The 2018 Global Point Prevalence Survey of antimicrobial consumption and resistance in 47 Canadian hospitals: a cross-sectional survey.
Patient-level surveillance of antimicrobial use (AMU) in Canadian hospitals empowers the reduction of inappropriate AMU and was piloted in 2017 among 14 hospitals in Canada. We aimed to describe AMU on the basis of patient-level data in Canadian hospitals in 2018 in terms of antimicrobial prescribing prevalence and proportions, antimicrobial indications, and agent selection in medical, surgical and intensive care wards. Canadian adult, pediatric and neonatal hospitals were invited to participate in the standardized web-based cross-sectional Global Point Prevalence Survey of Antimicrobial Consumption and Resistance (Global-PPS) conducted in 2018. An identified site administrator assigned all wards admitting inpatients to specific surveyors. A physician, pharmacist or nurse with infectious disease training performed the survey. The primary outcomes were point prevalence rates for AMU over the study period regarding prescriptions, indications and agent selection in medical, surgical and intensive care wards. The secondary outcomes were AMU for resistant organisms and practice appropriateness evaluated on the basis of quality indicators. Antimicrobial consumption is presented in terms of prevalence and proportions. Forty-seven of 118 (39.8%) hospitals participated in the survey; 9 hospitals were primary care centres, 15 were secondary care centres and 23 were tertiary or specialized care centres. Of 13 272 patients included, 33.5% (n = 4447) received a total of 6525 antimicrobials. Overall, 74.1% (4832/6525) of antimicrobials were for therapeutic use, 12.6% (n = 825) were for medical prophylaxis, 8.9% (n = 578) were for surgical prophylaxis, 2.2% (n = 143) were for other use and 2.3% (n = 147) were for unidentified reasons. A diagnosis or indication was documented in the patient's file at the initiation for 87.3% (n = 5699) of antimicrobials; 62.9% (n = 4106) of antimicrobials had a stop or review date; and 72.0% (n = 4697) of prescriptions were guided by local guidelines. Overall, three-quarters of AMU was for therapeutic use across participating hospitals. Canadian hospitals should be further incentivized to create and adapt local guidelines on the basis of recent antimicrobial resistance data.


Hospital-physician relations: two tracks and the decline of the voluntary medical staff model.
Data from the most recent Community Tracking Study (CTS) interviews in twelve nationally representative metropolitan areas indicate that hospitals are increasingly employing physicians, particularly specialists. Nonemployed physicians are separating from hospitals passively by refusing to serve on medical staff committees or take emergency department call, and actively by creating specialized facilities, such as ambulatory surgery centers (ASCs), to compete for hospitals' most profitable services. Employment is more common and physician-owned ASCs are less common in consolidated hospital markets. The interviews also suggest other factors motivating physician employment by, or separation from, hospitals, and likely consequences of these trends.


Effect of odanacatib on bone turnover markers, bone density and geometry of the spine and hip of ovariectomized monkeys: a head-to-head comparison with alendronate.
Odanacatib (ODN) is a selective and reversible Cathepsin K (CatK) inhibitor currently being developed as a once weekly treatment for osteoporosis. Here, effects of ODN compared to alendronate (ALN) on bone turnover, DXA-based areal bone mineral density (aBMD), QCT-based volumetric BMD (vBMD) and geometric parameters were studied in ovariectomized (OVX) rhesus monkeys. Treatment was initiated 10 days after ovariectomy and continued for 20 months. The study consisted of four groups: L-ODN (2 mg/kg, daily p.o.), H-ODN (8/4 mg/kg daily p.o.), ALN (15 μg/kg, twice weekly, s.c.), and VEH (vehicle, daily, p.o.). L-ODN and ALN doses were selected to approximate the clinical exposures of the ODN 50-mg and ALN 70-mg once-weekly, respectively. L-ODN and ALN effectively reduced bone resorption markers uNTx and sCTx compared to VEH. There was no additional efficacy with these markers achieved with H-ODN. Conversely, ODN displayed inversely dose-dependent reduction of bone formation markers, sP1NP and sBSAP, and L-ODN reduced formation to a lesser degree than ALN. At month 18 post-OVX, L-ODN showed robust increases in lumbar spine aBMD (11.4%, p<0.001), spine trabecular vBMD (13.7%, p<0.001), femoral neck (FN) integral (int) vBMD (9.0%, p<0.001) and sub-trochanteric proximal femur (SubTrPF) int vBMD, (6.4%, p<0.001) compared to baseline. L-ODN significantly increased FN cortical thickness (Ct.Th) and cortical bone mineral content (Ct.BMC) by 22.5% (p<0.001) and 21.8% (p<0.001), respectively, and SubTrPF Ct.Th and Ct.BMC by 10.9% (p<0.001) and 11.3% (p<0.001) respectively. Compared to ALN, L-ODN significantly increased FN Ct. BMC by 8.7% (p<0.05), and SubTrPF Ct.Th by 7.6% (p<0.05) and Ct.BMC by 6.2% (p<0.05). H-ODN showed no additional efficacy compared to L-ODN in OVX-monkeys in prevention mode. Taken together, the results from this study have demonstrated that administration of ODN at levels which approximate clinical exposure in OVX-monkeys had comparable efficacy to ALN in DXA-based aBMD and QCT-based vBMD. However, FN cortical mineral content clearly demonstrated superior efficacy of ODN versus ALN in this model of estrogen-deficient non-human primates.


Pulmonary nodules resembling bronchioloalveolar carcinoma in adolescent cancer patients.
Pulmonary nodules morphologically indistinguishable from bronchioloalveolar carcinoma (BAC) were found in two adolescent cancer patients postchemotherapy. A solitary nodule was noted at thoracotomy for a single computerized tomography (CT) scan lesion in a 16-yr-old male, 6 yr after diagnosis of Ewing's sarcoma. A similar nodule was found in a 19-yr-old male coincident with resection of multiple lung metastases of a testicular germ cell tumor. Both lesions were discrete nodular masses (1 cm and 0.5 cm) consisting of atypical epithelial cells with a papillary and lepidic growth pattern and surrounded by histologically normal appearing lung. Immunohistochemistry of both cases was positive for laminoorganel (LO) antigen, which is found in normal type II pneumocytes, and one nodule showed carcinoembryonic antigen (CEA) staining. Quantitative DNA analysis in one case indicated aneuploidy. Thus the morphology, immunohistochemistry, and DNA content of these lesions suggest that they may represent early lung cancers despite the highly unusual clinical context. The extreme rarity of BAC in this age group makes this report significant in light of heightening concern about second malignancies in pediatric cancer patients and reports of chemically induced pulmonary adenomas in mice. It also underscores the importance of basing therapeutic decisions on a histologic diagnosis of lung nodules in cancer patients rather than assuming the presence of metastatic disease.


Xpert MTB/RIF: a new pillar in diagnosis of extrapulmonary tuberculosis?
Approximately 10 to 15% of tuberculosis (TB) cases in India are estimated to have extrapulmonary disease, and due to a lack of diagnostic means, they often remain untreated. The early detection of Mycobacterium tuberculosis and multidrug resistance is a priority in TB diagnosis to improve the successful treatment rate of TB and reduce transmission. The Xpert MTB/RIF (Xpert) test, recently endorsed by the World Health Organization for the detection of pulmonary TB, was evaluated to test its utility in 547 patients with suspected extrapulmonary tuberculosis. Five hundred forty-seven extrapulmonary specimens were split and processed simultaneously for both culture (solid and liquid) and Xpert testing. For culture, the sensitivity was low, 53% (150/283 specimens). Xpert sensitivity and specificity results were assessed in comparison to a composite reference standard made up of smear and culture results and clinical, radiological, and histological findings. The sensitivity of the Xpert assay was 81% (228/283 specimens) (64% [89/138] for smear-negative cases and 96% [139/145] for smear-positive cases), with a specificity of 99.6%. The sensitivity was found to be high for the majority of specimen types (63 to 100%) except for cerebrospinal fluid, the sensitivity of which was 29% (2/7 specimens). The Xpert test correctly identified 98% of phenotypic rifampin (RIF)-resistant cases and 94% of phenotypic RIF-susceptible cases. Sequencing of the 6 discrepant samples resolved 3 of them, resulting in an increased specificity of 98%. In conclusion, the results of this study suggest that the Xpert test also shows good potential for the diagnosis of extrapulmonary TB and that its ease of use makes it applicable for countries where TB is endemic.


Global repression by tailless during segmentation.
The orphan nuclear receptor Tailless (Tll) exhibits conserved roles in brain formation and maintenance that are shared, for example, with vertebrate orthologous forms (Tlx). However, the early expression of tll in two gap domains in the segmentation cascade of Drosophila is unusual even for most other insects. Here we investigate tll regulation on pair-rule stripes. With ectopic misexpression of tll we detected unexpected repression of almost all pair-rule stripes of hairy (h), even-skipped (eve), runt (run), and fushi-tarazu (ftz). Examining Tll embryonic ChIP-chip data with regions mapped as Cis-Regulatory Modules (CRMs) of pair-rule stripes we verified Tll interactions to these regions. With the ChIP-chip data we also verified Tll interactions to the CRMs of gap domains and in the misexpression assay, Tll-mediated repression on Kruppel (Kr), kni (kni) and giant (gt) according to their differential sensitivity to Tll. These results with gap genes confirmed previous data from the literature and argue against indirect repression roles of Tll in the striped pattern. Moreover, the prediction of Tll binding sites in the CRMs of eve stripes and the mathematical modeling of their removal using an experimentally validated theoretical framework shows effects on eve stripes compatible with the absence of a repressor binding to the CRMs. In addition, modeling increased tll levels in the embryo results in the differential repression of eve stripes, agreeing well with the results of the misexpression assay. In genetic assays we investigated eve 5, that is strongly repressed by the ectopic domain and representative of more central stripes not previously implied to be under direct regulation of tll. While this stripe is little affected in tll-, its posterior border is expanded in gt- but detected with even greater expansion in gt-;tll-. We end up by discussing tll with key roles in combinatorial repression mechanisms to contain the expression of medial patterns of the segmentation cascade in the extremities of the embryo.


Pathologic findings in long-term cardiac transplants.
Since the introduction of cardiac transplantation at our institution 15 years ago, major advances have occurred in the monitoring and treatment of these patients, resulting in many long-term survivors. We defined the pathologic features in 14 cardiac transplants with survival times longer than one year. Only one heart showed no evidence of rejection, while the remaining 13 hearts showed advanced chronic rejection, which was the main cause of death or of graft failure in 11 patients. One patient died of gastric carcinoma, one of Kaposi's sarcoma, and one of cerebral embolus. The most obtrusive change in the donor hearts was an obliterative arteritis, which in the epicardial coronary arteries mimicked atherosclerosis. Superadded thrombosis often resulted in myocardial infarction. These severe vascular lesions bore no constant relationship to survival time and took from 1.1 to 12.5 years to evolve.


HDV infection in immigrant populations.
Little data have been published so far on the epidemiological aspects of hepatitis D virus (HDV) infection in immigrant populations and even poorer is the information on the virological, phylogenetic, and clinical aspects of this infection in these populations. This review article, aimed primarily at physicians caring for immigrants, summarizes the information available on HDV infection and analyzes data on this topic concerning the immigrant populations. The prevalence of HDV infection in HBsAg-positive immigrants varies according to the country of origin. For example, in immigrants from sub-Saharan Africa, this prevalence is higher in those born in Equatorial Guinea (24.4%) than those from other African countries (10.3%). The epidemiological impact of HDV infection linked to migratory flows is a function of the different endemicity between countries of origin and countries in which a new existence has been established. This impact is high when immigrants from areas endemic to HDV infection (eg, Equatorial Guinea) settle in areas of low endemicity (eg, Germany or England, with a prevalence of around 4%), while the impact is lesser or nonexistent if the migratory flows are directed toward countries with intermediate endemicity (eg, Italy and Greece, with a prevalence of around 10%). This impact of immigration on HDV epidemiology can be strong when HDV endemicity is high in the country of origin and low in the host country and slight when immigrants move to high or medium endemic countries.


General practitioners' immediate management of men presenting with urethral symptoms.
To describe the immediate reported management, by general practitioners (GPs), of men presenting with symptoms of urethral discharge, or dysuria only. All 692 GPs in practice in Brent, Harrow, Ealing, Hammersmith, and Hounslow (UK). Data were collected using a GP completed questionnaire concerning the management of the last male patient seen, aged less than 40 years, complaining of urethral discharge, and the last male patient under 40 years complaining of dysuria only. The response rate among GPs was 52%. Fifty three per cent of men with urethral symptoms, 86% of men with a urethral discharge and 24% with dysuria only, were identified by GPs and referred without investigation or treatment to a genitourinary medicine clinic. Of men with dysuria only, 93% of investigations by GPs were reported to include a mid-stream urine (MSU) specimen for bacteriology, and 19% a urethral swab for chlamydia. Seventy eight per cent of GPs reported using treatments with a broad spectrum antibiotic, 53% with trimethoprim, whilst 14% of GPs reported using a tetracycline in common use to treat non-gonococcal urethritis. Urine specimens were reported to be "culture positive" in 41% of men who had an MSU specimen tested, and 15% of men who had a urethral swab tested were reported to be chlamydia positive. The GPs included in this study were not a full sample, or representative of all the GPs, and the data are retrospective. Nevertheless, we found a large difference in GPs reported management for men with urethral symptoms according to whether or not urethral discharge was a reported complaint. Reported management is likely to be, at least, indicative of actual management. Therefore, the results suggest that assessment by GPs of men presenting with dysuria should be explored and more appropriate management strategies defined.


Skin-derived tenocyte-like cells for the treatment of patellar tendinopathy.
Recent research of lateral elbow tendinopathy has led to the use of laboratory-amplified tenocyte-like cells. Ultrasound-guided injection of autologous skin-derived tendon-like cells are effective compared with other injectable therapies for the treatment of refractory patellar tendinosis. Randomized controlled trial; Level of evidence, 1. From 60 patellar tendons in 46 patients with refractory patellar tendinopathy, a 4-mm skin biopsy was sampled to grow tenocyte-like collagen-producing cells. Patients were allocated into 2 groups: (1) injection with laboratory-prepared, amplified collagen-producing cells derived from dermal fibroblasts and suspended in autologous plasma from centrifuged autologous whole blood or (2) injection with autologous plasma alone. Injections were made into the sites of hypoechogenicity, intrasubstance tears, and fibrillar discontinuity within the patellar tendon. The Victorian Institute of Sport Assessment (VISA) score was used to assess pain, severity, and functional disability. Ultrasound was performed to assess structural and blood flow changes, evaluating 4 criteria: tendon thickness, hypoechogenicity, intrasubstance tears, and neovascularity. In the cell group, mean VISA scores improved from 44 ± 15 before treatment to 75 ± 17 at 6 months; in the plasma group, from 50 ± 18 to 70 ± 14. Estimated average difference between groups was 8.1, a significantly higher score in the cell group. Patients treated with collagen-producing cells also had significantly faster improvement and a highly significant effect of treatment, with the difference between groups estimated as 2.5 per unit increase in 1/√time. One patient treated with cell therapy had a late rupture and progressed to surgery; histopathology showed normal tendon structure. Ultrasound-guided injection of autologous skin-derived tendon-like cells can be safely used in the short term to treat patellar tendinopathy, with faster response of treatment and significantly greater improvement in pain and function than with plasma alone.


Adaptation of anammox bacteria to low temperature via gradual acclimation and cold shocks: Distinctions in protein expression, membrane composition and activities.
Anammox bacteria enable efficient removal of nitrogen from sewage in processes involving partial nitritation and anammox (PN/A) or nitrification, partial denitrification, and anammox (N-PdN/A). In mild climates, anammox bacteria must be adapted to ≤15 °C, typically by gradual temperature decrease; however, this takes months or years. To reduce the time necessary for the adaptation, an unconventional method of 'cold shocks' is promising, involving hours-long exposure of anammox biomass to extremely low temperatures. We compared the efficacies of gradual temperature decrease and cold shocks to increase the metabolic activity of anammox (fed batch reactor, planktonic "Ca. Kuenenia"). We assessed the cold shock mechanism on the level of protein expression (quantitative shot-gun proteomics, LCHRMS/MS) and the structure of membrane lipids (UPLCHRMS/MS). The shocked culture was more active (0.66±0.06 vs 0.48±0.06 kg-N/kg-VSS/d) and maintained the relative content of N-respiration proteins at levels consistent levels with the initial state, whereas the content of these proteins decreased in gradually acclimated culture. Cold shocks also induced a more efficient expression of potential cold shock proteins (e.g. ppiD, UspA, pqqC), while putative cold shock proteins CspB and TypA were upregulated in both cultures. Ladderane lipids characteristic for anammox evolved to a similar end-point in both cultures; this confirms their role in anammox bacteria adaptation to cold and indicates a three-pronged adaptation mechanism (ladderane alkyl length, introduction of shorter non-ladderane alkyls, polar headgroup). Overall, we show the outstanding potential of cold shocks for low-temperature adaptation of anammox bacteria and provide yet unreported detailed mechanisms of anammox adaptation to low temperatures.


Molecular dynamics simulation of photodissociation of carbon monoxide from hemoglobin.
A molecular dynamics simulation of the photodissociation of carbon monoxide from the alpha subunit of hemoglobin is described. To initiate photodissociation, trajectories of the liganded molecule were interrupted, the iron-carbon monoxide bond was broken, and the parameters of the iron-nitrogen bonds were simultaneously altered to produce a deoxyheme conformation. Heme potential functions were used that reproduce the energies and forces for the iron out-of-plane motion obtained from quantum mechanical calculations. The effect of the protein on the rate and extent of the displacement of the iron from the porphyrin plane was assessed by comparing the results with those obtained for an isolated complex of heme with imidazole and carbon monoxide. The half-time for the displacement of the iron from the porphyrin plane was found to be 50-150 fs for both the protein and the isolated complex. These results support the interpretation of optical absorption studies using 250-fs laser pulses that the iron is displaced from the porphyrin plane within 350 fs in both hemoglobin and a free heme complex in solution.


Helicobacter pylori seroconversion in asymptomatic blood donors: a five-year follow-up.
Several techniques have been developed to diagnose Helicobacter pylori infection and two noninvasive methods are available: carbon 13-urea breath test (UBT) and serology. Measurement of IgG serum antibodies by enzyme-linked immunosorbent assay (ELISA) is a reliable and inexpensive method for detection of infection. The aim of this study was to assess the seroconversion by different techniques after five to eight years. In 1990, 588 of 1,010 asymptomatic donors were found to be seronegative by ELISA, based on an H. pylori whole-cell suspension lysate (sensitivity and specificity: 92% and 97%). In 1995 serum samples from 418 of 588 seronegative donors were collected and retested using the same antigen. 411 of 418 samples were frankly negative, and 7 donors were found to be seroconverted. This group of seven sera represents the object of the study. They were retested by ELISA and western blotting using a different antigen (NCTC). To standardize our techniques, sera from 43 H. pylori positive and 47 H. pylori negative patients according to culture, histology, urease test, and UBT were used. The cutoff for ELISA-NCTC was 0.53 AI (absorbance index) (mean value + 2 SD), and for western blotting was negativity for CagA or <10 bands (sensitivity and specificity: 95% and 96%; 98% and 81% for ELISA and western blotting respectively). According to the results obtained in 1990 and 1995, seven donors were found to be seroconverted by ELISA using sonicated antigen; in five the seroconversion was confirmed by ELISA using NCTC antigen and in two there was concordance with WB. Four of the seven donors were contacted and asked to undergo UBT and a further serum sample was drawn to be reassessed in 1998. A seroconversion was found in all four donors by ELISA, while WB and UBT confirmed the seroconversion in only three of four donors. In conclusion the in-house ELISA used performed well compared to other theoretically better serologic assays and confirmed the low seroconversion rate for H. pylori infection in adult populations living in developed countries.


Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes.
Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders.


Safety assessment of HEA-enriched Cordyceps cicadae mycelia on the central nervous system (CNS), cardiovascular system, and respiratory system in ICR male mice.
Cordyceps cicadae, an entomopathogenic fungus, is a source of traditional Chinese medicine in China. Due to the low yield of wild C. cicadae, artificial cultivation approaches will be needed to meet the increasing market demand. Using bioreactor culture can increase mass production and the abundance of the active component, N6-(2-hydroxyethyl)-adenosine (HEA). Here, we describe a safety assessment for a novel mycelium preparation method. Many studies have confirmed the safety of C. cicadae mycelia. However, the acute safety pharmacology of the C. cicadae enriched with the high HEA (3.90 mg/g) compound has not been evaluated. This study evaluated the central nervous system (CNS), cardiovascular system, and respiratory system in ICR male mice via oral gavage administration. For each requested item, two batches of eight mice tested on a vehicle (0.5% carboxymethyl cellulose, CMC) and C. cicadae mycelia (1,000 mg/kg) were performed. The heart rate at 60 min for the vehicle and C. cicadae mycelium treatment was 700.3 ± 55.4 and 603.0 ± 42.3 bpm, respectively (p = .4279). For echocardiographic analysis, the LV mass of the vehicle and drug treatment was 86.7 ± 6.4 and 80.2 ± 7.7, respectively (p = .0933). In the respiratory test, the tidal volume of the vehicle and drug treatments was 0.11 ± 0.01 and 0.14 ± 0.01 at 60 min, respectively (p = .4262). These results demonstrate that the oral administration of HEA-enriched C. cicadae mycelia is safe for the CNS, cardiovascular, and respiratory systems.


An oral mixed fat load is followed by a modest anti-inflammatory adipocytokine response in overweight patients with metabolic syndrome.
We investigated the postprandial changes in plasma levels of adipocytokines in overweight patients with metabolic syndrome after an oral fat load. After an oral fat load and during a prolonged fast, blood was drawn at 0, 2, 3, 4 and 8 h for measurement of adiponectin, adipsin, cathepsin S, chemerin, hepatic growth factor, interferon-γ-inducible protein-10, leptin, macrophage chemoattractant protein-1, macrophage migration inhibitory factor, nerve growth factor, retinol binding protein-4, resistin, serum amyloid A1, tissue inhibitor of metalloproteinase-1 and thrombopoietin using a microbead-based Luminex assay. Area under the curves (AUC) were calculated and compared. Plasma adiponectin levels were higher after an oral fat load compared to fasting at t = 2 h (950 ± 513 vs. -1,881 ± 713 ng/ml) while the plasma levels for adipsin (-9 ± 5 vs. 16 ± 5 ng/ml), chemerin (-122 ± 35 vs. 13 ± 21 ng/ml), SAA-1 (-391 ± 213 vs. 522 ± 173 ng/ml) and TPO (-335 ± 144 vs. 622 ± 216 ng/ml) were lower after an oral fat load compared to fasting. The baseline corrected AUC for IP-10 was higher after fat load compared to fasting (median -116 pg h/ml; IQR -270 to 10 vs. -21 pg h/ml; IQR -136 to 418 (p = 0.047). In conclusion, in overweight male subjects with the metabolic syndrome, an oral fat load is accompanied with a modest anti-inflammatory response of adipose tissue-derived adipocytokines.


Frameless stereotaxy of the brain.
Today's neurosurgical journals are replete with advertisements for systems designed to provide image guidance during surgery. These so-called "frameless" stereotactic systems provide the surgeon with navigational information, relating the location of instruments in the operative field to preoperative imaging data. Such information minimizes invasiveness by more accurately selecting the best trajectory to the lesion, ensures more precise identification of normal structures, and guides complete removal of a lesion. To achieve these goals, all of these systems utilize the stereotactic principle of co-registration of the patient with an imaging study. This review will trace the development of image-guided surgery from its origins in frame-based stereotaxy to its current use as a surgical navigation methodology. A review of the more prevalent techniques and available systems will be presented, along with examples of specific applications of surgical navigation. Finally, some of the future directions of frameless stereotaxy will be discussed.


Skin toxicity and quality of life during treatment with panitumumab for RAS wild-type metastatic colorectal carcinoma: results from three randomised clinical trials.
Epidermal growth factor receptor inhibitors such as panitumumab are associated with characteristic skin toxicities. We summarise data from three panitumumab clinical trials to investigate the potential impact of skin toxicity on quality of life (QoL) in patients with metastatic colorectal cancer (mCRC). The studies were randomised, open-label trials comparing standard treatment (first-line FOLFOX4 [n = 456], second-line FOLFIRI [n = 381], or best supportive care [n = 114]) with or without panitumumab in adults with KRAS/NRAS (RAS) wild-type mCRC. QoL was assessed using the EuroQoL 5-domain health state index (HSI) and overall health rating (OHR) measures. Impact of skin toxicity on changes in QoL scores was estimated using a linear mixed-effects model. Worst skin toxicity was defined in separate models as a subgroup variable or as a measure over time. Regardless of analysis method, there were no statistically significant differences between the panitumumab and comparator arms in any of the studies in terms of change in HSI or OHR scores. There were no statistically significant differences in QoL outcomes between patients with worst skin toxicity grade <3 and those with grade ≥3. In addition, there were no statistically significant differences between the panitumumab and comparator arms in subgroups of patients with worst skin toxicity of grade <3 and ≥3. Addition of panitumumab to chemotherapy in RAS wild-type mCRC has no statistically significant negative effect on overall QoL, despite skin toxicity. Skin toxicity of worst grade ≥3 appeared to have similar impact on QoL as skin toxicity of grade <3.


Effect of Weight Loss Medications on Hepatic Steatosis and Steatohepatitis: A Systematic Review.
Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in individuals with obesity. Although multiple pharmacotherapeutics are in development, currently there are limited strategies specifically targeting NAFLD. This systematic review summarizes the existing literature on hepatic effects of medications used for weight loss. Glucagon-like peptide 1 (GLP-1) agonists are the best-studied in this regard, and evidence consistently demonstrates reduction in liver fat content, sometimes accompanied by improvements in histological features of steatohepatitis and reductions in serum markers of hepatic injury such as alanine aminotransferase (ALT). It remains unclear whether these benefits are independent of the weight loss caused by these agents. Literature is limited regarding effects of orlistat, but a small number of reports suggest that orlistat reduces liver fat content and improves histologic features of NASH, benefits which may also be driven primarily by weight loss. A sizeable body of literature on hepatic effects of metformin yields mixed results, with a probability of modest benefit, but no consistent signal for strong benefit. There are insufficient data on hepatic effects of topiramate, phentermine, naltrexone, bupropion, and lorcaserin. Finally, a few studies to date suggest that sodium-glucose co-transporter-2 (SGLT2) inhibitors may reduce liver fat content and cause modest reductions in ALT, but further study is needed to better characterize these effects. Based on available data, GLP-1 agonists have the strongest evidence base demonstrating beneficial effects on NAFLD, but it is not clear if any weight loss medication has effects on NAFLD superior to those of nutritional modification and exercise alone.


[Subgaleal lipomas: ultrasound findings].
Lipomas are frequent benign soft tissue tumors. They are classified as superficial or deep. In the head, they are localized under the galea or epicraneal aponeurosis. Clinically they present as non symptomatic smooth tumors. To describe ultrasound (US) findings of subgaleal lipomas. Retrospective review of seven patients aged between 31 and 52 years (five males) with subgaleal lipomas. AH lipomas were localized in the forehead. At US, they appeared as solid masses; 43% were isoechoic and 47% hyperechoic compared to subcutaneous tissue. The average size was 13 mm. They had a semi spherical shape, with a flat base and a convex surface, a regular margin, no vascular vessels at Doppler ultrasound and were surrounded by the galea. In this series of patients, all masses had a similar US appearance that suggested the diagnosis of lipoma.


Highly Porous Poly(high internal phase emulsion) Membranes with "Open-Cell" Structure and CO2-Switchable Wettability Used for Controlled Oil/Water Separation.
Polymer membranes with switchable wettability have promising applications in smart separation. Hereby, we report highly porous poly(styrene-co-N,N-(diethylamino)ethyl methacrylate) (i.e., poly(St-co-DEA)) membranes with "open-cell" structure and CO2-switchable wettability prepared from water-in-oil (W/O) high internal phase emulsion (HIPE) templates. The open-cell porous structure facilitates fluid penetration through the membranes. The combination of CO2-switchable functionality and porous microstructure enable the membrane with CO2-switchable wettability from hydrophobic or superoleophilic to hydrophilic or superoleophobic through CO2 treatment in an aqueous system. This type of membrane can be used for gravity-driven CO2-controlled oil/water separation, in which oil selectively penetrates through the membrane and separates from water. After being treated with CO2 switching wettability of the membrane, a reversed separation of water and oil can be achieved. Such a wettability switch is fully reversible, and the membrane could be regenerated through simple removal of CO2 and oil residual through drying. This facile and cost-effective approach represents the development of the first CO2-switchable polyHIPE system, which is promising for smart separation in a large volume.


High prevalence of Tropheryma whipplei in Lao kindergarten children.
Tropheryma whipplei is a bacterium commonly found in feces of young children in Africa, but with no data from Asia. We estimated the prevalence of T. whipplei carriage in feces of children in Lao PDR (Laos). Using specific quantitative real-time PCR, followed by genotyping for each positive specimen, we estimated the prevalence of T. whipplei in 113 feces from 106 children in Vientiane, the Lao PDR (Laos). T. whipplei was detected in 48% (51/106) of children. Those aged ≤ 4 years were significantly less frequently positive (17/52, 33%) than older children (34/54, 63%; p< 0.001). Positive samples were genotyped. Eight genotypes were detected including 7 specific to Laos. Genotype 2, previously detected in Europe, was circulating (21% of positive children) in 2 kindergartens (Chompet and Akad). Genotypes 136 and 138 were specific to Chompet (21% and 15.8%, respectively) whereas genotype 139 was specific to Akad (10.55%). T. whipplei is a widely distributed bacterium, highly prevalent in feces of healthy children in Laos. Further research is needed to identify the public health significance of this finding.


Lessons learned after a three-year store and forward teledermatology experience using internet: Strengths and limitations.
This paper presents a three-year teledermatology evaluation experience. The aim is to explain the methodology followed, present the evaluation results, discuss critically the issues that emerged during the experience and report the main lessons learned. A complete design and evaluation methodology was conducted to fully address significant issues arising from other previous teledermatology experiences. First, system-design requirements and image quality issues were studied. Then, a detailed clinical concordance study was undertaken to determine the accuracy of diagnoses made using teledermatology in order to assess different dermatological clinics. Finally, an impact study on the health system was performed. Furthermore, clinical, technical, social and alignment outcomes were analyzed during the study and at the end of it, in order to understand how emerging factors affected the final setup of the teledermatology system. The most important results reported in this study can be summarized as follows. (1) A complete web-based environment for teledermatology support was developed as a result of a dynamic evaluation process with clinical personnel. (2) A total of 120 teleconsultations (82 pediatric and 28 adult) were made during the clinical concordance study. Concordance analysis was carried out for each dermatological disease group. High concordance rates were found in pediatrics for inflammatory dermatoses (76%) and also for adults (75%) with infections and infestations. (3) Physicians were satisfied with the teledermatology system but the time dedicated to consultation in primary care was a limiting factor (19min for each teleconsultation). (4) An extensive discussion about the successful and the limiting aspects of the teledermatology experience revealed the reasons behind the final decision not to proceed with its implementation. It was considered not to be aligned with Health Care Organization (HCO) strategy and consequently did not achieve high-level support for its long-term implementation. A high degree of diagnostic accuracy both for pediatric and adult consultations was achieved using the teledermatology system with affordable technical requirements. Its usefulness for filtering dermatological referrals was also demonstrated in the study. Nevertheless, other factors such as the reorganization required for the physicians' time schedule, remuneration issues, absence of EHR (electronic health record) integration and lack of interaction with the HCO were important limiting factors. This led to the conclusion that under the evaluation conditions long-term set-up was not possible. It was also concluded that HCO participation would have been essential for both the evaluation study and the long-term set-up of the system.


Cost-cutting opportunities through direct contracting.
In summary, high-quality mental health care can be made affordable and obtainable for the average employee or dependent. The goal of ensuring ethical and appropriate mental health and substance abuse services can be achieved. The consequences of inadequate mental health services are higher usage of medical services and lower levels of employee satisfaction and performance. The direct contract approach offers the most viable alternative to achieving a sound, ethical, and cost-effective mental health care benefits program. Finally, in an era of rapid health care reform, it is important to ensure that the contracted provider group keeps fully abreast of and in compliance with emerging regulatory trends.


Spectral changes of interhemispheric crosstalk during movement instabilities.
Bimanual coordination requires the functional integration of the activity in various cortical, subcortical, spinal, and peripheral neural structures. We challenged this functional integration by destabilizing bimanual 5:8 tapping through an increase in movement tempo, while measuring brain and muscle activity using magnetoencephalography and electromyography. Movement instabilities were characterized by a drop in frequency locking. Time-frequency analysis revealed movement-related beta amplitude modulation in bilateral motor areas as well as movement-related corticospinal entrainment. Both of these synchronization patterns depended on movement tempo suggesting that the timescale needed for the upregulation and downregulation of beta synchrony in rhythmic tapping poses constraints on motor performance. Bilateral phase locking over movement cycles appeared to be mediated by beta-frequency oscillations and constrained by its phase dynamics. The timescale of beta synchrony thus seems to play a key role in achieving timed phase synchrony in the motor cortex and along the neural axis. Once event-related desynchronization-synchronization cycles cannot be build up properly, inhibition may become inadequate, resulting in a reduction of the stability of performance, which may eventually become unstable.


Personalized treatment strategies in glioblastoma: MGMT promoter methylation status.
The identification of molecular genetic biomarkers considerably increased our current understanding of glioma genesis, prognostic evaluation, and treatment planning. In glioblastoma, the most malignant intrinsic brain tumor entity in adults, the promoter methylation status of the gene encoding for the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) indicates increased efficacy of current standard of care, which is concomitant and adjuvant chemoradiotherapy with the alkylating agent temozolomide. In the elderly, MGMT promoter methylation status has recently been introduced to be a predictive biomarker that can be used for stratification of treatment regimes. This review gives a short summery of epidemiological, clinical, diagnostic, and treatment aspects of patients who are currently diagnosed with glioblastoma. The most important molecular genetic markers and epigenetic alterations in glioblastoma are summarized. Special focus is given to the physiological function of DNA methylation-in particular, of the MGMT gene promoter, its clinical relevance, technical aspects of status assessment, its correlation with MGMT mRNA and protein expressions, and its place within the management cascade of glioblastoma patients.


Short-term training: when do repeated bouts of resistance exercise become training?
Chronic resistance training induces increases in muscle fibre cross-sectional area (CSA), otherwise known as hypertrophy. This is due to an increased volume percentage of myofibrillarproteins within a given fibre. The exact time-course for muscle fibre hypertrophy is not well-documented but appears to require at least 6-7 weeks of regular resistive training at reasonably high intensity before increases in fibre CSA are deemed significant. Proposed training-induced changes in neural drive are hypothesized to increase strength due to increased synchrony of motor unit firing, reducedant agonist muscle activity, and/or a reduction in any bilateral strength deficit. Nonetheless, increases in muscle protein synthesis were observed following an isolated bout of resistance exercise. In addition, muscle balance was positive, following resistance exercise when amino acids were infused/ingested. This showed that protein accretion occurred during the postexercise period. The implications of this hypothesis for training-induced increases in strength are discussed.


Hybridization drives genetic erosion in sympatric desert fishes of western North America.
Many species have evolved or currently coexist in sympatry due to differential adaptation in a heterogeneous environment. However, anthropogenic habitat modifications can either disrupt reproductive barriers or obscure environmental conditions which underlie fitness gradients. In this study, we evaluated the potential for an anthropogenically-mediated shift in reproductive boundaries that separate two historically sympatric fish species (Gila cypha and G. robusta) endemic to the Colorado River Basin using ddRAD sequencing of 368 individuals. We first examined the integrity of reproductive isolation while in sympatry and allopatry, then characterized hybrid ancestries using genealogical assignment tests. We tested for localized erosion of reproductive isolation by comparing site-wise genomic clines against global patterns and identified a breakdown in the drainage-wide pattern of selection against interspecific heterozygotes. This, in turn, allowed for the formation of a hybrid swarm in one tributary, and asymmetric introgression where species co-occur. We also detected a weak but significant relationship between genetic purity and degree of consumptive water removal, suggesting a role for anthropogenic habitat modifications in undermining species boundaries or expanding historically limited introgression. In addition, results from basin-wide genomic clines suggested that hybrids and parental forms are adaptively nonequivalent. If so, then a failure to manage for hybridization will exacerbate the long-term extinction risk in parental populations. These results reinforce the role of anthropogenic habitat modification in promoting interspecific introgression in sympatric species by relaxing divergent selection. This, in turn, underscores a broader role for hybridization in decreasing global biodiversity within rapidly deteriorating environments.


Functional modulation of brain sodium channels by protein kinase C phosphorylation.
Voltage-gated sodium channels, which are responsible for the generation of action potentials in the brain, are phosphorylated by protein kinase C (PKC) in purified form. Activation of PKC decreases peak sodium current up to 80 percent and slows its inactivation for sodium channels in rat brain neurons and for rat brain type IIA sodium channel alpha subunits heterologously expressed in Chinese hamster ovary cells. These effects are specific for PKC because they can be blocked by specific peptide inhibitors of PKC and can be reproduced by direct application of PKC to the cytoplasmic surface of sodium channels in excised inside-out membrane patches. Modulation of brain sodium channels by PKC is likely to have important effects on signal transduction and synaptic transmission in the central nervous system.


Applications of quadtree, octree, and binary tree decomposition techniques to shape analysis and pattern recognition.
The binary tree, quadtree, and octree decomposition techniques are widely used in computer graphics and image processing problems. Here, the techniques are reexamined for pattern recognition and shape analysis applications. It has been shown that the quadtree and octree techniques can be used to find the shape hull of a set of points in space while their n-dimensional generalization can be used for divisive hierarchical clustering. Similarly, an n-dimensional binary tree decomposition of feature space can be used for efficient pattern classifier design. Illustrative examples are presented to show the usefulness and efficiency of these hierarchical decomposition techniques.


Shiga toxins: intracellular trafficking to the ER leading to activation of host cell stress responses.
Despite efforts to improve hygenic conditions and regulate food and drinking water safety, the enteric pathogens, Shiga toxin-producing Escherichia coli (STEC) and Shigella dysenteriae serotype 1 remain major public health concerns due to widespread outbreaks and the severity of extra-intestinal diseases they cause, including acute renal failure and central nervous system complications. Shiga toxins are the key virulence factors expressed by these pathogens mediating extra-intestinal disease. Delivery of the toxins to the endoplasmic reticulum (ER) results in host cell protein synthesis inhibition, activation of the ribotoxic stress response, the ER stress response, and in some cases, the induction of apoptosis. Intrinsic and/or extrinsic apoptosis inducing pathways are involved in executing cell death following intoxication. In this review we provide an overview of the current understanding Shiga toxin intracellular trafficking, host cellular responses to the toxin and ER stress-induced apoptosis with an emphasis on recent findings.


Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription.
The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPR(ER)) to restore ER homeostasis. The AAA(+) ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPR(ER) genes. Although the mechanisms associated with protein degradation are now well established, the molecular events involved in the regulation of gene transcription by p97/CDC-48 remain unclear. Using a reporter-based genome-wide RNAi screen in combination with quantitative proteomic analysis in Caenorhabditis elegans, we have identified RUVB-2, a AAA(+) ATPase, as a novel repressor of a subset of UPR(ER) genes. We show that degradation of RUVB-2 by CDC-48 enhances expression of ER stress response genes through an XBP1-dependent mechanism. The functional interplay between CDC-48 and RUVB-2 in controlling transcription of select UPR(ER) genes appears conserved in human cells. Together, these results describe a novel role for p97/CDC-48, whereby its role in protein degradation is integrated with its role in regulating expression of ER stress response genes.


Beyond the data deluge: data integration and bio-ontologies.
Biomedical research is increasingly a data-driven science. New technologies support the generation of genome-scale data sets of sequences, sequence variants, transcripts, and proteins; genetic elements underpinning understanding of biomedicine and disease. Information systems designed to manage these data, and the functional insights (biological knowledge) that come from the analysis of these data, are critical to mining large, heterogeneous data sets for new biologically relevant patterns, to generating hypotheses for experimental validation, and ultimately, to building models of how biological systems work. Bio-ontologies have an essential role in supporting two key approaches to effective interpretation of genome-scale data sets: data integration and comparative genomics. To date, bio-ontologies such as the Gene Ontology have been used primarily in community genome databases as structured controlled terminologies and as data aggregators. In this paper we use the Gene Ontology (GO) and the Mouse Genome Informatics (MGI) database as use cases to illustrate the impact of bio-ontologies on data integration and for comparative genomics. Despite the profound impact ontologies are having on the digital categorization of biological knowledge, new biomedical research and the expanding and changing nature of biological information have limited the development of bio-ontologies to support dynamic reasoning for knowledge discovery.


Trauma mortality in mature trauma systems: are we doing better? An analysis of trauma mortality patterns, 1997-2008.
Advances in care such as damage control surgery, hemostatic resuscitation, protocol-driven cerebral perfusion management, and lung-protective ventilation have promised to improve survival after major trauma. We examined injury severity, mortality, and preventability in a mature trauma system during a 12-year period to assess the overall benefits of these and other improvements. Using the institutional trauma registry and the quality management database, we analyzed the outcome and the cause of death for all primary trauma admissions from July 1, 1996, to June 30, 2008, and linked these data with patient demographics, hospital length of stay, time to death, predicted probability of survival, and peer review of in-hospital deaths. Through fiscal year (FY) 2007, primary trauma admissions increased in number, injury severity, and age. Performance benchmarked against predicted probability of survival improved. Mortality through this era ranged from 3% to 3.7% and worsened slightly overall (p = 0.04). However, among those patients admitted with Injury Severity Score 17-25, survival improved significantly (p = 0.0003). Traumatic brain injury (TBI) accounted for 51.6% of deaths; acute hemorrhage, 30%; and multiple organ failure, 10.5%. Median time to death for uncontrollable hemorrhage, TBI, multiple organ failure was 2 hours, 24 hours, and 15 days, respectively. These patterns did not change significantly over time. Survival after severe trauma and survival benchmarked against predicted risk improved significantly at our center during the past 12 years despite generally increasing age and worsening injuries. Advances in trauma care have kept pace with an aging population and greater severity of injury, but overall survival has not improved.


Weight loss in tumour-bearing mice is not associated with changes in resistin gene expression in white adipose tissue.
Resistin, a product of white adipose tissue, is postulated to induce insulin resistance in obesity and regulate adipocyte differentiation. The aim of this study was to examine resistin gene expression in adipose tissue from mice bearing the MAC16 adenocarcinoma, which induces cancer cachexia with marked wasting of adipose tissue and skeletal muscle mass. MAC16-bearing mice lost weight progressively over the period following tumour transplantation, while the weight of control mice remained stable. Leptin mRNA in gonadal fat was 50 % lower in MAC16 mice than in controls (p < 0.05). Plasma insulin concentrations were also significantly lower in the MAC16 group (p < 0.05). However, resistin mRNA level in gonadal fat in MAC16 mice was similar to controls (94 % of controls). Thus, despite severe weight loss and significant falls in leptin expression and insulin concentration, resistin gene expression appears unchanged in white adipose tissue of mice with MAC16 tumour. Maintenance of resistin production may help inhibit the formation of new adipocytes in cancer cachexia.


A member of the phylogenetically conserved CAD family of transcriptional regulators is dramatically up-regulated during the programmed cell death of skeletal muscle in the tobacco hawkmoth Manduca sexta.
The intersegmental muscles (ISMs) of the tobacco hawkmoth Manduca sexta participate in the emergence behavior of the adult moth at the end of metamorphosis and then die during the subsequent 30-hr period. The trigger for this death is a decline in the circulating titer of the insect molting hormone 20-hydroxyecdysone (20-HE). Previous work has demonstrated that the ability of the ISMs to die is dependent on new gene expression. Using a differential hybridization cloning strategy, a cDNA library made from the ISMs committed to die was screened, and four up-regulated clones were isolated. One clone, 18-56, was selected for this study. Northern and Western analysis demonstrated that while clone 18-56 was expressed in all tissues examined and during every stage of ISM development, there was a dramatic increase in expression at both mRNA and protein levels when the ISMs became committed to die. If ISM death was delayed by an injection of 20-HE on the day proceeding adult emergence, 18-56 expression remained at basal levels. Immunocytochemistry demonstrated that 18-56 protein was located predominantly in nuclei prior to the commitment of the ISMs to die and then accumulated to high levels in cytoplasm at the time of cell death. DNA sequence analysis revealed that 18-56 protein shares 74% identity with yeast SUG1 and 92% with human Trip1, both of which are members of the conserved CAD (Conserved ATPase-containing Domain) family of putative transcriptional regulators. To verify that these genes shared functional as well as sequence homology, Manduca clone 18-56 was transformed into a yeast mutant for SUG1 function. Manduca 18-56 was able to both complement the lethal SUG1 phenotype and to suppress the transcriptional activity of a SUG1 mutation in yeast. Taken together, these data support the hypothesis that members of the phylogenetically conserved CAD family participate in important basal and developmental processes.


Training Pediatric Fellows in Palliative Care: A Pilot Comparison of Simulation Training and Didactic Education.
Pediatric fellows receive little palliative care (PC) education and have few opportunities to practice communication skills. In this pilot study, we assessed (1) the relative effectiveness of simulation-based versus didactic education, (2) communication skill retention, and (3) effect on PC consultation rates. Thirty-five pediatric fellows in cardiology, critical care, hematology/oncology, and neonatology at two institutions enrolled: 17 in the intervention (simulation-based) group (single institution) and 18 in the control (didactic education) group (second institution). Intervention group participants participated in a two-day program over three months (three simulations and videotaped PC panel). Control group participants received written education designed to be similar in content and time. (1) Self-assessment questionnaires were completed at baseline, post-intervention and three months; mean between-group differences for each outcome measure were assessed. (2) External reviewers rated simulation-group encounters on nine communication domains. Within-group changes over time were assessed. (3) The simulation-based site's PC consultations were compared in the six months pre- and post-intervention. Compared to the control group, participants in the intervention group improved in self-efficacy (p = 0.003) and perceived adequacy of medical education (p < 0.001), but not knowledge (p = 0.20). Reviewers noted nonsustained improvement in four domains: relationship building (p = 0.01), opening discussion (p = 0.03), gathering information (p = 0.01), and communicating accurate information (p = 0.04). PC consultation rate increased 64%, an improvement when normalized to average daily census (p = 0.04). This simulation-based curriculum is an effective method for improving PC comfort, education, and consults. More frequent practice is likely needed to lead to sustained improvements in communication competence.


Treatment of discarded blood units: disinfection with hypochlorite / formalin versus steam sterilization.
Blood bank regulations and bio medical waste rules of India advocate disinfection of contaminated blood units. Incineration is not recommended due to poly-vinyl chloride (PVC) content of blood bags. This study was designed to evaluate the efficacy of chemical disinfection of blood units deliberately contaminated with Staphylococcus aureus and E. coli with 1 and 6 % hypochlorite, 10% formalin and 33% formaldehyde and autoclaving of blood units contaminated with the above mentioned vegetative forms and B. stearothermophilus spores. Only 33 % formaldehyde could bring about 5 log reduction of bacteria but it is highly irritating and toxic. Autoclaving at 15 lbs pressure for 2 hours uniformly inactivated the vegetative forms and B. stearothermophilus spores. Thus, autoclaving of PVC blood bags is a safer and reliable method compared to chemical disinfection.


The skin as a medium for sensory substitution.
The last 50 years or so has seen great optimism concerning the potential of sensory substitution and augmentation devices to enhance the lives of those with (or even those without) some form of sensory loss (in practice, this has typically meant those who are blind or suffering from low vision). One commonly discussed solution for those individuals who are blind has been to use one of a range of tactile-visual sensory substitution systems that represent objects captured by a camera as outline images on the skin surface in real-time (what Loomis, Klatzky and Giudice, 2012, term general-purpose sensory substitution devices). However, despite the fact that touch, like vision, initially codes information spatiotopically, I would like to argue that a number of fundamental perceptual, attentional, and cognitive limitations constraining the processing of tactile information mean that the skin surface is unlikely ever to provide such general-purpose sensory substitution capabilities. At present, there is little evidence to suggest that the extensive cortical plasticity that has been demonstrated in those who have lost (or never had) a sense can do much to overcome the limitations associated with trying to perceive high rates of spatiotemporally varying information presented via the skin surface (no matter whether that surface be the back, stomach, forehead, or tongue). Instead, the use of the skin will likely be restricted to various special-purpose devices that enable specific activities such as navigation, the control of locomotion, pattern perception, etc.


Staying alive: dalmation mediated blocking of apoptosis is essential for tissue maintenance.
In an EMS screen for mutations disrupting tracheal development, we identified new alleles of the dalmation (dmt) gene, which had previously been shown to affect peripheral nervous system (PNS) development. Here, we demonstrate that dmt loss results in programmed cell death, disrupting PNS patterning and leading to large gaps in the salivary duct and trachea. Dmt loss results in increased expression of the proapoptotic regulator genes head involution defective (hid) and reaper (rpr), and deletion of these genes or tissue-specific expression of the baculoviral apoptotic inhibitor P35 rescues the dmt defects. dmt is also required to protect cells from irradiation induced expression of hid and rpr during the irradiation resistant stage, which begins as cells become irreversibly committed to their final fates. Thus, we propose that Dmt keeps cells alive by blocking activation of hid and rpr as cells become irreversibly committed.


Pattern formation in 8-cell composite embryos of Xenopus laevis.
We have shown in defect experiments that an 8-cell embryo of Xenopus laevis consists of three kinds of cells, that is, animal, vegetal dorsal and vegetal ventral cells, and that cells of different kinds are distinctly different in their developmental capacity. Complete pattern formation occurs in any defect embryo which contains at least two animal, one vegetal dorsal and one vegetal ventral cell. In the present transplantation experiments, we replaced one or two cells of one 8-cell embryo by those of another to obtain 29 series of composite embryos, in which the cell composition of an embryo and/or the dorsoventral orientation of individual cells differed from those of a normal 8-cell embryo. The resulting embryos were examined macroscopically when controls reached stage 26 (tailbud stage) and later. The results showed that both the two animal dorsal cells or one vegetal dorsal cell could be replaced by animal ventral cells or a vegetal ventral cell, respectively, without any detectable effect on pattern formation, irrespective of the ventrodorsal direction of the ventral cells. On the other hand, replacement of an animal ventral or a vegetal ventral cell by an animal dorsal or a vegetal dorsal cell, respectively, made most composite embryos twins. Twins were also formed when a left-handed vegetal dorsal cell was replaced by a right-handed counterpart and vice versa. In these composite embryos, the dorsoventral orientation of the transplanted cell was different from that of a resident dorsal cell or cells of a recipient, and several lines of evidence show that the dorsal cell transplanted in an off-axis orientation is responsible for twin formation. Thus, dorsal cells have the capacity to form dorsal axial structures at later stages and this capacity is localized on the dorsal side, and endows the cells with polarity. On the other hand, ventral cells did not have this capacity or polarity, judging from the fact that their orientation had no effect on pattern formation. One vegetal dorsal or ventral cell could be replaced by an animal dorsal or ventral cell, respectively, without any marked effect. However, replacement of two vegetal cells by animal ones and of one or two animal cells by vegetal ones resulted in deficiency of vegetal cells and oedema and in deficiency of animal cells and incomplete invagination, respectively. Twin formation in composite embryos with animal dorsal cells in place of animal ventral ones is discussed in consideration of findings in recombination experiments by Nieuwkoop.


17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis.
Estradiol (E2) stimulates the growth and inflammation in the ectopic endometriotic tissue that commonly resides on the pelvic organs. Several clinical and laboratory-based observations are indicative of resistance to progesterone action in endometriosis. The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptor (PR). In normal endometrium, progesterone acts via PR on stromal cells to induce secretion of paracrine factor(s) that in turn stimulate neighboring epithelial cells to express the enzyme 17beta-hydroxysteroid dehydrogenase type 2 (HSD17B2). HSD17B2 is an extremely efficient enzyme and rapidly metabolizes the biologically potent estrogen E2 to weakly estrogenic estrone. In endometriotic tissue, progesterone is incapable of inducing epithelial HSD17B2 expression due to a defect in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate HSD17B2 may be due to the very low levels of PR observed in vivo in endometriotic tissue. The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this mitogen. The molecular details of this physiological paracrine interaction between the stroma and epithelium in normal endometrium and its lack thereof in endometriosis are discussed.


Conversion of Norepinephrine to 3,4-Dihdroxymandelic Acid in Escherichia coli Requires the QseBC Quorum-Sensing System and the FeaR Transcription Factor.
The detection of norepinephrine (NE) as a chemoattractant by Escherichia coli strain K-12 requires the combined action of the TynA monoamine oxidase and the FeaB aromatic aldehyde dehydrogenase. The role of these enzymes is to convert NE into 3,4-dihydroxymandelic acid (DHMA), which is a potent chemoattractant sensed by the Tsr chemoreceptor. These two enzymes must be induced by prior exposure to NE, and cells that are exposed to NE for the first time initially show minimal chemotaxis toward it. The induction of TynA and FeaB requires the QseC quorum-sensing histidine kinase, and the signaling cascade requires new protein synthesis. Here, we demonstrate that the cognate response regulator for QseC, the transcription factor QseB, is also required for induction. The related quorum-sensing kinase QseE appears not to be part of the signaling pathway, but its cognate response regulator, QseF, which is also a substrate for phosphotransfer from QseC, plays a nonessential role. The promoter of the feaR gene, which encodes a transcription factor that has been shown to be essential for the expression of tynA and feaB, has two predicted QseB-binding sites. One of these sites appears to be in an appropriate position to stimulate transcription from the P1 promoter of the feaR gene. This study unites two well-known pathways: one for expression of genes regulated by catecholamines (QseBC) and one for expression of genes required for metabolism of aromatic amines (FeaR, TynA, and FeaB). This cross talk allows E. coli to convert the host-derived and chemotactically inert NE into the potent bacterial chemoattractant DHMA.IMPORTANCE The chemotaxis of E. coli K-12 to norepinephrine (NE) requires the conversion of NE to 3,4-dihydroxymandleic acid (DHMA), and DHMA is both an attractant and inducer of virulence gene expression for a pathogenic enterohemorrhagic E. coli (EHEC) strain. The induction of virulence by DHMA and NE requires QseC. The results described here show that the cognate response regulator for QseC, QseB, is also required for conversion of NE into DHMA. Production of DHMA requires induction of a pathway involved in the metabolism of aromatic amines. Thus, the QseBC sensory system provides a direct link between virulence and chemotaxis, suggesting that chemotaxis to host signaling molecules may require that those molecules are first metabolized by bacterial enzymes to generate the actual chemoattractant.


Celastrol Alleviates Mitochondrial Oxidative Stress and Brain Injury After Intracerebral Hemorrhage by Promoting OPA1-Dependent Mitochondrial Fusion.
Mitochondrial oxidative stress is one of the characteristics of secondary brain injury (SBI) after intracerebral hemorrhage (ICH), contributing largely to the apoptosis of neurons. Celastrol, a quinone methide triterpene that possesses antioxidant and mitochondrial protective properties, has emerged as a neuroprotective agent. However, the activity of celastrol has not been tested in ICH-induced SBI. In this study, we found that celastrol could effectively alleviate neurological function deficits and reduce brain oedema and neuronal apoptosis caused by ICH. Through electron microscopy, we found that celastrol could significantly attenuate mitochondrial morphology impairment. Therefore, we tested the regulatory proteins of mitochondrial dynamics and found that celastrol could reverse the downwards trend of OPA1 expression after ICH. In view of this, by culturing OPA1-deficient primary neurons and constructing neuron-specific OPA1 conditional knockout mice, we found that the protective effects of celastrol on mitochondrial morphology and function after ICH were counteracted in the absence of OPA1. Further experiments also showed that OPA1 is indispensable for the protective effects of celastrol on ICH-induced secondary brain injury. In summary, we have demonstrated that celastrol is a potential drug for the treatment of ICH and have revealed a novel mechanism by which celastrol exerts its antioxidant effects by promoting OPA1-mediated mitochondrial fusion.


Infected myocardial hydatid cyst imitating left ventricular aneurysm.
We report a case of infected intracardiac hydatid cyst in a patient who had complaints of chest pain, exertional dyspnea, palpitation, evening fever and fatigue. Echocardiography demonstrated a left ventricular apical cystic mass in 7 cm diameter. Magnetic resonance imaging and hemagglutination test confirmed the diagnosis. Single capsulated cyst full of pus was surgically removed by using cardio-pulmonary bypass. Histopathological examination revealed an infected hydatid cyst. Postoperative recovery was uneventful and the patient remains free of symptoms after one year of follow-up.


[Development, identification and application of 33 monoclonal antibodies against cardiac troponin T].
The aim of this study is to prepare and characterize cardiac troponin T (cTnT) monoclonal antibodies (mAb), and further develop a chemiluminescence quantitative detection assay for cTnT. BALB/c mice were immunized with recombinant cTnT antigen, and specific mAbs were prepared using conventional hybridoma technique and screened by indirect ELISA method. To identify the epitopes, several cTnT peptide fragments were synthesized or expressed by genetic engineering. A double antibody sandwich ELISA method was used to screen the mAb pairs for cTnT detection, and the automatic chemiluminescence detection assay for cTnT was developed. In total 220 clinical specimens were used for system comparison between our assay and Roche cTnT assay; further performance characteristics was evaluated by testing 238 clinical samples and 784 physical examination samples. We successfully screened 33 strains of hybridoms against cTnT, and the mAbs' epitopes were identified. Mab E16H8 and C8G11 with a detection limit of 10 pg/mL cTnT antigen were selected to develop the full automatic chemiluminescence quantitative assay. The correlation coefficient of our reagent with Roche's was 0.959 9, with a coincidence rate of 95%. The assay presented a sensitivity of 97.5%, and a specificity of 99.15% in detection of clinical samples. The cTnT concentration was less than 0.080 6 ng/mL in 99% of general population, which agrees with the definition of WHO on patients with acute myocardial infarction (AMI). In summary, we developed monoclonal antibodies against predominant epitopes for diagnostics of cTnT, and an automatic tubular chemiluminescence quantitative detection assay was further developed, which presents a high coincidence rate with Roche's.


Fattening performance and carcass traits of Baladi and Shami-Baladi kids.
Goat is considered very important ruminant animals that are raised in Jordan; however, the production of the local breeds is low to moderate, and thus, some genetic improvement programs could have a positive effect on the performance of the local breeds. The objective of this study was to investigate the effect of crossing Baladi (BB) goat with Shami. A total of 30 newly weaned goat kids (15 BB and 15Shami-Baladi [SB] kids) were evaluated for growth performance and carcass traits. The trial lasted for 77 days (7 days for adaptation and 70 days for data collection). Feed intake was measured on a daily basis; body weight of kids was measured at the beginning of the study and biweekly thereafter. At the end of the trial, kids were slaughtered to examine carcass traits. Dry matter intake, initial weight, final weight, and average daily gain (ADG) were not affected by kid's breed type. In addition, breed type of kids showed no significant effect on feed efficiency (feed:gain). Hot and cold carcass weight and dressing percentage were also not affected by kid's breed type. Kid breed type had no significant effect on shoulder, rack, and legs percentages. However, SB kids had a higher loin cut percentage compared to BB kids. In addition, Musculus longissimus depth was higher for SB kids. Results of this study indicate that crossing SB goat breeds did not have a significant effect on either growth performance or carcass traits. Further studies using reciprocal cross may reveal different results.


Risk models for patients with localised renal cell carcinoma.
We conducted a retrospective analysis of our series to assess the factors that influenced disease-free survival (DFS) and cancer-specific survival (CSS) for patients with localised renal cell carcinoma (RCC). We also created our own risk groups. Between January 1990 and December 2012, 596 patients underwent surgery for localised RCC (clear cell, papillary or chromophobe). Using Cox regression models, we analysed the clinical-pathological variables that influenced DFS and CSS and designed risk groups for DFS and CSS with the variables. The median follow-up for the series was 5.96 years. By the end of the study, 112 patients (18.8%) had a recurrence of the disease, with DFS rates of 82%, 77% and 72% at 5, 10 and 15 years, respectively. The independent factors that influenced DFS in the multivariate study were the following: A Furhman grade of 3-4, haematuria, lymphocytic or vascular invasion, the presence of tumour necrosis and a disease stage pT3-pT4. Furthermore, by the end of the study, 57 patients (9.6%) died due to renal cancer, with CSS rates of 92%, 86% and 83% at 5, 10 and 15 years, respectively. The independent factors that influenced CSS in the multivariate study were the following: A Furhman grade of 3-4, perinephric fat invasion and the presence of tumour necrosis. Factors in addition to the disease stage pT3-pT4 in patients with localised RCC are important, such as the presence of haematuria and lymphocytic or vascular invasion for DFS. A Furhman grade of 3-4 and the presence of tumour necrosis are especially relevant for DFS and CSS.


Unexpected Cartilage Phenotype in CD4-Cre-Conditional SOS-Deficient Mice.
RAS signaling is central to many cellular processes and SOS proteins promote RAS activation. To investigate the role of SOS proteins in T cell biology, we crossed Sos1f/fSos2-/- mice to CD4-Cre transgenic mice. We previously reported an effect of these mutations on T cell signaling and T cell migration. Unexpectedly, we observed nodules on the joints of greater than 90% of these mutant mice at 5 months of age, especially on the carpal joints. As the mice aged further, some also displayed joint stiffness, hind limb paralysis, and lameness. Histological analysis indicated that the abnormal growth in joints originated from dysplastic chondrocytes. Second harmonic generation imaging of the carpal nodules revealed that nodules were encased by rich collagen fibrous networks. Nodules formed in mice also deficient in RAG2, indicating that conventional T cells, which undergo rearrangement of the T cell antigen receptor, are not required for this phenotype. CD4-Cre expression in a subset of cells, either immune lineage cells (e.g., non-conventional T cells) or non-immune lineage cells (e.g., chondrocytes) likely mediates the dramatic phenotype observed in this study. Disruptions of genes in the RAS signaling pathway are especially likely to cause this phenotype. These results also serve as a cautionary tale to those intending to use CD4-Cre transgenic mice to specifically delete genes in conventional T cells.


[Bladder exstrophy-epispadias complex: management and preliminary results].
Retrospective evaluation of operative techniques and perioperative management as related to the primary anatomical and functional situation as well as analysis of the preliminary postoperative results regarding kidney function, continence and complications. From October 1992 to April 2003, 21 patients with bladder exstrophy-epispadias complex were treated, consisting of 12 children with untreated exstrophy and 9 who had undergone unsuccessful previous operations. Single-stage complete repair using the Erlangen concept was done during the first weeks of life in 8 infants and before school age in 3 children. One 13 year old girl had received a primary Mainz pouch II. The 9 unsuccessfully operated patients required a variety of different operations. The mean follow-up of 17 regularly controlled children was 62 months (range 3 to 129 months). In all children global kidney function remained stable, while reflux or obstruction was responsible for impaired unilateral split function ranging between 31 % and 45 % in 5. Four children were continent day and night after complete single-stage repair, 4 after ureterosigmoidostomy or Mainz pouch II and 5 after augmentation. In the newborn with previously untreated exstrophy-epispadias, we recommend single-stage complete functional reconstruction within the first weeks of life. Continence without loss of kidney function can be achieved in 50 % of these children. If adequate bladder capacity and continence cannot be achieved, an augmentation procedure or Mainz pouch II is our method of choice.


[Benign schwannomas of the nasal cavity: report of one case].
The authors report one rare case of enormous benign nasal schwannoma. One side nasal obstruction and whitish aspect of tumor at the end nasal exam are the most common signs seen in all patients. This type of tumor is very rare pathology in the surgeons practice. Despite the case that it is not a Cancer, Schwannoma maybe very dangerous pathology. Radiologically, we have noted large tumor and calcification within the tumor. Histological diagnosis may sometimes be difficult and needs the immunohistochemical assessment. Complete tumor resection is the best way to cure the definitively the patients without tumor recurrence.


Risk communication during disease outbreak response in post-Ebola Liberia: experiences in Sinoe and Grand Kru counties.
Lessons learned from the Ebola virus disease (EVD) outbreak enabled Liberia to develop a health plan for strengthening public health capacity against potential public health threats. risk communication is one of the core pillars that provide life-saving information and knowledge for the public to take preventive and proactive actions against public health threats. These were applied in response to the post-ebola meningococcal septicemia and meningitis outbreaks in Sinoe and Grand Kru counties. This paper documents risk communication experiences in these post-ebola outbreaks in Liberia. Risk Communication and health promotion strategies were deployed in developing response plans and promptly disseminating key messages to affected communities to mitigate the risks. Other strategies included engagement of community leaders, partnership with the media and dissemination of messages through the community radios, active monitoring community risk perceptions and compliance, rumor management, mobile stage and interpersonal communication (IPC) during the Meningococcal disease outbreaks in Sinoe and Grand Kru counties. In Sinoe, about 36,891 households or families in 10 health districts were reached through IPC and dialogue. Circulating rumors such as "Ebola" was the cause of deaths was timely and promptly mitigated. There was increased trust and adherence to health advice including prompt reporting of sick people to the nearest health facility in the two counties. Risk communication and health promotion encouraged community support and involvement in any response to public threats and events. No doubt, risk communication and health promotion play an important role in preparedness and response to public health emergencies.


Screening for Alzheimer's disease among illiterate elderly: accuracy analysis for multiple instruments.
One of the challenges in screening for dementia in developing countries is related to performance differences due to educational and cultural factors. This study evaluated the accuracy of single screening tests as well as combined protocols including the Mini-Mental State Examination (MMSE), Verbal Fluency animal category (VF), Clock Drawing test (CDT), and Pfeffer Functional Activities Questionnaire (PFAQ) to discriminate illiterate elderly with and without Alzheimer's disease (AD) in a clinical sample. Cross-sectional study with 66 illiterate outpatients diagnosed with mild and moderate AD and 40 illiterate normal controls. Diagnosis of AD was based on NINCDS-ADRDA. All patients were submitted to a diagnostic protocol including a clinical interview based on the CAMDEX sections. ROC curves area analyses were carried out to compare sensitivity and specificity for the cognitive tests to differentiate the two groups (each test separately and in two by two combinations). Scores for all cognitive (MMSE, CDT, VF) and functional assessments (PFAQ) were significantly different between the two groups (p < 0.001). The best screening instruments for this sample of illiterate elderly were the MMSE and the PFAQ. The cut-off scores for the MMSE, VF, CDT, and PFAQ were 17.5, 7.5, 2.5, and 11.5, respectively. The most sensitive combination came from the MMSE and PFAQ (94.1%), and the best specificity was observed with the combination of the MMSE and CDT (89%). Illiterate patients can be successfully screened for AD using well-known screening instruments, especially in combined protocols.


Postmenopausal bone mineral density: relationship to calcium intake, calcium absorption, residual estrogen, body composition, and physical activity.
Physical and lifestyle data were collected from 62 postmenopausal women who had declined hormone replacement therapy. Potential predictor variables were examined for their associations with bone mineral density (BMD) of the lumbar spine and femoral neck as assessed by dual x-ray absorptiometry. Body weight demonstrated the strongest association with lumbar BMD; lean body mass demonstrated the strongest association with femoral BMD. Together with the natural logarithm of the number of years since menopause (ln YSM) these anthropometric variables explained 36 and 34% of the variability of femoral and lumbar BMD, respectively. Serum estradiol levels demonstrated a weak positive association with BMD, which lost statistical significance after adjustment for body mass. Similarly, cardiovascular fitness was positively associated with femoral BMD prior to but not following adjustment for body mass. Controlling for years since menopause and body mass, the product of dietary calcium and calcium absorption demonstrated a weak positive correlation with femoral BMD (partial r = 0.30). The intake of tea was positively and significantly associated with both bone density measurements. In multiple regression analysis, femoral BMD was best explained by the lean body mass, ln YSM, and the daily intake of tea (r2 = 0.50). Similarly, lumbar BMD was best explained by body weight, ln YSM, and intake of tea (r2 = 0.44). Body mass is a major predictor of postmenopausal bone density at the hip and spine. A positive association between dietary calcium and BMD was detected only by taking into account the intestinal absorptive efficiency.


Functional and morphologic benefits in early detection of neovascular age-related macular degeneration using the preferential hyperacuity perimeter.
To estimate the usefulness of preferential hyperacuity perimetry (PHP) in detecting conversion of early to late age-related macular degeneration in the Carotenoids and co-antioxidants in patients with Age-Related Maculopathy, a multicenter randomized controlled clinical trial. This was a nested case control study within the Carotenoids and co-antioxidants in patients with Age-Related Maculopathy (CARMA) clinical trial and included all participants enrolled in a single center (n = 200). Data are from participants who progressed to neovascular age-related macular degeneration (nvAMD) during time on study, Group 1 (n = 10) before the use of PHP and Group 2 (n = 10) during use of PHP. We also randomly selected 21 other participants (Group 3) who did not progress to nvAMD during time on study as a control group. Change in best-corrected visual acuity and contrast sensitivity and size of neovascular lesion at detection of conversion to nvAMD in Groups 1 and 2. At detection of nvAMD, mean best-corrected visual acuity in Group 1 was 57.5 letters versus 67.4 in Group 2. In Group 1, the change in best-corrected visual acuity from baseline to detection of nvAMD was twice that of Group 2 (21.6 ± 9.0 versus 11.9 ± 10.7) with a mean difference of 9.7 letters (95% confidence interval, 0.41 to 19.0, P = 0.04, independent-samples t-test). The size of the neovascular lesion at detection was 3.06 mm in Group 1 versus 0.89 mm in Group 2 (P = 0.02). Two thirds of the participants in Group 2 were asymptomatic at detection of nvAMD compared with one fifth in Group 1. Preferential hyperacuity perimetry distortion maps were abnormal in 9 of 10 eyes in Group 2, which were confirmed by optical coherence tomography. Of the 21 eyes in Group 3, PHP maps were normal in 18 and abnormal in 3. Preferential hyperacuity perimetry detected abnormalities in central visual function with high reliability. Eyes with nvAMD lesions detected by PHP had smaller lesions and better function when compared with the group before the introduction of PHP. The false-negative rate was <10% on PHP. The PHP distortion map was helpful in alerting clinicians to the presence of subclinical nvAMD.


Methylphenidate significantly improves driving performance of adults with attention-deficit hyperactivity disorder: a randomized crossover trial.
Although patients with attention-deficit hyperactivity disorder (ADHD) have reported improved driving performance on methylphenidate, limited evidence exists to support an effect of treatment on driving performance and some regions prohibit driving on methylphenidate. A randomized, crossover trial examining the effects of methylphenidate versus placebo on highway driving in 18 adults with ADHD was carried out. After three days of no treatment, patients received either their usual methylphenidate dose (mean: 14.7 mg; range: 10-30 mg) or placebo and then the opposite treatment after a six to seven days washout period. Patients performed a 100 km driving test during normal traffic, 1.5 h after treatment administration. Standard deviation of lateral position (SDLP), the weaving of the car, was the primary outcome measure. Secondary outcome measurements included the standard deviation of speed and patient reports of driving performance. Driving performance was significantly better in the methylphenidate than in the placebo condition, as reflected by the SDLP difference (2.3 cm, 95% CI = 0.8-3.8, P = 0.004). Variation in speed was similar on treatment and on placebo (-0.05 km/h, 95% CI = -0.4 to 0.2, P = 0.70). Among adults with ADHD, with a history of a positive clinical response to methylphenidate, methylphenidate significantly improves driving performance.


In-depth analyses of lncRNA and circRNA expression in the hippocampus of LPS-induced AD mice by Byu d Mar 25.
Byu d Mar 25 (BM25) has been verified to have neuroprotective effects in Alzheimer's disease (AD) mice. However, the molecular mechanism remains unclear. We aimed to investigate the expression profiling of lncRNAs and circRNAs by microarray analysis. Six hippocampus from LPS-mediated AD mice model treated with (normal saline (NS) (n = 3) and AD mice model treated with BM25 (n = 3) were selected. Microarray analysis was performed to detect the expression profiles of lncRNAs and circRNAs in hippocampus. Differentially expressed (DE) lncRNAs, mRNAs and circRNAs were identified through scatter plot and volcano plot filtering with a threshold of fold-change ≥2 and P ≤ 0.05. Co-expression network is analyzed by Circos software. Cis - and Trans - regulation were analyzed using RIsearch-2.0 and FEELNC softwares. LncRNA-transcription factors (TFs) and LncRNA-Target-TFs network were analyzed by Clusterprofiler software. The prediction of miRNAs bind to circRNAs were performed with miRNAbase. A total of 113 DElncRNAs, 117 DEmRNAs, and 4 DEcircRNAs were detected. The pathway analysis showed the mRNAs that correlated with lncRNAs were involved in apoptosis, inflammatory mediator regulation of TRP channels, NF-kappa B and PI3K-Akt signaling pathway. The lncRNA-TFs network analysis suggested the lncRNAs were mostly regulated by Ncoa1, Phf5a, Klf6, Lmx1b, and Pax3. Additionally, lncRNA-target-TFs network analysis indicated the GATA6, Junb, Smad1, Twist1, and Mafb mostly regulate the same lncRNAs: XR_001783430.1 and NR_051982.1. Furthermore, 480 miRNAs were predicted binding to 4 identified circRNAs. The BM25 may affect AD by regulating the expression of lncRNAs and circRNAs, which could regulate the expressions of mRNAs or miRNAs by LncRNA-Target-TFs network.


A new zirconium inorganic building brick forming metal organic frameworks with exceptional stability.
Porous crystals are strategic materials with industrial applications within petrochemistry, catalysis, gas storage, and selective separation. Their unique properties are based on the molecular-scale porous character. However, a principal limitation of zeolites and similar oxide-based materials is the relatively small size of the pores, typically in the range of medium-sized molecules, limiting their use in pharmaceutical and fine chemical applications. Metal organic frameworks (MOFs) provided a breakthrough in this respect. New MOFs appear at a high and an increasing pace, but the appearances of new, stable inorganic building bricks are rare. Here we present a new zirconium-based inorganic building brick that allows the synthesis of very high surface area MOFs with unprecedented stability. The high stability is based on the combination of strong Zr-O bonds and the ability of the inner Zr6-cluster to rearrange reversibly upon removal or addition of mu3-OH groups, without any changes in the connecting carboxylates. The weak thermal, chemical, and mechanical stability of most MOFs is probably the most important property that limits their use in large scale industrial applications. The Zr-MOFs presented in this work have the toughness needed for industrial applications; decomposition temperature above 500 degrees C and resistance to most chemicals, and they remain crystalline even after exposure to 10 tons/cm2 of external pressure.


Cancer risks in ulcerative colitis patients.
Patients diagnosed with ulcerative colitis (UC) are known to be at an increased risk of colorectal and liver cancers and leukemia. UC is an autoimmune disease, which may present a wider spectrum of cancers. We wanted to examine the risk of cancer in a large population of UC patients in order to reach high statistical power. A UC research database was constructed by identifying UC patients from the Swedish Hospital Discharge Register and cancer patients from the Cancer Registry. Follow-up of 27,606 UC patients hospitalized for the first time during the years 1964-2004 identified 2,058 patients with cancer. Standardized incidence ratios were calculated for cancer in UC patients by comparing to subjects without hospitalization for UC. The novel tumor sites in UC patients included small intestinal (carcinoid), pancreatic, breast and prostate cancers, nonthyroid endocrine gland tumors, non-Hodgkin lymphoma and multiple myeloma. A total of 11 sites showed an increased risk, which remained at 6 sites when tumors diagnosed in the year of UC hospitalization were excluded; even chronic myeloid leukemia was in excess. Cancer risks depended on the age at first hospitalization for UC. The SIRs for colon, rectal, liver and pancreatic cancers declined by age at hospitalization for UC, while for endocrine tumors the older patients were at higher risk. Our large study identified novel subsequent cancers in UC patients. However, some of these, including small intestinal carcinoids, prostate cancers and nonthyroid endocrine tumors, may be in excess because of intensified medical surveillance of the patients.


Enhanced rat islet function and survival in vitro using a biomimetic self-assembled nanomatrix gel.
Peptide amphiphile (PA) is a peptide-based biomaterial that can self-assemble into a nanostructured gel-like scaffold, mimicking the chemical and biological complexity of natural extracellular matrix. To evaluate the capacity of the PA scaffold to improve islet function and survival in vitro, rat islets were cultured in three different groups--(1) bare group: isolated rat islets cultured in a 12-well nontissue culture-treated plate; (2) insert group: isolated rat islets cultured in modified insert chambers; (3) nanomatrix group: isolated rat islets encapsulated within the PA nanomatrix gel and cultured in modified insert chambers. Over 14 days, both the bare and insert groups showed a marked decrease in insulin secretion, whereas the nanomatrix group maintained glucose-stimulated insulin secretion. Moreover, entire islets in the nanomatrix gel stained positive for dithizone up to 14 days, indicating better maintained glucose-stimulated insulin production. Fluorescein diacetate/propidium iodide staining results also verified necrosis in the bare and insert groups after 7 days, whereas the PA nanomatrix gel maintained islet viability after 14 days. Thus, these results demonstrate the potential of PAs as an intermediary scaffold for increasing the efficacy of pancreatic islet transplantation.


Increased plasma-immune cytokines throughout the high-dose melphalan-induced lymphodepletion in patients with multiple myeloma: a window for adoptive immunotherapy.
High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is a standard treatment for patients with multiple myeloma. However, lymphocyte reconstitution is impaired after HDM. Recent work has suggested that the lymphopenia period occurring after various immunosuppressive or chemotherapy treatments may provide an interesting opportunity for adoptive antitumor immunotherapy. The objective of this study was to determine an immunotherapy window after HDM and ASCT, evaluating T cell lymphopenia, and measuring circulating immune cytokine concentrations in patients with multiple myeloma. The counts of T cell subpopulations reached a nadir at day 8 post-ASCT (day 10 post-HDM) and recovered by day 30. IL-6, IL-7, and IL-15 plasma levels increased on a median day 8 post-ASCT, respectively, 35-fold, 8-fold, and 10-fold compared with pre-HDM levels (p < or = 0.05). The increases in IL-7 and IL-15 levels were inversely correlated to the absolute lymphocyte count, unlike monocyte or myeloid counts. Furthermore, we have shown that CD3 T cells present in the ASC graft are activated, die rapidly when they are cultured without cytokine in vitro, and that addition of IL-7 or IL-15 could induce their survival and proliferation. In conclusion, the early lymphodepletion period, occurring 4-11 d post-HDM and ASCT, is associated with an increase of circulating immune cytokines and could be an optimal window to enhance the survival and proliferation of polyclonal T cells present in the ASC autograft and also of specific antimyeloma T cells previously expanded in vitro.


Limit-feeding a high-energy diet to meet energy requirements in the dry period alters plasma metabolite concentrations but does not affect intake or milk production in early lactation.
Limit-feeding dry cows a high-energy diet may enable adequate energy intake to be sustained as parturition approaches, thus reducing the extent of negative energy balance after parturition. Our objective was to evaluate the effect of dry period feeding strategy on plasma concentrations of hormones and metabolites that reflect energy status. Multiparous Holstein cows (n = 18) were dried off 45 d before expected parturition, paired by expected calving date, parity, and previous lactation milk yield, and randomly assigned to 1 of 2 dry-period diets formulated to meet nutrient requirements at ad libitum or limited intakes. All cows were fed the same diet for ad libitum intake after parturition. Prepartum dry matter intake (DMI) for limit-fed cows was 9.4 kg/d vs. 13.7 kg/d for cows fed ad libitum. During the dry period, limit-fed cows consumed enough feed to meet calculated energy requirements, and ad libitum-fed cows were in positive calculated net energy for lactation (NE(L)) balance (0.02 vs. 6.37 Mcal/d, respectively). After parturition, milk yield, milk protein concentration, DMI, body condition score, and body weight were not affected by the prepartum treatments. Cows limit fed during the dry period had a less-negative calculated energy balance during wk 1 postpartum. Milk fat concentration and yield were greater for the ad libitum treatment during wk 1 but were lower in wk 2 and 3 postpartum. Plasma insulin and glucose concentrations decreased after calving. Plasma insulin concentration was greater in ad libitum-fed cows on d -2 relative to calving, but did not differ by dietary treatment at other times. Plasma glucose concentrations were lower before and after parturition for cows limit-fed during the dry period. Plasma nonesterified fatty acid concentrations peaked after parturition on d 1 and 4 for the limit-fed and ad libitum treatments, respectively, and were greater for limit-fed cows on d -18, -9, -5, and -2. Plasma tumor necrosis factor-alpha concentrations did not differ by treatment in either the pre- or postpartum period, but tended to decrease after parturition. Apart from a reduction in body energy loss in the first week after calving, limit feeding a higher NE(L) diet during the dry period had little effect on intake and milk production during the first month of lactation.