A Review of Cyber-Ranges and Test-Beds: Current and Future Trends.
Cyber situational awareness has been proven to be of value in forming a comprehensive understanding of threats and vulnerabilities within organisations, as the degree of exposure is governed by the prevailing levels of cyber-hygiene and established processes. A more accurate assessment of the security provision informs on the most vulnerable environments that necessitate more diligent management. The rapid proliferation in the automation of cyber-attacks is reducing the gap between information and operational technologies and the need to review the current levels of robustness against new sophisticated cyber-attacks, trends, technologies and mitigation countermeasures has become pressing. A deeper characterisation is also the basis with which to predict future vulnerabilities in turn guiding the most appropriate deployment technologies. Thus, refreshing established practices and the scope of the training to support the decision making of users and operators. The foundation of the training provision is the use of Cyber-Ranges (CRs) and Test-Beds (TBs), platforms/tools that help inculcate a deeper understanding of the evolution of an attack and the methodology to deploy the most impactful countermeasures to arrest breaches. In this paper, an evaluation of documented CR and TB platforms is evaluated. CRs and TBs are segmented by type, technology, threat scenarios, applications and the scope of attainable training. To enrich the analysis of documented CR and TB research and cap the study, a taxonomy is developed to provide a broader comprehension of the future of CRs and TBs. The taxonomy elaborates on the CRs/TBs dimensions, as well as, highlighting a diminishing differentiation between application areas.


Immunohistochemical detection of TAS2R38 protein in human taste cells.
The sense of taste plays an important role in the evaluation of the nutrient composition of consumed food. Bitter taste in particular is believed to serve a warning function against the ingestion of poisonous substances. In the past years enormous progress was made in the characterization of bitter taste receptors, including their gene expression patterns, pharmacological features and presumed physiological roles in gustatory as well as in non-gustatory tissues. However, due to a lack in TAS2R-specifc antibodies the localization of receptor proteins within gustatory tissues has never been analyzed. In the present study we have screened a panel of commercially available antisera raised against human bitter taste receptors by immunocytochemical experiments. One of these antisera was found to be highly specific for the human bitter taste receptor TAS2R38. We further demonstrate that this antibody is able to detect heterologously expressed TAS2R38 protein on Western blots. The antiserum is, however, not able to interfere significantly with TAS2R38 function in cell based calcium imaging analyses. Most importantly, we were able to demonstrate the presence of TAS2R38 protein in human gustatory papillae. Using double immunofluorescence we show that TAS2R38-positive cells form a subpopulation of PLCbeta2 expressing cells. On a subcellular level the localization of this bitter taste receptor is neither restricted to the cell surface nor particularly enriched at the level of the microvilli protruding into the pore region of the taste buds, but rather evenly distributed over the entire cell body.


[Psychotic symptoms as a side-effect of omeprazole].
A 12-year-old girl with no psychiatric history developed psychotic symptoms, including formal thought disorder and delusional ideas after omeprazole was initiated. Given the co-occurrence of omeprazole initiation and the start of these symptoms, omeprazole was discontinued and replaced by ranitidine which led to immediate symptom reduction followed by complete remission. Although the proton pump inhibitor (ppi) omeprazole is considered safe and is commonly prescribed, it can cause rare major psychiatric side-effects. Despite conducting a literature search to uncover a possible causal mechanism to explain these side-effects, no conclusive explanatio was found.


Can Andean medicine coexist with biomedical healthcare? A comparison of two rural communities in Peru and Bolivia.
It is commonly assumed that indigenous medical systems remain strong in developing countries because biomedicine is physically inaccessible or financially not affordable. This paper compares the health-seeking behavior of households from rural Andean communities at a Peruvian and a Bolivian study site. The main research question was whether the increased presence of biomedicine led to a displacement of Andean indigenous medical practices or to coexistence of the two healing traditions. Open-ended interviews and free listing exercises were conducted between June 2006 and December 2008 with 18 households at each study site. Qualitative identification of households' therapeutic strategies and use of remedies was carried out by means of content analysis of interview transcriptions and inductive interference. Furthermore, a quantitative assessment of the incidence of culture-bound illnesses in local ethnobiological inventories was performed. Our findings indicate that the health-seeking behavior of the Andean households in this study is independent of the degree of availability of biomedical facilities in terms of quality of services provided, physical accessibility, and financial affordability, except for specific practices such as childbirth. Preference for natural remedies over pharmaceuticals coexists with biomedical healthcare that is both accessible and affordable. Furthermore, our results show that greater access to biomedicine does not lead to less prevalence of Andean indigenous medical knowledge, as represented by the levels of knowledge about culture-bound illnesses. The take-home lesson for health policy-makers from this study is that the main obstacle to use of biomedicine in resource-poor rural areas might not be infrastructural or economic alone. Rather, it may lie in lack of sufficient recognition by biomedical practitioners of the value and importance of indigenous medical systems. We propose that the implementation of health care in indigenous communities be designed as a process of joint development of complementary knowledge and practices from indigenous and biomedical health traditions.


Epidemic of hepatitis E in a military unit in Abbotrabad, Pakistan.
An outbreak of hepatitis caused by hepatitis E virus (HEV) in Abbottabad, Pakistan was traced to fecal contamination of a water system. Of 109 men hospitalized with hepatitis, 104 (95%) had serologic evidence of acute hepatitis E (IgM antibody to HEV [anti-HEV]), three (3%) probably had acute hepatitis E (high titers of IgG anti-HEV without IgM), and two had acute hepatitis A. Among a subset of 44 men with acute hepatitis E from whom three serum specimens were obtained over a four-month period, the anti-HEV IgG geometric mean titers (GMTs) decreased from 1,519 during the outbreak to 657 at four months. The IgM anti-HEV was detected in 40 (91%) of 44 sera obtained at admission (GMT = 533 during acute disease), but in only six (14%) four months later. The prevalence of anti-HEV in this population before the outbreak was estimated to be 30%. The presence of IgG anti-HEV appeared to protect against clinical hepatitis or development of serologic evidence of new infection with HEV. This is the second major epidemic of hepatitis E in the Pakistani military confirmed by an anti-HEV enzyme-linked immunosorbent assay (ELISA). Evidence that pre-existing antibody as measured by this ELISA protects against disease is important for assessment of vaccine development.


On the use of administrative databases to support planning activities: the case of the evaluation of neonatal case-mix in the Emilia-Romagna region using DRG and APR-DRG classification systems.
There are several versions of the Diagnosis Related Group (DRG) classification systems that are used for case-mix analysis, utilization review, prospective payment, and planning applications. The objective of this study was to assess the adequacy of two of these DRG systems--Medicare DRG and All Patient Refined DRG--to classify neonatal patients. The first part of the paper contains a descriptive analysis that outlines the major differences between the two systems in terms of classification logic and variables used in the assignment process. The second part examines the statistical performance of each system on the basis of the administrative data collected in all public hospitals of the Emilia-Romagna region relating to neonates discharged in 1997 and 1998. The Medicare DRG are less developed in terms of classification structure and yield a poorer statistical performance in terms of reduction in variance for length of stay. This is important because, for specific areas, a more refined system can prove useful at regional level to remove systematic biases in the measurement of case-mix due to the structural characteristics of the Medicare DRGs classification system.


Toward ultimate miniaturization of high Q silicon traveling-wave microresonators.
High Q traveling-wave resonators (TWR)s are one of the key building block components for VLSI Photonics and photonic integrated circuits (PIC). However, dense VLSI integration requires small footprint resonators. While photonic crystal resonators have shown the record in simultaneous high Q (~10(5)-10(6)) and very small mode volumes; the structural simplicity of TWRs has motivated many ongoing researches on miniaturization of these resonators with maintaining Q in the same range. In this paper, we investigate the scaling issues of silicon traveling-wave microresonators down to ultimate miniaturization levels in SOI platforms. Two main constraints that are considered during this down scaling are: 1) Preservation of the intrinsic Q of the resonator at high values, and 2) Compatibility of resonator with passive (active) integration by preserving the SiO(2) BOX layer (plus a thin Si slab layer for P-N junction fabrication). Microdisk and microdonut (an intermediate design between disk and ring shape) are considered for high Q, miniaturization, and single-mode operation over a wide wavelength range (as high as the free-spectral range). Theoretical and experimental results for miniaturized resonators are demonstrated and Q's as high as ~10(5) for resonators as small as 1.5 μm radius are achieved.


Immediate endovascular stent-graft repair of an acute traumatic rupture of the thoracic aorta: case report and subject review.
We describe a case of emergency endovascular stent-graft placement for acute traumatic rupture of the thoracic aorta in a patient with an associated unstable type II odontoid fracture. The stent-graft placement procedure was performed within 4 hours of admission under sedation and local anaesthesia while the neck remained externally splinted. After exclusion of the rupture the patient could then undergo treatment of the associated cervical fracture and other injuries.


Multiple endocrine neoplasia type 1 with upper gastrointestinal hemorrhage and perforation: a case report and review.
Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary syndrome known to predispose subjects to endocrine neoplasms in a variety of tissues such as the parathyroid glands, pituitary gland, pancreas and gastrointestinal tract. We herein report a patient with a past history of pituitary adenoma, presenting with symptoms of chronic diarrhea for nearly one year and a sudden upper gastrointestinal hemorrhage as well as perforation without signs. Nodules in the duodenum and in the uncinate process and tail of pancreas and enlargement of the parathyroid glands were detected on preoperative imaging. Gastroscopy revealed significant ulceration and esophageal reflux diseases. The patient underwent subtotal parathyroidectomy and autotransplantation, pylorus-preserving pancreaticoduodenectomy and pancreatic tail resection and recovered well. The results observed in our patient suggest that perforation and bleeding of intestine might be symptoms of Zollinger-Ellison Syndrome in patients with MEN1.


Assessing the relative ages of admixture in the bovine hybrid zones of Africa and the Near East using X chromosome haplotype mosaicism.
Historical hybridization events between the two subspecies of cattle, Bos taurus and B. indicus, have occurred in several regions of the world, while other populations have remained nonadmixed. We typed closely linked X chromosome microsatellites in cattle populations with differing histories of admixture from Africa, Europe, the Near East, and India. Haplotype breakdown will occur as admixed populations age, and longer ancestral haplotypes will remain intact in more recently admixed populations compared to older ones. We genotyped male animals from these populations, obtaining unambiguous haplotypes, and measured levels of linkage disequilibrium (LD) and ancestral mosaicism. Extensive LD, likely to be the result of ongoing admixture, was discovered in hybrid cattle populations from the perimeter of the tsetse zone in West Africa. A Bayesian method to assign microsatellite allele ancestry was used to designate the likely origin of each chromosomal segment and assess the relative ages of admixture in the populations. A gradient of the age of admixture in the African continent emerged, where older admixture has produced more fragmented haplotypes in the south, and longer intact haplotypes, indicating more recent hybridization, feature in the northwest.


T cell cross-reactivity and conformational changes during TCR engagement.
All thymically selected T cells are inherently cross-reactive, yet many data indicate a fine specificity in antigen recognition, which enables virus escape from immune control by mutation in infections such as the human immunodeficiency virus (HIV). To address this paradox, we analyzed the fine specificity of T cells recognizing a human histocompatibility leukocyte antigen (HLA)-A2-restricted, strongly immunodominant, HIV gag epitope (SLFNTVATL). The majority of 171 variant peptides tested bound HLA-A2, but only one third were recognized. Surprisingly, one recognized variant (SLYNTVATL) showed marked differences in structure when bound to HLA-A2. T cell receptor (TCR) recognition of variants of these two peptides implied that they adopted the same conformation in the TCR-peptide-major histocompatibility complex (MHC) complex. However, the on-rate kinetics of TCR binding were identical, implying that conformational changes at the TCR-peptide-MHC binding interface occur after an initial permissive antigen contact. These findings have implications for the rational design of vaccines targeting viruses with unstable genomes.


Modulation of genotoxicity and endocrine disruptive effects of malathion by dietary honeybee pollen and propolis in Nile tilapia (Oreochromis niloticus).
The present study aimed at verifying the usefulness of dietary 2.5% bee-pollen (BP) or propolis (PROP) to overcome the genotoxic and endocrine disruptive effects of malathion polluted water in Oreochromis niloticus (O. niloticus). The acute toxicity test was conducted in O. niloticus in various concentrations (0-8 ppm); mortality rate was assessed daily for 96 h. The 96 h-LC50 was 5 ppm and therefore 1/5 of the median lethal concentration (1 ppm) was used for chronic toxicity assessment. In experiment (1), fish (n = 8/group) were kept on a diet (BP/PROP or without additive (control)) and exposed daily to malathion in water at concentration of 5 ppm for 96 h "acute toxicity experiment". Protective efficiency against the malathion was verified through chromosomal aberrations (CA), micronucleus (MN) and DNA-fragmentation assessment. Survival rate in control, BP and PROP groups was 37.5%, 50.0% and 100.0%, respectively. Fish in BP and PROP groups showed a significant (P < 0.05) reduction in the frequency of CA (57.14% and 40.66%), MN (53.13% and 40.63%) and DNA-fragmentation (53.08% and 30.00%). In experiment (2), fish (10 males and 5 females/group) were kept on a diet with/without BP for 21 days before malathion-exposure in water at concentration of 0 ppm (control) or 1 ppm (Exposed) for further 10 days "chronic toxicity experiment". BP significantly (P < 0.05) reduced CA (86.33%), MN (82.22%) and DNA-fragmentation (93.11%), prolonged the sperm motility when exposed to 0.01 ppm of pollutant in vitro and increased the estradiol level in females comparing to control. In conclusion, BP can be used as a feed additive for fish prone to be raised in integrated fish farms or cage culture due to its potency to chemo-protect against genotoxicity and sperm-teratogenicity persuaded by malathion-exposure.


Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial.
Cognitive behavioral therapy (CBT) and hypnotic medications are efficacious for short-term treatment of insomnia, but few patients achieve complete remission with any single treatment. It is unclear whether combined or maintenance therapies would enhance outcome. To evaluate the added value of medication over CBT alone for acute treatment of insomnia and the effects of maintenance therapies on long-term outcome. Prospective, randomized controlled trial involving 2-stage therapy for 160 adults with persistent insomnia treated at a university hospital sleep center in Canada between January 2002 and April 2005. Participants received CBT alone or CBT plus 10 mg/d (taken at bedtime) of zolpidem for an initial 6-week therapy, followed by extended 6-month therapy. Patients initially treated with CBT attended monthly maintenance CBT for 6 months or received no additional treatment and those initially treated with combined therapy (CBT plus 10 mg/d of zolpidem) continued with CBT plus intermittent use of zolpidem or CBT only. Sleep onset latency, time awake after sleep onset, total sleep time, and sleep efficiency derived from daily diaries (primary outcomes); treatment response and remission rates derived from the Insomnia Severity Index (secondary outcomes). Cognitive behavioral therapy used singly or in combination with zolpidem produced significant improvements in sleep latency, time awake after sleep onset, and sleep efficiency during initial therapy (all P<.001); a larger increase of sleep time was obtained with the combined approach (P = .04). Both CBT alone and CBT plus zolpidem produced similar rates of treatment responders (60% [45/75] vs 61% [45/74], respectively; P = .84) and treatment remissions (39% [29/75] vs 44% [33/74], respectively; P = .52) with the 6-week acute treatment, but combined therapy produced a higher remission rate compared with CBT alone during the 6-month extended therapy phase and the 6-month follow-up period (56% [43/74 and 32/59] vs 43% [34/75 and 28/68]; P = .05). The best long-term outcome was obtained with patients treated with combined therapy initially, followed by CBT alone, as evidenced by higher remission rates at the 6-month follow-up compared with patients who continued to take zolpidem during extended therapy (68% [20/30] vs 42% [12/29]; P = .04). In patients with persistent insomnia, the addition of medication to CBT produced added benefits during acute therapy, but long-term outcome was optimized when medication is discontinued during maintenance CBT. clinicaltrials.gov Identifier: NCT00042146.


Improving the Prediction of Emergency Department Crowding: A Time Series Analysis Including Road Traffic Flow.
Crowding in emergency departments (ED) has a negative impact on quality of care and can be averted by allocating additional resources based on predictive crowding models. However, there is a lack in effective external overall predictors, particularly those representing public activity. This study, therefore, examines public activity measured by regional road traffic flow as an external predictor of ED crowding in an urban hospital. Seasonal autoregressive cross-validated models (SARIMA) were compared with respect to their forecasting error on ED crowding data. It could be shown that inclusion of inflowing road traffic into a SARIMA model effectively improved prediction errors. The results provide evidence that circadian patterns of medical emergencies are connected to human activity levels in the region and could be captured by public monitoring of traffic flow. In order to corroborate this model, data from further years and additional regions need to be considered. It would also be interesting to study public activity by additional variables.


Immunoglobulin G subclass-specific responses against Plasmodium falciparum merozoite antigens are associated with control of parasitemia and protection from symptomatic illness.
Substantial evidence indicates that antibodies to Plasmodium falciparum merozoite antigens play a role in protection from malaria, although the precise targets and mechanisms mediating immunity remain unclear. Different malaria antigens induce distinct immunoglobulin G (IgG) subclass responses, but the importance of different responses in protective immunity from malaria is not known and the factors determining subclass responses in vivo are poorly understood. We examined IgG and IgG subclass responses to the merozoite antigens MSP1-19 (the 19-kDa C-terminal region of merozoite surface protein 1), MSP2 (merozoite surface protein 2), and AMA-1 (apical membrane antigen 1), including different polymorphic variants of these antigens, in a longitudinal cohort of children in Papua New Guinea. IgG1 and IgG3 were the predominant subclasses of antibodies to each antigen, and all antibody responses increased in association with age and exposure without evidence of increasing polarization toward one subclass. The profiles of IgG subclasses differed somewhat for different alleles of MSP2 but not for different variants of AMA-1. Individuals did not appear to have a propensity to make a specific subclass response irrespective of the antigen. Instead, data suggest that subclass responses to each antigen are generated independently among individuals and that antigen properties, rather than host factors, are the major determinants of IgG subclass responses. High levels of AMA-1-specific IgG3 and MSP1-19-specific IgG1 were strongly predictive of a reduced risk of symptomatic malaria and high-density P. falciparum infections. However, no antibody response was significantly associated with protection from parasitization per se. Our findings have major implications for understanding human immunity and for malaria vaccine development and evaluation.


Circulating Tumour Cells in Patients with Malignant Lung Tumors Undergoing Radio-frequency Ablation.
Radiofrequency ablation (RFA) is an increasingly utilised technique in patients with surgically-untreatable lesions. The effect of this therapy on circulating tumor cells (CTCs) is unknown. As far as we are aware of, this is the first study to evaluate the effects of RFA on CTCs in patients with malignant lung tumors immediately post-treatment. Nine patients with primary or metastatic lung tumors underwent RFA therapy from June to November 2013. Blood samples were taken before and after RFA, and filtered through the ScreenCell CTC capture device. A general increase in CTCs in 7 out of the 9 cases was found, the largest increases were seen in the metastatic group. This study demonstrates that the manipulation and ablative procedure of lung tumors leads to immediate dissemination of tumor cells, the effects of which are unknown and require further investigation.


Performance improvement evaluation of forward aeromedical evacuation platforms in Operation Enduring Freedom.
The following three helicopter-based medical evacuation platforms operate in Southern Afghanistan: the US Army emergency medical technician (basic)-led DUSTOFF, US Air Force paramedic-led PEDRO, and UK physician-led medical emergency response team (MERT). Nearly 90% of battlefield deaths occur in the prehospital phase, comparative outcomes for these en route care platforms are unknown. The objective of this investigation was to characterize the nature of injuries in patients transported by three evacuation platforms. In addition, it aimed to compare observed versus predicted mortality among these provider groups. A performance improvement study involving 975 coalition patients injured in Southern Afghanistan, transported from the point of injury to a military hospital, was performed. All patients were alive on admission with prehospital documentation recorded in the US Department of Defense Trauma Registry from June 2009 to June 2011. The main outcome measure was in-hospital mortality and observed versus predicted (Trauma and Injury Severity Score [TRISS]) survival were the primary end points. MERT transported more amputation and polytrauma casualties and included patients with higher mean Injury Severity Score (ISS) compared with PEDRO and DUSTOFF (16 [13] vs. 11 [10] and 10 [10] respectively; p < 0.001). DUSTOFF was excluded from the subgroup analysis owing to insufficient numbers of severely injured casualties with only one death. The overall mortality for MERT and PEDRO was similar (4.2% vs. 4.6%, p = 0.967). Stratifying by ISS, there was lower mortality in MERT compared with PEDRO in the range of 20 to 29 (4.8% vs. 16.2%, p = 0.021). The observed mortality among PEDRO casualties was as predicted with the exception of the range of 20 to 29, while mortality in MERT was lower than predicted for all ISS groups with greater than 10. MERT achieves greater than predicted survival, which may be related to the additional capabilities onboard. This supports the adoption of a versatile medical evacuation system with scalable crew and equipment configurations that adapt to meet the medical, tactical, and operational needs of future conflicts.


Controlled growth of vertically aligned ultrathin In2S3 nanosheet arrays for photoelectrochemical water splitting.
This paper reports a facile solvothermal method for the in situ growth of vertically aligned In2S3 nanosheet arrays (NSAs) on fluorine-doped tin oxide substrates. The as-synthesized two-dimensional graphene-like In2S3 nanosheets show an ultrathin thickness down to 3.7 nm consisting of the duodenary interplanar spacing of the (222) plane and a tunable bandgap varying from 2.32 to 2.58 eV. The film thickness and nanosheet density of the In2S3 NSAs can be adjusted by varying the reaction time and precursor concentration. The In2S3 NSAs with a higher film thickness exhibit relatively higher photocurrent due to their stronger light absorption as well as larger surface area for sufficient charge separation and redox reaction. The photoelectrochemical performance of the In2S3 photoanodes can be greatly enhanced by constructing an effective heterojunction with ZnO to promote the photocarrier separation. The In2S3/ZnO NSAs have demonstrated an optimal photocurrent density of 349.1 μA cm-2 at 1.2 V vs. RHE and a maximum incident photon to current efficiency of 10.26% at 380 nm, which are 13.5 and 38 times higher than those of the pristine In2S3 counterparts, respectively.


Estimation of electronic coupling in pi-stacked donor-bridge-acceptor systems: correction of the two-state model.
Comparison of donor-acceptor electronic couplings calculated within two-state and three-state models suggests that the two-state treatment can provide unreliable estimates of V(da) because of neglecting the multistate effects. We show that in most cases accurate values of the electronic coupling in a pi stack, where donor and acceptor are separated by a bridging unit, can be obtained as V(da) = (E(2)-E(1))mu(12)R(da) + (2E(3)-E(1)-E(2))2mu(13)mu(23)R(da) (2), where E(1), E(2), and E(3) are adiabatic energies of the ground, charge-transfer, and bridge states, respectively, mu(ij) is the transition dipole moments between the states i and j, and R(da) is the distance between the planes of donor and acceptor. In this expression based on the generalized Mulliken-Hush approach, the first term corresponds to the coupling derived within a two-state model, whereas the second term is the superexchange correction accounting for the bridge effect. The formula is extended to bridges consisting of several subunits. The influence of the donor-acceptor energy mismatch on the excess charge distribution, adiabatic dipole and transition moments, and electronic couplings is examined. A diagnostic is developed to determine whether the two-state approach can be applied. Based on numerical results, we showed that the superexchange correction considerably improves estimates of the donor-acceptor coupling derived within a two-state approach. In most cases when the two-state scheme fails, the formula gives reliable results which are in good agreement (within 5%) with the data of the three-state generalized Mulliken-Hush model.


Validating regulatory predictions from diverse bacteria with mutant fitness data.
Although transcriptional regulation is fundamental to understanding bacterial physiology, the targets of most bacterial transcription factors are not known. Comparative genomics has been used to identify likely targets of some of these transcription factors, but these predictions typically lack experimental support. Here, we used mutant fitness data, which measures the importance of each gene for a bacterium's growth across many conditions, to test regulatory predictions from RegPrecise, a curated collection of comparative genomics predictions. Because characterized transcription factors often have correlated fitness with one of their targets (either positively or negatively), correlated fitness patterns provide support for the comparative genomics predictions. At a false discovery rate of 3%, we identified significant cofitness for at least one target of 158 TFs in 107 ortholog groups and from 24 bacteria. Thus, high-throughput genetics can be used to identify a high-confidence subset of the sequence-based regulatory predictions.


Cognitive Testing to Identify Children With ADHD Who Do and Do Not Respond to Methylphenidate.
To explore the utility of cognitive measures for predicting response of children and adolescents to methylphenidate (MPH). Participants from the International Study to Predict Optimized Treatment-in ADHD (iSPOT-A) completed a cognitive test battery prior to receiving 6 weeks of MPH. The responder criterion was a 25% reduction in ADHD-Rating Scale-IV scores. Receiver Operator Characteristics (ROC) classified non-responders from responders with maximal sensitivity and specificity. Overall, 62% of participants responded to MPH. Response rates for ROC-identified groups ranged from 18% to 85%. Non-responders showed compromised cognition related to switching of attention, sustained attention, planning, and impulsivity. One group of responders were 10 years of age or older and had impaired switching of attention and impulsivity; a second group had enhanced switching of attention, normal or higher Continuous Performance Task (CPT) scores, and above average scores on digit span. Cognitive tests may provide a simple, low-cost tool for treatment planning for children and adolescents with ADHD.


β2-adrenergic stimulation enhances Ca2+ release and contractile properties of skeletal muscles, and counteracts exercise-induced reductions in Na+-K+-ATPase Vmax in trained men.
The aim of the present study was to examine the effect of β2-adrenergic stimulation on skeletal muscle contractile properties, sarcoplasmic reticulum (SR) rates of Ca(2+) release and uptake, and Na(+)-K(+)-ATPase activity before and after fatiguing exercise in trained men. The study consisted of two experiments (EXP1, n = 10 males, EXP2, n = 20 males), where β2-adrenoceptor agonist (terbutaline) or placebo was randomly administered in double-blinded crossover designs. In EXP1, maximal voluntary isometric contraction (MVC) of m. quadriceps was measured, followed by exercise to fatigue at 120% of maximal oxygen uptake (V̇O2, max ). A muscle biopsy was taken after MVC (non-fatigue) and at time of fatigue. In EXP2, contractile properties of m. quadriceps were measured with electrical stimulations before (non-fatigue) and after two fatiguing 45 s sprints. Non-fatigued MVCs were 6 ± 3 and 6 ± 2% higher (P < 0.05) with terbutaline than placebo in EXP1 and EXP2, respectively. Furthermore, peak twitch force was 11 ± 7% higher (P < 0.01) with terbutaline than placebo at non-fatigue. After sprints, MVC declined (P < 0.05) to the same levels with terbutaline as placebo, whereas peak twitch force was lower (P < 0.05) and half-relaxation time was prolonged (P < 0.05) with terbutaline. Rates of SR Ca(2+) release and uptake at 400 nm [Ca(2+)] were 15 ± 5 and 14 ± 5% (P < 0.05) higher, respectively, with terbutaline than placebo at non-fatigue, but declined (P < 0.05) to similar levels at time of fatigue. Na(+)-K(+)-ATPase activity was unaffected by terbutaline compared with placebo at non-fatigue, but terbutaline counteracted exercise-induced reductions in maximum rate of activity (Vmax) at time of fatigue. In conclusion, increased contractile force induced by β2-adrenergic stimulation is associated with enhanced rate of Ca(2+) release in humans. While β2-adrenergic stimulation elicits positive inotropic and lusitropic effects on non-fatigued m. quadriceps, these effects are blunted when muscles fatigue.


NaHSO4-SiO2 as an efficient and chemoselective catalyst, for the synthesis of acylal from aldehydes under, solvent-free conditions.
Structurally diverse aldehydes are successfully converted into acylals (1,1-diacetates) with acetic anhydride using NaHSO4-SiO2 as a mild, convenient and inexpensive catalyst under solvent-free conditions. The noteworthy features of the present system are shorter reaction times, and mild and solvent-free conditions. Furthermore, it offers chemoselective protection of aldehydes. Both aromatic and aliphatic aldehydes reacts smoothly with acetic anhydride in presence of silica supported sodium hydrogen sulphate to afford the corresponding 1,1-diacetates in good to excellent yields. We studied competitive reactions for the acylation of aldehydes in the presence of ketones using silica supported sodium hydrogen sulphate as a catalyst. Using this catalytic system, the highly selective conversion of an aldehyde in the presence of ketone was observed. NaHSO4-SiO2 is a chemoselective and highly efficient catalyst for acylal formation from aldehydes. The advantages of this methodology over the reported methods is the availability of the starting materials, simplicity of acylation procedure, a clean work-up, a short reaction time, high yields and reusability.


Poly(ethylene imine) impurities induce n-doping reaction in organic (semi)conductors.
Volatile impurities contained in polyethyleneimine (PEI), and identified as ethyleneimine dimers and trimers, are reported. These N-based molecules show a strong reducing character, as demonstrated by the change in electrical conductivity of organic (semi)conductors exposed to the PEI vapor. The results prove that electron transfer rather than a dipole effect at the electrode interface is the origin of the work-function modification by the PEI-based layers.


In situ high-energy X-ray diffraction study of a bioactive calcium silicate foam immersed in simulated body fluid.
The method of in situ time-resolved high-energy X-ray diffraction, using the intrinsically highly collimated X-ray beam generated by the European Synchrotron Radiation Facility, is demonstrated. A specially designed cell, which allows the addition of liquid components, has been used to study the reaction mechanisms of a foamed bioactive calcia-silica sol-gel glass immersed in simulated body fluid. Analysis of the X-ray diffraction data from this experiment provides atomic distances, via the pair correlation functions, at different stages of the dissolution of the glass and of the associated calcium phosphate, and ultimately hydroxyapatite, i.e. bone mineral, formation. Hence, changes in the atomic scale structure can be analysed as a function of reaction time, giving an insight into the evolution of the structure of both the glass matrix and the hydroxyapatite surface growth.


Life satisfaction of young adults with spina bifida.
This study concerns life satisfaction and its determinants in Dutch young adults with spina bifida (SB). Data on life satisfaction (Life Satisfaction Questionnaire [LiSat-9]) were related to hydrocephalus, lesion level, disabilities, and demographic variables. In total, 179 young adults with SB participated (41% male, age range 16-25y; 79% SB aperta, 67% hydrocephalus [HC], 39% wheelchair-dependent). Most were satisfied with their life as a whole (24% dissatisfied). No difference was found from a population reference group (28% dissatisfied). Highest proportions of dissatisfaction were found for financial situation (44%), partnership relations (49%), and sex life (55%). Least dissatisfaction was found for contact with friends (17%) and families (15%). Young adults with SB and HC were more satisfied with their financial situation and family life but were less satisfied with self-care ability and partnership relations than those without HC and the reference group. However, except for self-care ability, relationships between life satisfaction and having SB were weak. In conclusion, self-care ability and partnership relations were rated least favourable and may need more attention from care providers. Overall, SB does not seem to be an important determinant of life satisfaction.


The Importance of Consistent Global Forest Aboveground Biomass Product Validation.
Several upcoming satellite missions have core science requirements to produce data for accurate forest aboveground biomass mapping. Largely because of these mission datasets, the number of available biomass products is expected to greatly increase over the coming decade. Despite the recognized importance of biomass mapping for a wide range of science, policy and management applications, there remains no community accepted standard for satellite-based biomass map validation. The Committee on Earth Observing Satellites (CEOS) is developing a protocol to fill this need in advance of the next generation of biomass-relevant satellites, and this paper presents a review of biomass validation practices from a CEOS perspective. We outline the wide range of anticipated user requirements for product accuracy assessment and provide recommendations for the validation of biomass products. These recommendations include the collection of new, high-quality in situ data and the use of airborne lidar biomass maps as tools toward transparent multi-resolution validation. Adoption of community-vetted validation standards and practices will facilitate the uptake of the next generation of biomass products.


The influence of body mass on foot dimensions during pregnancy.
In this study, a time-series approach was used to measure women's feet to accurately analyze changes in foot size and body mass during pregnancy. One-hundred women who were pregnant for the first time were asked to respond to questions on subjective complaints of foot discomfort listed in a questionnaire. Among these 100 women, a sample of 30 was obtained and used to measure the women's feet from the twentieth week of the gestation period until labor. The data (from 5 of the 30 women) were used to establish a prediction model for the influence of body mass on changes in foot size during pregnancy. The results indicate that the women subjectively complained that their shoes were too tight, resulting in foot discomfort. From the twentieth to the thirty-eighth week of pregnancy, the average increase in foot length, width, and back foot surface was 0.86 cm (3.6%), 0.25 cm (2.6%), and 18.36 cm(2) (11.9%), respectively. The height of the arch decreased by an average of 0.52 cm (-24.2%). Body mass accounted for more than 90% of the variation (R(2)) in foot dimensions during pregnancy and, thus indicated satisfactory predictive ability. The prediction model developed in this study can serve as a reference for clinical applications and shoe design to prevent women from experiencing extreme discomfort in their feet during pregnancy.


The effect of aerobic versus strength-based training on high-sensitivity C-reactive protein in older adults.
Increased levels of inflammatory markers, namely, high-sensitive C-reactive protein (hs-CRP), have been associated with several chronic diseases including atherosclerosis, type 2 diabetes and hypertension. Forty-five women and men aged >64 years participated in the study and were randomly assigned to two exercise intervention groups and a non-exercising control group. The participants assigned to the exercising groups followed a 16-week exercise protocol based either on aerobic training (AT) or strength training (ST) followed by a further 16 weeks off-training period. The control group (C) remained sedentary throughout the study. Evaluation of body mass, BMI, waist circumference, aerobic endurance, lower-body strength, upper-body strength, triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol and hs-CRP were performed at baseline, after 16 weeks (post-training for the exercise groups) and at 32 weeks (follow-up). Both, AT and ST groups significantly increased functional fitness at the end of the exercise programs when compared to baseline values. hs-CRP concentrations were maintained throughout the study for the C group, while decreasing 10% at 16 weeks and 51% at 32 weeks for the AT group. In the ST group the hs-CRP concentrations decreased by 11 and 39% at 16 and 32 weeks, respectively. Decreases in hs-CRP concentrations were statistically significant for the AT and ST groups at the 32-week evaluation when compared to baseline. Reduction in hs-CRP concentrations seemed to be associated with strength gains and adiposity loss.


From lignocellulose to plastics: Knowledge transfer on the degradation approaches by fungi.
In this review, we argue that there is much to be learned by transferring knowledge from research on lignocellulose degradation to that on plastic. Plastic waste accumulates in the environment to hazardous levels, because it is inherently recalcitrant to biological degradation. Plants evolved lignocellulose to be resistant to degradation, but with time, fungi became capable of utilising it for their nutrition. Examples of how fungal strategies to degrade lignocellulose could be insightful for plastic degradation include how fungi overcome the hydrophobicity of lignin (e.g. production of hydrophobins) and crystallinity of cellulose (e.g. oxidative approaches). In parallel, knowledge of the methods for understanding lignocellulose degradation could be insightful such as advanced microscopy, genomic and post-genomic approaches (e.g. gene expression analysis). The known limitations of biological lignocellulose degradation, such as the necessity for physiochemical pretreatments for biofuel production, can be predictive of potential restrictions of biological plastic degradation. Taking lessons from lignocellulose degradation for plastic degradation is also important for biosafety as engineered plastic-degrading fungi could also have increased plant biomass degrading capabilities. Even though plastics are significantly different from lignocellulose because they lack hydrolysable C-C or C-O bonds and therefore have higher recalcitrance, there are apparent similarities, e.g. both types of compounds are mixtures of hydrophobic polymers with amorphous and crystalline regions, and both require hydrolases and oxidoreductases for their degradation. Thus, many lessons could be learned from fungal lignocellulose degradation.


Searching for maintenance in exercise interventions for cancer survivors.
Translating evidence-based exercise interventions into practice is important for expanding the capacity to support cancer survivors. Using the reach, efficacy/effectiveness, adoption, implementation, and maintenance (RE-AIM) framework and scoping study methodology, we addressed the research question, "What is known about the maintenance of exercise interventions for cancer survivors that would inform translation from research to practice and community settings?" Maintenance was investigated at the individual and setting level. Literature searches were performed in the PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Sport Discus databases for articles published from January 2009 to June 2012. Abstracts were judged using a priori criteria for the survivor population, exercise intervention, and maintenance on the individual or setting level. We included completed and planned randomized controlled trials (RCTs) and other study designs. Publications meeting the criteria were reviewed and coded. Of the 211 abstracts meeting patient and exercise criteria, 24 (19 RCTs) met the maintenance criteria. Nine of the 12 completed RCTs demonstrated maintenance of intervention outcomes after 3 to 14 months of follow-up. The planned RCTs described interventions lasting 2 to 4.5 months and maintenance intervals lasting 3 to 12 months following the active intervention. Maintenance at the setting level was reported in one publication. On the individual level, intervention outcomes were maintained in most studies, in a variety of settings and survivor subpopulations. Maintenance on the setting level was scarcely addressed. This scoping study suggests several strategies that could be taken by agencies, clinicians, and researchers to develop more effective and sustainable exercise programs for cancer survivors. Many benefits of exercise training are maintained for months after cancer survivors complete controlled research studies but relatively little is known about how to translate research to sustainable community-based exercise programs. A better understanding of how programs can be sustained in practice beyond short-term research or grant funding is needed to support a growing number of survivors.


Simple empirical assessment of beta-cell function by a constant infusion of glucose test in normal and type 2 (non-insulin-dependent) diabetic subjects.
The plasma insulin or C-peptide response to a 90-min constant glucose infusion 5 mg.kg ideal body weight-1.min-1 provides Beta-cell assessment comparable to more intensive methods. In 14 diet-treated Type 2 (non-insulin-dependent) diabetic subjects and 12 non-diabetic subjects, plasma insulin and C-peptide concentrations gave near linear plots against simultaneous glucose values. The 'glucose-insulin and glucose-C-peptide vectors' (G-I and G-C vectors), could be extrapolated to predict insulin and C-peptide levels during a 12 mmol/l hyperglycaemic clamp. Predicted concentrations correlated with clamp concentrations, r = 0.94 and r = 0.98 respectively, p less than 0.001, validating the vectors as empirical glucose dose-response curves. The vector slopes correlated highly with %Beta, a mathematical model-derived measure of Beta-cell function using constant infusion of glucose model assessment, Spearman r = 0.95 and 0.93 for insulin and C-peptide, respectively. G-I vector slopes in 21 diet-treated Type 2 diabetic subjects with fasting glucose (mean + 1 SD) 7.5 +/- 2.3 mmol/l, were lower than in 28 non-diabetic subjects, (geometric mean, 1 SD range, 8.4 pmol/mmol (3.3-21.0) and 25.1 pmol/mmol (14.3-44.1), p less than 0.001, respectively), indicating an impaired Beta-cell response. The G-I vector slopes correlated with obesity in both groups (r = 0.54 p less than 0.02 and 0.72, p less than 0.001 respectively), and, in 15 non-diabetic subjects, correlated inversely with insulin sensitivity as measured by a euglycaemic clamp (r = -0.66, p less than 0.01). Thus, Beta-cell function needs to be interpreted in relation to obesity/insulin resistance and, taking obesity into account, only 4 of 21 diabetic patients had Beta-cell function (G-I vector slope) in the non-diabetic range. The fasting plasma glucose in the diabetic subjects correlated inversely with the obesity-corrected G-I and G-C vector slopes (partial r = -0.57, p less than 0.01 and -0.86, p less than 0.001, respectively). The insulin or C-peptide response to the glucose infusion provides a direct empirical measure of the Beta-cell function, which can be interpreted in relation to obesity or to insulin resistance to assess underlying pancreatic responsiveness.


Sensitivity of scalp 10-20 EEG and magnetoencephalography.
Although previous studies have investigated the sensitivity of electroencephalography (EEG) and magnetoencephalography (MEG) to detect spikes by comparing simultaneous recordings, there are no published reports that focus on the relationship between spike dipole orientation or sensitivity of scalp EEG/MEG and the "gold standard" of intracranial recording (stereotactic EEG). We evaluated two patients with focal epilepsy; one with lateral temporal focus and the other with insular focus. Two MEG recordings were performed for both patients, each recorded simultaneously with initially scalp EEG, based on international 10-20 electrode placement with additional electrodes for anterior temporal regions, and subsequently stereotactic EEG. Localisation of MEG spike dipoles from both studies was concordant and all MEG spikes were detected by stereotactic EEG. For the patient with lateral temporal epilepsy, spike sensitivity of MEG and scalp EEG (relative to stereotactic EEG) was 55 and 0%, respectively. Of note, in this case, MEG spike dipoles were oriented tangentially to scalp surface in a tight cluster; the angle of the spike dipole to the vertical line was 3.6 degrees. For the patient with insular epilepsy, spike sensitivity of MEG and scalp EEG (relative to stereotactic EEG) was 83 and 44%, respectively; the angle of the spike dipole to the vertical line was 45.3 degrees. For the patient with lateral temporal epilepsy, tangential spikes from the lateral temporal cortex were difficult to detect based on scalp 10-20 EEG and for the patient with insular epilepsy, it was possible to evaluate operculum insular sources using MEG. We believe that these findings may be important for the interpretation of clinical EEG and MEG.


Animal mindreading: what's the problem?
Research on mindreading in animals has the potential to address fundamental questions about the nature and origins of the human capacity to ascribe mental states, but it is a research programme that seems to be in trouble. Between 1978 and 2000 several groups used a range of methods, some with considerable promise, to ask whether animals can understand a variety of mental states. Since that time, many enthusiasts have become sceptics, empirical methods have become more limited, and it is no longer clear what research on animal mindreading is trying to find. In this article I suggest that the problems are theoretical and methodological: there is difficulty in conceptualising alternatives to 'full-blown' mindreading, and reluctance to use the kinds of empirical methods necessary to distinguish mindreading from other psychological mechanisms. I also suggest ways of tackling the theoretical and methodological problems that draw on recent studies of mindreading in humans, and the resources of experimental psychology more generally. In combination with the use of inanimate control stimuli, species that are unlikely to be capable of mindreading, and the 'goggles method', these approaches could restore both vigour and rigour to research on animal mindreading.


Structural and functional connectivity in the default mode network in 22q11.2 deletion syndrome.
The neural endophenotype associated with 22q11.2 deletion syndrome (22q11DS) includes deviant cortical development and alterations in brain connectivity. Resting-state functional magnetic resonance imaging (fMRI) findings also reported disconnectivity within the default mode network (DMN). In this study, we explored the relationship between functional and structural DMN connectivity and their changes with age in patients with 22q11DS in comparison to control participants. Given previous evidence of an association between DMN disconnectivity and the manifestation of psychotic symptoms, we further investigated this relationship in our group of patients with 22q11DS. T1-weighted, diffusion, and resting-state fMRI scans were acquired from 41 patients with 22q11DS and 43 control participants aged 6 to 28 years. A data-driven approach based on independent component analysis (ICA) was used to identify the DMN and to define regions of interest for the structural and functional connectivity analysis. Prodromal psychotic symptoms were assessed in adolescents and adults using the positive symptom scores of the Structured Interview of Prodromal Syndromes (SIPS). Connectivity measures were compared between groups and correlated with age. Repeating the between-group analysis in three different age bins further assessed the presence of age-related alterations in DMN connectivity. Structural and functional connectivity measures were then correlated with the SIPS scores. A simultaneous reduction of functional and structural connectivity between core medial nodes of the DMN was observed. Furthermore, structural connectivity measures significantly increased with age in the control group but not in patients with 22q11DS, suggesting the presence of an age-related alteration of the DMN structural connections. No correlations were found between the DMN disconnectivity and expression of prodromal symptoms in 22q11DS. These findings indicate the presence of functional and structural DMN disconnectivity in 22q11DS and that patients with 22q11DS fail to develop normal structural connections between medial DMN nodes. This suggests the presence of altered neurodevelopmental trajectories in 22q11DS.


The splicing regulators TIA1 and TIAL1 are required for the expression of the DNA damage repair machinery during B cell lymphopoiesis.
B cell lymphopoiesis requires dynamic modulation of the B cell transcriptome for timely coordination of somatic mutagenesis and DNA repair in progenitor B (pro-B) cells. Here, we show that, in pro-B cells, the RNA-binding proteins T cell intracellular antigen 1 (TIA1) and TIA1-like protein (TIAL1) act redundantly to enable developmental progression. They are global splicing regulators that control the expression of hundreds of mRNAs, including those involved in DNA damage repair. Mechanistically, TIA1 and TIAL1 bind to 5' splice sites for exon definition, splicing, and expression of DNA damage sensors, such as Chek2 and Rif1. In their absence, pro-B cells show exacerbated DNA damage, altered P53 expression, and increased cell death. Our study uncovers the importance of tight regulation of RNA splicing by TIA1 and TIAL1 for the expression of integrative transcriptional programs that control DNA damage sensing and repair during B cell development.


Oral cleft prevention program (OCPP).
Oral clefts are one of the most common birth defects with significant medical, psychosocial, and economic ramifications. Oral clefts have a complex etiology with genetic and environmental risk factors. There are suggestive results for decreased risks of cleft occurrence and recurrence with folic acid supplements taken at preconception and during pregnancy with a stronger evidence for higher than lower doses in preventing recurrence. Yet previous studies have suffered from considerable design limitations particularly non-randomization into treatment. There is also well-documented effectiveness for folic acid in preventing neural tube defect occurrence at 0.4 mg and recurrence with 4 mg. Given the substantial burden of clefting on the individual and the family and the supportive data for the effectiveness of folic acid supplementation as well as its low cost, a randomized clinical trial of the effectiveness of high versus low dose folic acid for prevention of cleft recurrence is warranted. This study will assess the effect of 4 mg and 0.4 mg doses of folic acid, taken on a daily basis during preconception and up to 3 months of pregnancy by women who are at risk of having a child with nonsyndromic cleft lip with/without palate (NSCL/P), on the recurrence of NSCL/P. The total sample will include about 6,000 women (that either have NSCL/P or that have at least one child with NSCL/P) randomly assigned to the 4 mg and the 0.4 mg folic acid study groups. The study will also compare the recurrence rates of NSCL/P in the total sample of subjects, as well as the two study groups (4 mg, 0.4 mg) to that of a historical control group. The study has been approved by IRBs (ethics committees) of all involved sites. Results will be disseminated through publications and presentations at scientific meetings. The costs related to oral clefts are high, including long term psychological and socio-economic effects. This study provides an opportunity for huge savings in not only money but the overall quality of life. This may help establish more specific clinical guidelines for oral cleft prevention so that the intervention can be better tailored for at-risk women. CLINICALTRIALS.GOV IDENTIFIER: NCT00397917.


When did plants become important to leaf-nosed bats? Diversification of feeding habits in the family Phyllostomidae.
A great proportion of bats of the New World family Phyllostomidae feed on fruit, nectar and pollen, and many of them present adaptations to feed also on insects and small vertebrates. So far, attempts to examine the diversification of feeding specialization in this group, and particularly the evolution of nectarivory and frugivory, have provided contradictory results. Here we propose a molecular phylogenetic hypothesis for phyllostomids. On the basis of a matrix of feeding habits that takes into account geographical and seasonal variation, we tested different hypotheses of the evolution of feeding specializations in the group. We find strong support for the evolutionary model of a direct dietary diversification from insectivory. The estimates of divergence times of phyllostomid bats and the reconstruction of ancestral states with a Bayesian approach support the parallel evolution of frugivory in five lineages and of nectarivory in three lineages during the Miocene. On the basis of these findings, and recent dietary studies, we propose that during the evolution of phyllostomids switches to new feeding mechanisms to access to abundant and/or underexploited resources provided selective advantages that favoured the appearance of ecological innovations independently in different lineages of the family. We did not find evidences to support or reject the hypothesis that the insectivorous most recent common ancestor of all phyllostomids was also phytophagous.


Integrated multi-omics characterization reveals a distinctive metabolic signature and the role of NDUFA4L2 in promoting angiogenesis, chemoresistance, and mitochondrial dysfunction in clear cell renal cell carcinoma.
An altered metabolism is involved in the development of clear cell - renal cell carcinoma (ccRCC), and in this tumor many altered genes play a fundamental role in controlling cell metabolic activities. We delineated a large-scale metabolomic profile of human ccRCC, and integrated it with transcriptomic data to connect the variations in cancer metabolism with gene expression changes. Moreover, to better analyze the specific contribution of metabolic gene alterations potentially associated with tumorigenesis and tumor progression, we evaluated the transcription profile of primary renal tumor cells. Untargeted metabolomic analysis revealed a signature of an increased glucose uptake and utilization in ccRCC. In addition, metabolites related to pentose phosphate pathway were also altered in the tumor samples in association with changes in Krebs cycle intermediates and related metabolites. We identified NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) as the most highly expressed gene in renal cancer cells and evaluated its role in sustaining angiogenesis, chemoresistance, and mitochondrial dysfunction. Finally, we showed that silencing of NDUFA4L2 affects cell viability, increases mitochondrial mass, and induces ROS generation in hypoxia.


Genomic Analysis of the Only Blind Cichlid Reveals Extensive Inactivation in Eye and Pigment Formation Genes.
Trait loss represents an intriguing evolutionary problem, particularly when it occurs across independent lineages. Fishes in light-poor environments often evolve "troglomorphic" traits, including reduction or loss of both pigment and eyes. Here, we investigate the genomic basis of trait loss in a blind and depigmented African cichlid, Lamprologus lethops, and explore evolutionary forces (selection and drift) that may have contributed to these losses. This species, the only known blind cichlid, is endemic to the lower Congo River. Available evidence suggests that it inhabits deep, low-light habitats. Using genome sequencing, we show that genes related to eye formation and pigmentation, as well as other traits associated with troglomorphism, accumulated inactivating mutations rapidly after speciation. A number of the genes affected in L. lethops are also implicated in troglomorphic phenotypes in Mexican cavefish (Astyanax mexicanus) and other species. Analysis of heterozygosity patterns across the genome indicates that L. lethops underwent a significant population bottleneck roughly 1 Ma, after which effective population sizes remained low. Branch-length tests on a subset of genes with inactivating mutations show little evidence of directional selection; however, low overall heterozygosity may reduce statistical power to detect such signals. Overall, genome-wide patterns suggest that accelerated genetic drift from a severe bottleneck, perhaps aided by directional selection for the loss of physiologically expensive traits, caused inactivating mutations to fix rapidly in this species.


Activities of human DNA polymerase kappa in response to the major benzo[a]pyrene DNA adduct: error-free lesion bypass and extension synthesis from opposite the lesion.
In cells, the major benzo[a]pyrene DNA adduct is the highly mutagenic (+)-trans-anti-BPDE-N(2)-dG. In eukaryotes, little is known about lesion bypass of this DNA adduct during replication. Here, we show that purified human Polkappa can effectively bypass a template (+)-trans-anti-BPDE-N(2)-dG adduct in an error-free manner. Kinetic parameters indicate that Polkappa bypass of the (-)-trans-anti-BPDE-N(2)-dG adduct was approximately 41-fold more efficient compared to the (+)-trans-anti-BPDE-N(2)-dG adduct. Furthermore, we have found another activity of human Polkappa in response to the (+)- and (-)-trans-anti-BPDE-N(2)-dG adducts: extension synthesis from mispaired primer 3' ends opposite the lesion. In contrast, the two adducts strongly blocked DNA synthesis by the purified human Polbeta and the purified catalytic subunits of yeast Polalpha, Poldelta, and Pol epsilon right before the lesion. Extension by human Polkappa from the primer 3' G opposite the (+)- and (-)-trans-anti-BPDE-N(2)-dG adducts was mediated by a -1 deletion mechanism, probably resulting from re-aligning the primer G to pair with the next template C by Polkappa prior to DNA synthesis. Thus, sequence contexts 5' to the lesion strongly affect the fidelity and mechanism of the Polkappa-catalyzed extension synthesis. These results support a dual-function model of human Polkappa in bypass of BPDE DNA adducts: it may function both as an error-free bypass polymerase alone and an extension synthesis polymerase in combination with another polymerase.


Clinicopathological analysis on small cell carcinoma of the prostate in chinese patients.
To explore the clinical and pathological characteristics of small-cell carcinoma (SmCC) of the prostate and applicable treatment methods. We reported three cases of SmCC of the prostate diagnosed from 1999 to 2011 at the Chinese PLA General Hospital. We also reviewed clinical and pathological data of 26 cases in China reported over the same period. Serum prostate-specific antigen (PSA) levels were normal in 20 cases (76.9%) and elevated in six (23.1%). There was local invasion in 12 cases (46.2%) at the time of diagnosis; lymphatic vessel invasion and distant metastases were detected in eight (30.8%) and nine cases (34.6%) respectively. At the end of follow-up, 16 cases (61.5%) had died, eight (30.8%) survived, and two (7.7%) were missing. The median survival time was 8 months, and the 1-year survival rate was 23.2%. Statistical analysis showed that survival time was significantly correlated with chemotherapy treatment (p<0.05). However, serum PSA levels, surgical approach, pathological type, local invasion, lymphatic vessel invasion, and distant metastasis had no significant relationship with survival (p>0.05). SmCC of the prostate is a rare neoplasm typified by high malignancy, rapid progress, and poor prognosis. Pathological analysis is an important tool for confirming a diagnosis. Pure SmCC is usually not associated with an increase in serum PSA. Surgery, mixed with acinar adenocarcinoma components, and clinical staging do not correlate with prognosis; and chemotherapy was the only prognostic factor. For patients, diagnosed by preoperative biopsy, administering chemotherapy as the first-line treatment may improve outcomes.


Expression of O⁶-methylguanine-DNA methyltransferase in childhood medulloblastoma.
Medulloblastomas (MB) are the most common malignant brain tumors in childhood. Alkylator-based drugs are effective agents in the treatment of patients with MB. In several tumors, including malignant glioma, elevated O(6)-methylguanine-DNA methyltransferase (MGMT) expression levels or lack of MGMT promoter methylation have been found to be associated with resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ). In this study, we examined the MGMT status of MB and central nervous system primitive neuroectodermal tumor (PNET) cells and two large sets of primary MB. In seven MB/PNET cell lines investigated, MGMT promoter methylation was detected only in D425 human MB cells as assayed by the qualitative methylation-specific PCR and the more quantitative pyrosequencing assay. In D425 human MB cells, MGMT mRNA and protein expression was clearly lower when compared with the MGMT expression in the other MB/PNET cell lines. In MB/PNET cells, sensitivity towards TMZ and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) correlated with MGMT methylation and MGMT mRNA expression. Pyrosequencing in 67 primary MB samples revealed a mean percentage of MGMT methylation of 3.7-92% (mean: 13.25%, median: 10.67%). Percentage of MGMT methylation and MGMT mRNA expression as determined by quantitative RT-PCR correlated inversely (n = 46; Pearson correlation r (2) = 0.14, P = 0.01). We then analyzed MGMT mRNA expression in a second set of 47 formalin-fixed paraffin-embedded primary MB samples from clinically well-documented patients treated within the prospective randomized multicenter trial HIT'91. No association was found between MGMT mRNA expression and progression-free or overall survival. Therefore, it is not currently recommended to use MGMT mRNA expression analysis to determine who should receive alkylating agents and who should not.


Current Epidemiological Assessment of Bancroftian Filariasis in Tanga Region, Northeastern Tanzania.
Background. Tanzania started a countrywide lymphatic filariasis elimination programme in 2000 adopting the mass drug administration (MDA) strategy. The drug used for the programme was the combination of ivermectin and albendazole. However, there is limited information on the current epidemiological trend of the infections, where MDA implementation is ongoing. The present study aimed at assessing the current status of Bancroftian filariasis infection rate and morbidity where MDA has been distributed and administered for over eight rounds. Methodology. The study was a cross-sectional descriptive study involving 272 individuals (>18 years) from endemic communities in Tanga region where MDA has been implemented. Clinical, sociodemographic, and circulating filarial antigen (CFA) test was undertaken using immune chromatographic card test according to the manufacturer's instructions. Results. A total of 472 individuals were screened: 307/472 (65.1%) were males while 165/472 (34.9%) were females. The overall prevalence of CFA was 5.51%, that of hydrocoele was 73.2%, and that of lymphoedema was 16.0%. The prevalence of hydrocoele combined with lymphoedema was 5.5%. Conclusion. Our findings demonstrate a considerable reduction in filarial infection. However, there is clear evidence of ongoing transmission despite the 8 rounds of MDA. It is unlikely that the annual MDA would interrupt filarial transmission; therefore, additional strategies are needed to accelerate lymphatic filariasis control and elimination.


Lessons from scaling up a depression treatment program in primary care in Chile.
In Chile, the National Depression Detection and Treatment Program (Programa Nacional de Diagnóstico y Tratamiento de la Depresión, PNDTD) in primary care is a rare example of an evidence-based mental health program that was scaled up to the national level in a low- or middle-income country. This retrospective qualitative study aimed to better understand how policymakers made the decision to scale up mental health services to the national level, and to explore the elements, contexts, and processes that facilitated the decision to implement and sustain PNDTD. In-depth semistructured interviews with six key informants selected through intentional sampling were conducted in August-December 2008. Interviewees were senior officers at the Ministry of Health who were directly involved in the decision to scale up the program. Results yielded four elements pivotal to the decisionmaking process: scientific evidence, teamwork and leadership, strategic alliances, and program institutionalization. Each element contributed to building consensus, securing funding, attracting resources, and gaining lasting support from policymakers. Additionally, a review of available documentation led the authors to consider sociopolitical context and use of the media to be important factors. While research evidence for the effectiveness of mental health services in the primary care setting continues to accumulate, low- and middle-income countries should get started on the lengthy process of scaling up by incorporating the elements that led to decisionmaking and implementation of the PNDTD in Chile.


Effect of chronic sulfonylurea treatment on the myocardium of insulin-dependent diabetic rats.
Adult rats treated with high doses of streptozocin became progressively more hyperglycemic during the first month of the diabetic condition. Treatment of these rats with the sulfonylurea glyburide halted, and in some cases, reversed this process in a high percentage of the diabetics. Associated with the glyburide-mediated improvement in fasting blood glucose levels was an increase in myocardial glucose utilization and lactate production. The stimulation of myocardial glucose utilization by insulin was greater in glyburide-treated hearts, indicating that the hyperglycemic agent increased insulin responsiveness. The sulfonylurea also partially restored insulin sensitivity to the normal range. In agreement with previous studies, myocardial mechanical function was significantly impaired in the diabetic heart. When treated with glyburide, the severity of the mechanical defect was significantly less. The sulfonylurea also promoted an increase in myosin ATPase activity and a shift in the myosin isozyme pattern in favour of the most active V1 form. These results imply that glyburide therapy can provide benefit to the diabetic heart by improving energy metabolism and promoting a shift in myosin towards the most active form.


Engagement of S1P₁-degradative mechanisms leads to vascular leak in mice.
GPCR inhibitors are highly prevalent in modern therapeutics. However, interference with complex GPCR regulatory mechanisms leads to both therapeutic efficacy and adverse effects. Recently, the sphingosine-1-phosphate (S1P) receptor inhibitor FTY720 (also known as Fingolimod), which induces lymphopenia and prevents neuroinflammation, was adopted as a disease-modifying therapeutic in multiple sclerosis. Although highly efficacious, dose-dependent increases in adverse events have tempered its utility. We show here that FTY720P induces phosphorylation of the C-terminal domain of S1P receptor 1 (S1P₁) at multiple sites, resulting in GPCR internalization, polyubiquitinylation, and degradation. We also identified the ubiquitin E3 ligase WWP2 in the GPCR complex and demonstrated its requirement in FTY720-induced receptor degradation. GPCR degradation was not essential for the induction of lymphopenia, but was critical for pulmonary vascular leak in vivo. Prevention of receptor phosphorylation, internalization, and degradation inhibited vascular leak, which suggests that discrete mechanisms of S1P receptor regulation are responsible for the efficacy and adverse events associated with this class of therapeutics.


Genome-wide association analyses reveal complex genetic architecture underlying natural variation for flowering time in canola.
Optimum flowering time is the key to maximize canola production in order to meet global demand of vegetable oil, biodiesel and canola-meal. We reveal extensive variation in flowering time across diverse genotypes of canola under field, glasshouse and controlled environmental conditions. We conduct a genome-wide association study and identify 69 single nucleotide polymorphism (SNP) markers associated with flowering time, which are repeatedly detected across experiments. Several associated SNPs occur in clusters across the canola genome; seven of them were detected within 20 Kb regions of a priori candidate genes; FLOWERING LOCUS T, FRUITFUL, FLOWERING LOCUS C, CONSTANS, FRIGIDA, PHYTOCHROME B and an additional five SNPs were localized within 14 Kb of a previously identified quantitative trait loci for flowering time. Expression analyses showed that among FLC paralogs, BnFLC.A2 accounts for ~23% of natural variation in diverse accessions. Genome-wide association analysis for FLC expression levels mapped not only BnFLC.C2 but also other loci that contribute to variation in FLC expression. In addition to revealing the complex genetic architecture of flowering time variation, we demonstrate that the identified SNPs can be modelled to predict flowering time in diverse canola germplasm accurately and hence are suitable for genomic selection of adaptative traits in canola improvement programmes.


Acute sensitivity of nematode taxa to CuSO4 and relationships with feeding-type and life-history classification.
The acute sensitivity to CuSO4 of a broad range of nematode taxa was analyzed in order to assess the potential of changes to nematode community structure to serve as a practical tool for the bioindication of heavy-metal pollution. An easy-to-use experimental set-up was developed along with an appropriate mathematical response model in order to quantify the response characteristics of nematodes to CuSO4 pressure. Three similar experiments were conducted using water, dune sand, and sandy soil as media, each of which was subjected to 12 increasing concentrations of CuSO4. In total, 130 response curves representing 70 nematode taxa were produced and analyzed. CuSO4 concentrations were normalized for differences in efficiency among media due to different adsorption. At low CuSO4 concentrations, many taxa exhibited stimulation rather than inhibition regarding recovery efficiency. At higher concentrations, the concentration level at which 50% of the nematode population was recovered after a 24-h incubation (recovery concentration 50% [RC50]) varied widely among taxa and ranged from 0.01 to 4 mM/L CuSO4 (normalized to water). Stimulation of recovery efficiency and RC50 were negatively correlated with the colonizer-persister (C-P) classification of taxa, which discriminates nematodes according to their reproductive potential. The maturity index, which relates to a nematode community's state of disturbance and eutrophication, was negatively correlated with CuSO4 concentration. The properties of the applied test method are discussed as are the relationships between the investigated short-term toxicity effects and long-term toxicity processes in the field. From the large range of observed RC50 values, it is concluded that a meaningful sensitivity classification of nematodes should be possible and thus would allow for a sensitive bioindication of heavy-metal pollution. From the correlation between RC50 and C-P classification, the authors further conclude that the maturity index will, in addition to enrichment and disturbance, respond to heavy-metal pollution and thus may serve as a general indicator of soil health.


Subtelomeric CTCF and cohesin binding site organization using improved subtelomere assemblies and a novel annotation pipeline.
Mapping genome-wide data to human subtelomeres has been problematic due to the incomplete assembly and challenges of low-copy repetitive DNA elements. Here, we provide updated human subtelomere sequence assemblies that were extended by filling telomere-adjacent gaps using clone-based resources. A bioinformatic pipeline incorporating multiread mapping for annotation of the updated assemblies using short-read data sets was developed and implemented. Annotation of subtelomeric sequence features as well as mapping of CTCF and cohesin binding sites using ChIP-seq data sets from multiple human cell types confirmed that CTCF and cohesin bind within 3 kb of the start of terminal repeat tracts at many, but not all, subtelomeres. CTCF and cohesin co-occupancy were also enriched near internal telomere-like sequence (ITS) islands and the nonterminal boundaries of subtelomere repeat elements (SREs) in transformed lymphoblastoid cell lines (LCLs) and human embryonic stem cell (ES) lines, but were not significantly enriched in the primary fibroblast IMR90 cell line. Subtelomeric CTCF and cohesin sites predicted by ChIP-seq using our bioinformatics pipeline (but not predicted when only uniquely mapping reads were considered) were consistently validated by ChIP-qPCR. The colocalized CTCF and cohesin sites in SRE regions are candidates for mediating long-range chromatin interactions in the transcript-rich SRE region. A public browser for the integrated display of short-read sequence-based annotations relative to key subtelomere features such as the start of each terminal repeat tract, SRE identity and organization, and subtelomeric gene models was established.


Selection and characterization of RNAs that relieve transcriptional interference in Escherichia coli.
Oligonucleotide-directed triple helix formation offers a method for duplex DNA recognition, and has been proposed as an approach to the rational design of gene-specific repressors. Indeed, certain RNA and DNA oligonucleotides have previously been shown to bind duplex DNA and repress in vitro transcription by occluding the binding of transcription factors or RNA polymerase at target genes. While similar oligonucleotides have reportedly caused repression of target genes in cultured cells, physical evidence of triple helix formation in vivo is generally lacking. In the present study we wished to determine whether RNA transcripts could repress the activity of an Escherichia coli promoter in vivo by binding to the duplex promoter DNA. An in vivo genetic selection previously developed to identify DNA binding proteins was modified for this purpose. Using expression libraries encoding RNAs predisposed to forming triple helices with a DNA target site, we have selected RNA transcripts that confer survival to E.coli by disrupting transcriptional interference. Surprisingly, genetic and biochemical evidence shows that these RNAs do not form triple helices at the target promoter in vivo , despite the fact that they contain sequences capable of forming triple helices at the duplex DNA target in vitro . Rather, the selected RNAs appear to disrupt transcriptional interference via an antisense mechanism.


[Asbestos clinics and asbestos health examinations--findings from a questionnaire survey of implementing organizations].
In June 2005 the press reported that many former employees of a company which used asbestos, and individuals who lived near the company's factory, had been diagnosed with mesothelioma. This finding triggered concern and alarm in Japan. In response, many "asbestos clinics" were formed, and recognized medical institutions began to implement asbestos-related health examinations. We conducted a nationwide questionnaire survey to evaluate the activities in, and the challenges for, these medical institutions. We received 137 valid responses, more than half of which were from clinics and hospital-based "asbestos clinics" instigated after the "Kubota shock." Among the asbestos exposure history interviewing practices, job histories of the interviewee were prioritized, over place of residence, and possible exposure of family members. Standard questionnaires were utilized by over 70% of respondents. The practitioners reported problems with lack of manpower and evaluation of asbestos exposure. Examinees consulted attending physicians on a wide range of matters including asbestos-related diseases, asbestos exposure, and financial compensation. It is predicted that asbestos-related diseases in general, and mesothelioma in particular, will increase in the future. Accordingly, early detection and treatment should be accorded high priority. The organizations we surveyed have important roles to play. Although resources are limited, effective diagnosis and treatment are essential, and a system assisting organizations to make accurate and efficient identification of asbestos exposure hazards is imperative.


The IMGT/HLA database.
It is 12 years since the IMGT/HLA database was first released, providing the HLA community with a searchable repository of highly curated HLA sequences. The HLA complex is located within the 6p21.3 region of human chromosome 6 and contains more than 220 genes of diverse function. Many of the genes encode proteins of the immune system and are highly polymorphic. The naming of these HLA genes and alleles and their quality control is the responsibility of the WHO Nomenclature Committee for Factors of the HLA System. Through the work of the HLA Informatics Group and in collaboration with the European Bioinformatics Institute, we are able to provide public access to this data through the web site http://www.ebi.ac.uk/imgt/hla/. Regular updates to the web site ensure that new and confirmatory sequences are dispersed to the HLA community, and the wider research and clinical communities.


Cost-effectiveness of endovascular repair, open repair, and conservative management of splenic artery aneurysms.
Open repair (OPEN) and conservative management (CONS) have been the treatments of choice for splenic artery aneurysms (SAAs) for many years. Endovascular repair (EV) has been increasingly used with good short-term results. In this study, we evaluated the cost-effectiveness of OPEN, EV, and CONS for the treatment of SAAs. A decision analysis model was developed using TreeAge Pro 2013 software (TreeAge Inc, Williamstown, Mass) to evaluate the cost-effectiveness of the different treatments for SAAs. A hypothetical cohort of 10,000 55-year-old female patients with SAAs was assessed in the reference-case analysis. Perioperative mortality, disease-specific mortality rates, complications, rupture risks, and reinterventions were retrieved from a recent and extensive meta-analysis. Costs were analyzed with the 2014 Medicare database. The willingness to pay was set to $60,000/quality-adjusted life years (QALYs). Outcomes evaluated were QALYs, costs from the health care perspective, and the incremental cost-effectiveness ratio (ICER). Extensive sensitivity analyses were performed and different clinical scenarios evaluated. Probabilistic sensitivity analysis was performed to include the uncertainty around the variables. A flowchart for clinical decision-making was developed. For a 55-year-old female patient with a SAA, EV has the highest QALYs (11.32; 95% credibility interval [CI], 9.52-13.17), followed by OPEN (10.48; 95% CI, 8.75-12.25) and CONS (10.39; 95% CI, 8.96-11.87). The difference in effect for 55-year-old female patients between EV and OPEN is 0.84 QALY (95% CI, 0.42-1.34), comparable with 10 months in perfect health. EV is more effective and less costly than OPEN and more effective and more expensive compared with CONS, with an ICER of $17,154/QALY. Moreover, OPEN, with an ICER of $223,166/QALY, is not cost-effective compared with CONS. In elderly individuals (age >78 years), the ICER of EV vs CONS is $60,503/QALY and increases further with age, making EV no longer cost-effective. Very elderly patients (age >93 years) have higher QALYs and lower costs when treated with CONS. The EV group has the highest number of expected reinterventions, followed by CONS and OPEN, and the number of expected reinterventions decreases with age. EV is the most cost-effective treatment for most patient groups with SAAs, independent of the sex and risk profile of the patient. EV is superior to OPEN, being both cost-saving and more effective in all age groups. Elderly patients should be considered for CONS, based on the high costs in relation to the very small gain in health when treated with EV. The very elderly should be treated with CONS.


Morphological organ alterations and infectious diseases in brown trout Salmo trutta and rainbow trout Oncorhynchus mykiss exposed to polluted river water.
Poor water quality is discussed as a major factor causing a decline of brown trout populations in Swiss rivers. For our study we have chosen a river in the Swiss midlands, where the brown trout population has decreased dramatically during the last 10 yr and where feral fish have shown distinctive pathological alterations. The objective of our study was to investigate whether river water may be responsible for impaired fish health leading to an increased mortality in the river. In an active monitoring program, groups of brown and rainbow trout were exposed to polluted river water for 24 mo. Fish held in tap water served as a reference. Mortality, macroscopic and histopathologic changes, and infectious agents were investigated. Compared with the reference group, high mortality rates and severe pathological alterations of the inner organs were observed in fish held in river water. Especially gills, liver and kidney of these fish showed significantly higher changes than fish from tap water. These changes were dominated by degenerative and inflammatory reactions. Additionally, several infectious agents were diagnosed in fish exposed to river water. The most important findings were furunculosis and proliferative kidney disease. Brown trout seemed to be more sensitive than rainbow trout to environmental stress and infectious agents.


A novel calcium-binding protein is associated with tau proteins in tauopathy.
Tauopathies are a group of neurological disorders characterized by the presence of intraneuronal hyperphosphorylated and filamentous tau. Mutations in the tau gene have been found in kindred with tauopathy. The expression of the human tau mutant in transgenic mice induced neurodegeneration, indicating that tau plays a central pathological role. However, the molecular mechanism leading to tau-mediated neurodegeneration is poorly understood. To gain insights into the role that tau plays in neurodegeneration, human tau proteins were immunoprecipitated from brain lysates of the tauopathy mouse model JNPL3, which develops neurodegeneration in age-dependent manner. In the present work, a novel EF-hand domain-containing protein was found associated with tau proteins in brain lysate of 12-month-old JNPL3 mice. The association between tau proteins and the novel identified protein appears to be induced by the neurodegeneration process as these two proteins were not found associated in young JNPL3 mice. Consistently, the novel protein co-purified with the pathological sarkosyl insoluble tau in terminally ill JNPL3 mice. Calcium-binding assays demonstrated that this protein binds calcium effectively. Finally, the association between tau and the novel calcium-binding protein is conserved in human and enriched in Alzheimer's disease brain. Taken together, the identification of a novel calcium-binding protein associated with tau protein in terminally ill tauopathy mouse model and its confirmation in human brain lysate suggests that this association may play an important physiological and/or pathological role.


MEC-12, an alpha-tubulin required for touch sensitivity in C. elegans.
mec-12 is one of a dozen genes required for touch receptor neuron function in Caenorhabditis elegans. Some mec-12 mutants (mechanosensory-defective) lack the large-diameter microtubules that are characteristic of these neurons (15 protofilaments, as opposed to 11). Mutants of mec-7, a alpha-tubulin encoding gene, have a similar phenotype. We have identified the nature of mec-12 by germline transformation rescue and characterization of a point mutation. Sequence analysis of the mec-12 encoded product (MEC-12) indicates that it corresponds to a novel C. elegans alpha-tubulin. MEC-12 is the only identified C. elegans alpha-tubulin that contains a lysine at position 40, a known site of post-translational acetylation. Some mec-12 mutations eliminate microtubule acetylation as assayed immunocyto-chemically; phenotypic rescue using a MEC-12 variant lacking the lysine-40 showed that acetylation is not required for MEC-12 activity. Although functionally needed only in the touch neurons, mec-12 is expressed in several other neuron types. These results support the notion that tubulin isotype diversity contributes to the formation of distinct classes of microtubules; 15-protofilament microtubule assembly requires MEC-12 alpha-tubulin and MEC-7 beta-tubulin, which are both highly expressed in the touch receptor neurons. MEC-12 is the first reported alpha-tubulin isotype that appears to be required in a single class of neuronal microtubules.


Mechanisms of Resistance to First-Line Osimertinib in Hispanic Patients With EGFR Mutant Non-Small Cell Lung Cancer (FRESTON-CLICaP).
Osimertinib is a third generation EGFR-TKI inhibitor approved in the first-line setting for patients with advanced non-small cell lung cancer (NSCLC). Additionally, it represents the treatment of choice in patients who present with T790M mutations and evidence of relapse of the disease. Effectiveness and safety of this drug have been studied in multiple clinical trials and observational studies, however, information regarding outcomes among Hispanic patients treated with Osimertinib is scarce. The objective of this study was to examine real-world effectiveness and safety of first-line Osimertinib in a cohort of Hispanic patients with NSCLC, emphasizing post-progression outcomes. This is a multicenter, multinational, retrospective cohort study of Hispanic patients treated with Osimertinib as first-line for EGFR-mutated NSCLC. Patients with a confirmed diagnosis of metastatic EGFR-mutated NSCLC who received Osimertinib (80mg/day until evidence of disease progression or presence of intolerable adverse effects) were identified and included. NGS was performed in tumor samples or liquid biopsies among patients who had disease progression. The primary outcome was progression-free survival, and the secondary outcome was post-progression survival. A total of 94 patients from Mexico, Argentina, Costa Rica, Colombia, Panama, Chile and the USA were included, with a median age of 59 years. Identified mutations included EGFR Exon 19 deletions and EGFR pL858R point mutations. Median progression-free survival (PFS) was 14.4 months (95%CI 12.4-18.2 months). Lung/pleura and lymph nodes were the most common sites of progression. Median post-progression survival was 7.73 months (95%CI 4.07 months-Not reached). Factors which negatively affected PFS included presence of liver metastases at diagnosis and a tumor mutational burden > 5 mut/Mb. Treatment with first line osimertinib represents an effective and safe option for Hispanic patients with metastatic NSCLC. Liver metastases and a higher tumor mutation burden were associated with a lower PFS. Despite effectiveness, different mechanisms of resistance were identified among the patients in this cohort, including mutations which can be targeted by other therapeutic options.


Fungal infections in bone marrow transplant patients.
Invasive fungal infections have become the leading infectious cause of death in recipients of hematopoietic cell transplantation. Several factors have led to a renaissance in the study of invasive fungal infections. The growing incidence of both commonly encountered as well as emerging pathogens and the lethality of these infections coupled with the unprecedented number of available broad-spectrum antifungal drugs has lent a renewed vigor and enthusiasm to attempts to understand the pathogenesis of these diseases and, by doing so, improve prevention, diagnosis, and treatment. The following is a review of the primary research published from 2003 to the present that is pertinent to invasive fungal infection in the setting of hematopoietic cell transplantation. The main themes of published primary research during 2003 to the present include the efficacy and tolerability of antifungal prophylaxis, epidemiologic analyses of risk factors following nonmyeloablative preparative regimens, and more-detailed analyses of nonmyeloid immune responses. Although few definitive recommendations emerged from the studies during the review period, these investigations do contribute to a greater understanding of the immunobiology of invasive fungal infection and of the utility and limitations of newer antifungal agents in the prophylaxis or treatment of invasive fungal infection.


Cerebrospinal fluid chitinase-3-like 2 and chitotriosidase are potential prognostic biomarkers in early multiple sclerosis.
The role of chitinases and chitinase-like proteins in multiple sclerosis (MS) is currently unknown; however, cerebrospinal fluid (CSF) levels of chitinase 3-like 1 (CHI3L1) predict prognosis in early MS. Whether this applies to other chitinases and chitinase-like proteins is yet to be established. Our objective was to investigate the potential of chitinase 3-like 2 (CHI3L2) and chitotriosidase as prognostic biomarkers in optic neuritis (ON) as the first demyelinating episode and to evaluate the ability of CHI3L2 to predict long-term MS risk and disability. In a prospective cohort of 73 patients with ON as a first demyelinating episode and 26 age-matched healthy controls levels of CHI3L2 and chitotriosidase in CSF were explored by enzyme-linked immunosorbent assay. Associations with magnetic resonance imaging white matter lesions, CSF oligoclonal bands, immunoglobulin G index and leukocyte count were investigated. Long-term MS risk and disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite components) were examined in a retrospective cohort of 78 patients with ON as the first demyelinating episode (mean follow-up 14 years). The predictive ability of CHI3L2 was compared with CHI3L1. Cerebrospinal fluid levels of CHI3L2 and chitotriosidase were significantly elevated in patients with ON and were associated with MS risk measures. CHI3L2 levels predicted MS development after ON (hazard ratio 1.95, P = 0.00039, Cox regression) and cognitive impairment by the Paced Auditory Serial Addition Test (P = 0.0357, linear regression) at follow-up. In a multivariate analysis of MS risk, CHI3L2 performed better than CHI3L1. CHI3L2 and chitotriosidase are promising biomarkers in patients with a first demyelinating episode. Our findings thus support a role for these proteins as biomarkers in early MS.


Expression and localization of nuclear proteins in autosomal-dominant Emery-Dreifuss muscular dystrophy with LMNA R377H mutation.
The autosomal dominant form of Emery-Dreifuss muscular dystrophy (AD-EDMD) is caused by mutations in the gene encoding for the lamins A and C (LMNA). Lamins are intermediate filament proteins which form the nuclear lamina underlying the inner nuclear membrane. We have studied the expression and the localization of nuclear envelope proteins in three different cell types and muscle tissue of an AD-EDMD patient carrying a point mutation R377H in the lamin A/C gene. Lymphoblastoid cells, skin fibroblasts, primary myoblasts and muscle thin sections were studied by immunocytochemistry and electron microscopy. Cellular levels of A-type lamins were reduced compared to control cells. In contrast, the amount of emerin and lamin B appeared unaltered. Cell synchronization experiments showed that the reduction of the cellular level of A-type lamin was due to instability of lamin A. By electron microscopy, we identified a proportion of nuclei with morphological alterations in lymphoblastoid cells, fibroblasts and mature muscle fibres. Immunofluorescence microscopy showed that a major population of the lamin B receptor (LBR), an inner nuclear membrane protein, was recovered in the cytoplasm in association with the ER. In addition, the intranuclear organization of the active form of RNA polymerase II was markedly different in cells of this AD-EDMD patient. This aberrant intranuclear distribution was specifically observed in muscle cells where the pathology of EDMD predominates. From our results we conclude: Firstly, that structural alterations of the nuclei which are found only in a minor fraction of lymphoblastoid cells and mature muscle fibres are not sufficient to explain the clinical pathology of EDMD; Secondly, that wild type lamin A is required not only for the retention of LBR in the inner nuclear membrane but also for a correct localization of the transcriptionally active RNA pol II in muscle cells. We speculate that a rearrangement of the internal chromatin could lead to muscle-specific disease symptoms by interference with proper mRNA transcription.