Biomechanics of plant anchorage at early development stage.
We propose a minimal model for the response of seedlings to pullout constraints. Central to our approach is the idea of capturing not only average mechanical properties but also the stochastic component of the uprooting process. Our model accounts on one hand for the tensile elastic response of root fibres and on the other hand for the friction between root fibres and the soil matrix. We present for validation a dataset of 98 uprooting experiments using Avena sativa L. seedlings (common oat), growing in non-cohesive sediment under controlled conditions. We show that even if the architecture of the roots used in the experiments and, as a consequence, the components of our model are very basic, the uprooting curve (stress vs. strain) presents a complex response, with sudden jumps followed by partial elastic recovery. Depending on the maturity of the root system, we identify a crossover in the response of the seedling to the constraint. While for younger seedlings the anchorage rapidly fails after the peak force has been reached, more mature root systems recover from partial failures. Finally, we discuss the importance of the characteristics of the uprooting curve (maximal uprooting force and total uprooting work) regarding the ability of seedlings to withstand environmental constraints in terms of duration or intensity.


Birth mode is associated with earliest strain-conferred gut microbiome functions and immunostimulatory potential.
The rate of caesarean section delivery (CSD) is increasing worldwide. It remains unclear whether disruption of mother-to-neonate transmission of microbiota through CSD occurs and whether it affects human physiology. Here we perform metagenomic analysis of earliest gut microbial community structures and functions. We identify differences in encoded functions between microbiomes of vaginally delivered (VD) and CSD neonates. Several functional pathways are over-represented in VD neonates, including lipopolysaccharide (LPS) biosynthesis. We link these enriched functions to individual-specific strains, which are transmitted from mothers to neonates in case of VD. The stimulation of primary human immune cells with LPS isolated from early stool samples of VD neonates results in higher levels of tumour necrosis factor (TNF-α) and interleukin 18 (IL-18). Accordingly, the observed levels of TNF-α and IL-18 in neonatal blood plasma are higher after VD. Taken together, our results support that CSD disrupts mother-to-neonate transmission of specific microbial strains, linked functional repertoires and immune-stimulatory potential during a critical window for neonatal immune system priming.


Rapid bioinspired mineralization using cell membrane nanofragments and alkaline milieu.
Bone is a sophisticated organic-inorganic hybrid material, whose formation involves a complex spatio-temporal sequence of events regulated by the cells. A deeper understanding of the mechanisms behind bone mineralization at different size scales, and using a multidisciplinary approach, may uncover novel pathways for the design and fabrication of functional bone tissue in vitro. The objectives of this study were first to investigate the environmental factors that prime initial mineralization using the secondary ossification center as an in vivo model, and then to apply the obtained knowledge for rapid in vitro synthesis of bone-like tissue. First, the direct and robust measurement of pH showed that femur epiphysis is alkaline (pH ≅ 8.5) at the initial mineral stage at post-natal day 6. We showed that the alkaline milieu is decisive not only for alkaline phosphatase activity, which precedes mineral formation at P6, but also for determining initial mineral precipitation and spherical morphology. Next, engineering approaches were used to synthesize bone-like tissue based on alkaline milieu and artificial chondrocyte membrane nanofragments, previously shown to be the nucleation site for mineral formation. Interestingly, mineralization using artificial cell membrane nanofragments was achieved in just 1 day. Finally, ex vivo culture of femur epiphysis in alkaline pH strongly induced chondrocyte burst, which was previously shown to be the origin of chondrocyte membrane nanofragments, and also enhanced mineral formation. Taken together, these findings not only shed more light on the microenvironmental conditions that prime initial bone formation in vivo, but they also show that alkaline milieu can be used as an important factor for enhancing methods for in vitro synthesis of bone tissue.


Universal microbial diagnostics using random DNA probes.
Early identification of pathogens is essential for limiting development of therapy-resistant pathogens and mitigating infectious disease outbreaks. Most bacterial detection schemes use target-specific probes to differentiate pathogen species, creating time and cost inefficiencies in identifying newly discovered organisms. We present a novel universal microbial diagnostics (UMD) platform to screen for microbial organisms in an infectious sample, using a small number of random DNA probes that are agnostic to the target DNA sequences. Our platform leverages the theory of sparse signal recovery (compressive sensing) to identify the composition of a microbial sample that potentially contains novel or mutant species. We validated the UMD platform in vitro using five random probes to recover 11 pathogenic bacteria. We further demonstrated in silico that UMD can be generalized to screen for common human pathogens in different taxonomy levels. UMD's unorthodox sensing approach opens the door to more efficient and universal molecular diagnostics.


Effects of whole-body vibration training on explosive strength and postural control in young female athletes.
This study aimed to evaluate the effectiveness of a whole-body vibration training program to improve neuromuscular performance in young elite female athletes. Twenty-three women basketball players (14-18 years old) were randomly assigned to a control group (CG, n = 11) or to a whole-body vibration group (WBVG, n = 12). During the study period, both groups continued their usual training program, but the WBVG also underwent a 15-week vibration training program. We analyzed the countermovement jump test (CMJ), the 1-leg hop test for the right leg and for the left leg, and the single-limb standing balance for both legs and with eyes open and closed at 3 time points: before training (T1), after an 8-week training period (T2), and after a further 7-week training period (T3). Compared with the CG, CMJ increased significantly in the WBVG from T1 to T2 (6.47%, p < 0.001), T1 to T3 (10.07%, p = 0.005), and T2 to T3 (3.38%, p < 0.001). One-leg hop test for the right and left legs also showed significantly higher values in WBVG from T1 to T2 (10.12%, p < 0.001 and 9.63%, p = 0.002, respectively) and T1 to T3 (14.17%, p = 0.001 and 15.17%, p = 0.004, respectively). Lateral deviation of the center of pressure in the closed eyes test decreased significantly in WBVG for both right and left leg, from T1 to T2 (-22.20%, p = 0.043 and -34.77%, p < 0.001, respectively) and from T1 to T3 (-33.14%, p = 0.027 and -33.58%, p = 0.043, respectively) compared with the CG. In conclusion, our results show that a 15-week whole-body vibration training program improves explosive strength and postural stability in adolescent female basketball players.


Conductivity scaling in supercritical percolation of nanoparticles--not a power law.
The power-law behavior widely observed in supercritical percolation systems of conductive nanoparticles may merely be a phenomenological approximation to the true scaling law not yet discovered. In this work, we derive a comprehensive yet simple scaling law and verify its extensive applicability to various experimental and numerical systems. In contrast to the power law which lacks theoretical backing, the new scaling law is explanatory and predictive, and thereby helpful to gain more new insights into percolation systems of conductive nanoparticles.


Prevalence of Lynch syndrome among patients with newly diagnosed endometrial cancers.
Lynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. The identification of endometrial cancer (EC) patients with LS has the potential to influence life-saving interventions. We aimed to study the prevalence of LS among EC patients in our population. Universal screening for LS was applied for a consecutive series EC. Tumor testing using microsatellite instability (MSI), immunohistochemistry (IHC) for mismatch-repair (MMR) protein expression and MLH1-methylation analysis, when required, was used to select LS-suspicious cases. Sequencing of corresponding MMR genes was performed. One hundred and seventy-three EC (average age, 63 years) were screened. Sixty-one patients (35%) had abnormal IHC or MSI results. After MLH1 methylation analysis, 27 cases were considered suspicious of LS. From these, 22 were contacted and referred for genetic counseling. Nineteen pursued genetic testing and eight were diagnosed of LS. Mutations were more frequent in younger patients (<50 yrs). Three cases had either intact IHC or MSS and reinforce the need of implement the EC screening with both techniques. The prevalence of LS among EC patients was 4.6% (8/173); with a predictive frequency of 6.6% in the Spanish population. Universal screening of EC for LS is recommended.


Factors associated with perforator stroke after selective basilar artery angioplasty or stenting.
Perforator stroke is one of the most common complications of elective intracranial angioplasty and/or stenting, particularly in the basilar artery. Factors associated with the risk of post-procedural perforator stroke remain unexplored. We investigated factors affecting the risk of perforator stroke after basilar artery angioplasty and/or stenting. Consecutive patients undergoing basilar artery angioplasty and/or stenting due to symptomatic atherosclerotic stenosis were retrospectively included in this single-center study. Analyzed variables including demographic data, risk factors of atherosclerosis, symptoms, characteristics of imaging, and procedure factors were extracted from electronic health records or imaging data. The main outcome was perforator stroke associated with the procedure. Multivariate analysis that correlated factors with the occurrence of perforator stroke in these patients was performed. A total of 255 patients were included in the study. Perforator stroke associated with angioplasty and/or stenting was identified in 13 patients (5.1%). Variables with significant correlation with post-procedural perforator stroke included diabetes (OR 6.496; 95% CI 1.741 to 24.241; p=0.005), time from last symptom to procedure <18 days (OR 5.669; 95% CI 1.174 to 27.371; p=0.031), and pre-procedure stenosis percentage <88.4% (OR 5.882; 95% CI 1.465 to 23.608; p=0.012). Diabetes, time from last symptom to procedure, and pre-procedure stenosis percentage may be factors affecting the risk of perforator stroke associated with basilar artery angioplasty and/or stenting. These factors should be considered in planning of potential basilar artery angioplasty and/or stenting and prospectively evaluated in future multicenter trials.


In vitro evaluation of total venom-antivenin immune complex formation and binding parameters relevant to antivenin protection against venom toxicity and lethality based on size-exclusion high-performance liquid chromatography.
Total venom-antivenin immune complex formation and binding parameters relevant to antivenin protection against venom toxicity and lethality can be evaluated using size-exclusion high-performance liquid chromatography (SE-HPLC). Simple integration of regions within SE-HPLC elution profiles was used to compare binding characteristics of Crotalidae Polyvalent Immune Fab (Ovine) antivenin (FabAV) and Crotalus atrox (western diamondback rattlesnake; C. atrox), C. varidis varidis (prairie rattlesnake; C. v. v.), Agkistrodon contortrix contortrix (southern copperhead; A. c. c.), and A. piscivorus leukostoma (western cottonmouth; A. p. l.) venom. Areas associated with bound venom and antivenin ({Area(bnd)}) were evaluated using a logistic dose-response equation to estimate EC(50) and {Area(bnd)}(max). The relative magnitudes of EC(50), which inversely reflect venom-antivenin binding affinity, were C. atrox > C. v. v. > A. c. c. > A. p. l. Less than 50% of FabAV appeared to be reactive with each of the venoms based on {Area(bnd)}(max). Data was also consistent with FabAV binding to multiple sites on polyvalent antigens within the venoms. Evaluation of immune complex formation using SE-HPLC was compared to neutralization of phospholipase A(2) (PLA(2)) activity of C. atrox, A. c. c., and A. p. l. venom by FabAV as reported in the literature. Maximum neutralization of PLA(2) activity occurred, in general, prior to maximum immune complex formation. Venom-antivenin binding at EC(50) determined via SE-HPLC appeared to be greater than binding associated with neutralization of venom lethality in mice based on LD(50) and ED(50) reported by others. SE-HPLC analysis of venom-antivenin binding could provide a priori information, relevant to reducing the use of animals in evaluating antivenin protection against venom-induced toxicity and lethality.


Unveiling Molecular Changes in Water by Small Luminescent Nanoparticles.
Nowadays a large variety of applications are based on solid nanoparticles dispersed in liquids-so called nanofluids. The interaction between the fluid and the nanoparticles plays a decisive role in the physical properties of the nanofluid. A novel approach based on the nonradiative energy transfer between two small luminescent nanocrystals (GdVO4 :Nd3+ and GdVO4 :Yb3+ ) dispersed in water is used in this work to investigate how temperature affects both the processes of interaction between nanoparticles and the effect of the fluid on the nanoparticles. From a systematic analysis of the effect of temperature on the GdVO4 :Nd3+ → GdVO4 :Yb3+ interparticle energy transfer, it can be concluded that a dramatic increase in the energy transfer efficiency occurs for temperatures above 45 °C. This change is properly explained by taking into account a crossover existing in diverse water properties that occurs at about this temperature. The obtained results allow elucidation on the molecular arrangement of water molecules below and above this crossover temperature. In addition, it is observed that an energy transfer process is produced as a result of interparticle collisions that induce irreversible ion exchange between the interacting nanoparticles.


Similar and additive effects of ovariectomy and diabetes on insulin resistance and lipid metabolism.
Type 2 diabetes mellitus (T2DM) is among the leading causes of death in postmenopausal women. The disruption of ovarian function may contribute to the incidence of T2DM. The purpose of this study was to investigate the effects of ovariectomy and T2DM on glucose and lipid homeostasis, perilipin levels in adipose tissues, as a lipolytic regulator, and levels of certain adipokines. Ovariectomized (OVX) rats were used as a model for postmenopausal women. The study was performed on sham, OVX, sham diabetic, and OVX diabetic female rats. The results indicated that ovariectomy alters adipose tissue metabolism through reducing perilipin content in white adipose tissue (WAT); however it has no effect on perilipin level in brown adipose tissue (BAT). OVX diabetic females suffer from serious metabolic disturbances, suggested by exacerbation of insulin resistance in terms of disrupted lipid profile, higher HOMA-IR, hyperinsulinemia, higher leptin, and lower adiponectin concentrations. These metabolic derangements may underlie the predisposition for cardiovascular disease in women after menopause. Therefore, for efficient treatment, the menopausal status of diabetic female should be addressed, and the order of events is of great importance because ovariectomy following development of diabetes has more serious complications compared to development of diabetes as result of menopause.


Direct-to-Consumer Marketing of Cigar Products in the United States.
Although cigar use and sales have increased in the United States over the past decade, little is known about how these products are promoted. Direct-to-consumer (DTC) advertising is a common method used to promote tobacco products and may be a potential channel through which cigars are advertised. Comperemedia (Mintel) was used to acquire opt-in direct mail and email advertising for the top 10 cigar brands in the United States between January 2013 and July 2014. The advertisement and corresponding data on brand, advertising spend, and mail volume were downloaded and summarized. Promotions such as coupons, giveaways, and sweepstakes were also examined. A total of 92 unique advertisements met the search criteria and included two brands: Black & Mild (n = 77) and Swisher Sweets (n = 15). Expenditures on direct mail advertising during this period totaled $12 809 630. Black & Mild encompassed 80% of total direct mail volume and 78% of direct mail advertising expenditures. Almost all advertisements contained at least one promotion (88%) and included a URL to the product website (85%). The results suggest that Black & Mild and Swisher Sweets are the primary cigar brands using DTC advertising. Promotional offers were nearly ubiquitous among the advertisements, which may appeal to price-sensitive populations. Future studies should continue to examine cigar advertising via direct mail and email, in addition to other channels, such as the point-of-sale. Although cigar use and sales have increased in the United States over the past decade, there is limited data on cigar advertising. This article provides a snapshot of expenditures, volume, and promotional content of DTC cigar advertising in the United States between January 2013 and July 2014.


Snapshot of moving and expanding clones of Mycobacterium tuberculosis and their global distribution assessed by spoligotyping in an international study.
The present update on the global distribution of Mycobacterium tuberculosis complex spoligotypes provides both the octal and binary descriptions of the spoligotypes for M. tuberculosis complex, including Mycobacterium bovis, from >90 countries (13,008 patterns grouped into 813 shared types containing 11,708 isolates and 1,300 orphan patterns). A number of potential indices were developed to summarize the information on the biogeographical specificity of a given shared type, as well as its geographical spreading (matching code and spreading index, respectively). To facilitate the analysis of hundreds of spoligotypes each made up of a binary succession of 43 bits of information, a number of major and minor visual rules were also defined. A total of six major rules (A to F) with the precise description of the extra missing spacers (minor rules) were used to define 36 major clades (or families) of M. tuberculosis. Some major clades identified were the East African-Indian (EAI) clade, the Beijing clade, the Haarlem clade, the Latin American and Mediterranean (LAM) clade, the Central Asian (CAS) clade, a European clade of IS6110 low banders (X; highly prevalent in the United States and United Kingdom), and a widespread yet poorly defined clade (T). When the visual rules defined above were used for an automated labeling of the 813 shared types to define nine superfamilies of strains (Mycobacterium africanum, Beijing, M. bovis, EAI, CAS, T, Haarlem, X, and LAM), 96.9% of the shared types received a label, showing the potential for automated labeling of M. tuberculosis families in well-defined phylogeographical families. Intercontinental matches of shared types among eight continents and subcontinents (Africa, North America, Central America, South America, Europe, the Middle East and Central Asia, and the Far East) are analyzed and discussed.


Opening of large-conductance calcium-activated potassium channels by the substituted benzimidazolone NS004.
1. We used electrophysiological techniques to examine the effects of 5-trifluoromethyl-1-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benzimidaz ole- 2-one (NS004) on large-conductance calcium-activated potassium (BK) channels. 2. We used recordings from excised membrane patches (cell-attached and inside-out single-channel configurations) and whole-cell patch-clamp recordings to examine the effects of NS004 on single BK channels and whole-cell outward currents, respectively, in rat GH3 clonal pituitary tumor cells. We also tested NS004 on voltage-clamped BK channels isolated from rat brain plasma membrane preparations and reconstituted into planar lipid bilayers. Finally, we used two-electrode voltage-clamp techniques to study the effects of NS004 on currents expressed in Xenopus laevis oocytes by the recently described Slo BK clone from Drosophila. 3. In GH3 cells and in Xenopus oocytes expressing the Slo gene product NS004 produced an increase in an iberiotoxin- or tetraethylammonium-sensitive whole-cell outward current, respectively. NS004 produced a significant increase in the activity of single GH3 cell BK channels and rat brain BK channels reconstituted into planar lipid bilayers. In both systems this was characterized by an increase in channel mean open time, a decrease in interburst interval, and an apparent increase in channel voltage/calcium sensitivity. 4. These data indicate that NS004 could be useful for investigating the biophysical and molecular properties of BK channels and for determining the functional consequences of the opening of BK channels.


Longitudinal effects of mild traumatic brain injury and posttraumatic stress disorder comorbidity on postdeployment outcomes in national guard soldiers deployed to Iraq.
Troops deployed to Iraq and Afghanistan are at high risk for exposure to combat events resulting in mild traumatic brain injury (MTBI) or concussion and posttraumatic stress disorder (PTSD). The longer-term impact of combat-related concussion/MTBI and comorbid PTSD on troops' health and well-being is unknown. To assess longitudinal associations between concussion/MTBI and PTSD symptoms reported in theater and longer-term psychosocial outcomes in combat-deployed National Guard soldiers. Longitudinal cohort study. Participants were surveyed in Iraq 1 month before returning home (time 1) and 1 year later (time 2). Self-reports of concussion/MTBI and PTSD were assessed at times 1 and 2. Based on time 1 concussion/MTBI status (defined as an injury during deployment with loss of consciousness or altered mental status) and time 2 postdeployment probable PTSD status, soldiers were compared on a range of time 2 psychosocial outcomes. Nine hundred fifty-three US National Guard soldiers. The time 1 sample was assessed during redeployment transition briefings held at military installations in the Iraq combat theater. The time 2 sample was assessed using mailed surveys sent to the homes of US National Guard service members. Postconcussive, depression, and physical symptoms; alcohol use; social functioning; and quality of life assessed at time 2 using valid clinical instruments. The rate of self-reported concussion/MTBI during deployment was 9.2% at time 1 and 22.0% at time 2. Soldiers with a history of concussion/MTBI were more likely than those without to report postdeployment postconcussive symptoms and poorer psychosocial outcomes. However, after adjusting for PTSD symptoms, concussion/MTBI was not associated with postdeployment symptoms or outcomes. Time 1 PTSD symptoms more strongly predicted postdeployment symptoms and outcomes than did concussion/MTBI history. Although combat-related PTSD was strongly associated with postconcussive symptoms and psychosocial outcomes 1 year after soldiers returned from Iraq, there was little evidence of a long-term negative impact of concussion/MTBI history on these outcomes after accounting for PTSD. These findings and the 2-fold increase in reports of deployment-related concussion/MTBI history have important implications for screening and treatment.


Extracorporeal membrane oxygenation as a bridge to chemotherapy in an Orthodox Jewish patient.
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) for cardiopulmonary support offers survival possibilities to patients who otherwise would succumb to cardiac failure. Often referred to as "a bridge to recovery," involving a ventricular assist device or cardiac transplantation, this technology only affords temporary cardiopulmonary support. Physicians may have concerns about initiating VA-ECMO in patients who, in the absence of recovery or transfer to longer-term therapies, might assert religious or cultural objections to the terminal discontinuation of life-sustaining therapy (LST). We present a novel case of VA-ECMO use in an Orthodox Jewish woman with potentially curable lymphoma encasing her heart to demonstrate the value of anticipating and preemptively resolving foreseeable disputes. A 40-year-old Hasidic Orthodox Jewish woman with lymphoma encasing her right and left ventricles decompensated from heart failure before chemotherapy induction. The medical team, at an academic medical center in New York City, proposed VA-ECMO as a means for providing cardiopulmonary support to enable receipt of chemotherapy. Owing to the patient's religious tradition, which customarily prohibits terminal discontinuation of LST, clinical staff asked for an ethics consultation to plan for initiation and discontinuation of VA-ECMO. Meetings were held with the treating clinicians, clinical ethics consultants, family, religious leaders, and cultural liaisons. Through a deliberative process, VA-ECMO was reconceptualized as a bridge to treatment and not as an LST, a designation assigned to the chemotherapy on this occasion, given the mortal threat posed by the encasing tumor. Traditional religious objections to the terminal discontinuation of LST need not preclude initiation of VA-ECMO. The potential for disputes should be anticipated and steps taken to preemptively address such conflicts. The reconceptualization of VA-ECMO as a bridge to treatment, rather than as an LST, can allow patients with objections to the terminal discontinuation of LST to receive interventions, such as chemotherapy, that might otherwise be precluded by critical physiology.


Guinea pigs: a suitable animal model to study lipoprotein metabolism, atherosclerosis and inflammation.
Numerous animal models have been used to study diet effects on cholesterol and lipoprotein metabolism. However, most of those models differ from humans in the plasma distribution of cholesterol and in the processing of lipoproteins in the plasma compartment. Although transgenic or knock-out mice have been used to study a specific pathway involved in cholesterol metabolism, these data are of limited use because other metabolic pathways and responses to interventions may differ from the human condition. Carbohydrate restricted diets have been shown to reduce plasma triglycerides, increase HDL cholesterol and promote the formation of larger, less atherogenic LDL. However, the mechanisms behind these responses and the relation to atherosclerotic events in the aorta have not been explored in detail due to the lack of an appropriate animal model. Guinea pigs carry the majority of the cholesterol in LDL and possess cholesterol ester transfer protein and lipoprotein lipase activities, which results in reverse cholesterol transport and delipidation cascades equivalent to the human situation. Further, carbohydrate restriction has been shown to alter the distribution of LDL subfractions, to decrease cholesterol accumulation in aortas and to decrease aortic cytokine expression. It is the purpose of this review to discuss the use of guinea pigs as useful models to evaluate diet effects on lipoprotein metabolism, atherosclerosis and inflammation with an emphasis on carbohydrate restricted diets.


[The incidence of Demodex folliculorum in patients with chronic kidney deficiency].
The aim of this study was to evaluate the prevalence of Demodex folliculorum in immune suppressed patients. The present study was carried out on individuals being treated for chronic kidney deficiency and immune suppressed patients that were hospitalized in the Hemodialysis Units and Internal Disease Service of the Cumhuriyet University Hospital. Forty-seven patients with chronic kidney deficiency (CKD) and a control group of thirty-eight healthy and actively exercising individuals were included in this investigation. By means of a questionnaire given to the patients and control group, complaints of allergenic related dermal and optical disorders were detected and the prevalence of Demodex was also evaluated by this questionnaire. First, the presence of D. folliculorum was proven taking dermal specimens from the cheek of every individual. Afterwards, at least two eyelash specimens from the lower and upper eyelid-eyelash follicles of the right and left eyes were taken and examined in a drop of olive oil between slide and cover glass microscopically. The frequency of parasites in every preparation was also determined in each positive case. D. folliculorum was found in the eyelid-eyelash follicles of 6 (12.76 %) and 12 (25.53 %) of the dermal face specimens of the 47 chronic kidney deficiency patients. On the other hand, D. folliculorum was found in the eyes of 2 (5.26 %) persons and in the dermal face specimens of 7 (18.42 %) out of a total of 38 persons in the control group. In the present study, the difference in the Demodex prevalence and complaints of dermal disorder in the two groups was found to be insignificant. In the study group, the difference was insignificant as to dermal complaints and Demodex prevalence (p < 0.05), but considerably difference was observed between complaints about eyes and Demodex prevalence (p < 0.05). Consequently, it was concluded that Demodex folliculorum may be a cause of eye disorders such as blepharitis, and this parasite can be frequently observed in persons with immune system anomalies.


The control of stem cell morphology and differentiation using three-dimensional printed scaffold architecture.
In this work, we investigated the interactions of human mesenchymal stem cells (hMSCs) with three-dimensional (3D) printed scaffolds displaying different scaffold architectures. Pressure-assisted microsyringe system was used to fabricate scaffolds with square (SQR), hexagonal (HEX), and octagonal (OCT) architectures defined by various degrees of curvatures. OCT represents the highest degree of curvature followed by HEX, and SQR is composed of linear struts without curvature. Scaffolds were fabricated from poly(L-lactic acid) and poly(tyrosol carbonate). We found that hMSCs attached and spread by taking the shape of the individual struts, exhibiting high aspect ratios (ARs) and mean cell area when cultured on OCT scaffolds as compared with those cultured on HEX and SQR scaffolds. In contrast, cells appeared bulkier with low AR on SQR scaffolds. These significant changes in cell morphology directly correlate with the stem cell lineage commitment, such that 80 ± 1% of the hMSCs grown on OCT scaffolds differentiated into osteogenic lineage, compared with 70 ± 4% and 62 ± 2% of those grown on HEX and SQR scaffolds, respectively. Cells on OCT scaffolds also showed 2.5 times more alkaline phosphatase activity compared with cells on SQR scaffolds. This study demonstrates the importance of scaffold design to direct stem cell differentiation, and aids in the development of novel 3D scaffolds for bone regeneration.


High yield accelerated reactions in nonvolatile microthin films: chemical derivatization for analysis of single-cell intracellular fluid.
The identification of trace components from biological media can require derivatization under mild conditions for successful analysis by mass spectrometry (MS). When aqueous droplets (ca. 500 nL) containing a sugar and an amine as reagents are allowed to evaporate they may form long-lasting microthin films in which derivatization reactions can occur fast relative to reaction rates in bulk solution. Evidence is presented that these reactions are heterogeneous in nature and comparisons are made with reactions in pastes and in neat reagent mixtures. Moreover, these thin film reactors can be made stable for the long periods of time that may be necessary to give high product yields. The situation is typified by imine formation from reducing sugars which have reaction times of much more than 1 hour provided that small concentrations (e.g. 20 ppm) of nonvolatile solvents are included. After evaporation of almost all the water, the reaction occurs at an approximately constant rate for the first hour. The rate is two orders of magnitude faster than the reaction in the corresponding homogeneous saturated bulk solution. Conversion of the reagent to the Schiff base product is 67% to 96% efficient in these long-lasting thin films, in sharp contrast to the corresponding derivatization efficiencies in the bulk of less than 1%. This method was used to chemically derivatize and thus to identify, using tandem mass spectrometry, 29 reducing sugars in ca. 1 nL of intracellular fluid from a single onion epidermis cell. A formal description of the kinetics of reversible and irreversible second order reactions in thin films is provided. The effects of thermodynamic and kinetic factors are separated and the measured apparent acceleration factor is shown to represent the ratio of intrinsic rate constants for the microthin film reactor relative to the bulk reaction.


Lifestyle changes in middle age and risk of cancer: evidence from the European Prospective Investigation into Cancer and Nutrition.
In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers-including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others-using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95-0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07-1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65-0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk.


Improvement of identification methods for honeybee specific Lactic Acid Bacteria; future approaches.
Honeybees face many parasites and pathogens and consequently rely on a diverse set of individual and group-level defenses to prevent disease. The crop microbiota of Apis mellifera, composed of 13 Lactic Acid Bacterial (LAB) species within the genera Lactobacillus and Bifidobacterium, form a beneficial symbiotic relationship with each other and the honeybee to protect their niche and their host. Possibly playing a vital role in honeybee health, it is important that these honeybee specific Lactic Acid Bacterial (hbs-LAB) symbionts can be correctly identified, isolated and cultured, to further investigate their health promoting properties. We have previously reported successful identification to the strain level by culture-dependent methods and we recently sequenced and annotated the genomes of the 13 hbs-LAB. However, the hitherto applied techniques are unfortunately very time consuming, expensive and not ideal when analyzing a vast quantity of samples. In addition, other researchers have constantly failed to identify the 13 hbs-LAB from honeybee samples by using inadequate media and/or molecular techniques based on 16S rRNA gene sequencing with insufficient discriminatory power. The aim of this study was to develop better and more suitable methods for the identification and cultivation of hbs-LAB. We compared currently used bacterial cultivation media and could for the first time demonstrate a significant variation in the hbs-LAB basic requirements for optimal growth. We also present a new bacterial identification approach based on amplicon sequencing of a region of the 16S rRNA gene using the Illumina platform and an error correction software that can be used to successfully differentiate and rapidly identify the 13 hbs-LAB to the strain level.


Bone marrow features in Pearson syndrome with neonatal onset: A case report and review of the literature.
Pearson syndrome (PS) is a rare mitochondrial disorder that usually presents with transfusion-dependent macrocytic anemia, exocrine pancreatic dysfunction, and lactic acidosis. Typical bone marrow (BM) features are vacuolization in hematopoietic progenitors, hypocellularity, and ringed sideroblasts. At the neonatal age, PS may have a variable clinical onset. Moreover, there is little information about BM features at this age and the timing of their presentation. We report a neonatal case of PS that presented with refractory anemia and atypical BM features. We reviewed the BM findings in neonatal-onset PS cases to stress the importance and limitations of BM evaluation at this age.


Bond strengths of various resin cements to different ceramics.
This study evaluates the shear bond strength (SBS) of various resin cements to different ceramics. Composite resin cylinders of Z100 were fabricated and cemented to disks of feldspathic ceramic (Creation), leucite-reinforced feldspathic ceramic (Empress I), and densely sintered aluminum oxide ceramic (Procera AllCeram) using five resin cements: Panavia F (PAN), RelyX ARC (ARC), RelyX Unicem (RXU), RelyX Veneer, and Variolink II. SBS was measured after three days of water storage (baseline) and after artificial aging (180 days of water storage along with 12,000 thermal cycles). Failure mode of fractured specimens also was evaluated. Data were analyzed with Kruskal-Wallis and Mann-Whitney tests (α=0.05). RXU showed 1) the lowest baseline median SBS to feldspathic ceramic, which was not statistically different from PAN; 2) the lowest median baseline SBS to leucite-reinforced feldspathic and densely sintered aluminum-oxide ceramics. All cements performed similarly after aging, except for ARC (median 0.0 MPa) and PAN (median 16.2 MPa) in the densely sintered aluminum-oxide ceramic group. Resin cements perform differently when bonded to different ceramic substrates. While all test resin cements worked similarly in the long-term to feldspathic and leucite-reinforced feldspathic ceramics, only the MDP-containing resin cement provided durable bonds to densely sintered aluminum-oxide ceramic.


The impact of electronic prescribing systems on pharmacists' time and workflow: protocol for a time-and-motion study in English NHS hospitals.
Electronic prescribing (ePrescribing) systems are rapidly being introduced into National Health Systems (NHS) hospitals in England following their widespread earlier adoption into primary care settings. Such systems require substantial changes in the way pharmacists organise their work and perform their roles. There is however as yet limited evidence on the extent to which these changes may support or compromise efficient and safe working practices by pharmacists. Identifying and quantifying these changes, and their effects, is central to informing system and work practice design, as well as informing training and implementation processes. This protocol describes a study to measure the impact of ePrescribing systems on pharmacists' time and workflow. A direct observational controlled pre-post implementation time-and-motion study will be conducted in six wards at one NHS Trust over two observational periods. Pharmacists will be shadowed and details of all work tasks performed will be collected and time-stamped. Task distribution, frequency and duration will be measured and changes in these measures preimplementation and postimplementation, and between control and intervention wards will be measured. Interviews with pharmacists will investigate their perceptions of the impact of the ePrescribing systems on their work and will be conducted in both periods. The extent to which pharmacists' expectations of the impact of the ePrescribing systems on their work with postimplementation reports will be qualitatively explored, as will any differences between perceptions and results from the time-and-motion analysis. Institutional research ethics approval has been obtained from The University of Edinburgh. Local approval from the participating NHS Trust and informed consent from participating pharmacists have been obtained, while also complying with local governance requirements. The results of the study will be presented at conferences, published in peer-reviewed journals, and shared with members of our Patient and Public Involvement Group, to facilitate wider dissemination.


Comparative genomics of the mycobacteria.
The genus mycobacteria includes two important human pathogens Mycobacterium tuberculosis and Mycobacterium lepra. The former is reputed to have the highest annual global mortality of all pathogens. Their slow growth, virulence for humans and particular physiology makes these organisms extremely difficult to work with. However the rapid development of mycobacterial genomics following the completion of the Mycobacterium tuberculosis genome sequence provides the basis for a powerful new approach for the understanding of these organisms. Five further genome sequencing projects of closely related mycobacterial species with differing host range, virulence for humans and physiology are underway. A comparative genomic analysis of these species has the potential to define the genetic basis of these phenotypes which will be invaluable for the development of urgently needed new vaccines and drugs. This minireview summarises the different techniques that have been employed to compare these genomes and gives an overview of the wealth of data that has already been generated by mycobacterial comparative genomics.


Torticollis secondary to posterior fossa and cervical spinal cord tumors: report of five cases and literature review.
Torticollis is either congenital or acquired in childhood. Acquired torticollis is not a diagnosis but rather a sign of an underlying disorder. The causes of acquired torticollis include ligamentous, muscular, osseous, ocular, psychiatric, and neurologic disorders and may be a symptom of significant abnormalities of the spinal cord and brain, such as spinal syrinx or central nervous system neoplasia. Torticollis is rarely considered to be an initial clinical presentation of posterior fossa and cervical spinal cord tumors. We report five cases of pediatric tumors with torticollis at the onset: an astrocytoma originating from the medulla oblongata, another presumptive astrocytoma of the spinal cord located between C1 and C6 cervical vertebrae (not operated), an ependymoma located throughout the whole cervical spinal cord extending into the bulbomedullary junction, an astrocytoma originating from the bulbus and extending into the posterior fossa, and another case of a eosinophilic granuloma located extradurally through the anterior and posterior portions of the vertebral bodies from C3 to C7 producing the collapse of the sixth cervical vertebra. All five cases were seen in children, aged between 3 and 12 years. All these cases reflect the misinterpretation of this neurological sign and the lack of association with the possibility of spinal or posterior fossa tumor. This delay in the diagnosis of these diseases led to progressive neurological deterioration and to the increase in the tumor size, which made surgical intervention difficult and the prognosis unfavorable. Although torticollis secondary to tumors is rarely seen, it is necessary to be kept in mind in the differential diagnosis.


Effectiveness of cognitive behavioral therapy in the treatment of fibromyalgia syndrome: a meta-analytic literature review.
Fibromyalgia (FM) is a chronic disorder caused by a dysfunction of central nervous system sensitization. This syndrome is characterized by widespread pain and diffuse tenderness, but often also presents fatigue, sleep disturbances, and a whole range of symptoms such as morning stiffness, decreased physical function and dyscognition. FM is usually treated with pharmacological and non-pharmacological treatments. The non-pharmacological interventions include cognitive behavioral therapy (CBT), physiotherapy, acupuncture and patient education programs. In order to evaluate the efficacy of CBT and compare it with other non-pharmacological treatments, we performed a review of the meta-analytic literature. We evaluated the methodological quality of publications found by following the recommendations of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Data showed that CBT does not provide better results than other non-pharmacological treatments on outcomes of pain, fatigue, sleep disturbance and quality of life, at either a short or long-term evaluation. On the contrary, CBT seems to be more effective on symptoms of depression for a short period, whereas it considerably improves the pain self-management and reduces the number of visits to the doctor. The data currently available indicate that cost-effectiveness studies could help us to understand whether the reduction in the number of visits to the doctor could balance the cost of CBT to the health public system.


Chimeric Antigen Receptor (CAR) therapy for multiple myeloma.
The introduction of chimeric antigen receptor (CAR)-modified T cells has revolutionized immunotherapy and cancer treatment as a whole. However, so far, clinical efficacy has only been demonstrated for CD19-positive B cell lymphomas. For Multiple Myeloma (MM), the second most common haematological malignancy, there are currently no clinical results supporting the usefulness of the adoptive transfer of CAR-modified T cells. This might be related to the fact that an ideal surface target has not yet been identified or the presence of strong local immunosuppression in the tumour microenvironment, which is a hallmark of MM. In this review, we provide a comprehensive overview of promising target molecules for CAR T cell approaches in MM and we outline a number of ways in which the local immunosuppression in MM can be overcome. By providing a strategy for the design of CAR T cell treatments for MM we hope to transform this new therapeutic approach into a valuable tool within the therapeutic armamentarium for MM.


Ambulance demand: random events or predicable patterns?
Occupational, social and recreational routines follow temporal patterns, as does the onset of certain acute medical diseases and injuries. It is not known if the temporal nature of injury and disease transfers into patterns that can be observed in ambulance demand. This review examines eligible study findings that reported temporal (time of day, day of week and seasonal) patterns in ambulance demand. Electronic searches of Medline and Cumulative Index of Nursing and Allied Health Literature were conducted for papers published between 1980 and 2011. In addition, hand searching was conducted for unpublished government and ambulance service documents and reports for the same period. 38 studies examined temporal patterns in ambulance demand. Six studies reported trends in overall workload and 32 studies reported trends in a subset of ambulance demand, either as a specific case type or demographic group. Temporal patterns in overall demand were consistent between jurisdictions for time of day but varied for day of week and season. When analysed by case type, all jurisdictions reported similar time of day patterns, most jurisdictions had similar day of week patterns except for out-of-hospital cardiac arrest and similar seasonal patterns, except for trauma. Temporal patterns in case types were influenced by age and gender. Temporal patterns are present in ambulance demand and importantly these populations are distinct from those found in hospital datasets suggesting that variation in ambulance demand should not be inferred from hospital data alone. Case types seem to have similar temporal patterns across jurisdictions; thus, research where demand is broken down into case types would be generalisable to many ambulance services. This type of research can lead to improvements in ambulance service deliverables.


[Association between tumor necrosis factor-alpha promoter polymorphisms and type 2 diabetes and obesity in Chilean elderly women].
Tumor necrosis factor-alpha (TNF-alpha) has an increased expression in the adipose tissue of obese subjects and is involved in insulin resistance. To screen for associations between -308G/A, -238G/A, -376G/A and -163G/A genetic variants of the TNF-alpha gene, diabetes and obesity-related variables. A group of 263 elderly women aged 60-90 years were recruited. Among them, an oral glucose tolerance test was performed and serum lipids measured in 100 women. TNF-alpha genotypes were determined by polymerase chain reaction (PCR) and analysis of restriction fragment length polymorphisms. No significant differences were found when comparing allele frequencies in TNF-alpha polymorphisms of normal subjects with those having impaired glucose tolerance or type 2 diabetes. After excluding patients with previous diagnosis of diabetes, no significant differences by polymorphism carrier status were found for plasma levels of lipids, glucose and insulin. Additionally, no significant differences were found for the association between variables related to adiposity and the -308G/A polymorphisms. It is unlikely that polymorphisms in the promoter region of the TNF-alpha gene have a major influence in obesity and diabetes phenotypes in Chilean elderly women.


Pyrrole versus quinoline formation in the palladium catalyzed reaction of 2-alkynyl-3-bromothiophenes and 2-alkynyl-3-bromofurans with anilines. A combined experimental and computational study.
Benzofuroquinolines were prepared by a new type of Pd catalyzed annulation reaction. In the first step, 2-alkynyl-3-bromobenzofurans were prepared by Sonogashira reactions of 2,3-dibromobenzofuran. Their Pd catalyzed reaction with electron-rich anilines afforded benzofuroquinolines by a domino C-N coupling/annulation process. This reaction proceeds as a C,N-cyclization via the nitrogen atom and the ortho-carbon of the aniline. Similarly, furoquinolines were prepared from 2,3-dibromofuran. In contrast, benzofuropyrroles and furopyrroles were formed by N,N-cyclization when electron-poor anilines were used. Earlier, we reported results related to the thiophene and benzothiophene series. Quinolines were formed from 2,3-dibromobenzothiophene when electron rich anilines were used. In contrast, pyrroles were obtained in the case of electron-poor anilines. On the other hand, pyrroles were generally obtained, not depending on the type of aniline, when 2,3-dibromothiophene was employed as the starting material. In the present article, a detailed DFT study related to the mechanism (quinoline versus pyrrole formation) is reported which provides a rationalization of the selectivities observed for the furan, benzofuran, thiophene and benzothiophene series and for the different selectivities observed for electron-rich and -poor anilines.


Partial-occupancy binders identified by the Pan-Dataset Density Analysis method offer new chemical opportunities and reveal cryptic binding sites.
Crystallographic fragment screening uses low molecular weight compounds to probe the protein surface and although individual protein-fragment interactions are high quality, fragments commonly bind at low occupancy, historically making identification difficult. However, our new Pan-Dataset Density Analysis method readily identifies binders missed by conventional analysis: for fragment screening data of lysine-specific demethylase 4D (KDM4D), the hit rate increased from 0.9% to 10.6%. Previously unidentified fragments reveal multiple binding sites and demonstrate: the versatility of crystallographic fragment screening; that surprisingly large conformational changes are possible in crystals; and that low crystallographic occupancy does not by itself reflect a protein-ligand complex's significance.


Number-based visual generalisation in the honeybee.
Although the numerical abilities of many vertebrate species have been investigated in the scientific literature, there are few convincing accounts of invertebrate numerical competence. Honeybees, Apis mellifera, by virtue of their other impressive cognitive feats, are a prime candidate for investigations of this nature. We therefore used the well-established delayed match-to-sample paradigm, to test the limits of honeybees' ability to match two visual patterns solely on the basis of the shared number of elements in the two patterns. Using a y-maze, we found that bees can not only differentiate between patterns containing two and three elements, but can also use this prior knowledge to differentiate three from four, without any additional training. However, bees trained on the two versus three task could not distinguish between higher numbers, such as four versus five, four versus six, or five versus six. Control experiments confirmed that the bees were not using cues such as the colour of the exact configuration of the visual elements, the combined area or edge length of the elements, or illusory contours formed by the elements. To our knowledge, this is the first report of number-based visual generalisation by an invertebrate.


Upregulation of KCNE1 induces QT interval prolongation in patients with chronic heart failure.
Prolongation of the action potential duration (APD) is observed in ventricular myocytes isolated from the failing heart. The rapid component (I(Kr)) and the slow component (I(Ks)) of the delayed-rectifier potassium current (I(K)) are major determinants of the APD, but less information is available on the genomic modulation of I(K) in the remodeled human heart. The aim of the current study was to examine the relationship between I(K) transcripts and QT interval in surface electrocardiogram in patients with chronic heart failure (CHF). Total RNA was extracted from right ventricle endomyocardial biopsy samples in 21 CHF patients (age: 53+/-4 years, mean +/- SEM). The KCNH2 and KCNQ1 levels did not differ significantly between controls (New York Heart Association (NYHA) I, n=10) and CHF patients (NYHA II or III, n=11), whereas the KCNE1 level was significantly higher in CHF patients than in controls (relative mRNA levels normalized to GAPDH expression: 6.16+/-0.31 vs 7.70+/-0.46, p<0.05). The KCNE1/KCNQ1 ratio was higher in CHF patients than in controls (0.92+/-0.02 vs 1.06+/-0.05, p<0.05) and the KCNE1-KCNQ1 ratio was positively correlated with QT interval (r=0.70, p<0.05). Increasing the KCNE1 concentration caused a shift in activation voltage and slowed the activation kinetics of the KCNE1-KCNQ1 currents expressed in Xenopus oocytes. Prolongation of the APD and decrease in I(Ks) with increasing the amount of KCNE1 concentration were well predicted in a computer simulation. In mild-to-moderate CHF patients, the relative abundance of KCNE1 compared to KCNQ1 genes, at least in part, might contribute to the preferential prolongation of QT interval through reducing the net outward current during the plateau of the action potential.


Hybridization thermodynamics of DNA oligonucleotides during microchip capillary electrophoresis.
Capillary electrophoresis (CE) is a powerful analytical tool for performing separations and characterizing properties of charged species. For reacting species during a CE separation, local concentrations change leading to nonequilibrium conditions. Interpreting experimental data with such nonequilibrium reactive species is nontrivial due to the large number of variables involved in the system. In this work we develop a COMSOL multiphysics-based numerical model to simulate the electrokinetic mass transport of short interacting ssDNAs in microchip capillary electrophoresis. We probe the importance of the dissociation constant, K(D), and the concentration of DNA on the resulting observed mobility of the dsDNA peak, μ(w), by using a full sweep of parametric simulations. We find that the observed mobility is strongly dependent on the DNA concentration and K(D), as well as ssDNA concentration, and develop a relation with which to understand this dependence. Furthermore, we present experimental microchip capillary electrophoresis measurements of interacting 10 base ssDNA and its complement with changes in buffer ionic strength, DNA concentration, and DNA sequence to vary the system equilibria. We then compare our results to thermodynamically calculated K(D) values.


Supportive accountability: a model for providing human support to enhance adherence to eHealth interventions.
The effectiveness of and adherence to eHealth interventions is enhanced by human support. However, human support has largely not been manualized and has usually not been guided by clear models. The objective of this paper is to develop a clear theoretical model, based on relevant empirical literature, that can guide research into human support components of eHealth interventions. A review of the literature revealed little relevant information from clinical sciences. Applicable literature was drawn primarily from organizational psychology, motivation theory, and computer-mediated communication (CMC) research. We have developed a model, referred to as "Supportive Accountability." We argue that human support increases adherence through accountability to a coach who is seen as trustworthy, benevolent, and having expertise. Accountability should involve clear, process-oriented expectations that the patient is involved in determining. Reciprocity in the relationship, through which the patient derives clear benefits, should be explicit. The effect of accountability may be moderated by patient motivation. The more intrinsically motivated patients are, the less support they likely require. The process of support is also mediated by the communications medium (eg, telephone, instant messaging, email). Different communications media each have their own potential benefits and disadvantages. We discuss the specific components of accountability, motivation, and CMC medium in detail. The proposed model is a first step toward understanding how human support enhances adherence to eHealth interventions. Each component of the proposed model is a testable hypothesis. As we develop viable human support models, these should be manualized to facilitate dissemination.


Psychometric Evaluation of the D-Catch, an Instrument to Measure the Accuracy of Nursing Documentation.
To evaluate the psychometric properties of the D-Catch instrument. A cross-sectional methodological study. Validity and reliability were estimated with confirmatory factor analysis (CFA) and internal consistency and inter-rater reliability, respectively. A sample of 250 nursing documentations was selected. CFA showed the adequacy of a 1-factor model (chronologically descriptive accuracy) with an outlier item (nursing diagnosis accuracy). Internal consistency and inter-rater reliability were adequate. The D-Catch is a valid and reliable instrument for measuring the accuracy of nursing documentation. Caution is needed when measuring diagnostic accuracy since only one item measures this dimension. The D-Catch can be used as an indicator of the accuracy of nursing documentation and the quality of nursing care.


Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer.
Authors report the results of four meta-analyses of studies that examined the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and head and neck cancer (nine studies, 2076 cases and 4834 controls for C677T; four studies, 1439 cases and 3941 controls for A1298C), and lung cancer (ten studies, 5274 cases and 7435 controls for C677T; seven studies, 5098 cases and 6243 controls for A1298C). The summary odds ratio (OR) of head and neck cancer was 0.92 (95% CI: 0.76-1.11) for MTHFR 677 TT and 0.68 (95% CI: 0.37-1.26) for MTHFR 1298 CC. The OR of lung cancer was 1.22 [95% confidence interval (CI): 0.95-1.55] for MTHFR 677 TT and 1.07 (95% CI: 0.83-1.38) for MTHFR 1298 CC. Results from the meta-analysis of three studies on C677T stratified according to dietary folate intake showed an increased risk for individuals with low folate intake (OR = 1.37, 95% CI: 0.92-2.06 for head and neck and OR = 1.28, 95% CI: 0.97-1.68 for lung) versus high folate intake (OR = 0.85, 95% CI: 0.63-1.16 for head and neck, and OR = 0.94, 95% CI: 0.79-1.12 for lung). Despite the lack of formal statistical significance, these findings are consistent with the hypothesis that folate play a role in lung and head/neck carcinogenesis, and show the need to incorporate data on folate intake when interpreting results of MTHFR polymorphisms in relation to cancer risk.


Evolution of reduced pre-adult viability and larval growth rate in laboratory populations of Drosophila melanogaster selected for shorter development time.
Four large (n > 1000) populations of Drosophila melanogaster, derived from control populations maintained on a 3 week discrete generation cycle, were subjected to selection for fast development and early reproduction. Egg to eclosion survivorship and development time and dry weight at eclosion were monitored every 10 generations. Over 70 generations of selection, development time in the selected populations decreased by approximately 36 h relative to controls, a 20% decline. The difference in male and female development time was also reduced in the selected populations. Flies from the selected populations were increasingly lighter at eclosion than controls, with the reduction in dry weight at eclosion over 70 generations of selection being approximately 45% in males and 39% in females. Larval growth rate (dry weight at eclosion/development time) was also reduced in the selected lines over 70 generations, relative to controls, by approximately 32% in males and 24% in females. However, part of this relative reduction was due to an increase in growth rate of the controls populations, presumably an expression of adaptation to conditions in our laboratory. After 50 generations of selection had elapsed, a considerable and increasing pre-adult viability cost to faster development became apparent, with viability in the selected populations being about 22% less than that of controls at generation 70 of selection.


Impact of Movement Disorders on Management of Spinal Deformity in the Elderly.
Spinal deformities are frequent and disabling complications of movement disorders such as Parkinson disease and multiple system atrophy. The most distinct spinal deformities include camptocormia, antecollis, Pisa syndrome, and scoliosis. Spinal surgery has become lower risk and more efficacious for complex spinal deformities, and thus more appealing to patients, particularly those for whom conservative treatment is inappropriate or ineffective. Recent innovations and advances in spinal surgery have revolutionized the management of spinal deformities in elderly patients. However, spinal deformity surgeries in patients with Parkinson disease remain challenging. High rates of mechanical complications can necessitate revision surgery. The success of spinal surgery in patients with Parkinson disease depends on an interdisciplinary approach, including both surgeons and movement disorder specialists, to select appropriate surgical patients and manage postoperative movement in order to decrease mechanical failures. Achieving appropriate correction of sagittal alignment with strong biomechanical instrumentation and bone fusion is the key determinant of satisfactory results.


Semiprone position is superior to supine position for paediatric endotracheal intubation during massive regurgitation, a randomized crossover simulation trial.
Endotracheal intubation of patients with massive regurgitation represents a challenge in emergency airway management. Gastric contents tend to block suction catheters, and few treatment alternatives exist. Based on a technique that was successfully applied in our district, we wanted to examine if endotracheal intubation would be easier and quicker to perform when the patient is turned over to a semiprone position, as compared to the supine position. In a randomized crossover simulation trial, a child manikin with on-going regurgitation was intubated both in the supine and semiprone positions. Endpoints were experienced difficulty with the procedure and time to intubation, as well as visually confirmed intubation and first-pass success rate. Intubation in the semiprone position was significantly easier and faster compared to the supine position; the median experienced difficulty on a visual analogue scale was 27 and 65, respectively (p = 0.004), and the median time to intubation was 26 and 45 s, respectively (p = 0.001). There were no significant differences in frequency of visually confirmed intubation (16 and 18, p = 0.490) of first-pass success rate (17 and 18, p = 1.000). In this experiment, endotracheal intubation during massive regurgitation with the patient in the semiprone position was significantly easier and quicker to perform than in the supine position. Endotracheal intubation in the semiprone position can provide a quick rescue method in situations where airway management is hindered by massive regurgitation, and it represents a possible supplement to current airway management training.


Effects of Individualized and Standardized Interventions on Middle School Students With Reading Disabilities.
This study reports the effectiveness of a year-long, small-group, tertiary (Tier 3) intervention that examined 2 empirically derived but conceptually different treatments and a comparison condition. The researchers had randomly assigned all students to treatment or comparison conditions. The participants were seventh- and eighth-grade students from the previous year who received an intervention and did not meet exit criteria. The researchers assigned them to one of two treatments: standardized (n = 69) or individualized (n = 71) for 50 min a day, in group sizes of 5, for the entire school year. Comparison students received no researcher-provided intervention (n = 42). The researchers used multigroup modeling with nested comparisons to evaluate the statistical significance of Time 3 estimates. Students in both treatments outperformed the comparison students on assessments of decoding, fluency, and comprehension. Intervention type did not moderate the pattern of effects, although students in the standardized treatment had a small advantage over individualized students on word attack. This study provides a framework from which to refine further interventions for older students with reading disabilities.


Study of a Cohort of 1,886 Persons To Determine Changes in Antibody Reactivity to Borrelia burgdorferi 3 Months after a Tick Bite.
Lyme borreliosis is a tick-borne disease caused by the bacterium Borrelia burgdorferi. The most frequent clinical manifestation is a rash called erythema migrans. Changes in antibody reactivity to B. burgdorferi 3 months after a tick bite are measured using enzyme-linked immunosorbent assays (ELISAs). One assay is based on native purified flagellum antigen (IgG), and the other assay is based on a recombinant antigen called C6 (IgG or IgM). Paired samples were taken at the time of a tick bite and 3 months later from 1,886 persons in Sweden and the Åland Islands, Finland. The seroconversion or relative change is defined by dividing the measurement units from the second sample by those from the first sample. The threshold for the minimum level of significant change was defined at the 2.5% level to represent the random error level. The thresholds were a 2.7-fold rise for the flagellar IgG assay and a 1.8-fold rise for the C6 assay. Of 1,886 persons, 102/101 (5.4%) had a significant rise in antibody reactivity in the flagellar assay or the C6 assay. Among 40 cases with a diagnosis of Lyme borreliosis, the sensitivities corresponding to a rise in antibodies were 33% and 50% for the flagellar antigen and the C6 antigen, respectively. Graphical methods to display the antibody response and to choose thresholds for a rise in relative antibody reactivity are shown and discussed. In conclusion, 5.4% of people with tick bites showed a rise in Borrelia-specific antibodies above the 2.5% threshold in either ELISA but only 40 (2.1%) developed clinical Lyme borreliosis.


Post-infectious glomerulonephritis presenting as acute renal failure in a patient with Lyme disease.
We report a case of a patient with acute renal failure in Lyme disease-associated focal proliferative mesangial nephropathy. Lyme disease is a vector-borne disease caused by Borrelia burgdorferi, transmitted by the bite of an infected ixodes tick. Post-infectious glomerulonephritis (GN)secondary to Borrelia burgdorferi infection in man could be fatal, as it is in canine Lyme borreliosis. A 61-year old man with chronic ethanolic hepatitis was admitted to a provincial hospital, complaining of nausea, diarrhoea and loss of his sense of taste. A few days prior hospitalization, he had been bitten by a tick. He developed erythema gyratum repens in the right leg, thorax and face. Kidney function was altered despite normal urine flow: creatinine 5.04 mg/dl and BUN 126 mg/dl. Urinalysis showed light proteinuria and microscopic hematuria. IgG and IgM antibodies to Borrelia burgdorferi were detected by ELISA and Western blot confirmed the diagnosis. Renal biopsy showed mild mesangial proliferation and mesangial and paramesangial deposits on AFOG stain. A diagnosis of acute renal failure in Lyme disease-associated focal proliferative IgA nephropathy was made. Intravenous antibiotic medication was started (ceftriaxone 1 gram daily i.v.). The patient was later discharged, serum creatinine had decreased to 3.5 mg/dl with a BUN of 58 mg/dl, and a slight improvement was observed on follow-up. Borrelia burgdorferi is a possible cause of post-infectious GN in humans as it is in dogs. Difficulties in identifying Borrelia burgdorferi may also be one of the reasons for the paucity of reports on the association of this infection with glomerulonephritis in humans. Currently, various types of histological renal lesions have been reported.


Mechanism of Accumulation of Methylmercury in Rice ( Oryza sativa L.) in a Mercury Mining Area.
Rice consumption is the primary pathway for methylmercury (MeHg) exposure at inland mercury (Hg) mining areas of China. The sources and processes of formation and translocation for MeHg in rice plant are complex and remain largely unknown. In this study, rice ( Oryza sativa L.) was exposed to isotopically labeled dimethylmercury (DMe199Hg) in field experiments using open top chambers to explore the response of MeHg accumulation in rice tissues to different levels of DMe199Hg in air. Rice leaves assimilated DMeHg from air, which was subsequently largely stored in aboveground tissues, including the rice grain, with only a small amount reaching the root. Combining these experimental results with field investigations of DMeHg concentrations in air beneath the rice canopy in a Hg mining area, we estimate that 15.5%, 10.8%, and 8.50% MeHg in the brown rice, the leaf, and the upper stalk, respectively, could be derived from atmospheric sources of DMeHg, while 99.5% of MeHg in rice root originated from the rice soil-water system. These findings help refine the mechanism of MeHg accumulation in rice that, in addition to soil, a fraction of MeHg in rice plants can be derived from DMeHg emissions from flooded rice paddies in Hg mining areas.


A study of total serum alkaline phosphatase activity in men following partial gastrectomy.
Total serum alkaline phosphatase (SAP) activity has been measured in 463 men with partial gastrectomy (Polya type), and in a control group of 271 men with vagotomy with pyloroplasty or gastroenterostomy. An analysis of variance of the values in the range of 3.0 to 11.5 KA units/100 ml showed that the enzyme serum activity is influenced by three independent factors: age, ABO blood group, and the type of operation. Marginally raised levels (12.0-17.0 KA units/100 ml) were found to be affected by the same factors, and it was concluded that these levels do not, usually, indicate either bone or liver disease. In 18 men the total serum alkaline phosphatase was over 17.0 KA units: 16 had Paget's disease of bone, and two had liver disease.


Scope of radiological protection control measures.
In this report, the Commission recommends approaches to national authorities for their definition of the scope of radiological protection control measures through regulations, by using its principles of justification and optimisation. The report provides advice for deciding the radiation exposure situations that should be covered by the relevant regulations because their regulatory control can be justified, and, conversely, those that may be considered for exclusion from the regulations because their regulatory control is deemed to be unamenable and unjustified. It also provides advice on the situations resulting from regulated circumstances but which may be considered by regulators for exemption from complying with specific requirements because the application of these requirements is unwarranted and exemption is the optimum option. Thus, the report describes exclusion criteria for defining the scope of radiological protection regulations, exemption criteria for planned exposure situations, and the application of these concepts in emergency exposure situations and in existing exposure situations. The report also addresses specific exposure situations such as exposure to low-energy or low-intensity adventitious radiation, cosmic radiation, naturally occurring radioactive materials, radon, commodities, and low-level radioactive waste. The quantitative criteria in the report are intended only as generic suggestions to regulators for defining the regulatory scope, in the understanding that the definitive boundaries for establishing the situations that can be or need to be regulated will depend on national approaches.


Characterization of Leukocyte Formin FMNL1 Expression in Human Tissues.
Formins are cytoskeleton regulating proteins characterized by a common FH2 structural domain. As key players in the assembly of actin filaments, formins direct dynamic cytoskeletal processes that influence cell shape, movement and adhesion. The large number of formin genes, fifteen in the human, suggests distinct tasks and expression patterns for individual family members, in addition to overlapping functions. Several formins have been associated with invasive cell properties in experimental models, linking them to cancer biology. One example is FMNL1, which is considered to be a leukocyte formin and is known to be overexpressed in lymphomas. Studies on FMNL1 and many other formins have been hampered by a lack of research tools, especially antibodies suitable for staining paraffin-embedded formalin-fixed tissues. Here we characterize, using bioinformatics tools and a validated antibody, the expression pattern of FMNL1 in human tissues and study its subcellular distribution. Our results indicate that FMNL1 expression is not restricted to hematopoietic tissues and that neoexpression of FMNL1 can be seen in epithelial cancer.


Genomic Variation Influences Methanothermococcus Fitness in Marine Hydrothermal Systems.
Hydrogenotrophic methanogens are ubiquitous chemoautotrophic archaea inhabiting globally distributed deep-sea hydrothermal vent ecosystems and associated subseafloor niches within the rocky subseafloor, yet little is known about how they adapt and diversify in these habitats. To determine genomic variation and selection pressure within methanogenic populations at vents, we examined five Methanothermococcus single cell amplified genomes (SAGs) in conjunction with 15 metagenomes and 10 metatranscriptomes from venting fluids at two geochemically distinct hydrothermal vent fields on the Mid-Cayman Rise in the Caribbean Sea. We observed that some Methanothermococcus lineages and their transcripts were more abundant than others in individual vent sites, indicating differential fitness among lineages. The relative abundances of lineages represented by SAGs in each of the samples matched phylogenetic relationships based on single-copy universal genes, and genes related to nitrogen fixation and the CRISPR/Cas immune system were among those differentiating the clades. Lineages possessing these genes were less abundant than those missing that genomic region. Overall, patterns in nucleotide variation indicated that the population dynamics of Methanothermococcus were not governed by clonal expansions or selective sweeps, at least in the habitats and sampling times included in this study. Together, our results show that although specific lineages of Methanothermococcus co-exist in these habitats, some outcompete others, and possession of accessory metabolic functions does not necessarily provide a fitness advantage in these habitats in all conditions. This work highlights the power of combining single-cell, metagenomic, and metatranscriptomic datasets to determine how evolution shapes microbial abundance and diversity in hydrothermal vent ecosystems.


Women, e-waste, and technological solutions to climate change.
In this paper, we argue that a crossover class of climate change solutions (which we term "technological solutions") may disproportionately and adversely impact some populations over others. We begin by situating our discussion in the wider climate discourse, particularly with regard to the Millennium Development Goals (MDGs) and the Basel Convention. We then suggest that many of the most attractive technological solutions to climate change, such as solar energy and electric car batteries, will likely add to the rapidly growing stream of electronic waste ("e-waste"). This e-waste may have negative downstream effects on otherwise disenfranchised populations. We argue that e-waste burdens women unfairly and disproportionately, affecting their mortality/morbidity and fertility, as well as the development of their children. Building on this, we claim that these injustices are more accurately captured as problems of recognition rather than distribution, since women are often institutionally under-acknowledged both in the workplace and in the home. Without institutional support and representation, women and children are deprived of adequate safety equipment, health precautions, and health insurance. Finally, we return to the question of climate justice in the context of the human right to health and argue for greater inclusion and recognition of women waste workers and other disenfranchised groups in forging future climate agreements.


Automated synthesis and visualization of a chemotherapy treatment regimen network.
Cytotoxic treatments for cancer remain highly toxic, expensive, and variably efficacious. Many chemotherapy regimens are never directly compared in randomized clinical trials (RCTs); as a result, the vast majority of guideline recommendations are ultimately derived from human expert opinion. We introduce an automated network meta-analytic approach to this clinical problem, with nodes representing regimens and edges direct comparison via RCT(s). A chemotherapy regimen network is visualized for the primary treatment of chronic myelogenous leukemia (CML). Node and edge color, size, and opacity are all utilized to provide additional information about the quality and strength of the depicted evidence. Historical versions of the network are also created. With this approach, we were able to compactly compare the results of 17 CML regimens involving RCTs of 9700 patients, representing the accumulation of 45 years of evidence. Our results closely parallel the recommendations issued by a professional guidelines organization, the National Comprehensive Cancer Network (NCCN). This approach offers a novel method for interpreting complex clinical data, with potential implications for future objective guideline development.


Multiple transcripts of the neurofibromatosis type 1 gene in human brain and in brain tumours.
1. Neurofibromatosis type 1 is a common hereditary disorder characterized by the presence of multiple neurofibromas and café-au-lait spots, and is frequently associated with intellectual handicaps and brain tumours. The gene responsible for neurofibromatosis (the NF1 gene) codes for a protein of 2818 amino acids, termed neurofibromin, which has a domain related to mammalian ras GTPase-activating protein. 2. The NF1 gene gives rise to multiple transcripts generated by alternative splicing, that encode neurofibromin and its isoforms. These include type I mRNA coding for neurofibromin, type II mRNA coding for neurofibromin containing the insertion of 21 amino acids in the GTPase-activating protein-related related domain and mRNA coding for an N-terminal isoform lacking the GTPase-activating protein-related domain (N-isoform). 3. In the present study, the relative levels of mRNAs encoding type I, type II and N-isoform were determined by S1-nuclease mapping analysis in human brain tissue and in primary brain tumours obtained from patients with tumours unrelated to neurofibromatosis type 1. 4. These three mRNAs were expressed in all ten brain tumours and in every region of the brain examined, with the highest levels found in the cerebellum. Type I mRNA was the predominant form in the human brain except for the pons, whereas type II mRNA was predominantly expressed in eight out of ten primary brain tumours. 5. In contrast, N-isoform mRNA was similarly expressed in normal brain tissue and brain tumours. 6. These findings suggest that neurofibromin and its isoforms have important physiological roles in the human brain and that the altered expression of type I and type II mRNAs in brain tumours may be related to the tumorigenesis.


The role of natural killer cells in resistance to coccidiosis: investigations in a murine model.
Natural killer (NK) activity, detected by the lysis of Yac-1 target cells, was examined in splenic and mesenteric lymph node (MLN) cells throughout the course of infection with Eimeria vermiformis in BALB/c and C57B1/6 (B6) mice. These strains are, respectively, relatively resistant and susceptible to primary infections, which render them equally, and completely, resistant to challenge. Resting levels of NK activity were higher in B6 than in BALB/c, and B6 responded earlier in the course of infection than BALB/c, but splenic peak values were higher in BALB/c; the pattern of response in MLN cells was similar in both strains, but the peak was higher in BALB/c. At the time (7 days p.i.) of peak NK response in BALB/c mice there was, depending upon the choice of NK-resistant/lymphokine-activated killer (LAK)-sensitive target cells, either little (P388D1), or no (P815) splenic LAK activity. Challenge of immunized BALB/c mice did not evoke a detectable NK response. Although the higher NK activity in BALB/c mice correlated with greater control of primary infection, depletion of NK activity (demonstrated in splenic cells) in vivo by treatment with anti-asialo GM1 antibodies did not greatly affect the course of infection. Furthermore, this treatment did not augment the exacerbation of infection produced by treatment with anti-interferon-gamma (IFN-gamma) MoAb, indicating that, at least in this system, NK cells are not a fundamentally important source of this controlling cytokine of eimerian infections. The results suggest that NK cells may not greatly influence the outcome of coccidial infections.


Esophageal function testing with combined multichannel intraluminal impedance and manometry: multicenter study in healthy volunteers.
Combined multichannel intraluminal impedance and manometry (MII-EM) assesses esophageal function by simultaneous measurement of both pressure and bolus transit. Normative data for this method have not been published. The aim of this study was to establish normative data for combined MII-EM and to correlate liquid and viscous bolus transit by impedance with esophageal contractions by manometry. Forty-three normal volunteers recruited from 4 centers (15 women, 28 men; age range, 21-72 years) underwent combined MII-EM with a catheter containing 4 impedance-measuring segments and 4 solid-state pressure transducers. Each center recruited and analyzed subjects independently, according to pre-established criteria. Each subject received 20 x 5 mL swallows, 10 liquid and 10 viscous material. Tracings were analyzed manually for bolus presence time, bolus head advance time, segmental transit times, total bolus transit time, contraction amplitude, duration, and onset velocity. Ninety-seven and four-tenths percent of manometrically normal liquid and 96.1% of manometrically normal viscous swallows had complete bolus transit by impedance. Almost half (47.2%) of manometrically ineffective liquid and 34.7% of ineffective viscous swallows had complete bolus transit, whereas 91.7% of manometric simultaneous liquid swallows and 54.5% of simultaneous viscous swallows had complete bolus transit. More than 93% of normal individuals had at least 80% complete liquid or at least 70% complete viscous bolus transit. This study establishes normative data for combined MII-EM. Combined MII-EM may be a more sensitive tool in assessing esophageal function compared to standard manometry because impedance can distinguish different bolus transit patterns. Studies in patients with manometrically defined esophageal motility abnormalities should help clarify the functional importance of manometric ineffective and simultaneous swallows.


First ancient mitochondrial human genome from a prepastoralist southern African.
The oldest contemporary human mitochondrial lineages arose in Africa. The earliest divergent extant maternal offshoot, namely haplogroup L0d, is represented by click-speaking forager peoples of southern Africa. Broadly defined as Khoesan, contemporary Khoesan are today largely restricted to the semidesert regions of Namibia and Botswana, whereas archeological, historical, and genetic evidence promotes a once broader southerly dispersal of click-speaking peoples including southward migrating pastoralists and indigenous marine-foragers. No genetic data have been recovered from the indigenous peoples that once sustained life along the southern coastal waters of Africa prepastoral arrival. In this study we generate a complete mitochondrial genome from a 2,330-year-old male skeleton, confirmed through osteological and archeological analysis as practicing a marine-based forager existence. The ancient mtDNA represents a new L0d2c lineage (L0d2c1c) that is today, unlike its Khoe-language based sister-clades (L0d2c1a and L0d2c1b) most closely related to contemporary indigenous San-speakers (specifically Ju). Providing the first genomic evidence that prepastoral Southern African marine foragers carried the earliest diverged maternal modern human lineages, this study emphasizes the significance of Southern African archeological remains in defining early modern human origins.


Variation in the management of isolated craniosynostosis: a survey of the Synostosis Research Group.
OBJECTIVEThe authors created a collaborative network, the Synostosis Research Group (SynRG), to facilitate multicenter clinical research on craniosynostosis. To identify common and differing practice patterns within the network, they assessed the SynRG surgeons' management preferences for sagittal synostosis. These results will be incorporated into planning cooperative studies.METHODSThe SynRG consists of 12 surgeons at 5 clinical sites. An email survey was distributed to SynRG surgeons in late 2016, and responses were collected through early 2017. Responses were collated and analyzed descriptively.RESULTSAll of the surgeons-7 plastic/craniofacial surgeons and 5 neurosurgeons-completed the survey. They varied in both experience (1-24 years) and sagittal synostosis case volume in the preceding year (5-45 cases). Three sites routinely perform preoperative CT scans. The preferred surgical technique for children younger than 3 months is strip craniectomy (10/12 surgeons), whereas children older than 6 months are all treated with open cranial vault surgery. Pre-incision cefazolin, preoperative complete blood count panels, and an arterial line were used by most surgeons, but tranexamic acid was used routinely at 3 sites and never at the other 2 sites. Among surgeons performing endoscopic strip craniectomy surgery (SCS), most create a 5-cm-wide craniectomy, whereas 2 surgeons create a 2-cm strip. Four surgeons routinely send endoscopic SCS patients to the intensive care unit after surgery. Two of the 5 sites routinely obtain a CT scan within the 1st year after surgery.CONCLUSIONSThe SynRG surgeons vary substantially in the use of imaging, the choice of surgical procedure and technique, and follow-up. A collaborative network will provide the opportunity to study different practice patterns, reduce variation, and contribute multicenter data on the management of children with craniosynostosis.


Primary care clinicians' perceptions of antibiotic resistance: a multi-country qualitative interview study.
To explore and compare primary care clinicians' perceptions of antibiotic resistance in relation to the management of community-acquired lower respiratory tract infection (LRTI) in contrasting European settings. Qualitative interview study with 80 primary care clinicians in nine European countries. Data were subjected to a five-stage analytical framework approach (familiarization; developing a thematic framework from the interview questions and the themes emerging from the data; indexing; charting; and mapping to search for interpretations in the data). Preliminary analysis reports were sent to all network facilitators for validation. Most clinicians stated that antibiotic resistance was not a problem in their practice. Some recommended enhanced feedback about local resistance rates. Northern European respondents generally favoured using the narrowest-spectrum agent, motivated by containing resistance, whereas southern/eastern European respondents were more motivated by maximizing the potential of a rapid treatment effect and so justified empirical use of broad-spectrum antibiotics. Antibiotic treatment failure was ascribed largely to viral aetiology rather than resistant bacteria. Clinicians generally agreed that resistance will become more serious without enhanced antibiotic stewardship or new drug discovery. If current rates of antibiotic resistance are likely to result in important treatment failures, then provision of local resistance data is likely to enhance clinicians' sense of importance of the issue. Interventions to enhance the quality of antibiotic prescribing in primary care should address perceptions, particularly in the south and east of Europe, that possible advantages to patients from antibiotic treatment in general, and from newer broad-spectrum compared with narrow-spectrum agents, outweigh disadvantages to patients and society from associated effects on antibiotic resistance.


Sweat gland nerve fiber density and association with sudomotor function, symptoms, and risk factors in adolescents with type 1 diabetes.
To quantify sweat gland nerve fiber density in adolescents with diabetes. Additionally, to investigate associations between sudomotor innervation, sweat responses, and possible risk factors for sudomotor neuropathy. Cross-sectional study where 60 adolescents with type 1 diabetes (duration > 5 years) and 23 control subjects were included. Clinical data, quantitative sudomotor axon reflex test, and skin biopsies were obtained. Skin tissue was immunostained and imaged by confocal microscopy. Quantification of the sweat gland volume and three-dimensional reconstruction of the nerve fibers was performed using a design-unbiased technique. Adolescents with diabetes had a significant reduction of maximum and mean values of nerve fiber length and nerve fiber density in sweat glands compared to controls (p values < 0.05). No association between nerve fiber density and sweat responses was found (p = 0.21). In cases with reduced sweat gland nerve fiber length, nerve fiber density, and volume, the sweat response was reduced or absent. Height, systolic blood pressure, time in hypoglycemia, and total daily and basal/total insulin dose were positively correlated to sweat response, while low-density lipoprotein, and HbA1c were negatively correlated with sweat response (p values < 0.05). Other microvascular complications and high cholesterol levels increased the relative risk for reduced sweat gland nerve fiber density. Our findings of reduced sweat gland innervation in a selected group of adolescents add new knowledge about the structural changes that occur in autonomic nerves due to diabetes. Evaluating both the sweat gland innervation and sweat gland volume was important for understanding the association with sweat responses. Further research is needed to understand its clinical relevance.


A highly fluorinated lithium iron phosphate with interpenetrating lattices: electrochemistry and ionic conductivity.
Li5Fe2PO4F8, a new member of the family of alkali transition metal fluorophosphates, has been synthesized and characterized using single-crystal X-ray diffraction, 57Fe Mössbauer spectroscopy and magnetic susceptibility measurements. The existence of an infinite {-[PO4(FeF4)2]-}∞ tetrahedral network in an inter-penetrated diamond lattice, along with the presence of seven unique Li sites, presents interesting structural features of this structure-type for energy storage applications. The initial results of (de)lithiation reveal that a relatively low fraction of theoretical capacity may be utilized reversibly (0.2 Li+ ion per formula unit), possibly due to the lack of available free volume for Li+ insertion. The high Li content and the existence of large channels in all 3-dimensions of space also offer opportunities to study this material as a candidate for solid-state electrolytes. The results from electro-impedance measurements reveal the reasonable activation energy of Li diffusion (0.70 eV), which is also supported by theoretical calculations.


GATA4 knockdown in MA-10 Leydig cells identifies multiple target genes in the steroidogenic pathway.
GATA4 is an essential transcription factor required for the initiation of genital ridge formation, for normal testicular and ovarian differentiation at the time of sex determination, and for male and female fertility in adulthood. In spite of its crucial roles, the genes and/or gene networks that are ultimately regulated by GATA4 in gonadal tissues remain to be fully understood. This is particularly true for the steroidogenic lineages such as Leydig cells of the testis where many in vitro (promoter) studies have provided good circumstantial evidence that GATA4 is a key regulator of Leydig cell gene expression and steroidogenesis, but formal proof is still lacking. We therefore performed a microarray screening analysis of MA-10 Leydig cells in which Gata4 expression was knocked down using an siRNA strategy. Analysis identified several GATA4-regulated pathways including cholesterol synthesis, cholesterol transport, and especially steroidogenesis. A decrease in GATA4 protein was associated with decreased expression of steroidogenic genes previously suspected to be GATA4 targets such as Cyp11a1 and Star. Gata4 knockdown also led to an important decrease in other novel steroidogenic targets including Srd5a1, Gsta3, Hsd3b1, and Hsd3b6, as well as genes known to participate in cholesterol metabolism such as Scarb1, Ldlr, Soat1, Scap, and Cyp51. Consistent with the decreased expression of these genes, a reduction in GATA4 protein compromised the ability of MA-10 cells to produce steroids both basally and under hormone stimulation. These data therefore provide strong evidence that GATA4 is an essential transcription factor that sits atop of the Leydig cell steroidogenic program.


Haddad syndrome novel association with BRAF mutation.
This is a report of a 36 week male infant who suffered abdominal distension and difficulty opening bowels within first few days of life and showed a pattern of hypoventilation and apnea associated with sleep. His diagnostic studies confirmed the diagnosis of congenital central hypoventilation syndrome CCHS (PHOX2B mutation) and Hirschsprung's disease and later found a further mutation of BRAF oncogene. This describes a novel association between these mutations and the shared qualities of tumorigenesis between BRAF and PHOX2B.