De novo CD5+ diffuse large B-cell lymphomas. A heterogeneous group containing an unusual form of splenic lymphoma.
We reviewed our institutional experience with de novo CD5+, large B-cell lymphomas to determine whether they represent a distinct entity and are related to CD5+ small B-cell disorders. We identified 13 cases with multiparameter flow cytometry over a period of 58 months (5% of large B-cell lymphomas) in 7 females and 6 males. Three groups were identified. Group 1 (2 cases) had diffuse splenic red pulp involvement with a distinctive cordal pattern of infiltration, no other clinical evidence of mass disease, microscopic disseminated disease on further workup, and an identical immunoglobulin-negative immunophenotype. Group 2 cases (7 cases) were clinically and morphologically heterogeneous and had an immunophenotype resembling mantle cell lymphoma (FMC7-positive, CD23-). Group 3 (4 cases) had miscellaneous immunophenotypes, including one closely resembling chronic lymphocytic leukemia. Cyclin D1 was positive in only 1 of 10 evaluable cases (group 2). We conclude that CD5+ diffuse large B-cell lymphomas are heterogeneous; most cases do not seem to be related to chronic lymphocytic leukemia or mantle cell lymphoma. However, we identified a subgroup of primary splenic CD5+ large B-cell lymphoma with diffuse red pulp involvement and believe this may represent a distinct clinicopathologic entity.


Hybrid three-stage repair of mega-aortic syndrome with the Lupiae technique: 10-year results.
Mega-aortic syndrome (MAS) is a rare disease carrying a poor prognosis if treated conservatively. Open repairs of these aneurysms are invasive, while totally endovascular repairs are associated with higher rates of late reintervention due to endoleaks, compromising long-term prognosis. We describe the 10-year results of a hybrid three-stage approach to MAS using the Lupiae technique. Between 2006 and 2016, 27 patients with MAS extending from the ascending aorta to the iliac arteries (MAS type III) underwent: (I) a surgical aortic arch debranching, using the Vascutek Lupiae™ multibranched graft to create a proximal Dacron landing zone; (II) an abdominal aorta debranching to create a distal Dacron landing zone and (III) the implantation of multiple endovascular stents to exclude any residual aneurysm between the two landing zones. One patient died following the first stage, and another following the second stage of the repair (overall mortality 7.4%). The interval between the first and the second stage was 58.3±16.1 days. The interval between the second and the third stage was 47.7±13.1 days. Four-year survival was 88.6%±6.2% while 10-year survival was 51.7%±17.9%. One patient had a type III endoleak after the third stage that self-resolved within 6 months without intervention. No patient had type I or II endoleaks and none underwent redo procedures. Mean follow-up was 5.9±3.6 years and completeness was 100%. Three-stage hybrid repairs using the Lupiae technique can be safely performed in MAS type III patients. Short intervals between the stages should mitigate the risk of rupture during the waiting periods and may enhance patient compliance, but to achieve this, the burden and the complexity of the first stage must be carefully weighted. Our strategy improves the long-term survival of these patients compared to their natural history and is less invasive than an open repair. The adoption of Dacron landing zones appears to be associated with very low rates of reintervention due to endoleaks.


Characterization of a pentylenetetrazol-like interoceptive stimulus produced by ethanol withdrawal.
Rats were trained with food reinforcement to discriminate the anxiogenic drug pentylenetetrazol (PTZ, 20 mg/kg) from saline in a two-lever-choice task. In Experiment 1, ethanol, 8.25% w/v was given by gavage (7/day) for 4 days, with doses titrated to maintain moderate intoxication. After termination of ethanol, the rats exhibited mild overt signs of withdrawal and, in discrimination tests with saline as the test substance, they selected the PTZ lever, an effect reversed by ethanol, 2 g/kg, and by diazepam, 5 mg/kg. In Experiment 2, rats drank a nutritionally complete liquid diet containing ethanol, 4.5% w/v, for 1 week. They became tolerant to the intoxicating effect of ethanol, and blood ethanol concentration mounted with continued dosing. On termination of chronic ethanol, rats selected the PTZ lever before the onset of overt physical signs of withdrawal, and both measures returned to base line within 3 days. In Experiment 3 the percentage of rats selecting the PTZ lever after termination of ethanol depended upon the dose (up to 12.5 g/kg) and duration (up to a ceiling effect by 3 days) of ethanol administered chronically. These results indicate that a PTZ-like stimulus produced interoceptively can be demonstrated in the rat as an objective measure of ethanol withdrawal. This paradigm may provide insight into the symptom of anxiety associated with ethanol withdrawal.


The effects of systemic hypoxia on renal function in the anaesthetized rat.
1. In rats anaesthetized with Saffan, renal function was monitored from the left kidney from the 5th minute of spontaneous breathing of 12% O2 for two 20 min periods and during air breathing before, between and after the hypoxic periods. Two groups of animals (I and II) were used, each group comprising two subgroups in which the left kidney was innervated or denervated, respectively; in Group II, renal perfusion pressure (RPP) was maintained during the 2nd hypoxic period by occl97uding the distal aorta. 2. In both subgroups of Group I, both hypoxic periods produced hyperventilation, arterial PO2 falling to approximately 50 mmHg. Concomitantly, mean arterial pressure (MABP) fell by similar extents (approximately 23%, from a baseline level of 140 mmHg during the 2nd hypoxic period). In the innervated subgroup, renal vascular conductance (RVC) increased, but glomerular filtration rate (GFR) fell (by 48 and 6%, respectively, during the 2nd hypoxic period), while urine flow, absolute sodium excretion (UNaV) and fractional sodium excretion (FENa) fell (by 52, 63 and 61%, respectively). Baseline urine flow, UNaV and FENa were higher in the denervated subgroup, but hypoxia produced similar percentage changes from baseline in all variables. 3. In Group II, both subgroups showed similar changes during the 1st hypoxic period as the corresponding subgroups of Group I. However, during the 2nd hypoxic period when the fall in MABP was reduced to approximately 7%, the increase in RVC persisted only in the denervated subgroup; there was no significant change in GFR, urine flow, UNaV or FENa in either subgroup. 4. These results indicate that, in the rat, moderate hypoxia produces antidiuresis and antinatriuresis that are not dependent on the renal nerves, but are dependent on the hypoxia-induced fall in MABP. The fall in renal perfusion pressure (RPP) may directly determine renal function, but reflex influences upon the kidney initiated by, for example, arterial baroreceptor unloading, may play a role. The fall in GFR and increase in RVC, which persisted after denervation or when renal perfusion was controlled, implies a local dilatatory influence acting preferentially on the efferent arterioles.


Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells.
The antiviral activity of azidothymidine (AZT), dideoxycytidine (ddC), and dideoxyinosine (ddI) against HIV-1 was comparatively evaluated in PHA-stimulated PBM. The mean drug concentration which yielded 50% p24 Gag negative cultures were substantially different: 0.06, 0.2, and 6 microM for AZT, ddC, and ddI, respectively. We found that AZT was preferentially phosphorylated to its triphosphate (TP) form in PHA-PBM rather than unstimulated, resting PBM (R-PBM), producing 10- to 17-fold higher ratios of AZTTP/dTTP in PHA-PBM than in R-PBM. The phosphorylation of ddC and ddI to their TP forms was, however, much less efficient in PHA-PBM, resulting in approximately 5-fold and approximately 15-fold lower ratios of ddCTP/dCTP and ddATP/dATP, respectively, in PHA-PBM than in R-PBM. The comparative order of PHA-induced increase in cellular enzyme activities examined was: thymidine kinase > uridine kinase > deoxycytidine kinase > adenosine kinase > 5'-nucleotidase. We conclude that AZT, ddC, and ddI exert disproportionate antiviral effects depending on the activation state of the target cells, i.e., ddI and ddC exert antiviral activity more favorably in resting cells than in activated cells, while AZT preferentially protects activated cells against HIV infection. Considering that HIV-1 proviral DNA synthesis in resting lymphocytes is reportedly initiated at levels comparable with those of activated lymphocytes, the current data should have practical relevance in the design of anti-HIV chemotherapy, particularly combination chemotherapy.


Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas.
Examination of somatic epidermal growth factor receptor (EGFR) mutations is now a diagnostic routine for treatment of cancer using EGFR tyrosine kinase inhibitors (EGFR-TKI). Circulating tumor DNA is a promising target for noninvasive diagnostics. We evaluated its utility by quantitatively detecting activating and resistant mutations, which were measured with BEAMing (beads, emulsion, amplification, and magnetics). Twenty-three patients with lung cancer with progressive disease after EGFR-TKI treatment and 21 patients who had never been treated with EGFR-TKIs were studied. Their primary tumors were confirmed to have activating mutations. In the plasma DNA of each patient, the activating mutation found in the corresponding primary tumor and the T790M resistance mutation were quantified by BEAMing. In 32 of 44 patients, activating mutations were detected in the plasma DNA [72.7%; 95% confidence interval (CI), 58.0%-83.6%]. The T790M mutation was detected in 10 of 23 patients in the first group (43.5%; 95% CI, 25.6%-53.4%). The ratio of T790M to activating mutations ranged from 13.3% to 94.0%. The peak of the distribution of the mutation allele fraction in the plasma DNA was in the 0.1% to 1% range. The major advantage of BEAMing is its ability to calculate the fraction of T790M-positive alleles from the alleles with activating mutations. This feature enables the detection of increases and decreases in the number of T790M mutations in cancer cells, regardless of normal cell DNA contamination, which may be useful for monitoring disease progression. Circulating tumor DNA could potentially be used as an alternative method for EGFR mutation detection.


'It's bit of an eye opener' - A qualitative study of women's attitudes towards tanning, sun protection and a facial morphing intervention.
Skin cancer is to a large degree behaviourally preventable, meaning that evidence-based interventions have scope to make a difference. Previous research indicates that appearance-based interventions such as facial morphing may be more effective than health-based interventions, and that it can personalise the issue of skin cancer. This study examined attitudes to UV exposure, as well as reactions to a facial morphing intervention, through interviews with 25 women aged 35 years and older. Thematic analysis revealed four themes; two regarding attitudes to UV exposure (confusion and contradiction, and change and continuity), and two relating to the facial morphing intervention (negative reactions to UV-exposed photo and positive outcomes of the intervention). Women experienced a number of barriers to adopting safer behaviour in the sun; their current attitudes to UV exposure had been shaped by available information sources throughout their ageing. They expressed negative evaluations of the UV photo, which fed directly into motivation to reduce UV exposure. These results can be interpreted along the lines of goal-directed behaviour. This type of intervention has the potential to reduce UV exposure among this participant group, something that needs to be further investigated with randomised control trials.


Action of Actomyosin Contraction With Shh Modulation Drive Epithelial Folding in the Circumvallate Papilla.
The mouse tongue possesses three types of gustatory papillae: large circumvallate papillae (CVP), foliate papillae (FOP) and fungiform papillae (FFP). Although CVP is the largest papilla and contain a high density of taste buds, little is known about CVP development. Their transition from placode to dome-shape is particularly ambiguous. Understanding this phase is crucial since dome-shaped morphology is essential for proper localization of the imminent nerve fibers and taste buds. Here, we report actomyosin-dependent apical and basal constriction of epithelial cells during dynamic epithelial folding. Furthermore, actomyosin-dependent basal constriction requires focal adhesion kinase to guide dome-shape formation. Sonic hedgehog (Shh) is closely associated with the differentiation or survival of the neurons in CVP ganglion and cytoskeletal alteration in trench epithelial cells which regulate CVP morphogenesis. Our results demonstrate the CVP morphogenesis mechanism from placode to dome-shape by actomyosin-dependent cell shape change and suggest roles that Shh may play in trench and stromal core formation during CVP development.


Living cells in 1 of 2 frozen femoral heads.
Allogeneic, frozen bone is now the most commonly grafted tissue (Norman-Taylor and Villar 1997). Tissue banks collect bone material according to protocols developed with the aim of maintaining osseoinductive properties of grafts as well as preventing transmission of viral or bacterial diseases (Standards from the American Association of Tissue Banks (AATB) or from the European Association for Musculo-skeletal Transplanting (EAMST)). Standard procedures include cryopreservation of tissue at -80 degrees C, which is generally considered to devitalize the bone by killing all cells present, resulting in reduced immunogenicity of the graft. The osseoinductive properties of frozen, allogeneic bone grafts have therefore mainly been attributed to the dead bone matrix, that may provide osteoblast-stimulating growth factors and other essential proteins, and/or an osteoclast substrate to direct bone remodeling (Aspenberg et al. 1996, Kingsmill et al. 1999). Recently however, it was suggested that some cells in bone biopsies may survive standard bone bank freezing procotols. It is unclear whether vital cells are present in other bone banks and whether these cells can contribute to the clinical outcome of frozen allogeneic bone grafting. In this report, we show that frozen bone biopsies, obtained from the Erasmus Medical Center bone bank may contain living cells that can be cultured in vitro. These cultured cells were found to originate from the donor by genotyping.


Antioxidant effects of melatonin and coenzyme Q10 on oxidative damage caused by single-dose ochratoxin A in rat kidney.
In the study, the effects of relatively high single-dose of Ochratoxin A (OTA) and the antioxidant effects of Melatonin (Mel) and Coenzyme Q10 (CoQ10) on OTA-induced oxidative damages in rats were investigated. A total of 28 male Sprague-Dawley rats were divided into four groups of 7 rats each: Control, OTA, Mel+OTA and CoQ10+OTA groups. Malondialdehyde (MDA) levels in the plasma and glutathione (GSH) levels in whole blood were measured; kidneys (for histological inspection and for apoptosis detection by TUNEL method) and bone marrow samples (for chromosome aberration and mitotic index) were taken. The rats in the OTA group showed limited degeneration of tubular cells. In some tubules karyomegaly, desquamated cells and vacuolization were observed by light microscopy. Mel and CoQ10 treatment significantly reduced the severity of the lesions. MDA levels of the OTA group were significantly higher than the control, OTA+Mel and OTA+CoQ10 groups, while GSH levels were significantly lower than the control, OTA+Mel and OTA+CoQ10 groups. Higher incidences of apoptotic bodies were observed in the kidneys of the OTA group although OTA administration did not significantly change the incidence of apoptotic bodies when compared to the control and antioxidant administrated groups. Although the percentage of the mitotic index was lowest in the OTA group, no statistical difference was found among the groups. Additionally, OTA had no numerical and structural significant effects on chromosomes. It was observed that single-dose OTA administration caused oxidative damages in rat kidney and Mel or CoQ10 treatment appeared to ameliorate the OTA-induced tissue injuries.


Immunotransplantation preferentially expands T-effector cells over T-regulatory cells and cures large lymphoma tumors.
Ex vivo-expanded tumor-infiltrating lymphocytes infused into lymphodepleted recipients has clear antitumor efficacy. More practical sources of such antitumor lymphocytes would broaden the application of this approach. Previously, we described an in situ vaccination combining chemotherapy with intratumoral injection of CpG-enriched oligonucleotides, which induced T-cell immunity against established lymphoma. An ongoing clinical trial of this maneuver has demonstrated clinical responses in lymphoma patients. Here, we use this vaccine maneuver to generate immune cells for transfer into irradiated, syngeneic recipients. Transferred tumor-specific T-effector (T(eff)) cells preferentially expanded, increasing the T(eff)/T-regulatory (T(reg)) ratio in these "immunotransplantation" recipients and curing large and metastatic tumors. Donor T cells were necessary for tumor protection, and CD8 T-cell immune responses were enhanced by posttransplantation booster vaccination. Hematopoietic stem cell transplantation is a standard therapy for lymphoma. Therefore, in situ tumor vaccination followed by immunotransplantation of harvested tumor-specific T cells could be directly tested in clinical trials to treat otherwise resistant malignancies.


Intrinsic neuromodulation in the Tritonia swim CPG: the serotonergic dorsal swim interneurons act presynaptically to enhance transmitter release from interneuron C2.
Heterosynaptic enhancement of transmitter release is potentially very important for neuronal computation, yet, to our knowledge, no prior study has shown that stimulation of one neuron directly enhances release from an interneuron. Here, we demonstrate that in the marine mollusk Tritonia diomedea, the serotonergic dorsal swim interneurons (DSIs) heterosynaptically increase the amount of transmitter released from another interneuron, C2. Stimulation of a single DSI at physiological firing frequencies increases the size of synaptic potentials evoked by C2. This increase in synaptic efficacy is correlated with an increase in homosynaptic paired-pulse facilitation by C2. Thus, it is likely to be due to an enhancement of transmitter release from C2, rather than a postsynaptic action on the followers of C2. This is further supported by the fact that DSI stimulation enhances the strengths of all chemical synapses made by C2 within the swim network, regardless of their sign. Furthermore, DSI enhances the amplitude of C2 synaptic potentials recorded in neurons that DSI itself does not synapse with. Finally, DSI differentially modulates different synaptic inputs to the same postsynaptic target; while increasing C2-evoked EPSPs it simultaneously decreases the size of EPSPs evoked by other DSIs. The heterosynaptic facilitation of C2 synaptic potentials by DSI is not caused by a simple depolarization of C2, but may be a direct action on the transmitter release mechanism. This neuromodulatory effect, which is intrinsic to the circuitry of the central pattern generator for escape swimming in Tritonia, may be important for self-reconfiguration of the swim motor network.


Mass Drug Administration and beyond: how can we strengthen health systems to deliver complex interventions to eliminate neglected tropical diseases?
Achieving the 2020 goals for Neglected Tropical Diseases (NTDs) requires scale-up of Mass Drug Administration (MDA) which will require long-term commitment of national and global financing partners, strengthening national capacity and, at the community level, systems to monitor and evaluate activities and impact. For some settings and diseases, MDA is not appropriate and alternative interventions are required. Operational research is necessary to identify how existing MDA networks can deliver this more complex range of interventions equitably. The final stages of the different global programmes to eliminate NTDs require eliminating foci of transmission which are likely to persist in complex and remote rural settings. Operational research is required to identify how current tools and practices might be adapted to locate and eliminate these hard-to-reach foci. Chronic disabilities caused by NTDs will persist after transmission of pathogens ceases. Development and delivery of sustainable services to reduce the NTD-related disability is an urgent public health priority. LSTM and its partners are world leaders in developing and delivering interventions to control vector-borne NTDs and malaria, particularly in hard-to-reach settings in Africa. Our experience, partnerships and research capacity allows us to serve as a hub for developing, supporting, monitoring and evaluating global programmes to eliminate NTDs.


Integrated analyses of genome-wide DNA occupancy and expression profiling identify key genes and pathways involved in cellular transformation by a Marek's disease virus oncoprotein, Meq.
Marek's disease (MD) is an economically significant disease in chickens that is caused by the highly oncogenic Marek's disease virus (MDV). A major unanswered question is the mechanism of MDV-induced tumor formation. Meq, a bZIP transcription factor discovered in the 1990s, is critically involved in viral oncogenicity, but only a few of its host target genes have been described, impeding our understanding of MDV-induced tumorigenesis. Using chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray analysis, a high-confidence list of Meq binding sites in the chicken genome and a global transcriptome of Meq-responsive genes were generated. Meq binding sites were found to be enriched in the promoter regions of upregulated genes but not in those of downregulated genes. ChIP-seq was also performed for c-Jun, a known heterodimeric partner of Meq. The close location of binding sites of Meq and c-Jun was noted, suggesting cooperativity between these two factors in modulating transcription. Pathway analysis indicated that Meq transcriptionally regulates many genes that are part of several signaling pathways including the extracellular signal-regulated kinase /mitogen-activated protein kinase (ERK/MAPK), Jak-STAT, and ErbB pathways, which are critical for oncogenesis and/or include signaling mediators involved in apoptosis. Meq activates oncogenic signaling cascades by transcriptionally activating major kinases in the ERK/MAPK pathway and simultaneously repressing phosphatases, as verified using inhibitors of MEK and ERK1/2 in a cell proliferation assay. This study provides significant insights into the mechanistic basis of Meq-dependent cell transformation.


The polymorphic variant rs1800734 influences methylation acquisition and allele-specific TFAP4 binding in the MLH1 promoter leading to differential mRNA expression.
Expression of the mismatch repair gene MutL homolog 1 (MLH1) is silenced in a clinically important subgroup of sporadic colorectal cancers. These cancers exhibit hypermutability with microsatellite instability (MSI) and differ from microsatellite-stable (MSS) colorectal cancers in both prognosis and response to therapies. Loss of MLH1 is usually due to epigenetic silencing with associated promoter methylation; coding somatic mutations rarely occur. Here we use the presence of a colorectal cancer (CRC) risk variant (rs1800734) within the MLH1 promoter to investigate the poorly understood mechanisms of MLH1 promoter methylation and loss of expression. We confirm the association of rs1800734 with MSI+ but not MSS cancer risk in our own data and by meta-analysis. Using sensitive allele-specific detection methods, we demonstrate that MLH1 is the target gene for rs1800734 mediated cancer risk. In normal colon tissue, small allele-specific differences exist only in MLH1 promoter methylation, but not gene expression. In contrast, allele-specific differences in both MLH1 methylation and expression are present in MSI+ cancers. We show that MLH1 transcriptional repression is dependent on DNA methylation and can be reversed by a methylation inhibitor. The rs1800734 allele influences the rate of methylation loss and amount of re-expression. The transcription factor TFAP4 binds to the rs1800734 region but with much weaker binding to the risk than the protective allele. TFAP4 binding is absent on both alleles when promoter methylation is present. Thus we propose that TFAP4 binding shields the protective rs1800734 allele of the MLH1 promoter from BRAF induced DNA methylation more effectively than the risk allele.


Detection of inspiratory flow limitation during sleep by computer assisted respiratory inductive plethysmography.
The potential of respiratory inductive plethysmography (RIP) to detect inspiratory flow limitation during sleep was investigated. Sixteen sleep apnoea patients underwent polysomnography. Airflow by a flowmeter attached to a nasal mask, oesophageal and mask pressure were recorded along with calibrated RIP. Presence of inspiratory flow limitation was defined by constant or decreasing flow without pressure dependence throughout significant portions of inspiration, its absence by a linear or mildly alinear pressure:airflow relationship. Based on this standard, three of various computerized RIP derived parameters, with highest performance to detect flow limitation, were identified. They were combined to an inspiratory flow limitation, (IFL)-Index(RIP), which was validated prospectively in another 10 sleep apnoea patients. RIP derived fractional inspiratory time, peak to mean inspiratory flow ratio, and ribcage contribution to tidal volume had the highest accuracy to detect flow limitation (area under the receiver operating characteristic (ROC) curves 0.81, 0.76, 0.76, respectively, 160 comparisons). Prospective validation revealed an area under the ROC curve for the IFL-Index(RIP) to detect flow limitation of 0.89 (95% confidence interval 0.85 to 0.93, 200 comparisons) with sensitivity and specificity at the point of equality of 80%. It is concluded that inspiratory flow limitation may be assessed by computer assisted analysis of respiratory inductive plethysmography derived breathing patterns with clinically acceptable accuracy.


Unravelling first-generation pedigrees in wild endangered salmon populations using molecular genetic markers.
There is increasing interest in the use of molecular genetic data to infer genealogical relationships among individuals in the absence of parental information. Such analyses can provide insight into mating systems and estimations of heritability in the wild. In addition, accurate pedigree reconstruction among the founders of endangered populations being reared in captivity would be invaluable. Many breeding programs for endangered species attempt to minimize loss of genetic variation and inbreeding through strategies designed to minimize global co-ancestry, but they assume a lack of relatedness among the founders. Yet populations that are the target of such programs are generally in serious demographic decline, and many of the available founders may be closely related. Here we demonstrate determination of full and half-sib relationships among the wild founders of a captive breeding program involving two endangered Atlantic salmon populations using two different approaches and associated software, pedigree and colony. A large portion of the juveniles collected in these two rivers appear to be derived from surprisingly few females mating with a large number of males, probably small precocious parr. Another group of potential founders, obtained from a local hatchery, clearly originated from a small number of full-sib crosses. These results allowed us to prioritize individuals on the basis of conservation value, and are expected to help minimize loss of genetic variation through time. In addition, insight is provided into the number of contributing parents and the mating systems that produced this last generation of endangered wild Atlantic salmon.


Development of a cognitive bias methodology for measuring low mood in chimpanzees.
There is an ethical and scientific need for objective, well-validated measures of low mood in captive chimpanzees. We describe the development of a novel cognitive task designed to measure 'pessimistic' bias in judgments of expectation of reward, a cognitive marker of low mood previously validated in a wide range of species, and report training and test data from three common chimpanzees (Pan troglodytes). The chimpanzees were trained on an arbitrary visual discrimination in which lifting a pale grey paper cone was associated with reinforcement with a peanut, whereas lifting a dark grey cone was associated with no reward. The discrimination was trained by sequentially presenting the two cone types until significant differences in latency to touch the cone types emerged, and was confirmed by simultaneously presenting both cone types in choice trials. Subjects were subsequently tested on their latency to touch unrewarded cones of three intermediate shades of grey not previously seen. Pessimism was indicated by the similarity between the latency to touch intermediate cones and the latency to touch the trained, unreinforced, dark grey cones. Three subjects completed training and testing, two adult males and one adult female. All subjects learnt the discrimination (107-240 trials), and retained it during five sessions of testing. There was no evidence that latencies to lift intermediate cones increased over testing, as would have occurred if subjects learnt that these were never rewarded, suggesting that the task could be used for repeated testing of individual animals. There was a significant difference between subjects in their relative latencies to touch intermediate cones (pessimism index) that emerged following the second test session, and was not changed by the addition of further data. The most dominant male subject was least pessimistic, and the female most pessimistic. We argue that the task has the potential to be used to assess longitudinal changes in sub-clinical levels of low mood in chimpanzees, however further work with a larger sample of animals is required to validate this claim.


Changes in ganglioside metabolism during in vitro differentiation of quail embryo myoblasts.
The metabolism of gangliosides was studied during the in vitro differentiation of both normal quail myoblasts and myoblasts which have been transformed by a temperature-sensitive mutant of Rous sarcoma virus (RSV). These transformed cells can be maintained undifferentiated if incubated at 35 degrees C, but they will differentiate when shifted to 41 degrees C. (D. Montarras and M. Y. Fiszman (1983) J. Biol. Chem. 258, 3882-3888). The analysis of [14C]Glucosamine-labeled gangliosides by two-dimensional thin-layer chromatography reveals variations in the metabolism of the gangliosides during the process of differentiation. During the formation of myotubes, it was observed that the accumulation of GD1a is reduced, while the accumulation of GD3 is increased. Therefore, this results in the variation of the ratio GD3/GD1a which increases from 1.8 to 25 in the case of clones of transformed myoblasts, and from 0.5 to 1.7 in the case of uninfected myoblasts. These variations which have been observed seem to be specific of the myogenic differentiation since they cannot be reproduced when differentiation is inhibited by BUdR treatment or when fibroblasts reach confluency and are blocked in the G1 phase of cell cycle. Furthermore, the transformed myoblasts in vitro are shown to be a good model system since their gangliosides composition is very similar to that of muscle cells in vivo.


Dissolution DNP for in vivo preclinical studies.
The tremendous polarization enhancement afforded by dissolution dynamic nuclear polarization (DNP) can be taken advantage of to perform preclinical in vivo molecular and metabolic imaging. Following the injection of molecules that are hyperpolarized via dissolution DNP, real-time measurements of their biodistribution and metabolic conversion can be recorded. This technology therefore provides a unique and invaluable tool for probing cellular metabolism in vivo in animal models in a noninvasive manner. It gives the opportunity to follow and evaluate disease progression and treatment response without requiring ex vivo destructive tissue assays. Although its considerable potential has now been widely recognized, hyperpolarized magnetic resonance by dissolution DNP remains a challenging method to implement for routine in vivo preclinical measurements. The aim of this article is to provide an overview of the current state-of-the-art technology for preclinical applications and the challenges that need to be addressed to promote it and allow its wider dissemination in the near future.


The effect of chelating agents on cellular iron metabolism.
1. The effect of iron chelators on iron uptake, ferritin and total protein synthesis was studied in cultured Chang cells. Desferrioxamine depressed ferritin synthesis and completely inhibited iron uptake by ferritin protein. Rhodotorulic acid reduced iron uptake by the cells but had little effect on ferritin synthesis. Diethylenetriamine pentaacetic acid produced complete inhibition of iron uptake and all protein synthesis. 2,3-Dihydroxybenzoic acid (2,3-DHB) had no effect in this system. 2. When 2,3-DHB was incubated with a liver homogenate, its subsequent addition to a Chang cell culture resulted in depression of ferritin synthesis, iron uptake into the protein and some depression of total protein synthesis. Pretreatment of rhodotorulic acid did not affect its properties. 3. Non-ferritin iron in the Chang cell cytosol was dialysable, available for binding to transferrin and formed chelates which appeared, on gel chromatography, to be of low molecular weight. Gel chromatography of cytosol after incubation of the cells with chelating agents showed non-ferritin iron to be in a similar form. 4. Loss of non-ferritin iron from the cells occurred only when the transferrin in the medium was unsaturated. In the presence of chelating agents non-ferritin iron was lost from the cells even when transferrin was 100% saturated. 5. The results confirm the presence of an intracellular labile iron pool which is available for chelation, and demonstration that different iron chelators have different metabolic effects.


Implementation of independent nurse prescribing in UK mental health settings: focus on attention-deficit/hyperactivity disorder.
Legislative changes that came into effect in the UK in April 2012 gave nurse independent prescribers (NIPs) the power to prescribe schedule 2-5 controlled drugs. Therefore, suitably qualified UK nurses can now independently prescribe any drug for any medical condition within their clinical competence. The potential benefits of independent nurse prescribing include improved access to medications and more efficient use of skills within the National Health Service workforce. This review explores the published literature (to July 2013) to investigate whether the predicted benefits of NIPs in mental health settings can be supported by empirical evidence, with a specific focus on nurse-led management of patients with attention-deficit/hyperactivity disorder (ADHD). The most common pharmacological treatments for ADHD are controlled drugs. Therefore, the 2012 legislative changes allow nurse-led ADHD services to offer holistic packages of care for patients. Evidence suggests that independent prescribing by UK nurses is safe, clinically appropriate and associated with high levels of patient satisfaction. The quality of the nurse-patient relationship and nurses' ability to provide flexible follow-up services suggests that nurse-led ADHD services are well positioned to enhance the outcomes for patients and their parents/carers. However, the empirical evidence available to support the value of NIPs in mental health settings is limited. There is a need for additional high-quality data to verify scientifically the value of nurse-delivered ADHD care. This evidence will be invaluable in supporting the growth of nurse-led ADHD services and for those who support greater remuneration for the expanded role of NIPs.


Effects of methylprednisolone and 4-chloro-3-hydroxyanthranilic acid in experimental spinal cord injury in the guinea pig appear to be mediated by different and potentially complementary mechanisms.
Blinded, placebo-controlled, parallel treatment group studies of the effects of methylprednisolone (MP) or 4-chloro-3-hydroxyanthranilate (4-Cl-3-HAA) on behavioral outcome and quinolinic acid tissue levels from experimental thoracic spinal cord injury in adult guinea pigs. To compare the effects of treatment with high-dose MP, a corticosteroid, and 4-Cl-3-HAA, a compound that inhibits synthesis of the neurotoxin quinolinic acid (QUIN) by activated macrophages. To explore the effect of different times of treatment using these two approaches to ameliorating secondary tissue damage. Laboratory animal studies at the University of North Carolina, Chapel Hill, NC, USA. Standardized spinal cord injuries were produced in anesthetized guinea pigs, using lateral compression of the spinal cord. Behavioral impairment and recovery were measured by placing and toe-spread responses (motor function), cutaneus trunci muscle reflex receptive field areas and somatosensory-evoked potentials (sensory function). Tissue quinolinic acid levels were measured by gas chromatograph/mass spectrometry. The current experiments showed a reduction in delayed loss of motor and sensory function in the guinea pig with MP (150 mg kg(-1), intraperitoneally in split doses between 0.5 and 6 h), but no significant reduction in tissue QUIN. Improved sensory function was seen with a single dose of 60 mg kg(-1) MP intraperitoneally at 5 h after injury, but not at 10 h after injury. A single dose of 4-Cl-3-HAA at 5 h in the guinea pig did not produce the sensory and motor improvements seen in previous studies with 12 days of dosing, beginning at 5 h. These studies, together with earlier findings, indicate that both drugs can attenuate secondary pathologic damage after SCI, but through separate mechanisms. These are most likely an acute reduction by MP of oxidative processes and reduction by 4-Cl-3-HAA of QUIN synthesis.


Identifying the bottleneck of water oxidation by ab initio analysis of in situ optical absorbance spectrum.
Hematite's (α-Fe2O3) major limitation to efficiently splitting water using sunlight is the low rate of the oxygen evolution reaction (OER). Thus, identifying the OER rate limiting step is a cornerstone to enhancing the current under low applied potential. Different measurement techniques showed similar absorption difference spectra during a change in applied potential on the hematite anode below and above the onset of the OER in the dark and under light. This absorption change was shown to result from surface modification during the OER, but the specific surface species could not be resolved. On the basis of ab initio calculations, we analyze the calculated absorption spectra in relation to previous measurements. We provide for the first time solid evidence to specify H2O + *O → *OOH + H+ + e- as the rate limiting step and *O as the bottleneck intermediate of the hematite OER.


Coral microbiome composition along the northern Red Sea suggests high plasticity of bacterial and specificity of endosymbiotic dinoflagellate communities.
The capacity of reef-building corals to tolerate (or adapt to) heat stress is a key factor determining their resilience to future climate change. Changes in coral microbiome composition (particularly for microalgal endosymbionts and bacteria) is a potential mechanism that may assist corals to thrive in warm waters. The northern Red Sea experiences extreme temperatures anomalies, yet corals in this area rarely bleach suggesting possible refugia to climate change. However, the coral microbiome composition, and how it relates to the capacity to thrive in warm waters in this region, is entirely unknown. We investigated microbiomes for six coral species (Porites nodifera, Favia favus, Pocillopora damicornis, Seriatopora hystrix, Xenia umbellata, and Sarcophyton trocheliophorum) from five sites in the northern Red Sea spanning 4° of latitude and summer mean temperature ranges from 26.6 °C to 29.3 °C. A total of 19 distinct dinoflagellate endosymbionts were identified as belonging to three genera in the family Symbiodiniaceae (Symbiodinium, Cladocopium, and Durusdinium). Of these, 86% belonged to the genus Cladocopium, with notably five novel types (19%). The endosymbiont community showed a high degree of host-specificity despite the latitudinal gradient. In contrast, the diversity and composition of bacterial communities of the surface mucus layer (SML)-a compartment particularly sensitive to environmental change-varied significantly between sites, however for any given coral was species-specific. The conserved endosymbiotic community suggests high physiological plasticity to support holobiont productivity across the different latitudinal regimes. Further, the presence of five novel algal endosymbionts suggests selection of certain genotypes (or genetic adaptation) within the semi-isolated Red Sea. In contrast, the dynamic composition of bacteria associated with the SML across sites may contribute to holobiont function and broaden the ecological niche. In doing so, SML bacterial communities may aid holobiont local acclimatization (or adaptation) by readily responding to changes in the host environment. Our study provides novel insight about the selective and endemic nature of coral microbiomes along the northern Red Sea refugia.


The steel scrap age.
Steel production accounts for 25% of industrial carbon emissions. Long-term forecasts of steel demand and scrap supply are needed to develop strategies for how the steel industry could respond to industrialization and urbanization in the developing world while simultaneously reducing its environmental impact, and in particular, its carbon footprint. We developed a dynamic stock model to estimate future final demand for steel and the available scrap for 10 world regions. Based on evidence from developed countries, we assumed that per capita in-use stocks will saturate eventually. We determined the response of the entire steel cycle to stock saturation, in particular the future split between primary and secondary steel production. During the 21st century, steel demand may peak in the developed world, China, the Middle East, Latin America, and India. As China completes its industrialization, global primary steel production may peak between 2020 and 2030 and decline thereafter. We developed a capacity model to show how extensive trade of finished steel could prolong the lifetime of the Chinese steelmaking assets. Secondary steel production will more than double by 2050, and it may surpass primary production between 2050 and 2060: the late 21st century can become the steel scrap age.


Dynamics of Gut Microbiome in Giant Panda Cubs Reveal Transitional Microbes and Pathways in Early Life.
Adult giant pandas (Ailuropoda melanoleuca) express transitional characteristics in that they consume bamboos, despite their carnivore-like digestive tracts. Their genome contains no cellulolytic enzymes; therefore, understanding the development of the giant panda gut microbiome, especially in early life, is important for decoding the rules underlying gut microbial formation, inheritance and dietary transitions. With deep metagenomic sequencing, we investigated the gut microbiomes of two newborn giant panda brothers and their parents living in Macao, China, from 2016 to 2017. Both giant panda cubs exhibited progressive increases in gut microbial richness during growth, particularly from the 6th month after birth. Enterobacteriaceae dominated the gut microbial compositions in both adult giant pandas and cubs. A total of 583 co-abundance genes (CAGs) and about 79 metagenomic species (MGS) from bacteria or viruses displayed significant changes with age. Seven genera (Shewanella, Oblitimonas, Helicobacter, Haemophilus, Aeromonas, Listeria, and Fusobacterium) showed great importance with respect to gut microbial structural determination in the nursing stage of giant panda cubs. Furthermore, 10 orthologous gene functions and 44 pathways showed significant changes with age. Of the significant pathways, 16 from Escherichia, Klebsiella, Propionibacterium, Lactobacillus, and Lactococcus displayed marked differences between parents and their cubs at birth, while 29 pathways from Escherichia, Campylobacter and Lactobacillus exhibited significant increase in cubs from 6 to 9 months of age. In addition, oxidoreductases, transferases, and hydrolases dominated the significantly changed gut microbial enzymes during the growth of giant panda cubs, while few of them were involved in cellulose degradation. The findings indicated diet-stimulated gut microbiome transitions and the important role of Enterobacteriaceae in the guts of giant panda in early life.


Bio-nanopatterning of Surfaces.
Bio-nanopatterning of surfaces is a very active interdisciplinary field of research at the interface between biotechnology and nanotechnology. Precise patterning of biomolecules on surfaces with nanometre resolution has great potential in many medical and biological applications ranging from molecular diagnostics to advanced platforms for fundamental studies of molecular and cell biology. Bio-nanopatterning technology has advanced at a rapid pace in the last few years with a variety of patterning methodologies being developed for immobilising biomolecules such as DNA, peptides, proteins and viruses at the nanoscale on a broad range of substrates. In this review, the status of research and development are described, with particular focus on the recent advances on the use of nanolithographic techniques as tools for biomolecule immobilisation at the nanoscale. Present strengths and weaknesses, as well future challenges on the different nanolithographic bio-nanopatterning approaches are discussed.


Controlling the surface termination of NdGaO3 (110): the role of the gas atmosphere.
In this work the effect of gas atmosphere on the surface termination reconstruction of single crystal NdGaO3 (110) (NGO) during thermal annealing was analyzed. Using Low Energy Ion Scattering (LEIS) it has been possible to study the chemical composition of the first atomic layer of treated NGO single crystal samples. NGO has been analyzed both as-received and after a specific thermal treatment at 1000 °C under different gas fluxes (argon, nitrogen, static air, synthetic air, nitrogen plus 5% hydrogen and wet synthetic air respectively). Thermal annealing of perovskite single crystals, as already reported in the literature, is used to obtain a fully A-cation surface termination. Nevertheless the effect of the gas-atmosphere on this process has not been previously reported. By the use of sequential low energy Ar(+) sputtering combined with the primary ion LEIS analysis, the reconstruction of the outermost atomic layers has allowed the clarification of the mechanism of NGO neodymium surface enrichment. It is proposed that the gallium at the surface is submitted to a reduction/evaporation mechanism caused by low oxygen partial pressure and/or high water pressure in the vector gas. Below the first surface atomic layers of an as-received NGO single-crystal a gallium-rich phase has also been observed.


Guidelines for the application of surgery and endoprostheses in the palliation of obstructive jaundice in advanced cancer of the pancreas.
This study was set up to identify patient-related factors favoring the application of either surgery or endoprostheses in the palliation of obstructive jaundice in subsets of patients with cancer of the head of the pancreas or periampullary region. In the palliation of obstructive jaundice, surgical biliodigestive anastomosis has traditionally been performed. Surgical biliary bypass is associated with high mortality (15% to 30%) and morbidity rates (20% to 60%) but little recurrent obstructive jaundice (0% to 15%). Biliary drainage with endoscopically placed endoprostheses has a lower complication rate, but recurrent obstructive jaundice is seen in up to 20% to 50% of patients. Patients with advanced cancer of the head of the pancreas or periampullary region treated at the University Hospital Dijkzigt, Rotterdam, The Netherlands, between 1980 and 1990 were reviewed. In 148 patients, data were compared concerning the morbidity and hospital stay after the palliation of obstructive jaundice with endoscopic endoprostheses or surgical biliary bypasses. These patients were stratified for long (> 6 months) and short (< 6 months) survival times. In short-term survivors, the higher late morbidity rates after endoprostheses were offset by higher early morbidity rates and longer hospital stays after the surgical bypass. In long-term survivors, there was no difference in the hospital stay between the two groups, but the late morbidity rate was significantly higher in the endoprosthesis group. These data suggest that endoscopic endoprosthesis is the optimal palliation for patients surviving less than 6 months and surgical biliary bypass for those surviving more than 6 months. This policy necessitates the development of prognostic criteria, which were obtained by Cox proportional-hazards survival analysis. Advanced age, male sex, liver metastases, and large diameters of tumors were unfavorable prognostic factors. With these factors, the risk of short- or long-term survival can be predicted. It is hoped that the application of these data may allow a rational approach toward optimal palliative treatment of this form of malignant obstructive jaundice.


Effects of population dispersal on regional signaling networks: An example from northern Iroquoia.
The dispersal of Iroquoian groups from St. Lawrence River valley during the 15th and 16th centuries A.D. has been a source of archaeological inquiry for decades. Social network analysis presented here indicates that sites from Jefferson County, New York at the head of the St. Lawrence River controlled interactions within regional social signaling networks during the 15th century A.D. Measures indicate that Jefferson County sites were in brokerage liaison positions between sites in New York and Ontario. In the network for the subsequent century, to which no Jefferson County sites are assigned, no single group took the place of Jefferson County in controlling network flow. The dispersal of Jefferson County populations effectively ended this brokerage function concomitant with the emergence of the nascent Huron-Wendat and Iroquois confederacies and may have contributed to the escalation of conflict between these entities. These results add to a growing literature on the use of network analyses with archaeological data and contribute new insights into processes of population relocation and geopolitical realignment, as well as the role of borderlands and frontiers in nonstate societies.


Portal Nodes Screening for Large Scale Social Networks.
Network autoregression model (NAM), as a powerful tool to study user social behaviors on large scale social networks, has drawn great attention in recent years. In this paper, we are interested in identifying the influential users (i.e., portal nodes) in a social network under the framework of NAM. Especially, we consider the autoregression model that allows to have a heterogenous and sparse network effect coefficients. Therefore, the portal nodes take influential powers which are corresponding to the nonzero network effect coefficients. A screening procedure is designed to screen out the portal nodes and the strong screening consistency is established theoretically. A quasi maximum likelihood method is applied to estimate the influential powers. The asymptotic normality of the resulting estimator is established. Further selection procedure is given by taking advantage of the local linear approximation algorithm. Extensive numerical studies are conducted by using a Sina Weibo dataset for illustration purpose.


A dual mechanism linking NGF/proNGF imbalance and early inflammation to Alzheimer's disease neurodegeneration in the AD11 anti-NGF mouse model.
The neurotrophin Nerve Growth Factor (NGF) is essential for the maintenance and differentiation of basal forebrain cholinergic neurons. Since basal forebrain cholinergic neurons represent one major neuronal population affected and progressively degenerating in Alzheimer's disease (AD), interest has grown for NGF as a potential therapeutic agent in neurodegenerative disorders linked to aging, particularly for AD. However, no evidence was available, to link, in a cause-effect manner, deficits in NGF signalling to the broader activation in the Alzheimer's cascade, besides cholinergic deficits. The phenotypic analysis of the AD11 anti-NGF transgenic mouse, obtained by the "neuroantibodies" phenotypic protein knock out strategy, allowed demonstrating a direct causal link between NGF deprivation and AD pathology. Since then, extensive mechanistic studies on the AD11 model provided a new twist to the concept that alterations in NGF transport and signalling play a crucial role in sporadic Alzheimer's neurodegeneration, leading to the hypothesis of "Neurotrophic imbalance" as an upstream driver for sporadic AD. The results obtained with the AD11 anti-NGF mice highlight the fact that the particular mode of NGF neutralization, with an NGF antibody expressed in the brain, selectively interfering with mature NGF versus unprocessed proNGF, plays a major role in the mechanism of neurodegeneration, and could lead to new insights into the mechanisms of human sporadic AD. Here, we will review (1) the renewed neurotrophic imbalance hypothesis for AD and (2) the mechanisms underlying the neurodegenerative phenotype of AD11 anti-NGF mice.


The impact of differential antiviral immunity in children and adults.
The course of immune maturation has evolved to favour survival at each stage of development in early life. Fetal and neonatal immune adaptations facilitate intrauterine survival and provide early postnatal protection against extracellular pathogens, but they leave infants susceptible to intracellular pathogens such as viruses that are acquired perinatally. This Review focuses on three such pathogens--HIV, hepatitis B virus and cytomegalovirus--and relates the differential impact of these infections in infants and adults to the antiviral immunity that is generated at different ages. A better understanding of age-specific antiviral immunity may inform the development of integrated prevention, treatment and vaccine strategies to minimize the global disease burden resulting from these infections.


Anticoagulation in children: Making the most of little patients and little evidence.
Thrombotic complications are increasing at a steady and significant rate in children resulting in the more widespread use of anticoagulation in this population. Anticoagulant drugs in children can be divided into the standard agents (heparin, low molecular weight heparin, and vitamin K antagonists) and alternative agents (argatroban, bivalirudin, and fondaparinux). This review will compare and contrast the standard and alternative anticoagulants and suggest situations in which it may be appropriate to use argatroban, bivalirudin, and fondaparinux. Clearly, the standard anticoagulants all have significant shortcomings including variable pharmacokinetics, issues with therapeutic drug monitoring, frequency of administration, efficacy, and adverse effects. The alternative anticoagulants have properties which overcome these shortcomings and prospective clinical trial data are presented supporting the current and future use of these agents in place of the standard anticoagulants.


The economic rationale for investing in stunting reduction.
This paper outlines the economic rationale for investments that reduce stunting. We present a framework that illustrates the functional consequences of stunting in the 1000 days after conception throughout the life cycle: from childhood through to old age. We summarize the key empirical literature around each of the links in the life cycle, highlighting gaps in knowledge where they exist. We construct credible estimates of benefit-cost ratios for a plausible set of nutritional interventions to reduce stunting. There are considerable challenges in doing so that we document. We assume an uplift in income of 11% due to the prevention of one fifth of stunting and a 5% discount rate of future benefit streams. Our estimates of the country-specific benefit-cost ratios for investments that reduce stunting in 17 high-burden countries range from 3.6 (DRC) to 48 (Indonesia) with a median value of 18 (Bangladesh). Mindful that these results hinge on a number of assumptions, they compare favourably with other investments for which public funds compete.


Observer-Rated Alexithymia and its Relationship with the Five-Factor-Model of Personality.
Studies examining the relationship between alexithymia and personality exclusively employed self-report measures of alexithymia. In the present study, we examined the relationship of both observer-rated and self-reported alexithymia with the Big Five personality dimensions. We administered the Toronto Structured Interview for Alexithymia (TSIA) as an interview-based measure of alexithymia and, in addition, two self-report questionnaires, the 20-item Toronto Alexithymia Scale (TAS-20) and the Bermond-Vorst Alexithymia Questionnaire (BVAQ). Fifty-one university students were interviewed and completed the alexithymia scales and the NEO Five-Factor Inventory. In contrast to TAS-20 and BVAQ, the Difficulty identifying feelings (DIF) scale of the TSIA was found to be unrelated to neuroticism, suggesting that the frequently reported association between DIF and neuroticism could be due to the use of self-report scales. In contrast, the affective dimension of alexithymia, measured by the BVAQ, was even negatively related with neuroticism. Thus, a paucity of fantasy and little emotional arousal goes together with increased emotional stability. Furthermore, we revealed negative correlations between interview-based alexithymia scores and openness to experience and agreeableness, which cross-validated the self-report findings. Finally, extraversion and conscientiousness each showed only one negative correlation, namely with subscales of the BVAQ. Taken together, our findings show that on the basis of interviews there is no evidence for a relation of DIF with neuroticism, while associations of alexithymia with low openness to experience and low agreeableness emerged irrespective of assessment approach. The relations of alexithymia with personality are discussed in the light of different measurement approaches.


Restorative proctocolectomy with J-pouch ileoanal anastomosis.
Restorative proctocolectomy with ileoanal anastomosis, complemented by a pouch formed with the last foot of terminal ileum, is the procedure of choice for patients in need of surgical treatment for ulcerative colitis and familial polyposis. The procedure has undergone many technical modifications that have ensured a very high degree of continence and an acceptable number of daily bowel movements. Herein we describe the operative technique we use in the majority of our patients, a restorative proctocolectomy with hand-sewn J-pouch ileoanal anastomosis with protecting ileostomy. We also comment on the immediate postoperative care and on the long-term functional results.


Large-scale comparison of Liberase HI and collagenase NB1 utilized for human islet isolation.
For more than a decade Liberase HI was commonly used as the standard enzyme blend for clinical human islet isolation until enforced replacement by collagenase NB1 (NB1). This change resulted initially in a reduction in islet isolation outcome and transplant activities worldwide. This retrospective study was initiated to compare the efficiency of NB1 premium grade with Liberase in 197 human islet isolations. All pancreata were processed between January 2006 and June 2008 utilizing the same procedures for isolation and quality assessment except the administration of preselected lots of either Liberase (n = 101) or NB1 (n = 96). Utilizing Liberase, significantly more digested tissue and purified islet yield was produced compared to NB1. In contrast, the use of NB1 was associated with significantly higher purity and glucose stimulation index during dynamic perifusion. The expression of proinflammatory markers was almost identical except tissue factor expression, which was higher after utilization of Liberase. No difference was found in the percentage of pancreata fulfilling the criteria for clinical islet transplantation. The results suggest that Liberase is more efficient for pancreas dissociation than collagenase NB1 but seems to be more harmful to exocrine cells and islet tissue.


Tailored design of ruthenium molecular catalysts with 2,2'-bypyridine-6,6'-dicarboxylate and pyrazole based ligands for water oxidation.
With the incorporation of pyrazole and DMSO as axial ligands, a series of tailor-designed Ru water oxidation catalysts [Ru(bda)(DMSO)(L)] (H2bda = 2,2'-bypyridine-6,6'-dicarboxylic acid; DMSO = dimethyl sulfoxide; L = pyrazole, A-1; 4-Br-3-methyl pyrazole, B-1) and [Ru(bda)(L)2] (L = pyrazole, A-2; 4-Br-3-methyl pyrazole, B-2) have been generated in situ from their corresponding precursors [Ru(κ3(O,N,N)-bda)(DMSO)x(L)3-x] which are in a zwitterionic form with an extra pyrazole based ligand in the equatorial position. Formation of the active catalyst has been investigated under pH 1.0 conditions. Electrochemistry and water oxidation activity of these catalysts were investigated. By fine tuning of the catalyst structure, the turnover frequency was increased up to 500 s(-1) and the stability over 6000 turnovers.


Do effects of early child care extend to age 15 years? Results from the NICHD study of early child care and youth development.
Relations between nonrelative child care (birth to 4(1/2) years) and functioning at age 15 were examined (N = 1,364). Both quality and quantity of child care were linked to adolescent functioning. Effects were similar in size as those observed at younger ages. Higher quality care predicted higher cognitive-academic achievement at age 15, with escalating positive effects at higher levels of quality. The association between quality and achievement was mediated, in part, by earlier child-care effects on achievement. High-quality early child care also predicted youth reports of less externalizing behavior. More hours of nonrelative care predicted greater risk taking and impulsivity at age 15, relations that were partially mediated by earlier child-care effects on externalizing behaviors.


Physicians' perceptions of the risk of being sued.
We explore the deterrent effect of the tort system by assessing physician perceptions of the risk of being sued and the impact of those perceptions on their own practice. The data are from a mailed survey conducted in 1989 of a random sample of physicians who were practicing in New York State in 1984. The survey results were compared to the actual risk of suit using the between-group (Wald) test and logistic regression methods. We also surveyed physicians about practice changes undertaken in the last ten years, factors influencing practice standards, and the costs of being sued and included these in the analysis. On average, physicians estimate that 19.5 out of one hundred of their colleagues will be sued in a given year, approximately three times the actual rate, with significant differences by specialty, location, and suit history. Perceived risk is associated with self-reported changes in test-ordering frequency and reduction in practice scope. The median number of days lost from practice to defend a malpractice suit was three to five, and 6 percent of the physicians surveyed incurred some out-of-pocket expenses. These findings suggest that physicians respond to the messages sent by litigation in a manner consistent with the deterrent theory of tort litigation.


DimReader: Axis lines that explain non-linear projections.
Non-linear dimensionality reduction (NDR) methods such as LLE and t-SNE are popular with visualization researchers and experienced data analysts, but present serious problems of interpretation. In this paper, we present DimReader, a technique that recovers readable axes from such techniques. DimReader is based on analyzing infinitesimal perturbations of the dataset with respect to variables of interest. The perturbations define exactly how we want to change each point in the original dataset and we measure the effect that these changes have on the projection. The recovered axes are in direct analogy with the axis lines (grid lines) of traditional scatterplots. We also present methods for discovering perturbations on the input data that change the projection the most. The calculation of the perturbations is efficient and easily integrated into programs written in modern programming languages. We present results of DimReader on a variety of NDR methods and datasets both synthetic and real-life, and show how it can be used to compare different NDR methods. Finally, we discuss limitations of our proposal and situations where further research is needed.


Abnormal bone mineralization after fluoride treatment in osteoporosis: a small-angle x-ray-scattering study.
Sodium fluoride treatment of osteoporosis is known to stimulate bone formation and to increase bone mass, but recent clinical trials failed to prove its antifracture effectiveness. The formation of bone with abnormal structure and, therefore, increased fragility is discussed as a possible explanation. Until now, however, exact information on the mineral structure of osteoporotic bone after fluoride treatment has been lacking. Bone biopsies were taken from three patients with postmenopausal osteoporosis before and after fluoride treatment (60 mg NaF/day for 1-2 years), from one patient with iatrogenic fluorosis, as well as from three normal controls. The mineral in these samples was investigated by a combination of backscattered electron imaging and small-angle x-ray scattering. Depending on the total dose of fluoride, an increasing amount of new bone is laid down on the surface of preexisting trabeculae. Its mineral structure is identical to that of heavy fluorosis and is characterized by the presence of additional large crystals, presumably located outside the collagen fibrils. These large crystals, which are not present in the controls or in osteoporotic bone before fluoride treatment, contribute to increase the mineral density without significantly improving the biomechanical properties of the bone. The possible success of fluoride treatment depends not only on the amount of newly formed bone but also on the rate of bone turnover. Indeed, as soon as significant amounts of fluoride are present, bone turnover leads to the replacement of old (normal) bone by new (pathologically mineralized) bone.(ABSTRACT TRUNCATED AT 250 WORDS)


Hypothesis: Potentially Systemic Impacts of Elevated CO2 on the Human Proteome and Health.
Uniform CO2 during human evolution (180 to 280 ppm) resulted, because of the role of the CO2-bicarbonate buffer in regulating pH, in rather constant pH (7.35 to 7.45) in human fluids, cells and tissues, determining, in turn, the narrow pH range for optimal functioning of the human proteome. Herein, we hypothesize that chronic exposure to elevated pCO2 with increasing atmospheric CO2 (>400 ppm), and extended time spent in confined, crowded indoor atmospheres (pCO2 up to 5,000 ppm) with urban lifestyles, may be an important, largely overlooked driver of change in human proteome performance. The reduced pH (downregulated from 0.1 to 0.4 units below the optimum pH) of extant humans chronically exposed to elevated CO2 is likely to lead to proteome malfunction. This malfunction is due to protein misfolding, aggregation, charge distribution, and altered interaction with other molecules (e.g., nucleic acids, metals, proteins, and drugs). Such alterations would have systemic effects that help explain the prevalence of syndromes (obesity, diabetes, respiratory diseases, osteoporosis, cancer, and neurological disorders) characteristic of the modern lifestyle. Chronic exposure to elevated CO2 poses risks to human health that are too serious to be ignored and require testing with fit-for-purpose equipment and protocols along with indoor carbon capture technologies to bring CO2 levels down to approach levels (180-280 ppm) under which the human proteome evolved.


Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells.
In T cells, triggering of the T cell antigen receptor or of the co-stimulatory receptor CD28 can direct tyrosine phosphorylation of the signaling protein Vav. We investigated the role played by the protein tyrosine kinases Fyn, Lck, and ZAP-70 in these processes in a T cell hybridoma after physiological stimulation of the T cell receptor (TCR) and CD28. A dominant-negative mutant approach based on overexpression of catalytically inactive alleles of these kinases showed that CD28-induced Vav phosphorylation preferentially requires Fyn, whereas ZAP-70 had no role. Consistently, Vav was strongly phosphorylated in Lck-deficient JCAM-1 cells after CD28 ligation. In contrast, ZAP-70 appeared to control TCR-directed Vav phosphorylation. However, overexpression of ZAP-70 carrying a mutated Tyr315, contained within a motif previously suggested to be a Vav Src homology 2 domain binding site, had little or no effect. Immunoprecipitation assays showed that phosphorylated Vav associated with Fyn after CD28 triggering and that this interaction, likely to involve binding of Fyn Src homology 2 domain to Vav, was more strongly detectable after concomitant CD28 and TCR stimulation. These data suggest that Fyn plays a major role in controlling Vav phosphorylation upon T cell activation and that the mechanism implicating ZAP-70 in this process may be more complex than previously anticipated.


Plant expansins are a complex multigene family with an ancient evolutionary origin.
Expansins are a group of extracellular proteins that directly modify the mechanical properties of plant cell walls, leading to turgor-driven cell extension. Within the completely sequenced Arabidopsis genome, we identified 38 expansin sequences that fall into three discrete subfamilies. Based on phylogenetic analysis and shared intron patterns, we propose a new, systematic nomenclature of Arabidopsis expansins. Further phylogenetic analysis, including expansin sequences found here in monocots, pine (Pinus radiata, Pinus taeda), fern (Regnellidium diphyllum, Marsilea quadrifolia), and moss (Physcomitrella patens) indicate that the three plant expansin subfamilies arose and began diversifying very early in, if not before, colonization of land by plants. Closely related "expansin-like" sequences were also identified in the social amoeba, Dictyostelium discoidium, suggesting that these wall-modifying proteins have a very deep evolutionary origin.


Chronic intestinal inflammation alters hippocampal neurogenesis.
Adult neurogenesis in the subgranular zone of the hippocampus is involved in learning, memory, and mood control. Decreased hippocampal neurogenesis elicits significant behavioral changes, including cognitive impairment and depression. Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions of the intestinal tract, and cognitive dysfunction and depression frequently occur in patients suffering from this disorder. We therefore tested the effects of chronic intestinal inflammation on hippocampal neurogenesis. The dextran sodium sulfate (DSS) mouse model of IBD was used. Mice were treated with multiple-cycle administration of 3% wt/vol DSS in drinking water on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26. Mice were sacrificed on day 7 (acute phase of inflammation) or day 29 (chronic phase of inflammation) after the beginning of the treatment. During the acute phase of inflammation, we found increased plasma levels of IL-6 and TNF-α and increased expression of Iba1, a marker of activated microglia, accompanied by induced IL-6 and IL-1β, and the cyclin-dependent kinase inhibitor p21(Cip1) (p21) in hippocampus. During the chronic phase of inflammation, plasma levels of IL-6 were elevated. In the hippocampus, p21 protein levels were continued to be induced. Furthermore, markers of stem/early progenitor cells, including nestin and brain lipid binding protein (BLBP), and neuronal marker doublecortin (DCX) were all down-regulated, whereas glial fibrillary acidic protein (GFAP), a marker for astroglia, was induced. In addition, the number of proliferating precursors of neuronal lineage assessed by double Ki67 and DCX staining was significantly diminished in the hippocampus of DSS-treated animals, indicating decreased production of new neurons. We show for the first time that chronic intestinal inflammation alters hippocampal neurogenesis. As p21 arrests early neuronal progenitor proliferation, it is likely that p21 induction during acute phase of inflammation resulted in the reduction of hippocampal neurogenesis observed later, on day 29, after the beginning of DSS treatment. The reduction in hippocampal neurogenesis might underlie the behavioral manifestations that occur in patients with IBD.


Animal models of human anthrax: the Quest for the Holy Grail.
Anthrax is rare among humans, few data can be collected from infected individuals and they provide a fragmentary view of the dynamics of infection and human host-pathogen interactions. Therefore, the development of animal models is necessary. Anthrax has the particularity of being a toxi-infection, a combination of infection and toxemia. The ideal animal model would explore these two different facets and mimic human disease as much as possible. In the past decades, the main effort has been focused on modelling of inhalational anthrax and the perception of specific aspects of the infection has evolved in recent years. In this review, we consider criteria which can lead to the most appropriate choice of a given animal species for modelling human anthrax. We will highlight the positive input and limitations of different models and show that they are not mutually exclusive. On the contrary, their contribution to anthrax research can be more rewarding when taken in synergy. We will also present a reappraisal of inhalational anthrax and propose reflections on key points, such as portal of entry, connections between mediastinal lymph nodes, pleura and lymphatic drainage.


Optical detection of small changes in refractive indices in water by single-beam scattering.
We studied forward-scattered laser light that is produced when the light strikes an abrupt interface (air bubble in water) and when it passes unimpeded through diffused water layers caused by temperature gradients. Measured intensities of the scattered light indicated patterns that are due to both geometrical and physical optics. Distribution of intensities within the scattered beam changed with the average vertical temperature gradient. Shifts in locations of intensities indicated small changes in the index of refraction in the diffused scattering case.


Free microvascular transfer of the vermiform appendix for creation of a tracheo-oesophageal fistula: A new method of voice reconstruction.
Voice rehabilitation following laryngectomy can take many forms. As its basic premise, vibrating air must be transferred to the mouth where articulation takes place and speech can be produced. It requires a source of air, a conduit for transfer, and a mechanism for prevention of regurgitation and aspiration. Creating a tracheo-oesophageal fistula and maintaining it with a vascularised appendix has been the intention of this report. Three patients with an average age of 53 years underwent the procedure of free transfer of the appendix for voice restoration during the months of September 2004 through December 2004. All patients had laryngectomies and one had total cervical oesophageal reconstruction with a pedicled pectoralis major flap. Voice evaluation, swallowing function, and presence of aspiration were evaluated. All flaps survived without complications. The results of swallowing function were unaltered from preoperative levels. All flaps remained patent at an average follow-up period of 8 months. All three patients could produce loud voice, which was intelligible at a reasonable distance. Maximal phonation time was 4s in two patients and 5s in one patient. Voice rehabilitation using the free appendix flap can achieve a phonation time which is low and words and short phrases that are intelligible but limited so far to this level. The donor site morbidity is low and aspiration was not present. The results of this study indicate that this method may have a potential role in voice reconstruction but requires more experience and refinement of this technique.


Regulation of Salmonella enterica serovar typhimurium invasion genes by csrA.
Penetration of intestinal epithelial cells by Salmonella enterica serovar Typhimurium requires the expression of invasion genes, found in Salmonella pathogenicity island 1 (SPI1), that encode components of a type III secretion apparatus. These genes are controlled in a complex manner by regulators within SPI1, including HilA and InvF, and those outside SPI1, such as the two-component regulators PhoP/PhoQ and BarA/SirA. We report here that epithelial cell invasion requires the serovar Typhimurium homologue of Escherichia coli csrA, which encodes a regulator that alters the stability of specific mRNA targets. A deletion mutant of csrA was unable to efficiently invade cultured epithelial cells and showed reduced expression of four tested SPI1 genes, hilA, invF, sipC, and prgH. Overexpression of csrA from an induced araBAD promoter also negatively affected the expression of these genes, indicating that CsrA can act as both a positive and a negative regulator of SPI1 genes and suggesting that the bacterium must tightly control the level or activity of CsrA to achieve maximal invasion. We found that CsrA affected hilA, a regulator of the other three genes we tested, probably by controlling one or more genetic elements that regulate hilA. We also found that both the loss and the overexpression of csrA reduced the expression of two regulators of hilA, hilC and hilD, suggesting that csrA exerts its control of hilA through one or both of these regulators. We further found, however, that CsrA could affect the expression of both invF and sipC independent of its effects on hilA. One additional striking phenotype of the csrA mutant, not observed in a comparable E. coli mutant, was its slow growth. Phenotypic revertants that had normal growth rates, while maintaining the csrA mutation, were common. These suppressed strains, however, did not recover the ability to invade cultured cells, indicating that the csrA-mediated loss of invasion cannot be attributed simply to poor growth and that the growth and invasion deficits of the csrA mutant arise from effects of CsrA on different targets.


Interprofessional impressions among nursing and pharmacy students: a qualitative study to inform interprofessional education initiatives.
Medical care is increasingly complex and must draw upon the distinct, yet complementary skills of various health disciplines. Healthcare student integration through interprofessional education (IPE) activity is considered one way to promote early, and subsequently sustain, the principles of teamwork. However, It has been demonstrated that each profession has distinct profession-based subcultures, or common attitudes, beliefs and values, even among undergraduate students before commencing their training. We sought to evaluate if undergraduate pharmacy and nursing student in the Middle East had similarly formed attitudes and perceptions of each others' roles. Focus group and semi-structured interviews were conducted with undergraduate pharmacy and nursing students enrolled at Qatar University College of Pharmacy and University of Calgary - Qatar Nursing programs. An eight-question topic guide was developed following comprehensive literature review of reports of other interdisciplinary assessments (either quantitative and qualitative). Working theories were drawn by the two primary investigators based on relevant topic characteristics such as expressed roles and purposes for interacting with one other, patients, and physicians, to develop explanatory constructs for the findings and identify patterns in the data. Qualitative analysis of interviews were supported by NVivo10 (©) (QSR International 2013) software. One shared themes across both health professional groups evolved during data analysis: perceptions of collaborative roles. Discipline specific themes included pharmacist knowledge and visibility (nursing students) and nurses as informants and roles in total patient care (pharmacy students). As expected, students with little or no curricular-based structured experiential training yet largely drew upon personal experiences, whereas senior students, who did have some amount of professional context, often mirrored those that have been found in other studies investigating this interdisciplinary partnership in the clinical setting. Basic understanding of one another's roles were exhibited, but tended to closely follow traditional scripts that are particularly pervasive in the Middle East. Concepts arising from our work reinforces the importance of reaching interdisciplinary understanding through assorted formal and informal exposures and can inform ways in which future IPE initiatives can be developed among the various health professional training programs.


Predictive factors for identifying macrolide responder in treating chronic rhinosinusitis.
Low-dose macrolides (LDM) are anti-inflammatory agents with antineutrophilic activity, but patient selection for LDM therapy in treating chronic rhinosinusitis (CRS) is controversial. This study aimed to assess factors which predict LDM responders. A prospective cohort study was performed. Patients with CRS received roxithromycin (150 mg) once daily for 12 weeks. Nasal secretions and serology were collected. Nine predictors for LDM response were assessed: nasal secretion IgE, nasal secretion IL-5, serum IgE, serum eosinophils, serum neutrophils, nasal polyps, asthma, allergy, and aspirin hypersensitivity, using receiver-operating curve analysis and multivariable logistic regression. Macrolide responders were those with sino-nasal outcome test-22 improvement, symptoms visual analogue scale decreased to ≤ ≤ ≤5, and no rescue medication. One hundred CRS patients (mean age 47.4 +- 14.1 years, 45% male) were enrolled. Univariable logistic regression showed local total IgE less than 5.21; and serum eosinophils less than 2.2% associated with macrolide response. Multivariate models showed local total IgE maintained an independent association with macrolide response, with an ability to discriminate between responders and non-responders of 63%. Serum total IgE, nasal secretion IL-5, serum neutrophil, nasal polyp, asthma, allergy, and aspirin hypersensitivity showed no association with LDM response. Low total IgE level in the nasal secretion but not in the serum, predict LDM response.


Understanding AF Mechanisms Through Computational Modelling and Simulations.
AF is a progressive disease of the atria, involving complex mechanisms related to its initiation, maintenance and progression. Computational modelling provides a framework for integration of experimental and clinical findings, and has emerged as an essential part of mechanistic research in AF. The authors summarise recent advancements in development of multi-scale AF models and focus on the mechanistic links between alternations in atrial structure and electrophysiology with AF. Key AF mechanisms that have been explored using atrial modelling are pulmonary vein ectopy; atrial fibrosis and fibrosis distribution; atrial wall thickness heterogeneity; atrial adipose tissue infiltration; development of repolarisation alternans; cardiac ion channel mutations; and atrial stretch with mechano-electrical feedback. They review modelling approaches that capture variability at the cohort level and provide cohort-specific mechanistic insights. The authors conclude with a summary of future perspectives, as envisioned for the contributions of atrial modelling in the mechanistic understanding of AF.


Suicide in a rural area of coastal Kenya.
Suicide accounts for approximately 1.4% of deaths globally and is the 15th leading cause of death overall. There are no reliable data on the epidemiology of completed suicide in rural areas of many developing countries, yet suicide is an indicator of the sustainable development goals on health. Using data collected between 2008 and 2016 from the Kilifi Health and Demographic Surveillance System in rural Kenya, we retrospectively determined the incidence rate and risk factors for completed suicide. During the period, 104 people died by suicide, contributing to 0.78% (95% CI = 0.74-1.10) of all deaths. The mean annual incidence rate of suicide was 4.61 (95% CI = 3.80-5.58) per 100,000 person years of observation (pyo). The annual incidence rate for men was higher than that of women (IRR = 3.05, 95% CI = 1.98-4.70, p < 0.001) and it increased with age (IRR = 2.73, 95% CI = 2.30-3.24, p < 0.001). People aged > 64 years had the highest mean incidence rate of 18.58 (95% CI = 11.99-28.80) per 100,000 pyo. Completed suicide was associated with age, being male, and living in a house whose wall is made of scrap material, which is a proxy marker of extreme poverty in this region (OR = 5.5, 95% CI = 4.0-7.0, p = 0.02). Most cases (76%) completed suicide by hanging themselves. Spatial heterogeneity of rates of suicides was observed across the enumeration zones of the KHDSS. Suicide is common in this area, but the incidence of completed suicide in rural Kenya may be an underestimate of the true burden. Like in other studies, suicide was associated with older age, being male and poverty, but other medical and neuropsychiatric risk factors should be investigated in future studies.


Procalcitonin and C-reactive protein in the diagnosis and prediction of spontaneous bacterial peritonitis associated with chronic severe hepatitis B.
Procalcitonin (PCT), C-reactive protein (CRP), and white blood cells (WBCs) are inflammatory markers used to diagnose severe bacterial infections. We evaluated the diagnostic role of these markers and compared their accuracy for spontaneous bacterial peritonitis (SBP) associated with chronic severe hepatitis B (CSHB). PCT and CRP concentrations, WBC count, and other hematological parameters were measured in serum from 84 well-characterized patients with CSHB, of whom 42 had SBP. Receiver operating characteristics (ROC) curve analysis was performed to assess the diagnostic accuracy. PCT and CRP concentrations were significantly higher in the CSHB patients with SBP (n=42) than CSHB patients without SBP (n=42). PCT and CRP concentrations were more accurate than WBC count for the diagnosis of CSHB-associated SBP. The optimal cutoff value of PCT was 0.48 ng/mL. The PCT concentration was significantly correlated with the CRP concentration and WBC count. Serum PCT and CRP seems to be better markers than WBC for the diagnosis of CSHB patients with SBP.


Gene expression and isoform variation analysis using Affymetrix Exon Arrays.
Alternative splicing and isoform level expression profiling is an emerging field of interest within genomics. Splicing sensitive microarrays, with probes targeted to individual exons or exon-junctions, are becoming increasingly popular as a tool capable of both expression profiling and finer scale isoform detection. Despite their intuitive appeal, relatively little is known about the performance of such tools, particularly in comparison with more traditional 3' targeted microarrays. Here, we use the well studied Microarray Quality Control (MAQC) dataset to benchmark the Affymetrix Exon Array, and compare it to two other popular platforms: Illumina, and Affymetrix U133. We show that at the gene expression level, the Exon Array performs comparably with the two 3' targeted platforms. However, the interplatform correlation of the results is slightly lower than between the two 3' arrays. We show that some of the discrepancies stem from the RNA amplification protocols, e.g. the Exon Array is able to detect expression of non-polyadenylated transcripts. More importantly, we show that many other differences result from the ability of the Exon Array to monitor more detailed isoform-level changes; several examples illustrate that changes detected by the 3' platforms are actually isoform variations, and that the nature of these variations can be resolved using Exon Array data. Finally, we show how the Exon Array can be used to detect alternative isoform differences, such as alternative splicing, transcript termination, and alternative promoter usage. We discuss the possible pitfalls and false positives resulting from isoform-level analysis. The Exon Array is a valuable tool that can be used to profile gene expression while providing important additional information regarding the types of gene isoforms that are expressed and variable. However, analysis of alternative splicing requires much more hands on effort and visualization of results in order to correctly interpret the data, and generally results in considerably higher false positive rates than expression analysis. One of the main sources of error in the MAQC dataset is variation in amplification efficiency across transcripts, most likely caused by joint effects of elevated GC content in the 5' ends of genes and reduced likelihood of random-primed first strand synthesis in the 3' ends of genes. These effects are currently not adequately corrected using existing statistical methods. We outline approaches to reduce such errors by filtering out potentially problematic data.


Acute Effect of a Single Session of Pilates on Blood Pressure and Cardiac Autonomic Control in Middle-Aged Adults With Hypertension.
Rocha, J, Cunha, FA, Cordeiro, R, Monteiro, W, Pescatello, LS, and Farinatti, P. Acute effect of a single session of Pilates on blood pressure and cardiac autonomic control in middle-aged adults with hypertension. J Strength Cond Res 34(1): 114-123, 2020-We investigated the blood pressure (BP) and heart rate variability (HRV) responses to a single session of Pilates among adults with hypertension. Thirteen participants (7 women), aged 44-66 years, underwent Pilates and nonexercise control sessions separated by 48-72 hours in a randomized counterbalanced order. Blood pressure and HRV indices were simultaneously assessed 10 minutes before and 60 minutes after all sessions in the supine position: root mean square of successive differences (rMSSD), percentage of successive normal sinus RR intervals >50 ms (pNN50), SD of all normal sinus RR intervals over 24 hours (SDNN), and low-frequency (LF) and high-frequency (HF) bands. After an acute session of Pilates, the mean values for area under the curve for systolic BP (p = 0.004, corresponding to -7.4 ± 8.2 mm Hg) and mean arterial pressure (p = 0.023, corresponding to -5.3 ± 5.4 mm Hg) were significantly lower compared to the control session. No significant difference was detected for diastolic BP (-4.2 ± 4.7 mm Hg, p = 0.106). Concomitant to BP reduction, significant lowering of parasympathetic HRV indices occurred: RR intervals (-64.1 ± 69.9 ms·min, p = 0.043), rMSSD (-8.3 ± 15.4 ms·min, p = 0.013), pNN50 (-3.6 ± 13%·min, p = 0.028), and total power (-3,089.4 ± 5,938 m·min, p = 0.037). No difference was found for sympathetic markers: SDNN (-17.7 ± 34.6 ms·min, p = 0.100), LF (-5.2 ± 21,6 n.u.·min, p = 0.417), and LF:HF ratio (-0.3 ± 5.2 ratio·min, p = 0.422). In conclusion, a single session of Pilates reduced BP by ∼5-8 mm Hg in adults with hypertension during the first 60 minutes of post-exercise recovery. Acute BP reduction was concomitant to lowered cardiac parasympathetic activity. Our findings are promising for the use of Pilates as an alternative exercise modality to lower BP.


Nutritional Adequacy of the Specific Carbohydrate Diet in Pediatric Inflammatory Bowel Disease.
The specific carbohydrate diet (SCD) is an exclusion diet used as a therapy in inflammatory bowel disease. The aim of this study was to evaluate the nutritional adequacy of the SCD. Prospective dietary data for 12 weeks were analyzed for pediatric patients on the SCD. Intake of 20 key nutrients was compared to dietary recommended intake levels and nutrient intake data from similarly aged children from The National Health and Nutrition Examination Survey National Youth Fitness Survey in 2012. Nine patients enrolled, with 8 patients completing the study. Six of 8 individuals completing the study had gained weight, 1 individual had weight loss, and 1 had no change in weight. Energy intake was significantly greater than 100% of the recommended daily allowance (RDA)/adequate intake for 64% of daily intakes completed for this study. The majority of participants' daily intakes met or exceeded the RDA for vitamins B2, B3, B5, B6, B7, B12, C, A, and E. One hundred percent of participants' intakes were below the RDA for vitamin D. Seventy-five percent of daily intakes were less than the RDA for calcium. The upper limit was met or exceeded for magnesium in 42% of daily intakes. Average vitamin A intake was significantly greater than the upper limit (P = 0.01). Nutrient intake of pediatric inflammatory bowel disease patients on the SCD was adequate when compared with a healthy peer reference population, but adequacy was variable when compared with the dietary recommended intakes. Close monitoring with a multidisciplinary team for patients using the SCD as an alternative or adjunct therapy is recommend to ensure positive outcomes for overall patient health.


Cell type-specific structural plasticity of the ciliary transition zone in C. elegans.
The current consensus on cilia development posits that the ciliary transition zone (TZ) is formed via extension of nine centrosomal microtubules. In this model, TZ structure remains unchanged in microtubule number throughout the cilium life cycle. This model does not however explain structural variations of TZ structure seen in nature and could also lend itself to the misinterpretation that deviations from nine-doublet microtubule ultrastructure represent an abnormal phenotype. Thus, a better understanding of events that occur at the TZ in vivo during metazoan development is required. To address this issue, we characterized ultrastructure of two types of sensory cilia in developing Caenorhabditis elegans. We discovered that, in cephalic male (CEM) and inner labial quadrant (IL2Q) sensory neurons, ciliary TZs are structurally plastic and remodel from one structure to another during animal development. The number of microtubule doublets forming the TZ can be increased or decreased over time, depending on cilia type. Both cases result in structural TZ intermediates different from TZ in cilia of adult animals. In CEM cilia, axonemal extension and maturation occurs concurrently with TZ structural maturation. Our work extends the current model to include the structural plasticity of metazoan transition zone, which can be structurally delayed, maintained or remodelled in cell type-specific manner.


Imaging detected tenosynovitis of metacarpophalangeal and wrist joints: an increasingly recognised characteristic of rheumatoid arthritis.
Tenosynovitis is traditionally recognised at physical examination in patients with inflammatory rheumatic diseases, such as, e.g. psoriatic arthritis and (longstanding) rheumatoid arthritis (RA). The increasing use of sensitive imaging techniques (ultrasound, magnetic resonance imaging (MRI)) has recently revealed that subclinical tenosynovitis is prevalent in early RA and in patients in different phases of RA development (asymptomatic state, arthralgia, early arthritis). In this review, the recent findings on MRI-detected tenosynovitis and associations with RA development are highlighted, and an overview of the most reported inflamed tendon locations within the hand and wrist of patients in different disease phases is provided. The data presented show that tenosynovitis is one of the earliest inflammatory features in patients with imminent RA and associated with impairment of activities in daily life. The value of tenosynovitis as an outcome measure in RA is also discussed.


Inhibition of epinephrine-exacerbated coronary thrombus formation by prostacyclin in the dog.
We studied the effect of intravenous prostacyclin (PGI2) infusion on epinephrine exacerbation of platelet-mediated acute coronary thrombus formation in an in vivo canine model of coronary artery stenosis. Platelet thrombi form in mechanically stenosed dog circumflex coronary arteries, producing cyclical reductions in coronary blood flow (CRF) as measured with an electromagnetic flowmeter probe. In the present study nine of 10 dogs exhibited spontaneously occurring CRF. With epinephrine (E) infusions of 10 micrograms/min CRF frequency increased 64% (p less than 0.025), CRF magnitude increased 27.1% (p less than 0.05), and the rate of flow decline increased 112.8%, indicating that the rate of thrombus formation increased with E infusion (p less than 0.005). When an identical E infusion was accompanied by simultaneous PGI2 infusion (150 ng/kg/min), CRF were abolished in nine of 10 dogs and markedly inhibited in the other. After the 10 min of simultaneous E and PGI2 infusion, E infusion alone was continued. There was a recurrence of CRF within 2.49 +/- 0.89 min after cessation of PGI2 infusion. However, CRF frequency in the subsequent 10 min was less than the frequency of CRF during the initial E infusion (p less than 0.10) and not significantly different from that of the control period (no E infusion). The rate of flow decline and magnitude during the final E infusion after cessation of PGI2 infusion were not significantly different from those of the initial E infusion. Prostacyclin infusion in the coronary care unit may be potentially beneficial in cases of acute myocardial ischemia where elevated catecholamines are a thrombogenic stimulus.