Postcholecystectomy symptoms. A prospective study of gall stone patients before and two years after surgery.
The results of cholecystectomy in terms of symptomatic improvement were prospectively evaluated in 124 unselected gall stone patients interviewed before and two years after elective surgery. Indications for cholecystectomy were biliary pain (n = 65), previous complications of gall stone disease (n = 52), and flatulent dyspepsia (n = 7). At two years 93 patients could be re-evaluated, of whom only 49 (53%) were completely symptom free. Postcholecystectomy symptoms occurring in the remaining 44 patients were mainly flatulent dyspepsia (which had relapsed in 22 of 46 patients who suffered it preoperatively), dull abdominal pain or diarrhoea. Incisional hernia was present in five patients and one had recurrence of pain because of retained common bile duct stones. Symptomatic cures after cholecystectomy decreased with the duration of the preoperative history. The results reconfirm that cholecystectomy eradicates specific symptoms and complications of gall stone disease, but they also show that nearly one half of operated patients are dissatisfied with the procedure because of mild but distressing 'postcholecystectomy' symptoms. These are probably caused by previously undiagnosed functional gut disease associated with, but unrelated to, gall stones. A systemic approach to multisymptomatic patients with gall stones is recommended.


A 100-channel hermetically sealed implantable device for chronic wireless neurosensing applications.
A 100-channel fully implantable wireless broadband neural recording system was developed. It features 100 parallel broadband (0.1 Hz-7.8 kHz) neural recording channels, a medical grade 200 mAh Li-ion battery recharged inductively at 150 kHz , and data telemetry using 3.2 GHz to 3.8 GHz FSK modulated wireless link for 48 Mbps Manchester encoded data. All active electronics are hermetically sealed in a titanium enclosure with a sapphire window for electromagnetic transparency. A custom, high-density configuration of 100 individual hermetic feedthrough pins enable connection to an intracortical neural recording microelectrode array. A 100 MHz bandwidth custom receiver was built to remotely receive the FSK signal and achieved -77.7 dBm sensitivity with 10(-8) BER at 48 Mbps data rate. ESD testing on all the electronic inputs and outputs has proven that the implantable device satisfies the HBM Class-1B ESD Standard. In addition, the evaluation of the worst-case charge density delivered to the tissue from each I/O pin verifies the patient safety of the device in the event of failure. Finally, the functionality and reliability of the complete device has been tested on-bench and further validated chronically in ongoing freely moving swine and monkey animal trials for more than one year to date.


Polyoxygenated Cyclohexenes and Their Chlorinated Derivatives from the Leaves of Uvaria cherrevensis.
The chemical study of leaf extracts from Uvaria cherrevensis resulted in the identification of 11 new polyoxygenated cyclohexenes, cherrevenols A-K (1-11), and a new seco-cyclohexene derivative, cherrevenol L (12). Nine known compounds (13-21) were also isolated. Three of the isolated compounds are chlorinated polyoxygenated cyclohexenes. The structures of these compounds were determined using spectroscopic methods and, in some cases (compounds 2, 6, 8, and 10), single-crystal X-ray crystallographic structural analysis or chemical correlation (compounds 6 and 7). Compounds 6 and 7 were both isolated as scalemic mixtures (ee 23-24%).


Ligand-bound structures of the dengue virus protease reveal the active conformation.
Dengue is a mosquito-borne viral hemorrhagic disease that is a major threat to human health in tropical and subtropical regions. Here we report crystal structures of a peptide covalently bound to dengue virus serotype 3 (DENV-3) protease as well as the serine-protease inhibitor aprotinin bound to the same enzyme. These structures reveal, for the first time, a catalytically active, closed conformation of the DENV protease. In the presence of the peptide, the DENV-3 protease forms the closed conformation in which the hydrophilic β-hairpin region of NS2B wraps around the NS3 protease core, in a manner analogous to the structure of West Nile virus (WNV) protease. Our results confirm that flavivirus proteases form the closed conformation during proteolysis, as previously proposed for WNV. The current DENV-3 protease structures reveal the detailed interactions at the P4' to P3 sites of the substrate. The new structural information explains the sequence preference, particularly for long basic residues in the nonprime side, as well as the difference in substrate specificity between the WNV and DENV proteases at the prime side. Structural analysis of the DENV-3 protease-peptide complex revealed a pocket that is formed by residues from NS2B and NS3; this pocket also exists in the WNV NS2B/NS3 protease structure and could be targeted for potential antivirus development. The structural information presented in the current study is invaluable for the design of specific inhibitors of DENV protease.


The Biobanque québécoise de la COVID-19 (BQC19)-A cohort to prospectively study the clinical and biological determinants of COVID-19 clinical trajectories.
SARS-CoV-2 infection causing the novel coronavirus disease 2019 (COVID-19) has been responsible for more than 2.8 million deaths and nearly 125 million infections worldwide as of March 2021. In March 2020, the World Health Organization determined that the COVID-19 outbreak is a global pandemic. The urgency and magnitude of this pandemic demanded immediate action and coordination between local, regional, national, and international actors. In that mission, researchers require access to high-quality biological materials and data from SARS-CoV-2 infected and uninfected patients, covering the spectrum of disease manifestations. The "Biobanque québécoise de la COVID-19" (BQC19) is a pan-provincial initiative undertaken in Québec, Canada to enable the collection, storage and sharing of samples and data related to the COVID-19 crisis. As a disease-oriented biobank based on high-quality biosamples and clinical data of hospitalized and non-hospitalized SARS-CoV-2 PCR positive and negative individuals. The BQC19 follows a legal and ethical management framework approved by local health authorities. The biosamples include plasma, serum, peripheral blood mononuclear cells and DNA and RNA isolated from whole blood. In addition to the clinical variables, BQC19 will provide in-depth analytical data derived from the biosamples including whole genome and transcriptome sequencing, proteome and metabolome analyses, multiplex measurements of key circulating markers as well as anti-SARS-CoV-2 antibody responses. BQC19 will provide the scientific and medical communities access to data and samples to better understand, manage and ultimately limit, the impact of COVID-19. In this paper we present BQC19, describe the process according to which it is governed and organized, and address opportunities for future research collaborations. BQC19 aims to be a part of a global communal effort addressing the challenges of COVID-19.


Cadaverine is covalently linked to peptidoglycan in Selenomonas ruminantium.
Cadaverine was found to exist as a component of cell wall peptidoglycan of Selenomonas ruminantium, a strictly anaerobic bacterium. [14C]cadaverine added to the growth medium was incorporated into the cells, and about 70% of the total radioactivity incorporated was found in the peptidoglycan fraction. When the [14C]cadaverine-labeled peptidoglycan preparation was acid hydrolyzed, all of the 14C counts were recovered as cadaverine. The [14C]cadaverine-labeled peptidoglycan preparation was digested with lysozyme into three small fragments which were radioactive and were positive in ninhydrin reaction. One major spot, a compound of the fragments, was composed of alanine, glutamic acid, diaminopimelic acid, cadaverine, muramic acid, and glucosamine. One of the two amino groups of cadaverine was covalently linked to the peptidoglycan, and the other was free. The chemical composition of the peptidoglycan preparation of this strain was determined to be as follows: L-alanine-D-alanine-D-glutamic acid-meso-diaminopimelic acid-cadaverine-muramic acid-glucosamine (1.0:1.0:1.0:1.0:1.1:0.9:1.0).


Phospholipase D in Phytophthora infestans and its role in zoospore encystment.
We show that differentiation of zoospores of the late blight pathogen Phytophthora infestans into cysts, a process called encystment, was triggered by both phosphatidic acid (PA) and the G-protein activator mastoparan. Mastoparan induced the accumulation of PA, indicating that encystment by mastoparan most likely acts through PA. Likewise, mechanical agitation of zoospores, which often is used to induce synchronized encystment, resulted in increased levels of PA. The levels of diacylglycerolpyrophosphate (DGPP), the phosphorylation product of PA, increased simultaneously. Also in cysts, sporangiospores, and mycelium, mastoparan induced increases in the levels of PA and DGPP. Using an in vivo assay for phospholipase D (PLD) activity, it was shown that the mastoparan-induced increase in PA was due to a stimulation of the activity of this enzyme. Phospholipase C in combination with diacylglycerol (DAG) kinase activity also can generate PA, but activation of these enzymes by mastoparan was not detected under conditions selected to highlight 32P-PA production via DAG kinase. Primary and secondary butanol, which, like mastoparan, have been reported to activate G-proteins, also stimulated PLD activity, whereas the inactive tertiary isomer did not. Similarly, encystment was induced by n- and sec-butanol but not by tert-butanol. Together, these results show that Phytophthora infestans contains a mastoparan- and butanol-inducible PLD pathway and strongly indicate that PLD is involved in zoospore encystment. The role of G-proteins in this process is discussed.


Characterizing the time-perspective of nations with search engine query data.
Vast quantities of data on human behavior are being created by our everyday internet usage. Building upon a recent study by Preis, Moat, Stanley, and Bishop (2012), we used search engine query data to construct measures of the time-perspective of nations, and tested these measures against per-capita gross domestic product (GDP). The results indicate that nations with higher per-capita GDP are more focused on the future and less on the past, and that when these nations do focus on the past, it is more likely to be the distant past. These results demonstrate the viability of using nation-level data to build psychological constructs.


Comparing the Effect of Echinacea and Chlorhexidine Mouthwash on the Microbial Flora of Intubated Patients Admitted to the Intensive Care Unit.
Providing intubated patients admitted to the intensive care units with oral healthcare is one of the main tasks of nurses in order to prevent Ventilator-Associated Pneumonia (VAP). This study aimed at comparing the effects of two mouthwash solutions (echinacea and chlorhexidine) on the oral microbial flora of patients hospitalized in the intensive care units. In this clinical trial, 70 patients aged between18 and 65 years undergoing tracheal intubation through the mouth in three hospitals in Arak, were selected using simple random sampling and were randomly divided into two groups: the intervention group and the control group. The oral health checklist was used to collect the data (before and after the intervention). The samples were obtained from the orally intubated patients and were then cultured in selective media. Afterwards, the aerobic microbial growth was investigated in all culture media. The data were analyzed using SPSS software. The microbial flora in the echinacea group significantly decreased after the intervention (p < 0.0001) and it was also the case withmicrobial flora of the patients in the chlorhexidine group (p < 0.001). After 4 days, the oral microbial flora of the patients in the intervention group was lower than that of the patients in the control group (p < 0.001). The results showed that the echinacea solution was more effective in decreasing the oral microbial flora of patients in the intensive care unit. Given the benefits of the components of the herb Echinacea, it can be suggested as a viable alternative to chlorhexidine.


Single cell multi-omics characterise discrete human tendon cells populations that persist in vitro and on fibrous scaffolds.
Chronic tendinopathy represents a growing healthcare burden in the ageing global population. Curative therapies remain elusive as the mechanisms that underlie chronic inflammation in tendon disease remain unclear. Identifying and isolating key pathogenic and reparative cells is essential in developing precision therapies and implantable materials for improved tendon healing. Multiple discrete human tendon cell populations have been previously described ex vivo. To determine if these populations persist in vitro, healthy human hamstring tenocytes were cultured for 8 d on either tissue culture plastic or aligned electrospun fibres of absorbable polydioxanone. Novel single-cell surface proteomics combined with unbiased single-cell transcriptomics (CITE-Seq) was used to identify discrete tenocyte populations. 6 cell populations were found, 4 of which shared key gene expression determinants with ex vivo human cell clusters: PTX3_PAPPA, POSTN_SCX, DCN_LUM and ITGA7_NES. Surface proteomics found that PTX3_PAPPA cells were CD10+CD26+CD54+. ITGA7_NES cells were CD146+ and POSTN_SCX cells were CD90+CD95+CD10+. Culture on the aligned electrospun fibres favoured 3 cell subtypes (DCN_LUM, POSTN_SCX and PTX3_ PAPPA), promoting high expression of tendon-matrix-associated genes and upregulating gene sets enriched for TNF-a and IL-6/STAT3 signalling. Discrete human tendon cell subpopulations persisted in in vitro culture and could be recognised by specific gene and surface-protein signatures. Aligned polydioxanone fibres promoted the survival of 3 clusters, including pro-inflammatory PTX3-expressing CD10+CD26+CD54+ cells found in chronic tendon disease. These results improved the understanding of preferred culture conditions for different tenocyte subpopulations and informed the development of in vitro models of tendon disease.


Architecture of atrial musculature in humans.
To investigate the gross arrangement of the principal muscular bundles of the two atria, and to suggest how it may contribute to contraction and spread of atrial excitation. A prospective analysis based on anatomical examination of adult human hearts. A national heart and lung institute and a tertiary referral centre for cardiac disease. 9 normal postmortem human hearts. Dissection of atrial muscles with macrophotography. RESUltS--The atrial walls consist of circumferential and longitudinal muscular bundles, the former being arranged at the base of the atria with the latter predominating in the parietal walls. The muscular bundles in the right atrium are larger than those in the left. The main muscles forming the right atrial wall are the terminal crest and terminal pectinate muscles. The terminal crest, the most obvious muscle, is arranged longitudinally with its pectinate muscles connecting to the musculature of the atrioventricular vestibule. No structure resembling the terminal crest is seen in the left atrium. Instead the left atrial wall is composed of intermingled series of muscles, chief of these being the interatrial band and the septoatrial bundle. The former is arranged circumferentially at the atrial base, while the latter is mainly longitudinal. The wall of the right atrium is not of uniform thickness because of the presence of the terminal crest and its pectinate muscles on its internal surface. By contrast, the left atrial wall is much more uniform and its average thickness is greater than that of the right atrium. The rim of the oval fossa is the most important muscular structure on the septal surface and is formed by the infolded atrial walls. The other principal muscles of the atria attach to it, so that the rim provides mechanical support for overall movement of the atrial walls. Comparison of the gross arrangement of the atrial musculature with earlier echocardiographic measurements showed that this arrangement of the muscle explains movement of the atrioventricular ring and overall atrial contraction, and provides a suitable substrate for preferential conduction. The anatomical features of the atrial musculature explain the known facts concerning atrial contraction and preferential conduction.


Deciphering output coupling mechanisms in spiral microcavities with femtosecond light bullets.
A pump-probe two-photon-excited fluorescence technique deciphers in space and time the propagation of ballistic wave packets sustained by whispering-gallery modes (WGMs) in a spiral-shaped microcavity. Diffraction on the spiral discontinuity does not prevent the WGMs from closing. The resultant average Q of the resonator is 3 x 10(4) +/- 50%. Experimental results are compared with numerical simulations, providing evidence of a new contribution to output coupling: Part of the WGM evanescent wave is reflected at the spiral notch and leads to a propagating wave at an angle that matches the previously observed laser emission direction in 4-dicyanomethylene-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran-doped poly(methyl methacrylate) and InGaN spiral lasers.


Oligodendrogliomas: the Mayo Clinic experience.
Eighty-one patients with pure supratentorial oligodendrogliomas underwent surgery alone (19 patients) or surgery plus postoperative radiation therapy (63 patients) between the years 1960 and 1982. The median survival time and the 5-, 10-, and 15-year survival rates for these 82 patients were 7.1 years, 54%, 34%, and 24%, respectively; these values were significantly different from those for an age- and sex-matched normal reference population. Univariate and multivariate survival analyses were performed on 13 possible prognostic factors including: patient age and sex; presence of seizures; site, size, side, computerized tomography (CT) enhancement, grade, and calcification of the tumor; and treatment (extent of surgical resection, lobectomy, radiation dose, and radiation field). Of these factors, tumor grade as classified by the Kernohan and St. Anne-Mayo methods was most strongly associated with survival. Patients with Grade 1 or 2 tumors by either grading method had a median survival time and 5- and 10-year survival rates of approximately 9.8 years. 75%, and 46%, respectively, compared to 3.9 years, 41%, and 20% for those with Grade 3 or 4 tumors. The extent of surgical resection was also associated with survival. The 19 patients who underwent gross total resection of their tumor had a median survival time and 5- and 10-year survival rates of 12.6 years, 74%, and 59%, compared to 4.9 years, 46%, and 23%, respectively, for the 63 who had subtotal resection. When comparing the 19 patients who underwent surgery alone with the 63 who had surgery plus postoperative radiation therapy, there did not appear to be a survival benefit to be gained from the addition of postoperative radiation therapy. However, the patients who had surgery alone tended to have gross total resections and lower tumor grades. Analysis of the subset of 63 patients who underwent subtotal resection alone or with radiation therapy showed that the median survival time and 5- and 10-year survival rates were: 2 years, 25%, and 25% for the eight patients with subtotal resection alone; 4.5 years, 39%, and 20% for the 26 patients with surgery and low-dose (less than 5000 cGy) radiation therapy; and 7.9 years, 62%, and 31% for the 29 patients receiving surgery and high-dose radiation therapy (greater than or equal to 5000 cGy), respectively.


Mefloquine treatment for uncomplicated falciparum malaria in young children 6-24 months of age in northern Ghana.
Mefloquine (MQ) single dose 20 mg/kg treatment of falciparum malaria was evaluated in 186 children of 6-24 months of age in northern Ghana. There were 15 RII/RIII-type parasitologic failures, all with Day 2 MQ blood levels significantly lower than children whose parasitemias cleared before Day 7 and remained clear through 28 days. Predictors of RII/RIII parasitologic response were vomiting after MQ dosing, Day 2 MQ levels < 500 ng/mL, and undetectable Day 2 levels of the carboxymefloquine metabolite. There were 50 cases of delayed RI parasitologic failure, but 71% of these cases had undetectable Day 28 blood levels of MQ and drug levels in the remaining 29% ranged below the 620 ng/mL level that suppresses MQ sensitive strains of P. falciparum. Drug levels among infants that tolerated MQ well were not associated with age, weight, hemoglobin, parasitemia, and pre-existing symptoms of vomiting or diarrhea. An observed recurrent parasitemia of 34,400 trophozoites/microL against a MQ blood concentration of 550 ng/mL was taken as indication of tolerance to suppressive levels of the drug at this location.


Elementary school teachers' knowledge of attention deficit/hyperactivity disorder.
Teachers are often the first ones to suspect attention deficit/hyperactivity disorder (ADHD) in their students, because they are with them for most of the day and they know how normal students typically behave in classroom situations. The aim of this study is to assess the teachers' level of knowledge of ADHD and identify some factors affecting that knowledge. It is a cross-sectional study conducted among male and female elementary governmental schools in Madina city during the year 2017/1438. A pre-validated and translated self-administered questionnaire is used in data collection. It includes demographical questionnaire and the Knowledge of Attention Deficit Disorder Scale. The study included 416 teachers. Their age ranged between 22 and 66 years. The average percentage of knowledge regarding ADHD general information, symptoms/diagnosis, and treatment were 41.6 ± 15.1, 41.7 ± 15, and 30.7 ± 16.6, respectively. The average percentage of overall knowledge score regarding ADHD was 38 ± 11.3. Only experience in teaching (P = 0.042) and previous experience with a child with ADHD (P < 0.001) were significantly associated with teachers' knowledge regarding ADHD general information. Special need teachers had the highest score of knowledge regarding ADHD symptoms (mean rank was 283.7), P = 0.013, and they had the highest score of knowledge regarding ADHD treatment (mean rank was 261.9), P = 0.032. Teachers who reported previous experience with a child with ADHD expressed higher level of overall knowledge regarding ADHD, P < 0.001. The knowledge regarding ADHD among elementary school teachers in Madina is suboptimal, particularly regarding treatment.


Thermal lesions of the SCN do not abolish all gene expression rhythms in rat white adipose tissue, NAMPT remains rhythmic.
Obesity and type 2 diabetes mellitus are major health concerns worldwide. In obese-type 2 diabetic patients, the function of the central brain clock in the hypothalamus, as well as rhythmicity in white adipose tissue (WAT), are reduced. To better understand how peripheral clocks in white adipose tissue (WAT) are synchronized, we assessed the importance of the central brain clock for daily WAT rhythms. We compared gene expression rhythms of core clock genes (Bmal1, Per2, Cry1, Cry2, RevErbα, and DBP) and metabolic genes (SREBP1c, PPARα, PPARγ, FAS, LPL, HSL, CPT1b, Glut4, leptin, adiponectin, visfatin/NAMPT, and resistin) in epididymal and subcutaneous white adipose tissue (eWAT and sWAT) of SCN-lesioned and sham-lesioned rats housed in regular L/D conditions. Despite complete behavioral and hormonal arrhythmicity, SCN lesioning only abolished Cry2 and DBP rhythmicity in WAT, whereas the other clock gene rhythms were significantly reduced, but not completely abolished. We observed no major differences in the effect of SCN lesions between the two WAT depots. In contrast to clock genes, all metabolic genes lost their daily rhythmicity in WAT, with the exception of NAMPT. Interestingly, NAMPT rhythmicity was even less affected by SCN lesioning than the core clock genes, suggesting that it is either strongly coupled to the remaining rhythmicity in clock gene expression, or very sensitive to other external rhythmic factors. The L/D cycle could be such a rhythmic external factor that generates modulating signals by photic masking via the intrinsic photosensitive retinal ganglion cells in combination with the autonomic nervous system. Our findings indicate that in normal weight rats, gene expression rhythms in WAT can be maintained independent of the central brain clock.


The Manchester-Oxford Foot Questionnaire (MOXFQ): Development and validation of a summary index score.
The Manchester-Oxford Foot Questionnaire (MOXFQ) is a validated 16-item, patient-reported outcome measure for evaluating outcomes of foot or ankle surgery. The original development of the instrument identified three domains. This present study examined whether the three domains could legitimately be summed to provide a single summary index score. The MOXFQ and Short-Form (SF)-36 were administered to 671 patients before surgery of the foot or ankle. Data from the three domains of the MOXFQ (pain, walking/standing and social interaction) were subjected to higher order factor analysis. Reliability and validity of the summary index score was assessed. The mean age of the participants was 52.8 years (sd 15.68; 18 to 89). Higher order principle components factor analysis produced one factor, accounting for 74.7% of the variance. The newly derived single index score was found to be internally reliable (α = 0.93) and valid, achieving at least moderate correlations (r ≥ 0.5, p < 0.001) with related (pain/function) domains of the SF-36. Analyses indicated that data from the MOXFQ can be presented in summary form. The MOXFQ summary index score (MOXFQ-Index) provides an overall indication of the outcomes of foot and ankle surgery. Furthermore, the single index reduces the number of statistical comparisons, and hence the role of chance, when exploring MOXFQ data.


Monitoring the influx of new species through citizen science: the first introduced ant in Denmark.
Climate change and invasive species threaten biodiversity, yet rigorous monitoring of their impact can be costly. Citizen science is increasingly used as a tool for monitoring exotic species, because citizens are geographically and temporally dispersed, whereas scientists tend to cluster in museums and at universities. Here we report on the establishment of the first exotic ant taxon (Tetramorium immigrans) in Denmark, which was discovered by children participating in The Ant Hunt. The Ant Hunt is a citizen science project for children that we ran in 2017 and 2018, with a pilot study in 2015. T. immigrans was discovered in the Botanical Garden of the Natural History Museum of Denmark in 2015 and confirmed as established in 2018. This finding extends the northern range boundary of T. immigrans by almost 460 km. Using climatic niche modelling, we compared the climatic niche of T. immigrans in Europe with that of T. caespitum based on confirmed observations from 2006 to 2019. T. immigrans and T. caespitum had a 13% niche overlap, with T. immigrans showing stronger occurrence in warmer and drier areas compared to T. caespitum. Mapping the environmental niches onto geographic space identified several, currently uninhabited, areas as climatically suitable for the establishment of T. immigrans. Tetramorium immigrans was sampled almost three times as often in areas with artificial surfaces compared to T. caespitum, suggesting that T. immigrans may not be native to all of Europe and is being accidentally introduced by humans. Overall, citizen scientists collected data on ants closer to cities and harbours than scientists did and had a stronger bias towards areas of human disturbance. This increased sampling effort in areas of likely introduction of exotic species naturally increases the likelihood of discovering species sooner, making citizen science an excellent tool for exotic species monitoring, as long as trained scientists are involved in the identification process.


Inducible IL-12-producing B cells regulate Th2-mediated intestinal inflammation.
Our previous studies have identified a B-cell subset that is induced under inflammatory conditions in T-cell receptor alpha knockout (TCRalphaKO) mice and contributes to the attenuation of colitis by producing interleukin (IL)-10. However, it is unclear whether IL-10-producing B cells directly or indirectly regulate inflammation. Cytokine production of purified mesenteric lymph node (MLN) B cells was examined by flow cytometric analysis, enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, and RNase protection assay. To investigate the functional role of IL-12p70 in the pathogenesis of colitis in TCRalphaKO mice, IL-12p35-deficient TCRalpha double knockout mice were generated. In the absence of B cells or IL-10, IL-12p35 expression was significantly down-regulated in the MLN of TCRalphaKO mice. The expression of IL-12p35 was restored in the recipient B-cell-deficient TCRalpha double knockout (alphamicroDKO) mice by the transfer of B cells capable of producing IL-10. Notably, B cells predominantly produced IL-12p35 in the MLN through the help of IL-10-producing B cells. Functionally, IL-12 is involved in the regulation of the T-helper (Th) 2-mediated inflammation as indicated by the development of much more severe colitis in IL-12p35-deficient TCRalpha double knockout (alphap35DKO) mice compared with TCRalphaKO mice. In addition, transfer of MLN B cells from TCRalphaKO mice but not from alphap35DKO mice suppressed colitis in recipient alphamicroDKO mice. These studies have identified a novel IL-12-producing regulatory B-cell subset that develops under Th2-mediated intestinal inflammatory conditions and in the presence of IL-10 and is involved in the regulation of intestinal inflammation.


The genetic basis of spondyloarthritis.
Modern technological innovations have advanced our understanding of the genetic basis of spondyloarthritis. In ankylosing spondylitis (AS), where the major histocompatibility complex (MHC) accounts for nearly half of the predisposition, most comes from HLA-B27, for which 65 subtypes are now recognised, although other genes are also at work including HLA-B60 (B*40:01). Other genes have been identified, including those involved in peptide editing for loading onto class I MHC molecules (ERAP1) and cytokine genes such as interleukin 1A (IL-1A) and those involved in the Th17 network (IL-23R, an association seen primarily in Caucasians) and others. In acute anterior uveitis, these associations are also seen as well as a region on chromosome 9p and genes whose confirmation is under way. Psoriasis and psoriatic arthritis fall into this disease spectrum, with the largest region of susceptibility coming from the MHC (most likely HLA-C, ie, C*06:02 although additional influences are also being implicated), and most of the other genetic susceptibility coming from genes involved in cytokine production, specifically genes in the Th17 pathway (IL-12B, IL-23A and IL-23R, the latter, like in AS, not seen in Asians), genes in the nuclear factor κB pathway (TNFAIP3 and TNIP1) and genes in the Th2 pathway (IL-4 and IL-13). Given that more than half of patients with AS have evidence on colonoscopy of at least occult inflammatory bowel disease (IBD), it is not surprising that shared genetic influences are operative. In IBD, genes important in the innate immune response (NOD2), autophagy (ATG6L1) and regulation of the IL-23 pathway (IL-23R) play a role in disease susceptibility.


Ventilation-perfusion relationships during hemorrhagic hypotension and reinfusion in the dog.
The inert gas elimination technique was used to estimate pulmonary ventilation-perfusion (VA/Q) mismatching in heparinized, ventilated, anesthetized dogs during a 90-min period of hemorrhagic hypotension (mean arterial pressure 40 Torr) and subsequent reinfusion of the shed blood. Systemic and pulmonary arterial pressures, as well as cardiac output, were similar to those in previously reported studies using this protocol. Mean arterial O2 partial pressure (PO2) fell from 86 to 75 Torr after hemorrhage and rose to a mean value of 78 Torr after reinfusion. The VA/Q distributions showed that a mean of 56.7% of the ventilation was associated with unperfused or poorly perfused (VA/Q greater than 10) regions during hypotension (control 33.7%). After reinfusion, a mean of 47.8% of the ventilation was still directed to lung with little or no perfusion. This could not be explained on a hydrostatic basis, since pulmonary arterial pressure after reinfusion was greater than the control value. Shunt or blood flow to low VA/Q regions did not increase at any time during hemorrhagic hypotension or reinfusion. Microscopic examination of lung tissue revealed extensive leukocyte aggregation that was not seen in control animals. The mean diameter of obstructed pulmonary vessels was 35 microns (range 13.8-59.8 microns). Storing the shed blood in acid-citrate-dextrose instead of heparin had no significant effect on the extent of leukocyte aggregation. We suggest that leukocyte aggregation and margination may be related to the high VA/Q regions seen in these animals.


Selected base excision repair gene polymorphisms and susceptibility to biliary tract cancer and biliary stones: a population-based case-control study in China.
Base excision repair (BER) corrects DNA damage caused by oxidative stress and chronic inflammation, putative risk factors for cancer. To understand the relationship between genetic variation in BER genes and risk of biliary tract cancer and biliary stones, we examined non-synonymous polymorphisms in three key BER genes-x-ray repair cross-complementing group 1 (XRCC1) (R194W, rs1799782; R280H, rs25489 and R399Q, rs25487), apurinic/apyrimidinic endonuclease (APEX1) (D148E, rs3136820) and 8-oxoguanine DNA glycosylase (OGG1) (S326C, rs1052133), in a population-based study of 411 biliary tract cancer cases (237 gallbladder, 127 bile duct and 47 ampulla of Vater), 891 biliary (gallbladder or bile duct) stone cases and 786 population controls conducted in Shanghai, China. Compared with subjects carrying the XRCC1 194RR genotype, those with the WW genotype had a 1.9-fold risk of bile duct cancer [odds ratio (OR) = 1.9, 95% confidence interval (CI) = 1.1-3.5, P(trend) = 0.03], and compared with subjects carrying the XRCC1 280RR genotype, those with the XRCC1 280H allele had a 50% reduced risk of bile duct cancer (OR = 0.5, 95% CI = 0.3-0.9, P(trend) = 0.05). The effect of the R280H polymorphism persisted (P(trend) = 0.03), when all three XRCC1 polymorphisms were jointly considered in the model, a finding supported by the haplotype results (covariate-adjusted global permutation P = 0.03). We also found an inverse association between the APEX1 148E allele and gallbladder stones (P(trend) = 0.03), but no association for the OGG1 polymorphism. This study suggests that genetic variants in XRCC1 and APEX1 may alter susceptibility to biliary tract cancer and stones. Further studies are required to confirm the reported associations.


β-Elemene promotes cisplatin-induced cell death in human bladder cancer and other carcinomas.
Cisplatin-based combination treatment is the most effective systemic chemotherapy for bladder cancer; however, resistance to cisplatin remains a significant problem in the treatment of this disease. β-Elemene is a new natural compound that blocks cell-cycle progression and has a broad spectrum of antitumor activity. This study was conducted to explore the potential of β-elemene as a chemosensitizer for enhancing the therapeutic efficacy and potency of cisplatin in bladder cancer and other solid carcinomas. β-Elemene not only markedly inhibited cell growth and proliferation but also substantially increased cisplatin cytotoxicity towards human bladder cancer 5637 and T-24 cells. Similarly, β-elemene also enhanced cisplatin sensitivity and augmented cisplatin cytotoxicity in small-cell lung cancer and carcinomas of the brain, breast, cervix, ovary, and colorectal tract in vitro, with dose-modifying factors ranging from 5 to 124. β-Elemene-enhanced cisplatin cytotoxicity was associated with increased apoptotic cell death, as determined by DNA fragmentation, and increased activities of caspase-3, -7, -8, -9, and -10 in bladder cancer cell lines. Collectively, these results suggest that β-elemene augments the antitumor activity of cisplatin in human bladder cancer by enhancing the induction of cellular apoptosis via a caspase-dependent mechanism. Cisplatin combined with β-elemene as a chemosensitizer warrants further pre-clinical therapeutic studies and may be useful for the treatment of cisplatin-resistant bladder cancer and other types of carcinomas.


Molecular mechanism of 7,12-dimethylbenz[a]anthracene-induced immunosuppression: evidence for action via the interleukin-2 pathway.
Previous studies in this laboratory have demonstrated that exposure of mice to the carcinogenic polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene results in suppression of both humoral and cell-mediated immunity. This suppression is unaccompanied by any significant alteration in splenic lymphocyte subpopulation composition, suggesting that the immune deficit was due to a modulation of lymphocyte function. Additional studies implicated the T helper lymphocyte as the probable target for 7,12-dimethylbenz[a]anthracene-induced immunosuppression, apparently through an inhibition of interleukin 2 production. The purpose of the present study was to examine the mechanism of 7,12-dimethylbenz[a]anthracene-induced T lymphocyte dysfunction at the molecular level and to determine the consequences of 7,12-dimethylbenz[a]anthracene exposure on the interleukin 2 pathway. In vitro exposure of Con A-activated splenocytes to 7,12-dimethylbenz[a]anthracene resulted in suppression of the mitogenic response, suppressed interleukin 2 production, and reduced the expression of the high affinity receptor for interleukin 2. In contrast, expression of the low affinity interleukin 2 receptor was not affected. In addition, interleukin 2-dependent lymphoblasts and long term cultured splenocytes exhibited a dose-dependent decrease in proliferation following in vitro exposure to 7,12-dimethylbenz[a]anthracene. These results suggest that 7,12-dimethylbenz[a]anthracene-induced immunosuppression may be mediated, at least in part, through the interleukin 2/interleukin 2 receptor pathway.


Parenting stress of caregivers of young children who are HIV Positive.
Paediatric HIV remains a major challenge in Sub-Saharan Africa. Paediatric HIV is a multi-generational disorder with far-reaching implications for the whole family. Parenting stress in caregivers of HIV infected children has been studied in developed countries but never in South Africa. The aim of this study was to determine the extent of parenting stress in caregivers of children infected with HIV in South Africa. Further objectives were to monitor the levels of stress over one year after caregivers started attending a paediatric HIV clinic and to ascertain what factors were predictive of a decrease in parenting stress over that time. One hundred and twenty two caregiver and children dyads were recruited into this study. Caregivers completed the Parenting Stress Index/ Short form at baseline and after six and 12 months. Demographic information was collected and the children's heights, weights and CD4 counts were recorded at each visit. The families that participated in this study came from very poor socio-economic backgrounds. Eighty five percent of the children were still being cared for by their biological mothers. The parenting stress levels of the caregivers in this study were extremely high at baseline. Although the parenting stress levels did come down significantly over the study period (p< 0.001) they remained high and warrant further investigation and management. A better level of education, better housing facilities and fewer adults living in the household were the three most important factors predicting a decrease in parenting stress over a one year period. Parenting stress of caregivers of young children infected with HIV is extremely high and warrants further investigation and long term management.


Once-weekly ofatumumab in untreated or relapsed Waldenström's macroglobulinaemia: an open-label, single-arm, phase 2 study.
The development of more effective and safer treatments, especially non-chemotherapeutics, is needed for patients with Waldenström's macroglobulinaemia. The aim of the study was to assess the safety and clinical activity of intravenous ofatumumab monotherapy for untreated and relapsed Waldenström's macroglobulinaemia. We did a phase 2, open-label, single-arm study at six centres (hospitals and cancer clinics) in the USA. Patients aged at least 18 years who were diagnosed with untreated or relapsed Waldenström's macroglobulinaemia and required treatment, received up to three cycles of weekly ofatumumab for 5 weeks. For cycle 1, patients received one of two treatment regimens. Group A received ofatumumab 300 mg during week 1 followed by 1000 mg during weeks 2-4. Because of the acceptable safety of the 1000 mg dose in treatment group A and clinical activity of the 2000 mg dose established in chronic lymphocytic leukaemia, the study was amended on Dec 9, 2009, to change cycle 1 for group B who received ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. We followed up patients during weeks 5-16 for treatment group A and during weeks 6-16 for treatment group B (no treatment was given during this follow-up). Patients in both groups with stable disease or a minor response after 16 weeks were eligible to then receive a redosing cycle of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. We followed up patients during weeks 6-16 after the redosing cycle (no treatment was given during this follow-up). Patients responding to cycle 1 or the redosing cycle who developed disease progression within 36 months could receive cycle 2 of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2-5. The primary endpoint for this study was the proportion of patients who achieved an overall response (complete responses plus partial responses plus minor responses) after each treatment cycle in the intent-to-treat population every 4 weeks starting at week 8. This trial is registered at www.ClinicalTrials.gov, NCT00811733, and is now complete. Between March 17, 2009, and Feb 24, 2011, we enrolled and assigned 37 patients to treatment (15 in treatment group A and 22 in treatment group B). All 37 were included in the efficacy and safety analyses. 19 (51%, 95% CI 34·4-68·1) of 37 patients achieved an overall response after cycle 1 and 22 (59%, 42·1-75·2) of 37 achieved an overall response after the redosing cycle; 15 (41%) with partial responses, seven (19%) with minor responses. 13 patients received treatment cycle 2; ten (77%) of the 13 achieved a response. All 37 patients had at least one adverse event; 16 (43%) patients had events of grade 3 or more (30 grade 3, one grade 4). The most common grade 3 or 4 adverse events were infusion reactions (four [11%] of 37), chest pain (two [5%] of 37), haemolysis (two [5%] of 37), and neutropenia (two [5%] of 37). Two (9%) of 22 patients (both in treatment group B) had an IgM flare. 12 patients reported serious adverse events; haemolysis and pyrexia were the most common (each occurring in two [5%] of 37 patients). A high proportion of patients achieved an overall response with ofatumumab monotherapy and this treatment was well tolerated, with a low incidence of IgM flare. This therapy might be a non-chemotherapeutic treatment option for patients with Waldenström's macroglobulinaemia, especially those with high IgM concentrations. GlaxoSmithKline and Genmab.


Measurement of blood pressure for the diagnosis and management of hypertension in different ethnic groups: one size fits all.
Hypertension is a major risk factor for cardiovascular disease and prevalence varies by ethnic group. The diagnosis and management of blood pressure are informed by guidelines largely based on data from white populations. This study addressed whether accuracy of blood pressure measurement in terms of diagnosis of hypertension varies by ethnicity by comparing two measurement modalities (clinic blood pressure and home monitoring) with a reference standard of ambulatory BP monitoring in three ethnic groups. Cross-sectional population study (June 2010 - December 2012) with patients (40-75 years) of white British, South Asian and African Caribbean background with and without a previous diagnosis of hypertension recruited from 28 primary care practices. The study compared the test performance of clinic BP (using various protocols) and home-monitoring (1 week) with a reference standard of mean daytime ambulatory measurements using a threshold of 140/90 mmHg for clinic and 135/85 mmHg for out of office measurement. A total of 551 participants had complete data of whom 246 were white British, 147 South Asian and 158 African Caribbean. No consistent difference in accuracy of methods of blood pressure measurement was observed between ethnic groups with or without a prior diagnosis of hypertension: for people without hypertension, clinic measurement using three different methodologies had high specificity (75-97%) but variable sensitivity (33-65%) whereas home monitoring had sensitivity of 68-88% and specificity of 64-80%. For people with hypertension, detection of a raised blood pressure using clinic measurements had sensitivities of 34-69% with specificity of 73-92% and home monitoring had sensitivity (81-88%) and specificity (55-65%). For people without hypertension, ABPM remains the choice for diagnosing hypertension compared to the other modes of BP measurement regardless of ethnicity. Differences in accuracy of home monitoring and clinic monitoring (higher sensitivity of the former; higher specificity of the latter) were also not affected by ethnicity.


Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production.
As critical mediators of local and systemic inflammatory responses, cytokines are produced in the brain following ischaemic stroke. Some have been detected in the circulation of stroke patients, but their role and source is unclear. Focusing primarily on interleukin(IL)-1-related mechanisms, we serially measured plasma inflammatory markers, and the production of cytokines by whole blood, from 36 patients recruited within 12 h and followed up to 1 year after acute ischaemic stroke (AIS). Admission plasma IL-1 receptor antagonist (IL-1ra) concentration was elevated, relative to age-, sex-, and atherosclerosis-matched controls. IL-1beta, soluble IL-1 receptor type II, tumour necrosis factor (TNF)-alpha, TNF-RII, IL-10 and leptin concentrations did not significantly differ from controls, but peak soluble TNF receptor type I (sTNF-RI) in the first week correlated strongly with computed tomography infarct volume at 5-7 days, mRS and BI at 3 and 12 months. Neopterin was raised in patients at 5-7 d, relative to controls, and in subjects with significant atherosclerosis. Spontaneous IL-1beta, TNF-alpha and IL-6 gene and protein expression by blood cells was minimal, and induction of these cytokines by lipopolysaccharide (LPS) was significantly lower in patients than in controls during the first week. Minimum LPS-induced cytokine production correlated strongly with mRS and BI, and also with plasma cortisol. Absence of spontaneous whole blood gene activation or cytokine production suggests that peripheral blood cells are not the source of cytokines measured in plasma after AIS. Increased plasma IL-1ra within 12 h of AIS onset, the relationship between sTNF-RI and stroke severity, and suppressed cytokine induction suggests early activation of endogenous immunosuppressive mechanisms after AIS.


Subtrochanteric valgus osteotomy with monolateral external fixator in hips for patients with severe cerebral palsy.
Subtrochanteric valgus osteotomy has been used for painful hip joint dislocation in patients with severe cerebral palsy. The goal of this study was to evaluate 11 patients (17 hips) with severe cerebral palsy who had chronically dislocated and painful hips treated with subtrochanteric valgus osteotomy using a monolateral external fixator. A retrospective review was performed of 11 patients (average age, 17.8 years) with severe quadriplegic cerebral palsy with flexion-adduction contractures due to chronically dislocated and painful hips. A subtrochanteric valgus osteotomy with a monolateral fixator was performed in all patients. Patients were analyzed clinicoradiologically, and caregivers were asked about ease of handling, transfers, and perineal care. At an average follow-up of 37 months (range, 14-72 months), all caregivers were satisfied with the surgery and felt that their child was more comfortable and could sit with support for a longer time period and that perineal care, wheelchair mobilization, and transfers were much easier. A total of 11 complications in 7 patients were observed, including pin-tract infections, delayed consolidation, abduction deformity, and hypostatic pneumonia. The complication rate of subtrochanteric valgus osteotomy was comparable with other methods, and this method had the advantage of shorter surgical time, ease of application, no internal implant with lesser chance of infection or heterotopic calcification, and less intraoperative blood loss with less morbidity.


Transplantation of microcarrier-attached hepatocytes into 90% partially hepatectomized rats.
We previously reported a method of intraperitoneal transplantation of liver cells attached to collagen-coated microcarriers, which resulted in prolonged survival and function of the transplanted cells. In the present study, we evaluated the efficacy of liver cell transplantation in providing metabolic support during acute liver insufficiency induced by 90% partial hepatectomy in rats. Ninety per cent of the liver mass (all lobes except the caudate lobe) was resected, and the rats were provided with 5% dextrose orally ad libitum upon regaining consciousness. This regimen results in severe hypoglycemia and death within 48 hr. When microcarrier-attached liver cells were transplanted into syngeneic and allogeneic recipients 3 days prior to 90% partial hepatectomy, significantly higher blood glucose levels were observed (p less than 0.01), compared to the levels in control rats which received injections of microcarriers, liver cells or medium alone. There was a marked improvement in long-term survival (40% survived longer than 28 days; p less than 0.001) in rats transplanted with microcarriers-attached cells. None of the rats given injections of microcarriers, liver cells or medium alone survived beyond 5 days. When liver cells alone or attached to microcarriers were injected intraperitoneally immediately after 90% partial hepatectomy, all rats became hypoglycemic and died within 48 hr, suggesting that vascularization of the transplant is required for function of the transplanted hepatocytes. The results indicate that intraperitoneal transplantation of microcarrier-attached hepatocytes prior to 90% partial hepatectomy in rats provides acute metabolic support resulting in improved survival.


Interleukin-1 inhibition and fatigue in primary Sjögren's syndrome--a double blind, randomised clinical trial.
Fatigue is a major cause of disability in primary Sjögren's syndrome (pSS). Fatigue has similarities with sickness behaviour in animals; the latter mediated by pro-inflammatory cytokines, in particular interleukin (IL)-1, acting on neuronal brain cells. We hypothesised that IL-1 inhibition might improve fatigue in pSS patients; thus, we examined the effects and safety of an IL-1 receptor antagonist (anakinra) on fatigue. Twenty-six pSS patients participated in a double-blind, placebo-controlled parallel group study. Patients were randomised to receive either anakinra or a placebo for four weeks. Fatigue was evaluated by a fatigue visual analogue scale and the Fatigue Severity Scale. The primary outcome measure was a group-wise comparison of the fatigue scores at week 4, adjusted for baseline values. Secondary outcome measures included evaluation of laboratory results and safety. The proportion of patients in each group who experienced a 50% reduction in fatigue was regarded as a post-hoc outcome. All outcomes were measured at week 4. There was no significant difference between the groups in fatigue scores at week 4 compared to baseline after treatment with anakinra. However, six out of 12 patients on anakinra versus one out of 13 patients on the placebo reported a 50% reduction in fatigue VAS (p = 0.03). There were two serious adverse events in each group. This randomised, double-blind, placebo-controlled trial of IL-1 blockade did not find a significant reduction in fatigue in pSS in its primary endpoint. A 50% reduction in fatigue was analysed post-hoc, and significantly more patients on the active drug than on placebo reached this endpoint. Although not supported by the primary endpoint, this may indicate that IL-1 inhibition influences fatigue in patients with pSS. ClinicalTrials.gov NCT00683345.


PubMLST for Antigen Allele Mining to Inform Development of Gonorrhea Protein-Based Vaccines.
Neisseria gonorrhoeae (Ng) is a human-specific pathogen and the etiological agent of gonorrhea, a sexually transmitted infection with a significant global health burden. While often asymptomatic, untreated gonorrhea can lead to pelvic inflammatory disease, ectopic pregnancy, infertility, and increased transmission/acquisition of HIV. A protective gonorrhea vaccine may be the only way to control disease transmission in the future due to the inexorable development of antibiotic resistance. Subunit antigens are proven candidates for vaccine development due to their safety, cost-effectiveness, and rapid preparation. To inform protein-based gonorrhea vaccine design by including different antigen variants, herein we present bioinformatics mining of alleles and single nucleotide/amino acid polymorphisms using DNA/protein sequences of all Ng isolates deposited into the PubMLST database and MtrE and BamA as model antigens. We also present phylogenetic analyses that can be performed using sequence data to gain insights into the evolutionary relationships between the polymorphisms found among the population of isolates using a convenient tool: Molecular Evolutionary Genetics Analysis (MEGA) software. Finally, we perform antigen polymorphism mapping onto the MtrE and BamA structures. This methodology can be applied for rational vaccine design to increase vaccine coverage and cross-protection by heteroligand presentation achieved via inclusion of diverse antigen variants and is relevant to over 100 different species and genera deposited into the PubMLST family of databases.


Brain injury: quality of life's greatest challenge.
The objectives of this investigation were to (1) identify elements that comprise an acceptable quality of life (Q-L) post-traumatic brain injury (TBI) from the perspectives of patients and families, and (2) explore patient and family satisfaction with treatment decisions relevant to QoL. The authors created, tested, and administered two forms (patient; family) of a 35-question interview to 33 participants in a longitudinal TBI study (14 women, 19 men) and 33 associated family members. Men associated ratings of QoL with numerous variables, while women's responses revealed no significant relationships shared by QoL and other variables. Women reported a poorer QoL than did men. Older patients reported a better QoL than did younger patients. Families emphasized the family relationship, emotional control, and ability to concentrate when considering overall QoL. Patients did not. The majority of patients and families expressed satisfaction with decisions made about acute treatment. QoL research is essential to illuminate best practice models.


Deep RNA sequencing of L. monocytogenes reveals overlapping and extensive stationary phase and sigma B-dependent transcriptomes, including multiple highly transcribed noncoding RNAs.
Identification of specific genes and gene expression patterns important for bacterial survival, transmission and pathogenesis is critically needed to enable development of more effective pathogen control strategies. The stationary phase stress response transcriptome, including many sigmaB-dependent genes, was defined for the human bacterial pathogen Listeria monocytogenes using RNA sequencing (RNA-Seq) with the Illumina Genome Analyzer. Specifically, bacterial transcriptomes were compared between stationary phase cells of L. monocytogenes 10403S and an otherwise isogenic DeltasigB mutant, which does not express the alternative sigma factor sigmaB, a major regulator of genes contributing to stress response, including stresses encountered upon entry into stationary phase. Overall, 83% of all L. monocytogenes genes were transcribed in stationary phase cells; 42% of currently annotated L. monocytogenes genes showed medium to high transcript levels under these conditions. A total of 96 genes had significantly higher transcript levels in 10403S than in DeltasigB, indicating sigmaB-dependent transcription of these genes. RNA-Seq analyses indicate that a total of 67 noncoding RNA molecules (ncRNAs) are transcribed in stationary phase L. monocytogenes, including 7 previously unrecognized putative ncRNAs. Application of a dynamically trained Hidden Markov Model, in combination with RNA-Seq data, identified 65 putative sigmaB promoters upstream of 82 of the 96 sigmaB-dependent genes and upstream of the one sigmaB-dependent ncRNA. The RNA-Seq data also enabled annotation of putative operons as well as visualization of 5'- and 3'-UTR regions. The results from these studies provide powerful evidence that RNA-Seq data combined with appropriate bioinformatics tools allow quantitative characterization of prokaryotic transcriptomes, thus providing exciting new strategies for exploring transcriptional regulatory networks in bacteria.


Compression for venous leg ulcers.
To assess the effectiveness and cost-effectiveness of compression bandaging and stockings in the treatment of venous leg ulcers. Searches of 19 databases, hand searching of journals, conference proceedings and bibliographies. Manufacturers of compression bandages and stockings and an Advisory Panel were contacted for unpublished studies. Trials that evaluated compression bandaging or stockings, as a treatment for venous leg ulcers. There was no restriction on date or language. Ulcer healing was the primary endpoint. Details of eligible studies were extracted and summarised using a data extraction sheet. Data extraction was verified by two reviewers independently. Twenty two trials reporting 24 comparisons were identified. Compression was more effective than no compression (4/6 trials). When multi-layered systems were compared, elastic compression was more effective than non-elastic compression (5 trials). There was no difference in healing rates between 4-layer bandaging and other high compression multi-layered systems (3 trials). There was no difference in healing rates between elastomeric multi-layered systems (4 trials). Multi-layered high compression was more effective than single layer compression (4 trials). Compression stockings were evaluated in two trials. One found a high compression stocking plus a thrombo stocking to be more effective than a short stretch bandage. The second small trial reported no difference between the compression stockings and Unna's boot. There was insufficient data to draw conclusion about the relative cost-effectiveness of different regimens. Compression increases ulcer healing rates compared with no compression. Multi-layered systems are more effective than single-layered systems. High compression is more effective than low compression but there are no clear differences in the effectiveness of different types of high compression.


Post-genome wide association studies and functional analyses identify association of MPP7 gene variants with site-specific bone mineral density.
Our previous genome-wide association study (GWAS) in a Hong Kong Southern Chinese population with extreme bone mineral density (BMD) scores revealed suggestive association with MPP7, which ranked second after JAG1 as a candidate gene for BMD. To follow-up this suggestive signal, we replicated the top single-nucleotide polymorphism rs4317882 of MPP7 in three additional independent Asian-descent samples (n= 2684). The association of rs4317882 reached the genome-wide significance in the meta-analysis of all available subjects (P(meta)= 4.58 × 10(-8), n= 4204). Site heterogeneity was observed, with a larger effect on spine than hip BMD. Further functional studies in a zebrafish model revealed that vertebral bone mass was lower in an mpp7 knock-down model compared with the wide-type (P= 9.64 × 10(-4), n= 21). In addition, MPP7 was found to have constitutive expression in human bone-derived cells during osteogenesis. Immunostaining of murine MC3T3-E1 cells revealed that the Mpp7 protein is localized in the plasma membrane and intracytoplasmic compartment of osteoblasts. In an assessment of the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of transcriptional factor GATA2 to the risk allele 'A' but not the 'G' allele of rs4317882. An mRNA expression study in human peripheral blood mononuclear cells confirmed that the low BMD-related allele 'A' of rs4317882 was associated with lower MPP7 expression (P= 9.07 × 10(-3), n= 135). Our data suggest a genetic and functional association of MPP7 with BMD variation.


A prospective multicenter European study on flexible ureterorenoscopy for the management of renal stone.
The aim of this study was to describe the outcomes and the complications of retrograde intrarenal surgery (RIRS) for renal stones in a multi-institutional working group. From 2012 to 2014, we conducted a prospective study including all RIRS performed for kidney stones in 4 European centers. Demographic information, disease characteristics, and perioperative and postoperative data were gathered. Patients and stone data, procedure characteristics, results and safety outcomes were analyzed and compared by descriptive statistics. Complications were reported using the standardized Clavien system. Three hundred and fifty-six patients underwent 377 RIRS with holmium laser lithotripsy for renal stones. The RIRS was completed in all patients with a mean operative time of 63.5 min. The stone-free status was confirmed endoscopically and through fluoroscopic imaging after the first procedure in 73.6%. The second procedure was performed in twenty patients (5.6%) achieving an overall stone free rate of 78.9%. The overall complication rate was 15.1%. Intra-operative and post-operative complications were seen in 24 (6.7%) and 30 (8.4%) cases, respectively. RIRS is a minimally invasive procedure with good results in terms of stone-free and complications rate.


Comprehensive photoelectron spectroscopic study of anionic clusters of anthracene and its alkyl derivatives: electronic structures bridging molecules to bulk.
The evolution of the electronic structure of molecular aggregates is investigated using anion photoelectron (PE) spectroscopy for anionic clusters of anthracene (Ac) and its alkyl derivatives: 1-methylanthracene (1MA), 2-methylanthracene (2MA), 9-methylanthracene (9MA), 9,10-dimethylanthracene (DMA), and 2-tert-butylanthracene (2TBA). For their monomer anions (n=1), electron affinities are confined to the range from 0.47 to 0.59 eV and are well reproduced by density functional theory calculations, showing the isoelectronic character of these molecules. For cluster anions (n=2-100) of Ac and 2MA, two types of isomers I and II coexist over a wide size range: isomers I and II-1 (4< or =n<30) or isomers I and II-2 (n> or = approximately 40 for Ac and n> or = approximately 55 for 2MA). However, for the other alkyl-substituted Ac cluster anions (i.e., 1MA, 9MA, DMA, and 2TBA), only isomer I is exclusively formed, and neither isomer II-1 nor II-2 is observed. The vertical detachment energies (VDEs) of isomer I in all the anionic clusters depend almost linearly on n(-1/3). In contrast, the VDEs of isomers II-1 (n> or =14) and II-2 (n=40-100), appeared only in Ac and 2MA cluster anions, remain constant with n and are approximately 0.5 eV lower than those of isomer I. The PE spectra revealed the characteristics of each isomer: isomer I possesses a monomeric anion core that is gradually embedded into the interior of the cluster with increasing n. On the other hand, isomers II-1 and II-2 possess a multimeric (perhaps tetrameric) anion core, but they differ in the number of layers from which they are made up; monolayer (isomer II-1) and multilayers (isomer II-2) of a two-dimensionally ordered, finite herringbone-type structure, in which electron attachment produces only little geometrical rearrangement. Moreover, the agreement of the constant VDEs of isomer II-2 with the bulk data demonstrates the largely localized nature of the electronic polarization around the excess charge in a crystal-like environment, where about 50 molecules provide a charge stabilization energy comparable to the bulk.


Physical activity, sedentary behaviour and metabolic control following stroke: a cross-sectional and longitudinal study.
Physical activity and sedentary behaviour are key moderators of cardiovascular disease risk and metabolic control. Despite the importance of a physically active lifestyle, little is known about the effects of stroke on physical activity. We assessed physical activity and sedentary behaviour at three time points following stroke compared to a healthy control group. Physical activity and sedentary behaviour were objectively measured using a portable multi-sensor array in 31 stroke participants (73±9 years, National Institute of Health Stroke Scale 2±2, mobile 10 metres with/without aid) within seven days and at three and six months. Stroke data were compared with an age, sex and body mass index matched healthy control group (n = 31). Within seven days of stroke, total energy expenditure and physical activity were significantly lower and sedentary time higher in the stroke group compared to controls (total energy expenditure 1840±354 vs. 2220±489 kcal, physical activity 28±32 vs. 79±46 min/day, steps 3111±2290 vs. 7996±2649, sedentary time 1383±42 vs. 1339±44 min/day, p<0.01). At three months physical activity levels had increased (64±58 min/day) but plateaued by six months (66±68 min/day). Physical activity levels are reduced immediately post-stroke and remain below recommended levels for health and wellbeing at the three and six month time points. Clinicians should explore methods to increase physical activity and reduce sedentary behaviour in both the acute and later stages following stroke.


Preoperative C-Reactive Protein Values as a Potential Component in Outcome Prediction Models of Metastasized Renal Cell Carcinoma Patients Receiving Cytoreductive Nephrectomy.
To validate preoperative C-reactive protein (CRP) levels as a prognostic marker for survival in a metastasized renal cell carcinoma (mRCC) patient cohort receiving cytoreductive nephrectomy (CN). By chart review, 146 mRCC patients receiving CN at our tertiary referral centre from 1997 to 2015 were identified retrospectively. All relevant clinicopathological features including laboratory parameters were collected and correlated to overall survival, progression-free survival and cancer-specific survival (CSS). The mean follow-up was 23 months (range 1-168 months). Besides the already established scoring systems like the MSKCC criteria, an elevated preoperative CRP level (≥0.5 mg/dL) was an independent predictor of CSS in our study group including the chosen postoperative adjuvant therapies (TKI vs. immunotherapy vs. others). With regard to morbidity, patients with a good performance status, small tumour size and adequate renal function/haematopoiesis experienced less complication rates, thereby profiting more from CN. Our data provide indication that preoperative CRP levels should be implemented in nomograms regarding the outcome prediction in mRCC to identify candidates likely to profit from CN.


Behavioral momentum and relapse of extinguished operant responding.
Previous experiments on behavioral momentum have shown that relative resistance to extinction of operant behavior in the presence of a stimulus depends on the rate of reinforcement associated with that stimulus, even if some of those reinforcers occur independently of the behavior. We present three experiments examining whether the rate of reinforcement in the presence of a stimulus similarly modulates the relative relapse of operant behavior produced by reinstatement, resurgence, and renewal paradigms. During baseline conditions, pigeons responded for food reinforcement on variable-interval 120-sec schedules in alternating periods of exposure to two stimuli arranged by a multiple schedule. Additional response-independent food presentations were also delivered in the presence of one of the multiple-schedule stimuli. Consistent with previous research, baseline response rates were lower in the presence of the stimulus with the added response-independent reinforcement, and relative resistance to extinction was greater in the presence of that stimulus. In addition, following extinction, the relative relapse of responding produced by reinstatement, resurgence, and renewal paradigms was greater in the presence of the stimulus associated with the higher rate of reinforcement. We suggest that a model of extinction from behavioral momentum theory may be useful for understanding these results.


The road less traveled: transarterial embolization of dural arteriovenous fistulas via the ascending pharyngeal artery.
With the introduction of Onyx, transarterial embolization has become the most common endovascular approach to treating dural arteriovenous fistulas (dAVFs), often via the middle meningeal or occipital arteries. The ascending pharyngeal artery (APA) is a less frequently explored transarterial route because of its small caliber, potential anastomoses to the internal carotid and vertebral arteries, and vital supply to lower cranial nerves. To review our institutional experience and highlight the prevalence of APA supply to dAVFs and cases where it is a safe and effective pedicle for embolization. We reviewed our endovascular database (January 1, 1996 to March 1, 2016) for cranial dAVFs, evaluating dAVF characteristics and embolization results for those treated transarterially via the APA. Of 267 endovascularly treated dAVFs, 68 had APA supply (25%). Of these 68 dAVFs, embolization was carried out via this pedicle in 8 (12%) and 7 were ultimately occluded. No complications, including post-treatment cranial neuropathies or radiographic evidence of non-target embolization, were found. For 5 dAVFs, the APA was selected as the initial pedicle for embolization (two marginal sinus, one distal sigmoid, one cavernous, one tentorial). In four of these five cases, dAVF occlusion was achieved via the initial APA feeding artery pedicle. In one case, near-complete, stagnant occlusion was achieved after APA embolization; complete occlusion was achieved after adjunctive embolization of a single additional middle meningeal artery pedicle. In three other cases of complex transverse/sigmoid dAVFs, the APA was used after multiple attempts via middle meningeal and occipital artery pedicles. Occlusion was not achieved transarterially; two of these three dAVFs were ultimately occluded transvenously. In rare, select cases, the APA is an excellent route for transarterial embolization of cranial dAVFs.


Podocalyxin-like 1 is associated with tumor aggressiveness and metastatic gene expression in human oral squamous cell carcinoma.
Metastasis-mediated death remains a major challenge in cancer treatment due to the lack of identifiable biomarkers for early diagnosis. Identifying tumor-specific biomarkers is critical for the development of diagnostic and therapeutic tools. In the present study, we found that podocalyxin-like 1 (PODXL), a cell surface glycoprotein, was overexpressed in cancer tissues and was upregulated in lymph node metastatic tumor cells. The expression of PODXL was associated with the migratory ability of human oral squamous cell carcinoma (OSCC). Knockdown of PODXL by small hairpin RNA in the SAS OSCC cell line reduced tumor migration and invasion, and inhibited cell proliferation and colony formation. Suppression of PODXL resulted in downregulation of focal adhesion kinase (FAK) and paxillin phosphorylation. PODXL silencing inhibited filopodia formation, and suppressed F-actin and cortactin colocalization. In addition, PODXL expression was associated with the DNA methylation status, and treatment with the DNA methyltransferase inhibitor 5-aza-deoxycytidine increased the PODXL transcriptional level. Moreover, DNA microarray analysis data revealed that suppression of PODXL significantly affected subsets of genes associated with extracellular matrix organization, the epithelial-mesenchymal transition, and the expression of metastasis-related cytokines. Collectively, these data showed that the overexpression of PODXL may be associated with tumor aggressiveness and that PODXL could be a diagnostic biomarker for metastatic OSCC.


A RETROSPECTIVE REVIEW OF WESTERN LOWLAND GORILLA (GORILLA GORILLA GORILLA) MORTALITY IN EUROPEAN ZOOLOGIC COLLECTIONS BETWEEN 2004 AND 2014.
An understanding of the main causes of mortality among captive gorillas is imperative to promoting their optimal care, health, and welfare. A retrospective observational review of mortality among the European zoo-housed western lowland gorilla ( Gorilla gorilla gorilla) population from 2004 to 2014 was carried out. This is the first published study of mortality in this population. Relevant postmortem data were requested from each collection reporting a death during the study period. Age at death enabled grouping into discrete age categories. Deaths were classified according to cause. The main causes of death overall and for each age category and sex were identified. In total, 151 gorillas from 50 European collections died during the study period. Postmortem data were available for 119 (79%) of the deaths, of which 102 (86%) were classified by cause. Diseases of the digestive system were responsible for most (23%) deaths overall. Also of significance (each accounting for 15% overall mortality) were deaths due to external causes (especially trauma) among young gorillas and cardiovascular disease among adult and aged animals. Being a male gorilla was associated with an 8.77- and 5.40-fold increase in risk of death due to cardiovascular and respiratory disease, respectively. Death due to external causes was 4.45 times more likely among females than males. There was no statistically significant difference in life expectancy between male and female gorillas. The authors conclude that further work is needed to understand risk factors involved in the main causes of death and suggest a need for standardization with regard the approach to postmortem examination and data collection, sample collection, and storage across European zoos.


Energy metabolism in tumor cells.
In early studies on energy metabolism of tumor cells, it was proposed that the enhanced glycolysis was induced by a decreased oxidative phosphorylation. Since then it has been indiscriminately applied to all types of tumor cells that the ATP supply is mainly or only provided by glycolysis, without an appropriate experimental evaluation. In this review, the different genetic and biochemical mechanisms by which tumor cells achieve an enhanced glycolytic flux are analyzed. Furthermore, the proposed mechanisms that arguably lead to a decreased oxidative phosphorylation in tumor cells are discussed. As the O(2) concentration in hypoxic regions of tumors seems not to be limiting for the functioning of oxidative phosphorylation, this pathway is re-evaluated regarding oxidizable substrate utilization and its contribution to ATP supply versus glycolysis. In the tumor cell lines where the oxidative metabolism prevails over the glycolytic metabolism for ATP supply, the flux control distribution of both pathways is described. The effect of glycolytic and mitochondrial drugs on tumor energy metabolism and cellular proliferation is described and discussed. Similarly, the energy metabolic changes associated with inherent and acquired resistance to radiotherapy and chemotherapy of tumor cells, and those determined by positron emission tomography, are revised. It is proposed that energy metabolism may be an alternative therapeutic target for both hypoxic (glycolytic) and oxidative tumors.


Cardiology fellows-in-training are exposed to relatively high levels of radiation in the cath lab compared with staff interventional cardiologists-insights from the RECAP trial.
Interventional cardiologists are inevitably exposed to low-dose radiation, and consequently are at risk for radiation induced diseases like cataract and left-sided brain tumours. Operator behaviour may possibly be the largest influencer on radiation exposure. We hypothesised that awareness regarding radiation exposure grows as skill and the general experience in the catheterization laboratory increase. In this study we determined the difference in the relative radiation exposure of staff interventional cardiologists compared with cardiology fellows-in-training. During this prospective trial the operator's radiation exposure (E in µSv) was measured at chest height during 766 diagnostic catheterisations and percutaneous coronary interventions. Also, the patient exposure (DAP in mGy·cm2), representing the amount of radiation administered by the operator per procedure, was collected. The primary outcome of this study was the difference in relative exposure between staff interventional cardiologists versus cardiology fellows-in-training (E/DAP). From January to May 2017, staff interventional cardiologists performed 637 procedures and cardiology fellows-in-training 129 procedures. The performance of relatively complex procedures by staff interventional cardiologists resulted in a 74% higher use of radiation compared with fellows-in-training. Consequently, staff interventional cardiologists were exposed to 50% higher levels of actual radiation exposure. However, when correcting for the complexity of the procedure, by comparing the relative operator exposure (E/DAP), fellows-in-training were exposed to a 34% higher relative exposure compared with staff interventional cardiologists (p = 0.025). In the current study, when corrected for complexity, cardiology fellows-in-training were exposed to significantly higher radiation levels than staff interventional cardiologists during catheterisation procedures.


A viral over-expression system for the major malaria mosquito Anopheles gambiae.
Understanding pathogen/mosquito interactions is essential for developing novel strategies to control mosquito-borne diseases. Technical advances in reverse-genetics, such as RNA interference (RNAi), have facilitated elucidation of components of the mosquito immune system that are antagonistic to pathogen development, and host proteins essential for parasite development. Forward genetic approaches, however, are limited to generation of transgenic insects, and while powerful, mosquito transgenesis is a resource- and time-intensive technique that is not broadly available to most laboratories. The ability to easily "over-express" genes would enhance molecular studies in vector biology and expedite elucidation of pathogen-refractory genes without the need to make transgenic insects. We developed and characterized an efficient Anopheles gambiae densovirus (AgDNV) over-expression system for the major malaria vector Anopheles gambiae. High-levels of gene expression were detected at 3 days post-infection and increased over time, suggesting this is an effective system for gene induction. Strong expression was observed in the fat body and ovaries. We validated multiple short promoters for gene induction studies. Finally, we developed a polycistronic system to simultaneously express multiple genes of interest. This AgDNV-based toolset allows for consistent transduction of genes of interest and will be a powerful molecular tool for research in Anopheles gambiae mosquitoes.


Evaluation of a multimodal school-based depression and suicide prevention program among Dutch adolescents: design of a cluster-randomized controlled trial.
Since 2010, suicide has been the most important cause of mortality in youth aged 15 to 29 years in the Netherlands. Depression is an important risk factor for suicidal behaviors (i.e., suicide ideation, deliberate self-harm, planning, and suicide attempts) in adolescents. Adolescents who develop depressive symptoms, are also at risk for adult depression. This developmental continuity is especially noticeable in adolescents compared to other age groups; therefore, it is necessary to develop preventive strategies for teens. This study will test a multimodal school-based approach to suicide and depression prevention, which integrates universal and targeted approaches and includes various stakeholders (schools, adolescents, parents, and mental health professionals) simultaneously. We will perform a cluster randomized controlled trial (RCT) with an intervention and control condition to test the effectiveness of a school-based multimodal stepped-prevention program for depression and suicidal behaviors in adolescents. Adolescents in their second year of secondary education will participate in the study. The participants in the intervention condition will receive the entire multimodal stepped-preventive program comprising early screening and detection of suicidal behaviors and depressive symptoms, a safety net consisting of gatekeepers at school, followed by universal and indicated prevention. The participants in the control condition will undergo only the screening and the safety net of gatekeepers at schools. They will complete assessments at baseline, post-intervention, and 6, 12, and 24-month follow-up. Primary outcome will be suicidal behaviors measured at 12-months follow-up. Additionally, the present study will identify mechanisms that mediate and moderate the program effects and test the effect of the program on various secondary outcomes. If the school-based multimodal stepped-prevention program proves to be effective, it could be implemented in schools on a large scale. The study is registered in the Dutch Trial Register ( NTR6622 ).


Molecular characterization of a 7p15-21 homozygous deletion in a Wilms tumor.
Recent molecular studies have shown a relatively high rate of loss of heterozygosity (LOH) at band 7p15-21 in Wilms tumor. We previously reported that the minimal common region of LOH was located between markers D7S517 and D7S503 in bands 7p15-21. We also reported the identification of one Wilms tumor (GOS44) bearing a homozygous, interstitial deletion at a locus within this region. Homogeneous primary cell cultures have been derived from this tumor and have been used for all the subsequent analyses. Using PCR and a panel of STS markers mapping between D7S517 and D7S503, the physical boundaries of the homozygous deletion were determined to be between D7S638 and D7S644. The deleted region spans approximately 3 Mbp of genomic sequence and includes seven known genes (KIAA0744, KIAA0713, AHR, AGR2, NET6, HSPC028, and DGKB.) as well as five predicted genes with similarities to genes of known function (LOC-91802, -116364, -96009, -92511, and -92512). The proximal breakpoint was found to lie between exon 6 and exon 7 of KIAA0744, and the distal breakpoint lay between exon 17 and exon 18 of DGKB. It is unlikely that a functional fusion gene product was generated as a consequence of the fusion between these two genes, because they are oriented in opposite directions on the chromosome. This is the only reported homozygous deletion recorded so far in Wilms tumor, and it provides the means to identify the tumor-suppressor gene located in this deletion.


Comparison of PCR-RFLP and Genescan-based genotyping for analyzing infection dynamics of Plasmodium falciparum.
Parameters describing the infection dynamics of Plasmodium falciparum are important determinants of the potential impact of interventions and are potential outcome measurements for malaria intervention trials. Low parasite densities, periodic sequestration of parasites, and the presence of multiple concurrent infections make it essential to use molecular techniques to estimate the force of infection and duration of infections in endemic areas. We now compare two approaches for tracking individual genotypes of the highly polymorphic merozoite surface protein 2: 1) fluorescence-labeled polymerase chain reaction (PCR) and GeneScan-sizing and 2) restriction fragment length polymorphism (RFLP). We analyze samples from a longitudinal field study in Ghana and use statistical approaches that allow for imperfect detectability. The two methods gave broadly similar estimates of parasite dynamics, but GeneScan is more precise and can achieve a higher throughput. The analysis of parasite dynamics indicated an average duration of infection of 210 days by GeneScan versus 152 days by PCR-RFLP in the study population in Kassena-Nankana, Northern Ghana. This reflects the good performance of GeneScan-based genotyping for studies of parasite infection dynamics.


The Effect of Milk Constituents and Crowding Agents on Amyloid Fibril Formation by κ-Casein.
When not incorporated into the casein micelle, κ-casein, a major milk protein, rapidly forms amyloid fibrils at physiological pH and temperature. In this study, the effects of milk components (calcium, lactose, lipids, and heparan sulfate) and crowding agents on reduced and carboxymethylated (RCM) κ-casein fibril formation was investigated using far-UV circular dichroism spectroscopy, thioflavin T binding assays, and transmission electron microscopy. Longer-chain phosphatidylcholine lipids, which form the lining of milk ducts and milk fat globules, enhanced RCM κ-casein fibril formation irrespective of whether the lipids were in a monomeric or micellar state, whereas shorter-chain phospholipids and triglycerides had little effect. Heparan sulfate, a component of the milk fat globule membrane and catalyst of amyloid deposition in extracellular tissue, had little effect on the kinetics of RCM κ-casein fibril formation. Major nutritional components such as calcium and lactose also had no significant effect. Macromolecular crowding enhances protein-protein interactions, but in contrast to other fibril-forming species, the extent of RCM κ-casein fibril formation was reduced by the presence of a variety of crowding agents. These data are consistent with a mechanism of κ-casein fibril formation in which the rate-determining step is dissociation from the oligomer to give the highly amyloidogenic monomer. We conclude that the interaction of κ-casein with membrane-associated phospholipids along its secretory pathway may contribute to the development of amyloid deposits in mammary tissue. However, the formation of spherical oligomers such as casein micelles is favored over amyloid fibrils in the crowded environment of milk, within which the occurrence of amyloid fibrils is low.


Absorption enhancement of single silicon nanowire by tailoring rear metallic film for photovoltaic applications.
In this work, single-nanowire solar cells (SCs) in lying configuration with a tunable rear metallic film are presented. Compared to the standalone silicon nanowire (SiNW), a significant/broadband enhancement in the overall optical absorption of the SiNW with rear metallic nanoconfiguration was observed. The optimized fraction, corresponding to the maximal ultimate photocurrent, of the SiNW surrounded by metallic film was achieved by properly engineering the SiNW radius and metallic film thickness. The considered configuration can be effectively extended to the alternative configuration with a SiNW partially embedded in a metallic substrate, where the ultimate photocurrent density of the 100 nm radius SiNW can be improved by 75.50% relative to that of the freestanding SiNW. Our simulations verify that it is a promising route for developing highly efficient single nanowire SCs.


Origin and fate of repeats in bacteria.
We investigated 53 complete bacterial chromosomes for intrachromosomal repeats. In previous studies on eukaryote chromosomes, we proposed a model for the dynamics of repeats based on the continuous genesis of tandem repeats, followed by an active process of high deletion rate, counteracted by rearrangement events that may prevent the repeats from being deleted. The present study of long repeats in the genomes of Bacteria and Archaea suggests that our model of interspersed repeats dynamics may apply to them. Thus the duplication process might be a consequence of very ancient mechanisms shared by all three domains. Moreover, we show that there is a strong negative correlation between nucleotide composition bias and the repeat density of genomes. We hypothesise that in highly biased genomes, non-duplicated small repeats arise more frequently by random effects and are used as primers for duplication mechanisms, leading to a higher density of large repeats.


Salivary epithelial cells as model to study immune response against cutaneous pathogens.
The human skin not only provides passive protection as a physical barrier against external injury, but also mediates active surveillance via epidermal cell surface receptors that recognize and respond to potential invaders. Primary keratinocytes and immortalized cell lines, the commonly used sources to investigate immune responses of cutaneous epithelium are often difficult to obtain and/or potentially exhibit changes in cellular genetic make-up. Here we investigated the possibility of using salivary epithelial cells (SEC) to evaluate the host response to cutaneous microbes. Elevated secretion of IFN-γ and IL-12 was observed in the SEC stimulated with Staphylococcus aureus, a transient pathogen of the skin, as mono species biofilm as compared to SEC stimulated with a commensal microbe, the Staphylococcus epidermidis. Co-culture of the SEC with both microbes as dual species biofilm elicited maximum cytokine response. Stimulation with S. aureus alone but not with S. epidermidis alone induced maximum toll-like receptor-2 (TLR-2) expression in the SEC. Exposure to dual species biofilm induced a sustained upregulation of TLR-2 in the SEC for up to an hour. The data support novel application of the SEC as efficient biospecimen that may be used to investigate personalized response to cutaneous microflora.


Reductive amination catalyzed by iridium complexes using carbon monoxide as a reducing agent.
Development of novel, sustainable catalytic methodologies to provide access to amines represents a goal of fundamental importance. Herein we describe a systematic study for the construction of a variety of amines catalyzed by a well-defined homogeneous iridium complex using carbon monoxide as a reducing agent. The methodology was shown to be compatible with functional groups prone to reduction by hydrogen or complex hydrides.


Chemical Sensor Systems and Associated Algorithms for Fire Detection: A Review.
Indoor fire detection using gas chemical sensing has been a subject of investigation since the early nineties. This approach leverages the fact that, for certain types of fire, chemical volatiles appear before smoke particles do. Hence, systems based on chemical sensing can provide faster fire alarm responses than conventional smoke-based fire detectors. Moreover, since it is known that most casualties in fires are produced from toxic emissions rather than actual burns, gas-based fire detection could provide an additional level of safety to building occupants. In this line, since the 2000s, electrochemical cells for carbon monoxide sensing have been incorporated into fire detectors. Even systems relying exclusively on gas sensors have been explored as fire detectors. However, gas sensors respond to a large variety of volatiles beyond combustion products. As a result, chemical-based fire detectors require multivariate data processing techniques to ensure high sensitivity to fires and false alarm immunity. In this paper, we the survey toxic emissions produced in fires and defined standards for fire detection systems. We also review the state of the art of chemical sensor systems for fire detection and the associated signal and data processing algorithms. We also examine the experimental protocols used for the validation of the different approaches, as the complexity of the test measurements also impacts on reported sensitivity and specificity measures. All in all, further research and extensive test under different fire and nuisance scenarios are still required before gas-based fire detectors penetrate largely into the market. Nevertheless, the use of dynamic features and multivariate models that exploit sensor correlations seems imperative.


Pharmacogenomic trial design: use of a PK/PD model to explore warfarin dosing interventions through clinical trial simulation.
Variants of two genes, CYP2C9 and VKORC1, explain approximately one third of variability in warfarin maintenance dose requirements. However, the clinical utility of using this information in addition to clinical and demographic data ('pharmacogenomic-guidance') is unclear, as few comparative clinical trials have been conducted to date. The objective of this study was to explore the incremental effect of pharmacogenomic-guided warfarin dosing under various conditions using clinical trial simulation. We used an existing pharmacokinetic/pharmacodynamic model to perform clinical trial simulations of pharmacogenomic-guided versus standard of care warfarin therapy. The primary outcome was the percentage of patient time spent in therapeutic range over the first month of therapy. We assessed the influence of the frequency of INR monitoring, and the use of a loading dose and dose increase delay in patients with CYP2C9 variants. Pharmacogenomic guidance resulted in a 3-4 percentage point absolute increase in time spent in therapeutic range over the first month of therapy compared with standard of care. The improvement in time in range was greater when the frequency of INR monitoring in both arms was assumed to be lower. The absolute difference increased to 6-8 percentage points with the use of a loading dose and dose increase delay in patients with a CYP2C9 variant. Our initial results imply that pharmacogenomic-guided warfarin dosing may be more useful in settings with less intensive patient follow-up, and when adjustments are made for slower therapeutic response in patients with a CYP2C9 variant. Further pharmacokinetic/pharmacodynamic model development may be useful for warfarin pharmacogenomic trial design.


Functional organization of corticocortical projections from area 17 to area 18 in the cat's visual cortex.
We used anatomical and physiological methods to study the functional organization of the association projection from area 17 to area 18 in the cat's visual cortex. Neurons in area 17 projecting to area 18 (revealed by retrograde transport of fluorescent tracer) tend to be clustered over regions of layer 4 receiving input from the ipsilateral eye (visualized by anterograde transneuronal tracing). Since the contralateral input overlaps these ipsilateral patches, the association cells lie preferentially in regions that are likely to be binocularly innervated. Indeed, almost all cells recorded electrophysiologically within the association clusters were strongly binocular, whereas between the clusters, many neurons were dominated by the contralateral eye. There is sufficient jitter in the retinotopic organization of area 17 for the discontinuous distribution of association cells to provide a continuous representation of the visual field. Cells in each association cluster in the rostral part of area 17 project divergently to innervate a zone extending up to 3 mm wide, anteroposteriorly, in the superficial layers of area 18. The receptive fields of cells at any point in area 18 are larger than for the corresponding point in area 17. Neurons recorded at two points in area 18, separated by a distance equal to the limit of anatomical divergence of the projection from area 17, have receptive fields that overlap by an amount similar to the region of visual field covered by the receptive fields of cells in a single association cluster in area 17 at a similar retinotopic position. Thus, area 18 receives a full and strongly binocular representation of the visual field not only from the lateral geniculate nucleus but also from area 17. The divergence of the area 17 to 18 projection compensates for the difference in receptive field size by ensuring that the receptive fields of each cluster of projecting neurons overlap fairly precisely those of the recipient neurons in area 18.