in the Sudan.
Equine trypanosomosis (ET) is a protozoan disease affecting equines in many parts of the world. We examined 509 samples collected from geographically distinct regions in eastern, central and western Sudan to estimate the endemicity of ET using the generic ITS1-PCR diagnostic methods. Results revealed that horses and donkeys were infected by Trypanosoma brucei subgroup, Trypanosoma vivax, Trypanosoma simiae and Trypanosoma congolense. The prevalence of Trypanosoma spp. was higher in horses (12.7%, n=393) than in donkeys (3.4%, n=116). The highest prevalence was observed in South Darfur State (19.3%, n=202), followed by Kassala State (15.1%, n=86), Gadaref State (3.7%, n=82), and Khartoum State (2.6%, n=76). No trypanosomes were detected in the 63 samples collected from North Kurdofan State. We report for the first time the presence of T. simiae and T. congolense in horses in the Sudan. This study should alert veterinary services, authorized bodies to take action toward ET by undertaking countrywide epidemiological studies of the disease and adopting control strategies.


Development of a black gram [Vigna mungo (L.) Hepper] linkage map and its comparison with an azuki bean [Vigna angularis (Willd.) Ohwi and Ohashi] linkage map.
The Asian Vigna group of grain legumes consists of six domesticated species, among them black gram is widely grown in South Asia and to a lesser extent in Southeast Asia. We report the first genetic linkage map of black gram [Vigna mungo (L.) Hepper], constructed using a BC(1)F(1) population consisting of 180 individuals. The BC(1)F(1) population was analyzed in 61 SSR primer pairs, 56 RFLP probes, 27 AFLP loci and 1 morphological marker. About 148 marker loci could be assigned to the 11 linkage groups, which correspond to the haploid chromosome number of black gram. The linkage groups cover a total of 783 cM of the black gram genome. The number of markers per linkage group ranges from 6 to 23. The average distance between adjacent markers varied from 3.5 to 9.3 cM. The results of comparative genome mapping between black gram and azuki bean show that the linkage order of markers is highly conserved. However, inversions, insertions, deletions/duplications and a translocation were detected between the black gram and azuki bean linkage maps. The marker order on parts of linkage groups 1, 2 and 5 is reversed between the two species. One region on black gram linkage group 10 appears to correspond to part of azuki bean linkage group 1. The present study suggests that the azuki bean SSR markers can be widely used for Asian Vigna species and the black gram genetic linkage map will assist in improvement of this crop.


Infectious complications of peripherally inserted central venous catheters in children.
Peripherally inserted central venous catheters (PICCs) are frequently used in infants and children. However, only limited data are available on current infectious and noninfectious complications of PICCs in this patient population. The aim of the study is to define the current rate of infectious and noninfectious complications of PICCs, the causative agents, and to define possible risk factors associated with these complications. A prospective surveillance study was conducted at the Schneider Children Medical Center of Israel. All patients in whom a PICC was inserted between August 2004 and October 2006 were included. Demographic, clinical, and microbiologic data were collected by a questionnaire completed by the anesthesiologist at the time of insertion and removal of each catheter. Items covered epidemiologic, clinical, and microbiologic data. A total of 279 PICCs were inserted in 221 patients. There were no complications at insertion. Mean dwell time was 30 days. One hundred seventy-seven (63%) of all PICC placements were free of complications. Twenty-six catheters (9.3%) were dislodged accidentally; 38 (13.6%) were removed for mechanical problems: tears in 5, leaks in 12, and obstructions in 21; 38 (13.6%) were removed for an infectious complication: phlebitis in 13 (4.6%, 1.5/1000 PICC days), exit-site infection in 10 (3.5%, 1.1/1000 PICC days), PICC-associated bloodstream infection in 12 (4.3%, 1.4/1000 PICC days), and PICC-related bloodstream infection in 4 (1.4%, 0.4/1000 PICC days); 15 more were removed for presumed infection (5.3%, 1.7/1000 PICC days). On multivariate analysis, composite indication for PICC use and older patient age were significantly associated with infectious complications. PICCs are safe and may be used for prolonged periods. In our center, the rates of infectious complications are lower than for tunneled central venous catheters. Accidental dislodgement is not uncommon and may be prevented by use of sutures, occlusive dressing, and education of patients, families, and medical staff.


Toward an information-motivation-behavioral skills model of microbicide adherence in clinical trials.
Unless optimal adherence in microbicide clinical trials is ensured, an efficacious microbicide may be rejected after trial completion, or development of a promising microbicide may be stopped, because low adherence rates create the illusion of poor efficacy. We provide a framework with which to conceptualize and improve microbicide adherence in clinical trials, supported by a critical review of the empirical literature. The information-motivation-behavioral skills (IMB) model of microbicide adherence conceptualizes microbicide adherence in clinical trials and highlights factors that can be addressed in behavioral interventions to increase adherence in such trials. This model asserts that microbicide adherence-related information, motivation, and behavioral skills are fundamental determinants of adherent microbicide utilization. Specifically, information consists of objective facts about microbicide use (e.g., administration and dosage) as well as heuristics that facilitate use (e.g., microbicides must be used with all partners). Motivation to adhere consists of attitudes toward personal use of microbicides (e.g., evaluating the consequences of using microbicides as good or pleasant) as well as social norms that support their use (e.g., beliefs that a sexual partner approves use of microbicides). Behavioral skills consist of objective skills necessary for microbicide adherence (e.g., the ability to apply the microbicide correctly and consistently). Empirical evidence concerning microbicide acceptability and adherence to spermicides, medication, and condom use regimens support the utility of this model for understanding and promoting microbicide adherence in clinical trials.


Transcriptional maturation of the mouse auditory forebrain.
The maturation of the brain involves the coordinated expression of thousands of genes, proteins and regulatory elements over time. In sensory pathways, gene expression profiles are modified by age and sensory experience in a manner that differs between brain regions and cell types. In the auditory system of altricial animals, neuronal activity increases markedly after the opening of the ear canals, initiating events that culminate in the maturation of auditory circuitry in the brain. This window provides a unique opportunity to study how gene expression patterns are modified by the onset of sensory experience through maturity. As a tool for capturing these features, next-generation sequencing of total RNA (RNAseq) has tremendous utility, because the entire transcriptome can be screened to index expression of any gene. To date, whole transcriptome profiles have not been generated for any central auditory structure in any species at any age. In the present study, RNAseq was used to profile two regions of the mouse auditory forebrain (A1, primary auditory cortex; MG, medial geniculate) at key stages of postnatal development (P7, P14, P21, adult) before and after the onset of hearing (~P12). Hierarchical clustering, differential expression, and functional geneset enrichment analyses (GSEA) were used to profile the expression patterns of all genes. Selected genesets related to neurotransmission, developmental plasticity, critical periods and brain structure were highlighted. An accessible repository of the entire dataset was also constructed that permits extraction and screening of all data from the global through single-gene levels. To our knowledge, this is the first whole transcriptome sequencing study of the forebrain of any mammalian sensory system. Although the data are most relevant for the auditory system, they are generally applicable to forebrain structures in the visual and somatosensory systems, as well. The main findings were: (1) Global gene expression patterns were tightly clustered by postnatal age and brain region; (2) comparing A1 and MG, the total numbers of differentially expressed genes were comparable from P7 to P21, then dropped to nearly half by adulthood; (3) comparing successive age groups, the greatest numbers of differentially expressed genes were found between P7 and P14 in both regions, followed by a steady decline in numbers with age; (4) maturational trajectories in expression levels varied at the single gene level (increasing, decreasing, static, other); (5) between regions, the profiles of single genes were often asymmetric; (6) GSEA revealed that genesets related to neural activity and plasticity were typically upregulated from P7 to adult, while those related to structure tended to be downregulated; (7) GSEA and pathways analysis of selected functional networks were not predictive of expression patterns in the auditory forebrain for all genes, reflecting regional specificity at the single gene level. Gene expression in the auditory forebrain during postnatal development is in constant flux and becomes increasingly stable with age. Maturational changes are evident at the global through single gene levels. Transcriptome profiles in A1 and MG are distinct at all ages, and differ from other brain regions. The database generated by this study provides a rich foundation for the identification of novel developmental biomarkers, functional gene pathways, and targeted studies of postnatal maturation in the auditory forebrain.


Exploratory analysis of the relationships among different methods of assessing adherence and glycemic control in youth with type 1 diabetes mellitus.
The present study examined four methods of assessing diabetes adherence (self-report, diary measure, electronic monitoring, and provider rating) within a population of youth with Type I Diabetes Mellitus (T1DM). Comparisons were conducted among the four methods of assessing diabetes adherence. Associations among the seven different measures of blood glucose monitoring (BGM) and HbA1c were examined. An exploratory stepwise regression analysis was conducted to determine the best predictors of glycemic control (i.e., Hemoglobin A1c; HbA1c) while controlling for relevant demographic variables. The adherence measures appeared to be interrelated. The relationships between many of the BGM measures and HbA1c demonstrated a medium effect size. The Self Care Inventory (SCI) adjusted global score was the strongest predictor of HbA1c, even after taking the demographic variables into account. The SCI is a robust, easy-to-use, and cost-efficient measure of adherence that has a strong relationship to HbA1c. Demographic variables are important to examine within the context of different methods of assessing adherence. The research methodology utilized to assess both general diabetes adherence and more specific behavioral measurements of BGM should be clearly documented in future studies to ensure accurate interpretation of results.


Warfarin-induced artery calcification is accelerated by growth and vitamin D.
The present studies demonstrate that growth and vitamin D treatment enhance the extent of artery calcification in rats given sufficient doses of Warfarin to inhibit gamma-carboxylation of matrix Gla protein, a calcification inhibitor known to be expressed by smooth muscle cells and macrophages in the artery wall. The first series of experiments examined the influence of age and growth status on artery calcification in Warfarin-treated rats. Treatment for 2 weeks with Warfarin caused massive focal calcification of the artery media in 20-day-old rats and less extensive focal calcification in 42-day-old rats. In contrast, no artery calcification could be detected in 10-month-old adult rats even after 4 weeks of Warfarin treatment. To directly examine the importance of growth to Warfarin-induced artery calcification in animals of the same age, 20-day-old rats were fed for 2 weeks either an ad libitum diet or a 6-g/d restricted diet that maintains weight but prevents growth. Concurrent treatment of both dietary groups with Warfarin produced massive focal calcification of the artery media in the ad libitum-fed rats but no detectable artery calcification in the restricted-diet, growth-inhibited group. Although the explanation for the association between artery calcification and growth status cannot be determined from the present study, there was a relationship between higher serum phosphate and susceptibility to artery calcification, with 30% higher levels of serum phosphate in young, ad libitum-fed rats compared with either of the groups that was resistant to Warfarin-induced artery calcification, ie, the 10-month-old rats and the restricted-diet, growth-inhibited young rats. This observation suggests that increased susceptibility to Warfarin-induced artery calcification could be related to higher serum phosphate levels. The second set of experiments examined the possible synergy between vitamin D and Warfarin in artery calcification. High doses of vitamin D are known to cause calcification of the artery media in as little as 3 to 4 days. High doses of the vitamin K antagonist Warfarin are also known to cause calcification of the artery media, but at treatment times of 2 weeks or longer yet not at 1 week. In the current study, we investigated the synergy between these 2 treatments and found that concurrent Warfarin administration dramatically increased the extent of calcification in the media of vitamin D-treated rats at 3 and 4 days. There was a close parallel between the effect of vitamin D dose on artery calcification and the effect of vitamin D dose on the elevation of serum calcium, which suggests that vitamin D may induce artery calcification through its effect on serum calcium. Because Warfarin treatment had no effect on the elevation in serum calcium produced by vitamin D, the synergy between Warfarin and vitamin D is probably best explained by the hypothesis that Warfarin inhibits the activity of matrix Gla protein as a calcification inhibitor. High levels of matrix Gla protein are found at sites of artery calcification in rats treated with vitamin D plus Warfarin, and chemical analysis showed that the protein that accumulated was indeed not gamma-carboxylated. These observations indicate that although the gamma-carboxyglutamate residues of matrix Gla protein are apparently required for its function as a calcification inhibitor, they are not required for its accumulation at calcification sites.


Giant cell myocarditis.
Giant cell myocarditis is a rare and frequently fatal disorder of unknown origin that is defined histopathologically as diffuse myocardial necrosis with multinucleated giant cells in the absence of sarcoidlike granulomata. The clinical and pathologic features of lymphocytic myocarditis have been described in several recent publications, but the features of idiopathic giant cell myocarditis have not been adequately addressed. We describe five patients with idiopathic giant cell myocarditis who were seen at Stanford University over the past 10 years. In each case the onset was subacute congestive heart failure. After diagnosis each patient received immunosuppressive therapy and was evaluated for heart transplantation. Progressive heart failure and ventricular arrhythmias developed in all. Three died rapidly, two of progressive heart failure and one of sudden cause. Two patients underwent orthotopic heart transplantation and are currently alive, one with disease recurrence. Pathologic studies, including endomyocardial biopsy and evaluation of postmortem or explanted material at transplantation were reviewed. The pathologic studies provided additional support that the giant cells derive from a monocytic/histiocytic lineage. Segmental wall motion abnormalities suggest giant cell myocarditis can be a focal, as well as diffuse process at certain stages of its course. This experience is compared with published cases and implications for diagnosis and treatment are discussed. In view of the uniformly fatal nature of the disease, heart transplantation should be a serious consideration, and the patients evaluated once the diagnosis is established. Triple-drug immunosuppressive therapy should be considered at the time of diagnosis.


The power of symbolic capital in patient and public involvement in health research.
Policy-makers and health research funders increasingly require researchers to demonstrate that they have involved patients in the design and conduct of research. However, the extent to which patients and public have the power to get involved on an equal footing is dependent on their economic, cultural, social and symbolic capital. To explore power relations in patient and public involvement (PPI) in research, particularly how patients may wield symbolic capital to develop a more equal relationship. Narrative interviews with a maximum variation sample of 38 people involved as patients, carers or public in health research, analysed thematically. Symbolic capital may be demonstrated in a range of ways (sometimes alongside or in the absence of other forms of capital): illness experience, technical illness knowledge and the challenging outsider. Symbolic capital is unstable and dependent on others for recognition and legitimacy. Nonetheless, participants identify a gradual shift in power relations over time. Research into PPI has been conceptually and theoretically poor, limiting our understanding of its mechanisms and wider contextual elements. Our findings demonstrate the importance of reflecting on the forms of power and capital wielded by the health research community, and of acknowledging the way in which PPI is challenging the status quo. As one of the first papers to conceptualize how different forms of symbolic capital operate and their critical role in challenging the balance of power, our findings may help researchers better plan their PPI activities and reflect on their own power.


Latent learning in End Stage Renal Disease (ESRD).
Cognitive functions such as attention and memory are known to be impaired in End Stage Renal Disease (ESRD), but the sites of the neural changes underlying these impairments are uncertain. Patients and controls took part in a latent learning task, which had previously shown a dissociation between patients with Parkinson's disease and those with medial temporal damage. ESRD patients (n=24) and age and education-matched controls (n=24) were randomly assigned to either an exposed or unexposed condition. In Phase 1 of the task, participants learned that a cue (word) on the back of a schematic head predicted that the subsequently seen face would be smiling. For the exposed (but not unexposed) condition, an additional (irrelevant) colour cue was shown during presentation. In Phase 2, a different association, between colour and facial expression, was learned. Instructions were the same for each phase: participants had to predict whether the subsequently viewed face was going to be happy or sad. No difference in error rate between the groups was found in Phase 1, suggesting that patients and controls learned at a similar rate. However, in Phase 2, a significant interaction was found between group and condition, with exposed controls performing significantly worse than unexposed (therefore demonstrating learned irrelevance). In contrast, exposed patients made a similar number of errors to unexposed in Phase 2. The pattern of results in ESRD was different from that previously found in Parkinson's disease, suggesting a different neural origin.


Non-exercise physical activity in agricultural and urban people.
With evidence that urbanisation is associated with obesity, diabetes, hypertension and cardiovascular disease, this article compares daily physical activity between rural and urban dwellers. Specifically, it examines habitual daily activity levels, non-exercise activity thermogenesis (NEAT) and energy expenditure in agricultural and urban Jamaicans and urban North Americans. Ambulation was 60 per cent greater in rural Jamaicans than in the urban dwellers (4675 ± 2261 versus 2940 ± 1120 ambulation-attributed arbitrary units (AU)/day; P = 0.001). Levels of ambulation in lean urban Jamaicans were similar to those in lean urban North Americans, whereas obese urban dwellers walked less than their lean urban counterparts (2198 ± 516 versus 2793 ± 774 AU/day; P = 0.01). The data with respect to daily sitting mirrored the walking data; obese Americans sat for almost four hours more each day than rural Jamaicans (562 ± 78 versus 336 ± 68 minutes/day; P < 0.001). Urbanisation is associated with low levels of daily activity and NEAT.


AI-based detection of erythema migrans and disambiguation against other skin lesions.
This study examines the use of AI methods and deep learning (DL) for prescreening skin lesions and detecting the characteristic erythema migrans rash of acute Lyme disease. Accurate identification of erythema migrans allows for early diagnosis and treatment, which avoids the potential for later neurologic, rheumatologic, and cardiac complications of Lyme disease. We develop and test several deep learning models for detecting erythema migrans versus several other clinically relevant skin conditions, including cellulitis, tinea corporis, herpes zoster, erythema multiforme, lesions due to tick bites and insect bites, as well as non-pathogenic normal skin. We consider a set of clinically-relevant binary and multiclass classification problems of increasing complexity. We train the DL models on a combination of publicly available images and test on public images as well as images obtained in the clinical setting. We report performance metrics that measure agreement with a gold standard, as well as a receiver operating characteristic curve and associated area under the curve. On public images, we find that the DL system has an accuracy ranging from 71.58% (and 95% error margin equal to 3.77%) for an 8-class problem of EM versus 7 other classes including other skin pathologies, insect bites and normal skin, to 94.23% (3.66%) for a binary problem of EM vs. non-pathological skin. On clinical images of affected individuals, the DL system has a sensitivity of 88.55% (2.39%). These results suggest that a DL system can help in prescreening and referring individuals to physicians for earlier diagnosis and treatment, in the presence of clinically relevant confusers, thereby reducing further complications and morbidity.


Ammonia-modified Co(II) sites in zeolites: spin and electron density redistribution through the Co(II)-NO bond.
Electronic factors essential for the bonding of a non-innocent NO ligand to ammonia-modified Co(2+) sites in cobalt-exchanged zeolites are examined for small cluster models using DFT and advanced correlated wave function calculations. The analysis of charge transfer processes between the NO ligand and the cobalt center involves two protocols: valence-bond expansion of the multiconfiguration CASSCF wave function (in terms of fragment-localized active orbitals) and spin-resolved natural orbitals for chemical valence (SR-NOCV). Applicability of SR-NOCV analysis to transition metal complexes involving non-innocent fragments is critically assessed and the approach based on the CASSCF wave function turns out to be much more robust and systematic for all studied models. It is shown that the character and direction of electron density redistribution through the Co-N-O bond, quantified by relative share of the Co(II)-NO(0), Co(III)-NO(-), and Co(I)-NO(+) resonance structures in the total wave function, fully rationalize the activation of the N-O bond upon NH3 co-ligation (evidenced by calculated and measured red-shift of the NO stretching frequency and commonly ascribed to enhanced backdonation). The huge red-shift of νN-O is attributed to an effective electron transfer between the ammonia-modified Co(ii) centers and the NO antibonding π*-orbitals (related to the increased share of the Co(III)-NO(-) form). Unexpectedly, the effect is stronger for the singlet complex with three NH3 ligands than for that with five NH3 ligands bound to the cobalt center. Our results also indicate that high-efficiency electron transfers between the Co(ii) center and the NO ligand may be enabled for the selected spin state and disabled for the other spin state of the adduct. This illustrates how the cobalt center may serve to fine-tune the electronic communication between the NO ligand and its binding site.


Trauma, attentional biases, and revictimization among young adults.
Individuals with previous histories of trauma are at increased risk for subsequent victimization and the development of posttraumatic stress disorder, depression, and anxiety disorders. Attentional biases to threat-related stimuli are thought to impact one's ability to recognize future risk in his or her environment and may explain high rates of revictimization. Although the literature has identified three possible types of attentional biases among victims of trauma (i.e., interference, facilitation, and avoidance), findings are mixed. The current study examined attentional biases to threats among a sample of men and women with no, some, and multiple incident interpersonal and non-interpersonal trauma histories. It was hypothesized that those with multiple incident interpersonal trauma histories would demonstrate an interference effect (i.e., slower response times to threat-related words). Participants (N = 309) were 18- to 29-year-old college students. Self-report measures assessed trauma history, posttraumatic stress, and other psychological sequelae. Attentional biases were assessed using a dot probe computer task. Contrary to hypotheses, no significant differences in response times in the presence of threat-related words or neutral words were found among groups. Results suggest that multiple traumatized individuals do not exhibit attentional bias to threats compared to individuals with some or no trauma.


Genetic factors in congenital diaphragmatic hernia.
Congenital diaphragmatic hernia (CDH) is a relatively common birth defect associated with high mortality and morbidity. Although the exact etiology of most cases of CDH remains unknown, there is a growing body of evidence that genetic factors play an important role in the development of CDH. In this review, we examine key findings that are likely to form the basis for future research in this field. Specific topics include a short overview of normal and abnormal diaphragm development, a discussion of syndromic forms of CDH, a detailed review of chromosomal regions recurrently altered in CDH, a description of the retinoid hypothesis of CDH, and evidence of the roles of specific genes in the development of CDH.


Low-cost wearable data acquisition for stroke rehabilitation: a proof-of-concept study on accelerometry for functional task assessment.
An increasingly aging society and consequently rising number of patients with poststroke-related neurological dysfunctions are forcing the rehabilitation field to adapt to ever-growing demands. Although clinical reasoning within rehabilitation is dependent on patient movement performance analysis, current strategies for monitoring rehabilitation progress are based on subjective time-consuming assessment scales, not often applied. Therefore, a need exists for efficient nonsubjective monitoring methods. Wearable monitoring devices are rapidly becoming a recognized option in rehabilitation for quantitative measures. Developments in sensors, embedded technology, and smart textile are driving rehabilitation to adopt an objective, seamless, efficient, and cost-effective delivery system. This study aims to assist physiotherapists' clinical reasoning process through the incorporation of accelerometers as part of an electronic data acquisition system. A simple, low-cost, wearable device for poststroke rehabilitation progress monitoring was developed based on commercially available inertial sensors. Accelerometry data acquisition was performed for 4 first-time poststroke patients during a reach-press-return task. Preliminary studies revealed acceleration profiles of stroke patients through which it is possible to quantitatively assess the functional movement, identify compensatory strategies, and help define proper movement. An inertial data acquisition system was designed and developed as a low-cost option for monitoring rehabilitation. The device seeks to ease the data-gathering process by physiotherapists to complement current practices with accelerometry profiles and aid the development of quantifiable methodologies and protocols.


Oral nutritional supplementation accelerates skin wound healing: a randomized, placebo-controlled, double-arm, crossover study.
Nutritional therapy is critical for wound healing in people with severe malnutrition or specific metabolic deficiencies. Medical claims from manufacturers of many oral supplements are marketed to surgical patients for decreasing edema, bruising, and discomfort. The effect of supplementing nutrients on soft-tissue wound healing in otherwise normal, healthy adults is an area of clinical importance, but little information is available. Proteolytic enzymes have been reported to moderate the inflammatory cycle and may up-regulate the healing process. The goal of this study was to perform a clinical trial in normal, healthy adults that examined the effects of an oral nutritional supplement (InflammEnz, Enzymes, Inc., Parkville, Mo.) on soft-tissue healing times. Twenty-six normal, healthy volunteers were recruited into a randomized, crossover, placebo-controlled, clinical trial consisting of two phases, each lasting 21 days. In phase I, subjects were subjected to a 3-mm forearm skin biopsy and randomly received a placebo or oral supplement (four capsules per day for 7 days). After a 2-week washout period, a second biopsy was performed to start phase II, with each subject receiving the respective placebo or supplement capsules. Digital photographs were taken during wound healing in both phases and analyzed for wound areas (in square millimeters) and perimeters (in millimeters). Twenty-two subjects completed the clinical trial. On the basis of wound surface areas, 17 subjects had improved wound healing and five subjects did not respond or responded only slightly to the supplement treatment. The mean +/- SD healing time of the subjects responding to supplement-treated wounds was 15 +/- 2.2 days, compared with 18 +/- 2.5 days for the placebo group. The 17 percent acceleration of wound-healing time was significant (p < 0.005). In subjects responding to oral supplements, less redness in the wounds was observed that may have been associated with less inflammation. The authors' results demonstrate that InflammEnz oral supplementation accelerated soft-tissue wound healing in 77 percent of normal, healthy subjects studied. The authors' study validates observations made that this supplement modulates the wound-healing process and suggests that many patients with minor soft-tissue wounds may benefit from treatment.


The prognosis of childhood abdominal migraine.
To determine the clinical course of childhood abdominal migraine, seven to 10 years after the diagnosis. A total of 54 children with abdominal migraine were studied; 35 were identified from a population survey carried out on Aberdeen schoolchildren between 1991 and 1993, and 19 from outpatient records of children in the same age group who had attended the Royal Aberdeen Children's Hospital. Controls were 54 children who did not have abdominal pain in childhood, matched for age and sex, obtained from either the population survey or the patient administration system. Main outcome measures were presence or resolution of abdominal migraine and past or present history of headache fulfilling the International Headache Society (IHS) criteria for the diagnosis of migraine. Abdominal migraine had resolved in 31 cases (61%). Seventy per cent of cases with abdominal migraine were either current (52%) or previous (18%) sufferers from headaches that fulfilled the IHS criteria for migraine, compared to 20% of the controls. These results support the concept of abdominal migraine as a migraine prodrome, and suggest that our diagnostic criteria for the condition are robust.


Transgenic plants expressing geminivirus movement proteins: abnormal phenotypes and delayed infection by Tomato mottle virus in transgenic tomatoes expressing the Bean dwarf mosaic virus BV1 or BC1 proteins.
Transgenic tomato plants expressing wild-type or mutated BV1 or BC1 movement proteins from Bean dwarf mosaic virus (BDMV) were generated and examined for phenotypic effects and resistance to Tomato mottle virus (ToMoV). Fewer transgenic plants were recovered with the wild-type or mutated BC1 genes, compared with the wild-type or mutated BV1 genes. Transgenic tomato plants expressing the wild-type or mutated BV1 proteins appeared normal. Interestingly, although BDMV induces only a symptomless infection in tomato (i.e., BDMV is not well adapted to tomato), transgenic tomato plants expressing the BDMV BC1 protein showed a viral disease-like phenotype (i.e., stunted growth, and leaf mottling, curling, and distortion). This suggests that the symptomless phenotype of BDMV in tomato is not due to a host-specific defect in the BC1 protein. One transgenic line expressing the BC1 gene did not show the viral disease-like phenotype. This was associated with a deletion in the 3' region of the gene, which resulted in expression of a truncated BC1 protein. Several R0 plants, expressing either wild-type or mutated BV1 or BC1 proteins, showed a significant delay in ToMoV infection, compared with non-transformed plants. R1 progeny plants also showed a significant delay in ToMoV infection, but this delay was less than that in the R0 parents. These results also demonstrate that expression of viral movement proteins, in transgenic plants, can have deleterious effects on various aspects of plant development.


Risk and prevention of transmission of infectious diseases in dentistry.
Health care providers are at risk for infection with bloodborne pathogens, including hepatitis B virus, human immunodeficiency virus, and hepatitis C virus. Recommended infection control practices are applicable to all settings in which dental treatment is provided. Dentists remain at low risk for occupationally acquired human immunodeficiency virus. Dental health care workers, through occupational exposure, may have a 10 times greater risk of becoming a chronic hepatitis B carrier than the average citizen. Tuberculosis is caused by Mycobacterium tuberculosis. In general, persons suspected of having pulmonary or laryngeal tuberculosis should be considered infectious if they are coughing, are undergoing cough-inducing or aerosol-generating procedures, or have sputum smears positive for acid-fast bacilli. Although the possibility of transmission of bloodborne infections from dental health care workers to patients is considered to be small, precise risks have not been quantified by carefully designed epidemiologic studies. Emphasis should be placed on consistent adherence to recommended infection control strategies, including the use of protective barriers and appropriate methods of sterilization or disinfection. Each dental facility should develop a written protocol for instrument reprocessing, operatory cleanup, and management of injuries. Such efforts may lead to the development of safer and more effective medical devices, work practices, and personal protective equipment.


The next scientific revolution.
For decades, computer scientists have tried to teach computers to think like human experts. Until recently, most of those efforts have failed to come close to generating the creative insights and solutions that seem to come naturally to the best researchers, doctors, and engineers. But now, Tony Hey, a VP of Microsoft Research, says we're witnessing the dawn of a new generation of powerful computer tools that can "mash up" vast quantities of data from many sources, analyze them, and help produce revolutionary scientific discoveries. Hey and his colleagues call this new method of scientific exploration "machine learning." At Microsoft, a team has already used it to innovate a method of predicting with impressive accuracy whether a patient with congestive heart failure who is released from the hospital will be readmitted within 30 days. It was developed by directing a computer program to pore through hundreds of thousands of data points on 300,000 patients and "learn" the profiles of patients most likely to be rehospitalized. The economic impact of this prediction tool could be huge: If a hospital understands the likelihood that a patient will "bounce back," it can design programs to keep him stable and save thousands of dollars in health care costs. Similar efforts to uncover important correlations that could lead to scientific breakthroughs are under way in oceanography, conservation, and AIDS research. And in business, deep data exploration has the potential to unearth critical insights about customers, supply chains, advertising effectiveness, and more.


Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum.
In the current work, we conducted an immunocytochemical search for markers of ongoing neurogenesis (e.g. nestin) in auditory cortex from postmortem sections of autism spectrum disorder (ASD) and age-matched control donors. We found nestin labeling in cells of the vascular system, indicating blood vessels plasticity. Evidence of angiogenesis was seen throughout superior temporal cortex (primary auditory cortex), fusiform cortex (face recognition center), pons/midbrain and cerebellum in postmortem brains from ASD patients but not control brains. We found significant increases in both nestin and CD34, which are markers of angiogenesis localized to pericyte cells and endothelial cells, respectively. This labeling profile is indicative of splitting (intussusceptive), rather than sprouting, angiogenesis indicating the blood vessels are in constant flux rather than continually expanding.


On-chip Fourier-transform spectrometers and machine learning: a new route to smart photonic sensors.
Miniaturized silicon photonics spectrometers capable of detecting specific absorption features have great potential for mass market applications in medicine, environmental monitoring, and hazard detection. However, state-of-the-art silicon spectrometers are limited by fabrication imperfections and environmental conditions, especially temperature variations, since uncontrolled temperature drifts of only 0.1°C distort the retrieved spectrum precluding the detection and classification of the absorption features. Here we present a new strategy that exploits the robustness of machine learning algorithms to signal imperfections, enabling recognition of specific absorption features in a wide range of environmental conditions. We combine on-chip spatial heterodyne Fourier-transform spectrometers and supervised learning to classify different input spectra in the presence of fabrication errors, without temperature stabilization or monitoring. We experimentally show the differentiation of four different input spectra under an uncontrolled 10°C range of temperatures, about $ 100\times $100× increase in operational range, with a success rate up to 82.5% using state-of-the-art support vector machines and artificial neural networks.


Which literature retrieval method is most effective for GPs?
Evidence-based medicine requires new skills of physicians, including literature searching. To determine which literature retrieving method is most effective for GPs: the printed Index Medicus; Medline through Grateful Med; or Medline on CD-ROM. The design was a randomized comparative study. In a continuing medical education course, three groups of health care professionals (87 GPs and 16 other health care professionals) used one of the literature retrieval methods to retrieve citations on four search topics related to general practice. For the analysis in pairs, we used the search results of the 75 participants who completed all four assignments. As outcome measures, we used precision, recall and an overall search quality score; we also had a post-course questionnaire on personal characteristics, experience with computers, handling medical literature and satisfaction with course instruction and search results. The recall and overall search quality scores in the Index Medicus groups (n = 32) were higher (P = <0.001) than those in the CD-ROM groups (n = 31). In addition, the search quality scores in the Grateful Med groups (n = 12) were higher (P < 0.003) than those in the CD-ROM groups. There were no differences in precision. In the period 1994-1997, the printed Index Medicus was the most effective literature retrieval method for GPs. For inexperienced GPs, there is a need for training in electronic literature retrieval methods.


Two combinatorial patterns of telomere histone marks in plants with canonical and non-canonical telomere repeats.
Telomeres, nucleoprotein structures at the ends of linear eukaryotic chromosomes, are crucial for the maintenance of genome integrity. In most plants, telomeres consist of conserved tandem repeat units comprising the TTTAGGG motif. Recently, non-canonical telomeres were described in several plants and plant taxons, including the carnivorous plant Genlisea hispidula (TTCAGG/TTTCAGG), the genus Cestrum (Solanaceae; TTTTTTAGGG), and plants from the Asparagales order with either a vertebrate-type telomere repeat TTAGGG or Allium genus-specific CTCGGTTATGGG repeat. We analyzed epigenetic modifications of telomeric histones in plants with canonical and non-canonical telomeres, and further in telomeric chromatin captured from leaves of Nicotiana benthamiana transiently transformed by telomere CRISPR-dCas9-eGFP, and of Arabidopsis thaliana stably transformed with TALE_telo C-3×GFP. Two combinatorial patterns of telomeric histone modifications were identified: (i) an Arabidopsis-like pattern (A. thaliana, G. hispidula, Genlisea nigrocaulis, Allium cepa, Narcissus pseudonarcissus, Petunia hybrida, Solanum tuberosum, Solanum lycopersicum) with telomeric histones decorated predominantly by H3K9me2; (ii) a tobacco-like pattern (Nicotiana tabacum, N. benthamiana, C. elegans) with a strong H3K27me3 signal. Our data suggest that epigenetic modifications of plant telomere-associated histones are related neither to the sequence of the telomere motif nor to the lengths of the telomeres. Nor the phylogenetic position of the species plays the role; representatives of the Solanaceae family are included in both groups. As both patterns of histone marks are compatible with fully functional telomeres in respective plants, we conclude that the described specific differences in histone marks are not critical for telomere functions.


Surgical strategy for cervical dumbbell tumors based on a three-dimensional classification.
Forty-two patients with cervical dumbbell tumors were analyzed retrospectively using a new three-dimensional classification. To establish optimal surgical strategies, we considered shapes and three-dimensional locations of cervical dumbbell tumors based on diagnostic images and intraoperative findings. Eden's classification for dumbbell tumors of the spine, long considered a "gold standard," no longer is sufficient to determine surgical strategy in view of recent advances in computed tomography and magnetic resonance imaging. Forty-two cervical dumbbell tumors were characterized according to transverse-section images (Toyama classification; nine types) and craniocaudal extent of intervertebral and transverse foraminal involvement (IF and TF staging; three stages each). Type IIIa tumors, involving dura plus an intervertebral foramen, accounted for 50% of cases. A posterior approach was used in 35 patients; 7 others underwent a combined anterior and posterior approach. A posterior approach was used for all type IIa and IIIa tumors, and for some type IIIb (upper cervical), IV, and VI tumors; a combined posterior and anterior approach was used for type IIb and the remainder of type IV and VI. Reconstruction was performed using spinal instrumentation in 4 patients (9.5%). Resection was subtotal in 6 patients (14.3%) and total in 36 (85.7%). Systematic, imaging-based three-dimensional characterization of shape and location of cervical dumbbell tumors is essential for planning optimal surgery. The classification used here fulfills this need.


The composition of the gut microbiota shapes the colon mucus barrier.
Two C57BL/6 mice colonies maintained in two rooms of the same specific pathogen-free (SPF) facility were found to have different gut microbiota and a mucus phenotype that was specific for each colony. The thickness and growth of the colon mucus were similar in the two colonies. However, one colony had mucus that was impenetrable to bacteria or beads the size of bacteria-which is comparable to what we observed in free-living wild mice-whereas the other colony had an inner mucus layer penetrable to bacteria and beads. The different properties of the mucus depended on the microbiota, as they were transmissible by transfer of caecal microbiota to germ-free mice. Mice with an impenetrable mucus layer had increased amounts of Erysipelotrichi, whereas mice with a penetrable mucus layer had higher levels of Proteobacteria and TM7 bacteria in the distal colon mucus. Thus, our study shows that bacteria and their community structure affect mucus barrier properties in ways that can have implications for health and disease. It also highlights that genetically identical animals housed in the same facility can have rather distinct microbiotas and barrier structures.


Retinal spectral domain optical coherence tomography in early atrophic age-related macular degeneration (AMD) and a new metric for objective evaluation of the efficacy of ocular nutrition.
A challenge in ocular preventive medicine is identification of patients with early pathological retinal damage that might benefit from nutritional intervention. The purpose of this study is to evaluate retinal thinning (RT) in early atrophic age-related macular degeneration (AMD) against visual function data from the Zeaxanthin and Visual Function (ZVF) randomized double masked placebo controlled clinical trial (FDA IND #78973). Retrospective, observational case series of medical center veterans with minimal visible AMD retinopathy (AREDS Report #18 simplified grading 1.4/4.0 bilateral retinopathy). Foveal and extra-foveal four quadrant SDOCT RT measurements were evaluated in n = 54 clinical and ZVF AMD patients. RT by age was determined and compared to the OptoVue SD OCT normative database. RT by quadrant in a subset of n = 29 ZVF patients was correlated with contrast sensitivity and parafoveal blue cone increment thresholds. Foveal RT in AMD patients and non-AMD patients was preserved with age. Extrafoveal regions, however, showed significant slope differences between AMD patients and non-AMD patients, with the superior and nasal quadrants most vulnerable to retinal thinning (sup quad: -5.5 μm/decade thinning vs. Non-AMD: -1.1 μm/decade, P < 0.02; nasal quad: -5.0 μm/decade thinning vs. Non-AMD: -1.0 μm/decade, P < 0.04). Two measures of extrafoveal visual deterioration were correlated: A significant inverse correlation between % RT and contrast sensitivity (r = -0.33, P = 0.01, 2 Tailed Paired T) and an elevated extrafoveal increment blue cone threshold (r = +0.34, P = 0.01, 2 Tailed T). Additional SD OCT RT data for the non-AMD oldest age group (ages 82-91) is needed to fully substantiate the model. A simple new SD OCT clinical metric called "% extra-foveal RT" correlates well with functional visual loss in early AMD patients having minimal visible retinopathy. This metric can be used to follow the effect of repleting ocular nutrients, such as zinc, antioxidants, carotenoids, n-3 essential fats, resveratrol and vitamin D.


Is altering the availability of healthier vs. less-healthy options effective across socioeconomic groups? A mega-analysis.
Availability interventions have been hypothesised to make limited demands on conscious processes and, as a result, to be less likely to generate health inequalities than cognitively-oriented interventions. Here we synthesise existing evidence to examine whether the impact of altering the availability of healthier vs. less-healthy options differs by socioeconomic position. Individual-level data (21,360 observations from 7,375 participants) from six studies (conducted online (n = 4) and in laboratories (n = 2)) were pooled for mega-analysis. Multilevel logistic regressions analysed the impact of altering the availability of healthier options on selection of a healthier (rather than a less-healthy) option by socioeconomic position, assessed by (a) education and (b) income. Participants had over threefold higher odds of selecting a healthier option when the available range was predominantly healthier compared to selections when the range offered was predominantly less-healthy (odds ratio (OR): 3.8; 95%CIs: 3.5, 4.1). Less educated participants were less likely to select healthier options in each availability condition (ORs: 0.75-0.85; all p < 0.005), but there was no evidence of differences in healthier option selection by income. Compared to selections when the range offered was predominantly less-healthy, when predominantly healthier options were available there was a 31% increase in selecting healthier options for the most educated group vs 27% for the least educated. This modest degree of increased responsiveness in the most educated group appeared only to occur when healthier options were predominant. There was no evidence of any differential response to the intervention by income. Increasing the proportion of healthier options available increases the selection of healthier options across socioeconomic positions. Availability interventions may have a slightly larger beneficial effect on those with the highest levels of education in settings when healthier options predominate.


Mouse cytomegalovirus infection overrules T regulatory cell suppression on natural killer cells.
Cytomegalovirus establishes lifelong persistency in the host and leads to life threatening situations in immunocompromised patients. FoxP3+ T regulatory cells (Tregs) critically control and suppress innate and adaptive immune responses. However, their specific role during MCMV infection, especially pertaining to their interaction with NK cells, remains incompletely defined. To understand the contribution of Tregs on NK cell function during acute MCMV infection, we infected Treg depleted and undepleted DEREG mice with WT MCMV and examined Treg and NK cell frequency, number, activation and effector function in vivo. Our results reveal an increased frequency of activated Tregs within the CD4+ T cell population shortly after MCMV infection. Specific depletion of Tregs in DEREG mice under homeostatic conditions leads to an increase in NK cell number as well as to a higher activation status of these cells as compared with non-depleted controls. Interestingly, upon infection this effect on NK cells is completely neutralized in terms of cell frequency, CD69 expression and functionality with respect to IFN-γ production. Furthermore, composition of the NK cell population with regard to Ly49H expression remains unchanged. In contrast, absence of Tregs still boosts the general T cell response upon infection to a level comparable to the enhanced activation seen in uninfected mice. CD4+ T cells especially benefit from Treg depletion exhibiting a two-fold increase of CD69+ cells 40 h and IFN-γ+ cells 7 days p.i. while, MCMV infection per se induces robust CD8+ T cell activation which is also further augmented in Treg-depleted mice. Nevertheless, the viral burden in the liver and spleen remain unaltered upon Treg ablation during the course of infection. Thus, MCMV infection abolishes Treg suppressing effects on NK cells whereas T cells benefit from their absence during acute infection. This study provides novel information in understanding the collaborative interaction between NK cells and Tregs during a viral infection and provides further knowledge that could be adopted in therapeutic setups to improve current treatment of organ transplant patients where modulation of Tregs is envisioned as a strategy to overcome transplant rejection.


Transmittance enhancement of sapphires with antireflective subwavelength grating patterned UV polymer surface structures by soft lithography.
We report the total and diffuse transmission enhancement of sapphires with the ultraviolet curable SU8 polymer surface structures consisting of conical subwavelength gratings (SWGs) at one- and both-side surfaces for different periods. The SWGs patterns on the silicon templates were transferred into the SU8 polymer film surface on sapphires by a simple and cost-effective soft lithography technique. For the fabricated samples, the surface morphologies, wetting behaviors, and optical characteristics were investigated. For theoretical optical analysis, a rigorous coupled-wave analysis method was used. At a period of 350 nm, the sample with SWGs on SU8 film/sapphire exhibited a hydrophobic surface and higher total transmittance compared to the bare sapphire over a wide wavelength of 450-1000 nm. As the period of SWGs was increased, the low total transmittance region of < 85% was shifted towards the longer wavelengths and became broader while the diffuse transmittance was increased (i.e., larger haze ratio). For the samples with SWGs at both-side surfaces, the total and diffuse transmittance spectra were further enhanced compared to the samples with SWGs at one-side surface. The theoretical optical calculation results showed a similar trend to the experimentally measured data.


Experimental infection of calves, piglets and lambs with mixtures of invasive and enteropathogenic strains of Escherichia coli.
Mixtures of mutant organisms of an invasive (IN) strain, a strain enteropathogenic (EP) for calves, lambs and piglets, and a non-pathogenic (NP) strain of Escherichia coli, that could be differentiated from each other by their antibiotic resistances, were given orally to an immunoglobulin-negative (IG-) and an immunoglobulin-positive (IG+) calf, lamb and piglet. By the use of appropriate antibiotic-containing culture media, the concentrations of organisms of each of the three strains in the contents of the alimentary tracts and tissues (liver, spleen, kidney, blood and mesenteric lymph glands) of the animals were estimated when they were killed. In the three IG- animals, the IN strain proliferated in the tissues and the EP strain proliferated in the small intestines; in general, the concentrations of the IN strain in the small intestines and the EP strain in the tissues, apart from the mesenteric lymph glands, were as low as those of the NP strain in these sites. The only strain that proliferated in the small intestine of the IG+ animals was the EP strain, which proliferated in the small intestine of the calf and piglet; no organisms of either strain were isolated from the tissues of these three animals, except from their mesenteric lymph glands.


ProbABEL package for genome-wide association analysis of imputed data.
Over the last few years, genome-wide association (GWA) studies became a tool of choice for the identification of loci associated with complex traits. Currently, imputed single nucleotide polymorphisms (SNP) data are frequently used in GWA analyzes. Correct analysis of imputed data calls for the implementation of specific methods which take genotype imputation uncertainty into account. We developed the ProbABEL software package for the analysis of genome-wide imputed SNP data and quantitative, binary, and time-till-event outcomes under linear, logistic, and Cox proportional hazards models, respectively. For quantitative traits, the package also implements a fast two-step mixed model-based score test for association in samples with differential relationships, facilitating analysis in family-based studies, studies performed in human genetically isolated populations and outbred animal populations. ProbABEL package provides fast efficient way to analyze imputed data in genome-wide context and will facilitate future identification of complex trait loci.


Dentate Granule Cells Recruited in the Home Environment Display Distinctive Properties.
The dentate granule cells (DGCs) play a crucial role in learning and memory. Many studies have described the role and physiological properties of these sparsely active neurons using different behavioral contexts. However, the morpho-functional features of DGCs recruited in mice maintained in their home cage (without training), considered as a baseline condition, have not yet been established. Using fosGFP transgenic mice, we observed ex vivo that DGCs recruited in animals maintained in the home cage condition are mature neurons that display a longer dendritic tree and lower excitability compared with non-activated cells. The higher GABAA receptor-mediated shunting inhibition contributes to the lower excitability of DGCs activated in the home environment by shifting the input resistance towards lower values. Remarkably, that shunting inhibition is neither observed in non-activated DGCs nor in DGCs activated during training in virtual reality. In short, our results suggest that strong shunting inhibition and reduced excitability could constitute a distinctive neural signature of mature DGCs recruited in the context of the home environment.


Malpractice Litigation for Compartment Syndrome.
The aim of this study was to analyze litigation involving compartment syndrome to identify the causes and outcomes of such malpractice suits. A better understanding of such litigation may provide insight into areas where clinicians may make improvements in the delivery of care. Jury verdict reviews from the Westlaw database from January 1, 2010 to January 1, 2018 were reviewed. The search term "compartment syndrome" was used to identify cases and extract data on the specialty of the physician defendant, the demographics of the plaintiff, the allegation, and the verdict. A total of 124 individual cases involving the diagnosis of compartment syndrome were identified. Medical centers or the hospital was included as a defendant in 51.6% of cases. The most frequent physician defendants were orthopedic surgeons (45.96%) and emergency medicine physicians (20.16%), followed by cardiothoracic/vascular surgeons (16.93%). Failure to diagnose was the most frequently cited claim (71.8% of cases). Most plaintiffs were men, with a mean age of 36.7 years, suffering injuries for an average of 5 years before their verdict. Traumatic compartment syndrome of the lower extremity causing nerve damage was the most common complication attributed to failure to diagnose, leading to litigation. Forty cases (32.25%) were found for the plaintiff or settled, with an average award of $1,553,993.66. Our study offers a brief overview of the most common defendants, plaintiffs, and injuries involved in legal disputes involving compartment syndrome. Orthopedic surgeons were most commonly named; however, vascular surgeons may also be involved in these cases because of the large number of cases with associated arterial involvement. A significant percentage of cases were plaintiff verdicts or settled cases. Failure to diagnosis or delay in treatment was the most common causes of malpractice litigation. Compartment syndrome is a clinical diagnosis and requires a high level of suspicion for a timely diagnosis. Lack of objective criteria for diagnosis increases the chances of medical errors and makes it an area vulnerable to litigation.


Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma.
Elevated plasma concentrations of soluble VEGFA isoforms are associated with poor prognosis in parallel with improved response to treatment with the anti-VEGFA antibody bevacizumab. To uncover the underlying mechanism to these observations, we administered anti-VEGFA therapy to mice bearing luminescent mouse fibrosarcomas expressing single VEGFA isoforms or their wild-type counterparts expressing all isoforms (fs120, fs164, fs188, or fsWT). Expression of the more soluble isoforms conferred an advantage for lung metastasis from subcutaneous tumors (fs120/164 vs. fs188/WT); fs120 cells also produced more lung colonies than fs188 cells when injected intravenously. Metastasis from subcutaneous fs120 tumors was more sensitive than fs188 to treatment with the anti-VEGFA antibody B20-4.1.1. Despite elevated plasma levels of VEGFA in fs120 tumor-bearing mice and a dependence on VEGF receptor 1 activity for metastasis to the lung, B20-4.1.1 did not affect survival in the lung on intravenous injection. B20-4.1.1 inhibited subcutaneous tumor growth and decreased vascular density in both fs120 and fs188 tumors. However, migration of fs120, but not fs188 cells, in vitro was inhibited by B20-4.1.1. The greater survival of fs120 cells in the lung was associated with VEGFR1-dependent accumulation of CD11b-positive myeloid cells and higher expression of the VEGFR1 ligand, PlGF2, by the fs120 cells in vitro and in the plasma and lungs of fs120 tumor-bearing mice. We conclude that soluble VEGFA isoform expression increases fibrosarcoma metastasis through multiple mechanisms that vary in their sensitivity to anti-VEGF/VEGFR inhibition, with VEGFA-targeted therapy suppressing metastasis through effects on the primary tumor rather than the metastatic site. Cancer Res; 77(10); 2633-46. ©2017 AACR.


Comparative benzene-induced fatty acid changes in a Rhodococcus species and its benzene-sensitive mutant: possible role of myristic and oleic acids in tolerance.
A Gram positive bacterium of the genus Rhodococcus was isolated from a contaminated site in Sydney, Australia, for its ability to tolerate and degrade high concentrations of benzene. To identify fatty acids that may impart this Rhodococcus sp. with tolerance to toxic solvents, a benzene-sensitive strain, labeled M2b, was isolated using EMS mutagenesis. A comparative analysis of fatty acid profiles showed that strain M2b was unable to increase its saturated:unsaturated ratio of fatty acids to the level achieved by the w-t strain when both strains were challenged with benzene. This was due to M2b's increased abundance of myristic acid, and decreased abundance of oleic acid. In addition, by measuring the generalized polarization of the fluorescent membrane probe laurdan using fluorescence spectroscopy, we have shown for the first time the effects of an aromatic hydrocarbon on the membrane fluidity of a Rhodococcus sp. The fluidity of the membranes increased after only 0.5 hr of exposure to benzene, thus suggesting the partitioning of benzene within the lipid bilayer. The response of this Rhodococcus sp. to benzene may suggest a mechanism for how other microorganisms survive when toxic solvents are released within the vicinity of their environment.


Optimal slice thickness for cone-beam CT with on-board imager.
To find the optimal slice thickness (Δτ) setting for patient registration with kilovoltage cone-beam CT (kVCBCT) on the Varian On Board Imager (OBI) system by investigating the relationship of slice thickness to automatic registration accuracy and contrast-to-noise ratio. Automatic registration was performed on kVCBCT studies of the head and pelvis of a RANDO anthropomorphic phantom. Images were reconstructed with 1.0 ≤ Δτ (mm) ≤ 5.0 at 1.0 mm increments. The phantoms were offset by a known amount, and the suggested shifts were compared to the known shifts by calculating the residual error. A uniform cylindrical phantom with cylindrical inserts of various known CT numbers was scanned with kVCBCT at 1.0 ≤ Δτ (mm) ≤ 5.0 at increments of 0.5 mm. The contrast-to-noise ratios for the inserts were measured at each Δτ. For the planning CT slice thickness used in this study, there was no significant difference in residual error below a threshold equal to the planning CT slice thickness. For Δτ > 3.0 mm, residual error increased for both the head and pelvis phantom studies. The contrast-to-noise ratio is proportional to slice thickness until Δτ = 2.5 mm. Beyond this point, the contrast-to-noise ratio was not affected by Δτ. Automatic registration accuracy is greatest when 1.0 ≤ Δτ (mm) ≤ 3.0 is used. Contrast-to-noise ratio is optimal for the 2.5 ≤ Δτ (mm) ≤ 5.0 range. Therefore 2.5 ≤ Δτ (mm) ≤ 3.0 is recommended for kVCBCT patient registration where the planning CT is 3.0 mm.


Microbial responses to nitrogen addition in three contrasting grassland ecosystems.
The effects of global N enrichment on soil processes in grassland ecosystems have received relatively little study. We assessed microbial community response to experimental increases in N availability by measuring extracellular enzyme activity (EEA) in soils from three grasslands with contrasting edaphic and climatic characteristics: a semiarid grassland at the Sevilleta National Wildlife Refuge, New Mexico, USA (SEV), and mesic grasslands at Konza Prairie, Kansas, USA (KNZ) and Ukulinga Research Farm, KwaZulu-Natal, South Africa (SAF). We hypothesized that, with N enrichment, soil microbial communities would increase C and P acquisition activity, decrease N acquisition activity, and reduce oxidative enzyme production (leading to recalcitrant soil organic matter [SOM] accumulation), and that the magnitude of response would decrease with soil age (due to higher stabilization of enzyme pools and P limitation of response). Cellulolytic activities followed the pattern predicted, increasing 35-52% in the youngest soil (SEV), 10-14% in the intermediate soil (KNZ) and remaining constant in the oldest soil (SAF). The magnitude of phosphatase response did not vary among sites. N acquisition activity response was driven by the enzyme closest to its pH optimum in each soil: i.e., leucine aminopeptidase in alkaline soil, beta-N-acetylglucosaminidase in acidic soil. Oxidative enzyme activity varied widely across ecosystems, but did not decrease with N amendment at any site. Likewise, SOM and %C pools did not respond to N enrichment. Between-site variation in both soil properties and EEA exceeded any treatment response, and a large portion of EEA variability (leucine aminopeptidase and oxidative enzymes), 68% as shown by principal components analysis, was strongly related to soil pH (r = 0.91, P < 0.001). In these grassland ecosystems, soil microbial responses appear constrained by a molecular-scale (pH) edaphic factor, making potential breakdown rates of SOM resistant to N enrichment.


Comparison of frictional forces during the closure of extraction spaces in passive self-ligating brackets and conventionally ligated brackets using the finite element method.
This study compared the frictional force resulting from the bracket/archwire interface and the stress at the root/periodontal ligament/bone interface, between passive self-ligating brackets and conventionally ligated brackets, during the space closure stage. A cone beam tomography was taken to a female patient that required extraction of upper first premolars and passive self-ligating system; three months after its activation, a cone beam tomography was taken again. The designs of the maxillary bone and the entire system were possible through tomography images and stereomicroscopic photographs. Validation of the Finite Element Method (FEM) was achieved comparing the amount of movement seen through tomography images and the FEM. Space closure was simulated for each system through the FEM and a comparison was made between the frictional force at the bracket/archwire interface, and the root/periodontal ligament/bone interface. The most significant representation of frictional force at bracket/archwire interface and bone stress was found at the conventionally ligated system, while the passive self-ligating system accounted for the highest distribution of stress over the root. The FEM is an accurate tool used to quantify frictional force and stress concentration during the orthodontic closure. The passive self-ligating system was seen less frictional during the closure state compared to conventional brackets. Key words:Friction, orthodontic bracket, finite element analysis.


Simultaneous cadaver pancreas living-donor kidney transplantation: a new approach for the type 1 diabetic uremic patient.
To review the authors' experience with a new approach for type I diabetic uremic patients: simultaneous cadaver-donor pancreas and living-donor kidney transplant (SPLK). Simultaneous cadaver kidney and pancreas transplantation (SPK) and living-donor kidney transplantation alone followed by a solitary cadaver-donor pancreas transplant (PAK) have been the transplant options for type I diabetic uremic patients. SPK pancreas graft survival has historically exceeded that of solitary pancreas transplantation. Recent improvement in solitary pancreas transplant survival rates has narrowed the advantage seen with SPK. PAK, however, requires sequential transplant operations. In contrast to PAK and SPK, SPLK is a single operation that offers the potential benefits of living kidney donation: shorter waiting time, expansion of the organ donor pool, and improved short-term and long-term renal graft function. Between May 1998 and September 1999, the authors performed 30 SPLK procedures, coordinating the cadaver pancreas transplant with simultaneous transplantation of a laparoscopically removed living-donor kidney. Of the 30 SPLKs, 28 (93%) were portally and enterically drained. During the same period, the authors also performed 19 primary SPK and 17 primary PAK transplants. One-year pancreas, kidney, and patient survival rates were 88%, 95%, and 95% for SPLK recipients. One-year pancreas graft survival rates in SPK and PAK recipients were 84% and 71%. Of 30 SPLK transplants, 29 (97%) had immediate renal graft function, whereas 79% of SPK kidneys had immediate function. Reoperative rates, early readmission to the hospital, and initial length of stay were similar between SPLK and SPK recipients. SPLK recipients had a shorter wait time for transplantation. Early pancreas, kidney, and patient survival rates after SPLK are similar to those for SPK. Waiting time was significantly shortened. SPLK recipients had lower rates of delayed renal graft function than SPK recipients. Combining cadaver pancreas transplantation with living-donor kidney transplantation does not harm renal graft outcome. Given the advantages of living-donor kidney transplant, SPLK should be considered for all uremic type I diabetic patients with living donors.


Taxonomic implications of geographical variation in Rhinolophus affinis (Chiroptera: Rhinolophidae) in mainland Southeast Asia.
Rhinolophusaffinis sensu lato isdistributed throughout Southeast Asia. The taxonomic status of forms attributed to the species is unclear due to the limited sample size with incomplete datasets and the taxa have high variation in morphology and echolocation call frequency. The aim of the study was to evaluate the distribution and taxonomic status of the subspecific forms of R. affinis in mainland Southeast Asia using large sample size with multiple datasets, including morphological, acoustic, and genetic data, both to elucidate taxonomic relationships and to test for congruence between these datasets. Three morphological forms were confirmed within the region; two concur with previously recognized taxa, namely R.affinis macrurus andR.affinis superans,and are strongly supported by morphological and genetic data. The third form is morphologically distinct, but its taxonomic status remains unclear. It is probable that this third form represents a distinct taxonomic entity; however, more data are required to confirm this. R. a. macrurus is known from the north of peninsular Thailand, Cambodia, Myanmar, Laos, and Vietnam (Indochinese subregion); R. a. superans is found throughout the Thai-Malay Peninsula (Sundaic subregion); whilst the third form is presently known from east central Myanmar (Shan state) and lower northern Vietnam (Nghe An Province). Our results suggest that at least three morphological forms occur in mainland Southeast Asia including one form which appears to be new to science. Echolocation call data for R. affinis are not a robust taxonomic tool as it shows a significant degree of variation which is not explained or supported by genetic and morphological findings. This study highlights significant levels of morphological variation in mainland Southeast Asia and provides an essential basis for further studies aiming to understand the population genetics, phylogeography, and taxonomy of the species.


Phenotypic characterisation of Saccharomyces spp. for tolerance to 1-butanol.
Biofuels are expected to play a role in replacing crude oil as a liquid transportation fuel, and research into butanol has highlighted the importance of this alcohol as a fuel. Butanol has a higher energy density than ethanol, butanol-gasoline blends do not separate in the presence of water, and butanol is miscible with gasoline (Szulczyk, Int J Energy Environ 1(1):2876-2895, 40). Saccharomyces cerevisiae has been used as a fermentative organism in the biofuel industry producing ethanol from glucose derived from starchy plant material; however, it typically cannot tolerate butanol concentrations greater than 2 % (Luong, Biotechnol Bioeng 29 (2):242-248, 27). 90 Saccharomyces spp. strains were screened for tolerance to 1-butanol via a phenotypic microarray assay and we observed significant variation in response with the most tolerant strains (S. cerevisiae DBVPG1788, S. cerevisiae DBVPG6044 and S. cerevisiae YPS128) exhibiting tolerance to 4 % 1-butanol compared with S. uvarum and S. castelli strains, which were sensitive to 3 % 1-butanol. Response to butanol was confirmed using traditional yeast methodologies such as growth; it was observed that fermentations in the presence of butanol, when using strains with a tolerant background, were significantly faster. Assessing for genetic rationale for tolerance, it was observed that 1-butanol-tolerant strains, when compared with 1-butanol-sensitive strains, had an up-regulation of RPN4, a transcription factor which regulates proteasome genes. Analysing for the importance of RPN4, we observed that a Δrpn4 strain displayed a reduced rate of fermentation in the presence of 1-butanol when compared with the BY4741 background strain. This data will aid the development of breeding programmes to produce better strains for future bio-butanol production.


Altered macrophage differentiation and immune dysfunction in tumor development.
Tumors require a constant influx of myelomonocytic cells to support the angiogenesis and stroma remodeling needed for their growth. This is mediated by tumor-derived factors, which cause sustained myelopoiesis and the accumulation and functional differentiation of myelomonocytic cells, most of which are macrophages, at the tumor site. An important side effect of the accumulation and functional differentiation of these cells is that they can induce lymphocyte dysfunction. A complete understanding of the complex interplay between neoplastic and myelomonocytic cells might offer novel targets for therapeutic intervention aimed at depriving tumor cells of important growth support and enhancing the antitumor immune response.


In vitro antileishmanial activity of resveratrol originates from its cytotoxic potential against host cells.
In addition to a range of beneficial pharmacological activities, resveratrol is recently reported to have potential antileishmanial activities in vitro. The present study was conducted to evaluate the effect of resveratrol on promastigotes and amastigotes of transgenic Leishmania major expressing green fluorescent protein in comparison with its direct cytotoxic effects on host cells (bone marrow-derived and J774-G8 macrophages, respectively). As assessed by FACS analysis, resveratrol showed moderate antipromastigote activity at <35 µg/mL (153.2 µM) and promising effects at higher sample concentrations. In contrast, the green fluorescent protein signal as a measure of the intracellular parasites' viability was reduced in a concentration-dependent manner. Resveratrol strongly inhibited NO production, but did not display direct NO-scavenging activity in sodium nitroprusside solution. Western blotting indicated that resveratrol reduced recombinant interferon-γ/LPS-induced expression of iNOS protein. Microscopic studies, MTT evaluation, and FACS analysis showed significant cytotoxic effects on host cells in a concentration-dependent manner. This finding suggests that the in vitro antileishmanial activity of resveratrol is due to cytotoxic effects on host cells rather than attributable to a specific antiparasitic potential.


Performance Assessment of the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism Method for Rapid Detection of Susceptibility to Ethambutol and Molecular Prediction of Extensively Drug-resistant Tuberculosis in Clinical Isolates of Mycobacterium tuberculosis.
The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was employed for rapid detection of ethambutol (EMB) resistant clinical isolates of Mycobacterium tuberculosis. From 182 clinical isolates of M tuberculosis collected from different regions, 103 strains were entered in the investigation. DNA was extracted by Chelex 100 method and PCR was performed using specific primers for embB gene. Polymerase chain reaction products were digested with HaeIII and NlaII restriction endonucleases and the patterns of restriction fragments were analysed. Some randomly selected samples were sequenced. Out of 103 studied strains, 52 were resistant to EMB. The cases of secondary tuberculosis were 53 (51.50 ± 1.77%), and primary cases 50 (48.50 ± 1.77%; p > 0.05). From 63 extensively drug-resistant (XDR), pre-XDR and multidrug-resistant (MDR) isolates, 27 (87%), 18 (81.8%) and 7 (70%) strains were resistant to EMB, respectively. Results of PCR-RFLP method showed that from 27R EMB XDR isolates, 13 (sensitivity 48% with CI: 0.307, 0.66 and specificity 100%), from 18R EMB pre-XDR strains, 4 (sensitivity 22% with CI: 0.09, 0.45 and specificity 100%) and of 7R EMB MDR, 2 (sensitivity 28% with CI: 0.082, 0.64 and specificity 100%) had mutation in ATG-Met codon 306. Results of sequencing were concordant with RFLP method. Overall, sensitivity of the molecular method was 36.5% (CI: 0.09, 0.45) and specificity 100%. None of the 40 pansusceptible strains was embB306 mutants. Extensively drug-resistant strains had a higher proportion of embB306 mutants (43%) than pre-XDR and MDR isolates (odds ratio 6.78; p < 0.001). Fast detection of susceptibility to EMB drug is possible by PCR-RFLP. The embB306 locus is a candidate marker for rapid prediction of high resistance consisting of MDR and XDR forms to anti-tuberculosis drugs using this method.


Corns and calluses resulting from mechanical hyperkeratosis.
The formation of corns and calluses can be caused by mechanical stresses from faulty footgear (the wearing of poorly fitting shoes), abnormal foot mechanics (deformity of the foot exerting abnormal pressure), and high levels of activity. Corns and calluses result from hyperkeratosis, a normal physiologic response of the skin to chronic excessive pressure or friction. Treatment should provide symptomatic relief and alleviate the underlying mechanical cause. The lesions will usually disappear following the removal of the causative mechanical forces. Most lesions can be managed conservatively by the use of properly fitting shoes and padding to redistribute mechanical forces. Surgery is only indicated if conservative measures fail and should be aimed at correcting the abnormal mechanical stresses.


Patient pathways: solving the problem of institutional mortality in London during the later nineteenth century.
This paper confronts a major problem in relation to the metropolitan and urban mortality declines in Britain during the later nineteenth century: the extent to which cause-specific death rates at district level were distorted by an official failure to redistribute deaths occurring in institutions back to "normal" place of residence. Describing and analysing the manner in which hospital and infirmary provision in the capital during this period determined the geographical incidence of mortality, the article develops methodologies that bring the researcher progressively closer to more accurate spatial facts of demographic and epidemiological experience. Devoting separate sections to general voluntary and fever hospitals as well as to institutions administered by the Metropolitan Asylums Board, the paper also engages with similar problems in relation to workhouses and Poor Law infirmaries. By way of conclusion, it shows that, far from generating demographically trivial results, the process of redistribution radically revises the epidemiological history of London in the crucial years between the 1860s and the mid-1880s and provides a dataset that will allow controlled interrogation of the metropolitan mortality decline during this period.