Neural substrates of tactile object recognition: an fMRI study.
A functional magnetic resonance imaging (fMRI) study was conducted during which seven subjects carried out naturalistic tactile object recognition (TOR) of real objects. Activation maps, conjunctions across subjects, were compared between tasks involving TOR of common real objects, palpation of "nonsense" objects, and rest. The tactile tasks involved similar motor and sensory stimulation, allowing higher tactile recognition processes to be isolated. Compared to nonsense object palpation, the most prominent activation evoked by TOR was in secondary somatosensory areas in the parietal operculum (SII) and insula, confirming a modality-specific path for TOR. Prominent activation was also present in medial and lateral secondary motor cortices, but not in primary motor areas, supporting the high level of sensory and motor integration characteristic of object recognition in the tactile modality. Activation in a lateral occipitotemporal area associated previously with visual object recognition may support cross-modal collateral activation. Finally, activation in medial temporal and prefrontal areas may reflect a common final pathway of modality-independent object recognition. This study suggests that TOR involves a complex network including parietal and insular somatosensory association cortices, as well as occipitotemporal visual areas, prefrontal, and medial temporal supramodal areas, and medial and lateral secondary motor cortices. It confirms the involvement of somatosensory association areas in the recognition component of TOR, and the existence of a ventrolateral somatosensory pathway for TOR in intact subjects. It challenges the results of previous studies that emphasize the role of visual cortex rather than somatosensory association cortices in higher-level somatosensory cognition.


Sport and recreation-related injuries and fracture occurrence among emergency department attendees: implications for exercise prescription and injury prevention.
To investigate the epidemiology of sports and recreation-related injury (SRI) among emergency department (ED) attendees. Descriptive epidemiology study. An Irish university hospital ED. All patients aged over 4 years attending a large regional ED, during a 6-month period, for the treatment of SRI were prospectively surveyed. In all cases identified as SRI the attending physician completed a specifically designed questionnaire. It was postulated that recreation-related injury is a significant proportion of reported SRI. Fracture rate was highest in the 4-9-year age group (44%). On multivariate logistic regression the adjusted odds ratio (OR; 95% CI) of fracture was higher for children (vs adults) at 1.21 (1.0 to 1.45). The adjusted OR was higher for upper-limb 5.8 (4.5 to 7.6) and lower-limb injuries 1.87 (1.4 to 2.5) versus axial site of injury and for falls 2.2 (1.6 to 2.9) and external force 1.59 (1.2 to 2.1) versus an overextension mechanism of injury. In the same model, "play" was independently associated with fracture risk, adjusted OR 1.98 (1.2 to 3.0; p = 0.001) versus low-risk ball sports 1.0 (reference); an effect size similar to that seen for combat sports 1.96 (1.2 to 3.3; p = 0.01) and greater than that seen for presumed high-risk field sports 1.4 (0.9 to 2.0) Fall and subsequent upper-limb injury was the commonest mechanism underlying SRI fracture. Domestic "play" in all age groups at the time of injury accorded a higher fracture risk than field sports. Patient education regarding the dangers of unsupervised play and recreation represents a means of reducing the burden of SRI.


Apelin/APJ relieve diabetic cardiomyopathy by reducing microvascular dysfunction.
Microcirculatory injuries had been reported to be involved in diabetic cardiomyopathy, which was mainly related to endothelial cell dysfunction. Apelin, an adipokine that is upregulated in diabetes mellitus, was reported to improve endothelial cell dysfunction and attenuate cardiac insufficiency induced by ischemia and reperfusion. Therefore, it is hypothesized that apelin might be involved in alleviating endothelial cell dysfunction and followed cardiomyopathy in diabetes mellitus. The results showed that apelin improved endothelial cell dysfunction via decreasing apoptosis and expression of adhesion molecules and increasing proliferation, angiogenesis, and expression of E-cadherin, VEGFR 2 and Tie-2 in endothelial cells, which resulted in the attenuation of the capillary permeability in cardiac tissues and following diabetic cardiomyopathy. Meanwhile, the results from endothelial cell-specific APJ knockout mice and cultured endothelial cells confirmed that the effects of apelin on endothelial cells were dependent on APJ and the downstream NFκB pathways. In conclusion, apelin might reduce microvascular dysfunction induced by diabetes mellitus via improving endothelial dysfunction dependent on APJ activated NFκB pathways.


Single-dose intra-procedural ceftriaxone during endoscopic ultrasound fine-needle aspiration of pancreatic cysts is safe and effective: results from a single tertiary center.
Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) is universally used for the investigation and diagnosis of pancreatic cystic lesions (PCL). Infectious complications following EUS-FNA of PCL are rare. Antibiotic prophylaxis to reduce the risk of infection is recommended; however, there is no consensus on the optimal regimen or route of administration. Potential advantages of a single-dose intravenous (IV) antibiotic over a prolonged oral regimen include simplicity, guaranteed delivery and fewer antibiotic related adverse events, but there are only limited data to support this. We aimed to investigate the safety and efficacy of a single 1 g dose of IV ceftriaxone in preventing infectious complications following EUS-FNA of PCL. A retrospective analysis was conducted of EUS-FNA of PCL procedures performed at our center. We reviewed patient medical records for any presentation to a hospital in our district within 30 days of the procedure. An infectious complication was defined as fever/rigors, or bacteremia, or abdominal pain accompanied by imaging or laboratory results suggestive of infection, within 30 days of the procedure. Data collection included patient demographics, procedural data and outcome. EUS-FNA of 204 PCL (mean size 18.0 mm) was performed. Successful fluid aspiration was achieved in 94% of cases. Single-dose IV ceftriaxone was given in 146/204 (72%) cases. Four patients had a complication (pancreatitis n=1, post-procedural pain n=3). No infectious complications and no IV antibiotic-related adverse events were identified. A single dose of IV ceftriaxone appears to be a safe, effective and convenient intervention for preventing infectious complications after FNA.


Expression pattern of bcar3, a downstream target of Gata2, and its binding partner, bcar1, during Xenopus development.
Primitive hematopoiesis generates red blood cells that deliver oxygen to the developing embryo. Mesodermal cells commit to a primitive blood cell fate during gastrulation and, in order to do so the mesoderm must receive non-cell autonomous signals transmitted from other germ layers. In Xenopus, the transcription factor Gata2 functions in ectodermal cells to generate or transmit the non-cell autonomous signals. Here we have identified Breast Cancer Antiestrogen Resistance 3 (bcar3) as a gene that is induced in ectodermal cells downstream of Gata2. Bcar3 and its binding partner Bcar1 function to transduce integrin signaling, leading to changes in cellular morphology, motility and adhesion. We show that gata2, bcar3 and bcar1 are co-expressed in ventral ectoderm from early gastrula to early tailbud stages. At later stages of development, bcar3 and bcar1 are co-expressed in the spinal cord, notochord, fin mesenchyme and pronephros but each shows additional unique sites of expression. These co-expression and unique expression patterns suggest that Bcar3 and Bcar1 may function together but also independently during Xenopus development.


Fatal enteric plexus neuropathy after one dose of ipilimumab plus nivolumab: a case report.
Immune checkpoint inhibitors (ICIs) are the treatment of choice for several cancers and can be associated with remarkable clinical benefit, but can also cause serious immune-related adverse events (irAEs). Management of rare and severe irAEs is challenged by an incomplete knowledge of their natural history and pathogenetic mechanisms. We report a case of fatal acute-onset gastro-intestinal (GI) hypomotility from myenteric plexus neuropathy following a single dose of ipilimumab plus nivolumab given for treatment of Merkel cell carcinoma (MCC). A 66-year-old man with recurrent metastatic MCC involving several organs (liver, bones and disseminated retroperitoneal lymphadenopathy) developed profound pharyngeal dysphagia and ileus that started 7 days after receiving a single administration of combination immune checkpoint blockade consisting of nivolumab (3 mg/kg) and low-dose ipilimumab (1 mg/kg). A swallowing study showed oropharyngeal dysfunction and aspiration. Imaging studies were consistent with diffuse intestinal paresis. An extensive work-up did not reveal obvious causes of these symptoms, and enteric plexopathy was suspected. Empiric immune suppressive therapy was initiated urgently. Despite an escalating immunosuppressive regimen that included high dose steroids, tacrolimus and therapeutic plasma exchange, no improvement in GI motility was seen and the patient suffered repeated episodes of aspiration. Seven weeks after the onset of GI hypomotility, the patient succumbed to sepsis from intestinal perforations. At autopsy, histologic specimens obtained from the entire GI tract (pharynx to rectum) showed near complete loss of ganglion cells within the myenteric and submucosal plexuses. An associated inflammatory infiltrate was not seen, suggesting a 'burned out' phase of illness. C4d complement deposition was found at the ganglionic sites, suggesting antibody-mediated pathogenesis. Remarkably, at sites of previously suspected Merkel cell metastases, no residual viable Merkel cell carcinoma was identified. GI-tract paresis due to myenteric neuritis is a rarely reported toxicity of ICIs. Because the window of reversibility is likely to be very brief, quick and decisive interventions are warranted. Subtle functional and anatomic perturbations of the myenteric nervous system from the use of ICIs may be more prevalent than realized and should be suspected and addressed in both clinical and investigational settings.


Detection of antibodies against Sarcocystis neurona in cerebrospinal fluid from clinically normal neonatal foals.
To determine whether antibodies against Sarcocystis neurona could be detected in CSF from clinically normal neonatal (2 to 7 days old) and young (2 to 3 months old) foals. Prospective study. 15 clinically normal neonatal Thoroughbred foals. Serum and CSF samples were obtained from foals at 2 to 7 days of age and tested for antibodies against S. neurona by means of western blotting. Serum samples from the mares were also tested for antibodies against S. neurona. Additional CSF and blood samples were obtained from 5 foals between 13 and 41 days after birth and between 62 and 90 days after birth. Antibodies against S. neurona were detected in serum from 13 mares and their foals; antibodies against S. neurona were detected in CSF from 12 of these 13 foals. Degree of immunoreactivity in serum and CSF decreased over time, and antibodies against S. neurona were no longer detected in CSF from 2 foals 83 and 84 days after birth. However, antibodies could still be detected in CSF from the other 3 foals between 62 and 90 days after birth. Results indicate that antibodies against S. neurona can be detected in CSF from clinically normal neonatal (2 to 7 days old) foals born to seropositive mares. This suggests that western blotting of CSF cannot be reliably used to diagnose equine protozoal myeloencephalitis in foals < 3 months of age born to seropositive mares.


Protein kinase A intersects SRC signaling in membrane microdomains.
Regulation of Src kinase activity is tightly coupled to the phosphorylation status of the C-terminal regulatory tyrosine Tyr(527), which, when phosphorylated by Csk, represses Src. Here, we demonstrate that activation of Csk through a prostaglandin E(2)-cAMP-protein kinase A (PKA) pathway inhibits Src. This inhibitory pathway is operative in detergent-resistant membrane fractions where cAMP-elevating agents activate Csk, resulting in a concomitant decrease in Src activity. The inhibitory effect on Src depends on a detergent-resistant membrane-anchored Csk and co-localization of all components of the inhibitory pathway in membrane microdomains. Furthermore, epidermal growth factor-induced activation of Src and phosphorylation of the Src substrates Cbl and focal adhesion kinase are inhibited by activation of the cAMP-PKA-Csk pathway. We propose a novel mechanism whereby G protein-coupled receptors inhibit Src signaling by activation of Csk in a cAMP-PKA-dependent manner.


Inhibitory transmission in guinea pig stomach mediated by distinct receptors for pituitary adenylate cyclase-activating peptide.
Previous studies have shown that inhibitory transmission in guinea pig stomach involves an interplay between vasoactive intestinal peptide (VIP) and nitric oxide (NO). The present study examined the contribution of pituitary adenylate cyclase-activating peptide (PACAP), a homologous peptide present in gastric and intestinal myenteric neurons. VIP, PACAP-27 and PACAP-38 induced concentration-dependent relaxation that was partly inhibited by the antagonists VIP10-28 and PACAP6-38 and the NO synthase inhibitor NG-nitro-L-arginine (L-NNA). Only relaxation induced by PACAP-27 and PACAP-38 was partly inhibited by apamin. Electrical field stimulation (0.25-16 Hz) induced frequency-dependent relaxation and PACAP release (maximum of 35.7 fmol/100 mg-min or 7-fold above basal levels). Electrical field stimulation-induced relaxation was partly inhibited by a combination of selective monoclonal antibodies to PACAP-27 and PACAP-38 (42 +/- 7% at 16 Hz) and by the antagonists VIP10-28 (29 +/- 9%) and PACAP6-38 (29 +/- 3%). The relaxation was also partly inhibited by L-NNA (51 +/- 12% at 16 Hz) and apamin (36 +/- 4%). The effects of a combination of apamin and L-NNA were additive, amounting to 75 +/- 3% inhibition. The effect of L-NNA reflected inhibition of NO release from nerve terminals, as well as NO generation in muscle cells by the action of VIP and PACAP; the effect of apamin reflected blockade of the action of PACAP. Thus, inhibitory transmission in guinea pig gastric fundus represents the combined actions of VIP, PACAP and NO released from nerve terminals and NO generated in muscle cells. The postjunctional actions of PACAP are mediated by a VIP/PACAP-II receptor and by a PACAP-specific, apamin-sensitive receptor.


Docosahexaenoic acid intake decreases proliferation, increases apoptosis and decreases the invasive potential of the human breast carcinoma cell line MDA-MB-231.
Breast cancer is the most common cancer in women in industrialized countries. Environmental factors, such as differences in diet are likely to have an important influence on cancer emergence. Among these factors, n-3 polyunsaturated-fatty acids, such as docosahexaenoic acid (DHA), are good candidates for preventing breast cancer. Here we investigate the effect of DHA on the human breast cancer cell line MDA-MB-231 and show that DHA incorporation i) has an anti-proliferative effect, ii) induces apoptosis via a transient increase in caspase-3 activity and the promotion of nuclear condensation, and iii) reduces the invasive potential of MDA-MB-231 cells. To conclude, DHA may have beneficial effects as a result of slowing the proliferation of tumor cells, and minimizing their metastatic potential.


Evidence that the algI/algJ gene cassette, required for O acetylation of Pseudomonas aeruginosa alginate, evolved by lateral gene transfer.
Pseudomonas aeruginosa strains, isolated from chronically infected patients with cystic fibrosis, produce the O-acetylated extracellular polysaccharide, alginate, giving these strains a mucoid phenotype. O acetylation of alginate plays an important role in the ability of mucoid P. aeruginosa to form biofilms and to resist complement-mediated phagocytosis. The O-acetylation process is complex, requiring a protein with seven transmembrane domains (AlgI), a type II membrane protein (AlgJ), and a periplasmic protein (AlgF). The cellular localization of these proteins suggests a model wherein alginate is modified at the polymer level after the transport of O-acetyl groups to the periplasm. Here, we demonstrate that this mechanism for polysaccharide esterification may be common among bacteria, since AlgI homologs linked to type II membrane proteins are found in a variety of gram-positive and gram-negative bacteria. In some cases, genes for these homologs have been incorporated into polysaccharide biosynthetic operons other than for alginate biosynthesis. The phylogenies of AlgI do not correlate with the phylogeny of the host bacteria, based on 16S rRNA analysis. The algI homologs and the gene for their adjacent type II membrane protein present a mosaic pattern of gene arrangement, suggesting that individual components of the multigene cassette, as well as the entire cassette, evolved by lateral gene transfer. AlgJ and the other type II membrane proteins, although more diverged than AlgI, contain conserved motifs, including a motif surrounding a highly conserved histidine residue, which is required for alginate O-acetylation activity by AlgJ. The AlgI homologs also contain an ordered series of motifs that included conserved amino acid residues in the cytoplasmic domain CD-4; the transmembrane domains TM-C, TM-D, and TM-E; and the periplasmic domain PD-3. Site-directed mutagenesis studies were used to identify amino acids important for alginate O-acetylation activity, including those likely required for (i) the interaction of AlgI with the O-acetyl precursor in the cytoplasm, (ii) the export of the O-acetyl group across the cytoplasmic membrane, and (iii) the transfer of the O-acetyl group to a periplasmic protein or to alginate. These results indicate that AlgI belongs to a family of membrane proteins required for modification of polysaccharides and that a mechanism requiring an AlgI homolog and a type II membrane protein has evolved by lateral gene transfer for the esterification of many bacterial extracellular polysaccharides.


Comparison of a new lateral-flow chromatographic membrane immunoassay to viral culture for rapid detection and differentiation of influenza A and B viruses in respiratory specimens.
The performance of a new rapid lateral-flow chromatographic membrane immunoassay test kit for detection of influenza virus was evaluated and compared to that of viral culture in respiratory secretions collected from 400 adults and children seen at three large university hospitals during the recent 2003 influenza season. The rapid test provided results in 15 min, with excellent overall performance statistics (sensitivity, 94.4%; specificity, 100%; positive predictive value, 100%; negative predictive value, 97.5%). Both influenza A and B type viruses were reliably detected, with no significant difference in performance statistics noted by influenza virus type or by the center performing the test.


Leaking urine in Australian women: prevalence and associated conditions.
The paper aims to (1) assess the prevalence of leaking urine and to (2) explore associations between leaking urine and a variety of other symptoms, conditions, surgical procedures and life events in three large cohorts of Australian women, who are participants in the Australian Longitudinal Study on Women's Health. Young women aged 18-23 (N = 14,000), mid-age women, 45-50 (N = 13,738) and older women, 70-75 (N = 12,417), were recruited randomly from the national HIC/Medicare database. Leaking urine was reported by approximately one in eight young women [estimated prevalence 12.8% (95% CI: 12.2-13.3)] and one in three mid-age women [36.1% (CI: 35.2-37.0)] and older women [35.0% (CI: 34.1-35.9)]. Leaking urine was significantly associated with parity, conditions which increase the pressure on the pelvic floor such as constipation and obesity, past gynecological surgery and conditions which can impact on bladder control. The study showed that fewer than half the women had sought help for the problem and that younger women were less likely to be satisfied with the help available for this problem. Strategies for continence promotion, including opportunistic raising of the issue at the time of cervical screening and pregnancy care are suggested, so that the health and social outcomes of untreated chronic incontinence in women might be improved.


Location and structure of fibrous sheath formed after placing a tunneled hemodialysis catheter in a large pig model.
We evaluated the location and structure of the fibrous sheath formed after the placement of tunneled, cuffed hemodialysis catheters in large animals, 70 kg pigs. We focused on describing the location of the fibrous sheath in relation to the catheter. Its location explains the fibrous sheath's ability to cause catheter dysfunction by covering the catheter exit ports located at the catheter's tip. We used three animals. Each animal had a tunneled, cuffed, 15-French diameter hemodialysis catheter placed in the external jugular vein, with the tip at the junction of the superior vena cava and the right atrium. Two animals were sacrificed at 5 weeks and one animal at 17 weeks after catheter placement. The catheter and surrounding tissues were removed in one block. The fibrous sheath was dissected and longitudinally cut along the catheter to evaluate its extension in relation to the catheter. Relevant portions of the fibrous sheath were sent for pathology examination. The fibrous sheath covered the catheter in its entire length and circumference. It started at the entry site and continued without any interruption along the entire length of the catheter, including the tip. Its average thickness is 1 mm and has an inner cellular/inflammatory layer comprising lymphocytes, plasma cells, neutrophils, macrophages, multinucleated giant cells, and spindled cells and an outer layer comprising a mixture of collagen and fibroblasts. Our model showed that the fibrous sheath forms around all catheters and covers them in their entire length and circumference without any gaps.


Pooled analysis of 3 European case-control studies of ovarian cancer: II. Age at menarche and at menopause.
The role of age at menarche and at menopause on epithelial ovarian cancer risk was re-assessed in a combined analysis of 3 hospital-based case-control studies conducted in Italy, the United Kingdom and Greece, which produced a total of 1,140 cases and 2,724 controls. In the overall dataset, there was no evidence of an association with age at menarche: compared with women whose menarche occurred at age 15 or over, the relative risk (RR) estimates were 1.0 [95% confidence interval (CI) 0.8 to 1.2] for those with menarche at ages 12 to 14, and 1.0 (95% CI 0.8-1.2) for those with menarche below age 12. There was no consistent interaction between age at menarche and study centre or age at diagnosis. In relation to age at menopause, compared with women whose menopause occurred at age 44 or earlier, the RR was 1.4 between 45 and 49, 1.6 between 50 and 52 and 1.9 above 52. The strength of the association was apparently (but not significantly) greater in the British than in the Greek or Italian dataset. The effect of age at menopause tended to be long-lasting and, if anything, to increase across subsequent age-groups. The large dataset, and the replication of results in different studies, provide more definite and precise information than previously available on the absence of appreciable effect of age at menarche on subsequent ovarian cancer risk in developed countries. For age at menopause, there was a direct and consistent trend in risk, but the association was relatively weak, with RRs below 2 even between extreme categories.


Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice.
The transcription factor NF-E2-related factor 2 (Nrf2) plays an essential role in the mammalian response to chemical and oxidative stress through induction of hepatic phase II detoxification enzymes and regulation of glutathione (GSH). Enhanced liver damage in Nrf2-deficient mice treated with acetaminophen suggests a critical role for Nrf2; however, direct evidence for Nrf2 activation following acetaminophen exposure was previously lacking. We show that acetaminophen can initiate nuclear translocation of Nrf2 in vivo, with maximum levels reached after 1 hour, in a dose dependent manner, at doses below those causing overt liver damage. Furthermore, Nrf2 was shown to be functionally active, as assessed by the induction of epoxide hydrolase, heme oxygenase-1, and glutamate cysteine ligase gene expression. Increased nuclear Nrf2 was found to be associated with depletion of hepatic GSH. Activation of Nrf2 is considered to involve dissociation from a cytoplasmic inhibitor, Kelch-like ECH-associated protein 1 (Keap1), through a redox-sensitive mechanism involving either GSH depletion or direct chemical interaction through Michael addition. To investigate acetaminophen-induced Nrf2 activation we compared the actions of 2 other GSH depleters, diethyl maleate (DEM) and buthionine sulphoximine (BSO), only 1 of which (DEM) can function as a Michael acceptor. For each compound, greater than 60% depletion of GSH was achieved; however, in the case of BSO, this depletion did not cause nuclear translocation of Nrf2. In conclusion, GSH depletion alone is insufficient for Nrf2 activation: a more direct interaction is required, possibly involving chemical modification of Nrf2 or Keap1, which is facilitated by the prior loss of GSH.


Impact of exercise training program attendance and physical activity participation on six minute walk distance in patients with heart failure.
Background: Exercise training is recommended for all people with stable heart failure (HF) however adherence is poor. This study sought to describe exercise participation in recently hospitalized HF patients who participated in a 12-week exercise training program. The association between exercise training variables and improvement in 6-min walk distance (6MWD) was also investigated.Methods: This study is a secondary analysis of results from the intervention arm of the EJECTION-HF trial (ACTRN12608000263392), (n = 140). Exercise program attendance was defined according to session frequency (< 12 sessions vs ≥ 12 sessions) and attendance duration (< 6 weeks attendance vs ≥ 6 weeks) over the 12 weeks. Physical activity at baseline and follow up were reported according to self-report of 150 min of moderate intensity exercise per week. Primary outcome was change in 6MWD at 12 weeks.Results: Being physically active (OR 3.8, CI 1.3-11.5) and frequent program attendance (OR 2.7, CI 1.2-5.9) were associated with significant improvements in 6MWD. Program duration and baseline physical activity were not significantly associated with the outcome.Conclusions: Attainment of 150 min of moderate intensity exercise per week and at least weekly attendance at the program, were associated with significant improvements in 6MWD at follow up. Efforts should be made to assist patients with HF to achieve these targets.


Positron emission tomography for the assessment of myocardial viability: an evidence-based analysis.
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability, an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients undergoing viability assessment. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies that can be used for the assessment of myocardial viability: positron emission tomography, cardiac magnetic resonance imaging, dobutamine echocardiography, and dobutamine echocardiography with contrast, and single photon emission computed tomography.A 2005 review conducted by MAS determined that positron emission tomography was more sensitivity than dobutamine echocardiography and single photon emission tomography and dominated the other imaging modalities from a cost-effective standpoint. However, there was inadequate evidence to compare positron emission tomography and cardiac magnetic resonance imaging. Thus, this report focuses on this comparison only. For both technologies, an economic analysis was also completed.The Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlPOSITRON EMISSION TOMOGRAPHY FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY: An Evidence-Based AnalysisMAGNETIC RESONANCE IMAGING FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY: An Evidence-Based Analysis The objective of this analysis is to assess the effectiveness and safety of positron emission tomography (PET) imaging using F-18-fluorodeoxyglucose (FDG) for the assessment of myocardial viability. To evaluate the effectiveness of FDG PET viability imaging, the following outcomes are examined: the diagnostic accuracy of FDG PET for predicting functional recovery;the impact of PET viability imaging on prognosis (mortality and other patient outcomes); andthe contribution of PET viability imaging to treatment decision making and subsequent patient outcomes. CONDITION AND TARGET POPULATION LEFT VENTRICULAR SYSTOLIC DYSFUNCTION AND HEART FAILURE: Heart failure is a complex syndrome characterized by the heart's inability to maintain adequate blood circulation through the body leading to multiorgan abnormalities and, eventually, death. Patients with heart failure experience poor functional capacity, decreased quality of life, and increased risk of morbidity and mortality. In 2005, more than 71,000 Canadians died from cardiovascular disease, of which, 54% were due to ischemic heart disease. Left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD) is the primary cause of heart failure accounting for more than 70% of cases. The prevalence of heart failure was estimated at one percent of the Canadian population in 1989. Since then, the increase in the older population has undoubtedly resulted in a substantial increase in cases. Heart failure is associated with a poor prognosis: one-year mortality rates were 32.9% and 31.1% for men and women, respectively in Ontario between 1996 and 1997. IN GENERAL, THERE ARE THREE OPTIONS FOR THE TREATMENT OF HEART FAILURE: medical treatment, heart transplantation, and revascularization for those with CAD as the underlying cause. Concerning medical treatment, despite recent advances, mortality remains high among treated patients, while, heart transplantation is affected by the limited availability of donor hearts and consequently has long waiting lists. The third option, revascularization, is used to restore the flow of blood to the heart via coronary artery bypass grafting (CABG) or through minimally invasive percutaneous coronary interventions (balloon angioplasty and stenting). Both methods, however, are associated with important perioperative risks including mortality, so it is essential to properly select patients for this procedure. Left ventricular dysfunction may be permanent if a myocardial scar is formed, or it may be reversible after revascularization. Reversible LV dysfunction occurs when the myocardium is viable but dysfunctional (reduced contractility). Since only patients with dysfunctional but viable myocardium benefit from revascularization, the identification and quantification of the extent of myocardial viability is an important part of the work-up of patients with heart failure when determining the most appropriate treatment path. Various non-invasive cardiac imaging modalities can be used to assess patients in whom determination of viability is an important clinical issue, specifically: dobutamine echocardiography (echo),stress echo with contrast,SPECT using either technetium or thallium,cardiac magnetic resonance imaging (cardiac MRI), andpositron emission tomography (PET). Stress echocardiography can be used to detect viable myocardium. During the infusion of low dose dobutamine (5 - 10 μg/kg/min), an improvement of contractility in hypokinetic and akentic segments is indicative of the presence of viable myocardium. Alternatively, a low-high dose dobutamine protocol can be used in which a biphasic response characterized by improved contractile function during the low-dose infusion followed by a deterioration in contractility due to stress induced ischemia during the high dose dobutamine infusion (dobutamine dose up to 40 ug/kg/min) represents viable tissue. Newer techniques including echocardiography using contrast agents, harmonic imaging, and power doppler imaging may help to improve the diagnostic accuracy of echocardiographic assessment of myocardial viability. Intravenous contrast agents, which are high molecular weight inert gas microbubbles that act like red blood cells in the vascular space, can be used during echocardiography to assess myocardial viability. These agents allow for the assessment of myocardial blood flow (perfusion) and contractile function (as described above), as well as the simultaneous assessment of perfusion to make it possible to distinguish between stunned and hibernating myocardium. SPECT: SPECT can be performed using thallium-201 (Tl-201), a potassium analogue, or technetium-99 m labelled tracers. When Tl-201 is injected intravenously into a patient, it is taken up by the myocardial cells through regional perfusion, and Tl-201 is retained in the cell due to sodium/potassium ATPase pumps in the myocyte membrane. The stress-redistribution-reinjection protocol involves three sets of images. The first two image sets (taken immediately after stress and then three to four hours after stress) identify perfusion defects that may represent scar tissue or viable tissue that is severely hypoperfused. The third set of images is taken a few minutes after the re-injection of Tl-201 and after the second set of images is completed. These re-injection images identify viable tissue if the defects exhibit significant fill-in (> 10% increase in tracer uptake) on the re-injection images. The other common Tl-201 viability imaging protocol, rest-redistribution, involves SPECT imaging performed at rest five minutes after Tl-201 is injected and again three to four hours later. Viable tissue is identified if the delayed images exhibit significant fill-in of defects identified in the initial scans (> 10% increase in uptake) or if defects are fixed but the tracer activity is greater than 50%. There are two technetium-99 m tracers: sestamibi (MIBI) and tetrofosmin. The uptake and retention of these tracers is dependent on regional perfusion and the integrity of cellular membranes. Viability is assessed using one set of images at rest and is defined by segments with tracer activity greater than 50%. Cardiac magnetic resonance imaging (cardiac MRI) is a non-invasive, x-ray free technique that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed images of the structure and function of the heart. Two types of cardiac MRI are used to assess myocardial viability: dobutamine stress magnetic resonance imaging (DSMR) and delayed contrast-enhanced cardiac MRI (DE-MRI). DE-MRI, the most commonly used technique in Ontario, uses gadolinium-based contrast agents to define the transmural extent of scar, which can be visualized based on the intensity of the image. Hyper-enhanced regions correspond to irreversibly damaged myocardium. As the extent of hyper-enhancement increases, the amount of scar increases, so there is a lower the likelihood of functional recovery. Positron emission tomography (PET) is a nuclear medicine technique used to image tissues based on the distinct ways in which normal and abnormal tissues metabolize positron-emitting radionuclides. Radionuclides are radioactive analogs of common physiological substrates such as sugars, amino acids, and free fatty acids that are used by the body. The only licensed radionuclide used in PET imaging for viability assessment is F-18 fluorodeoxyglucose (FDG). During a PET scan, the radionuclides are injected into the body and as they decay, they emit positively charged particles (positrons) that travel several millimetres into tissue and collide with orbiting electrons. (ABSTRACT TRUNCATED)


Development of multimedia learning modules for teaching human anatomy: application to osteology and functional anatomy.
Computer-assisted learning (CAL) is growing quickly within academic programs. Although the anatomical commercial packages that are available for this learning have attractive advantages, they also have drawbacks: they are frequently not in the local language of the students, they do not perfectly answer the needs of the local academic program, and their cost is frequently more than students can afford. This study describes a relatively inexpensive method to create CAL tutorials, whose content can be fully customized to local academic needs in terms of both program and language. The study describes its use in creating multimedia learning modules (MLMs) about Osteology and joint kinematics. The pedagogical content in these modules was collected from objective experiments to give students the opportunity to access new scientific knowledge during their education. It can be replaced, as desired, by almost any content due to the flexibility of the production method. Each MLM consists of two complementary subelements: a multimedia theoretical lecture and a three-dimensional interactive laboratory. Such MLMs are in use at both the University of Brussels (ULB) and the National University of Rwanda (NUR). The development of this work was part of the VAKHUM project, and the pedagogical validation is currently being performed as part of the MULTIMOD project.


Circuit Investigations With Open-Source Miniaturized Microscopes: Past, Present and Future.
The ability to simultaneously image the spatiotemporal activity signatures from many neurons during unrestrained vertebrate behaviors has become possible through the development of miniaturized fluorescence microscopes, or miniscopes, sufficiently light to be carried by small animals such as bats, birds and rodents. Miniscopes have permitted the study of circuits underlying song vocalization, action sequencing, head-direction tuning, spatial memory encoding and sleep to name a few. The foundation for these microscopes has been laid over the last two decades through academic research with some of this work resulting in commercialization. More recently, open-source initiatives have led to an even broader adoption of miniscopes in the neuroscience community. Open-source designs allow for rapid modification and extension of their function, which has resulted in a new generation of miniscopes that now permit wire-free or wireless recording, concurrent electrophysiology and imaging, two-color fluorescence detection, simultaneous optical actuation and read-out as well as wide-field and volumetric light-field imaging. These novel miniscopes will further expand the toolset of those seeking affordable methods to probe neural circuit function during naturalistic behaviors. Here, we will discuss the early development, present use and future potential of miniscopes.


Note: stacked rings for terahertz wave-guiding.
We demonstrate the construction of corrugated waveguides using stacked rings to propagate terahertz frequencies. The waveguide allows propagation of the same fundamental mode as an optical-fiber, namely, the HE(11) mode. This simple concept opens the way for corrugated wave-guides up to several terahertz, maintaining beam characteristics as for terahertz applications.


Human keratinocyte culture. Identification and staging of epidermal cell subpopulations.
Stratification of human epidermal cells into multilayered sheets composed of basal and suprabasal layers (resembling the stratum germinativum and stratum spinosum of the epidermis) was studied in a dermal component-free culture system. Although no stratum corneum developed in vitro, this culture system provided a method to study early events in human keratinocyte differentiation. Multiparameter flow cytometric analysis of acridine orange-stained epidermal cells from these cultures revealed three distinct subpopulations differing in cell size, RNA content, and cell cycle kinetics. The first subpopulation was composed of small basal keratinocytes with low RNA content and a long generation time. The second subpopulation consisted of larger keratinocytes, having higher RNA content and a significantly shorter generation time. Finally, the third subpopulation contained the largest cells, which did not divide, and represent the more terminally differentiated keratinocytes. This in vitro approach provides discriminating cytochemical parameters by which the maturity of the epidermal cell sheets can be assessed prior to grafting onto human burn patients.


Detection of the bacterium, Xylella fastidiosa, in saliva of glassy-winged sharpshooter, Homalodisca vitripennis.
Homalodisca vitripennis (Germar) (Hemiptera: Cicadellidae), the glassy-winged sharpshooter, is one of the most important vectors of the bacterium, Xylella fastidiosa subsp. piercei (Xanthomonadales: Xanthomonadaceae) that causes Pierce's Disease in grapevines in California. In the present study we report a new method for studying pathogen transmission or probing behavior of H. vitripennis. When confined, H. vitripennis attempt to probe the surface of sterile containers 48 hours post-acquisition of X. f. piercei. The saliva deposited during attempted feeding probes was found to contain X. f. piercei. We observed no correlation between X. f. piercei titers in the foregut of H. vitripennis that fed on Xylella-infected grapevines and the presence of this bacterium in the deposited saliva. The infection rate after a 48 h post-acquisition feeding on healthy citrus and grapevines was observed to be 77% for H. vitripennis that fed on grapevines and 81% for H. vitripennis that fed on citrus, with no difference in the number of positive probing sites from H. vitripennis that fed on either grapevine or citrus. This method is amenable for individual assessment of X. f. piercei-infecuvity, with samples less likely to be affected by tissue contamination that is usually present in whole body extracts.


Transcriptional profiling of gastric epithelial cells infected with wild type or arginase-deficient Helicobacter pylori.
Helicobacter pylori causes acute and chronic gastric inflammation induced by proinflammatory cytokines and chemokines secreted by cells of the gastric mucosa, including gastric epithelial cells. Previous studies have demonstrated that the bacterial arginase, RocF, is involved in inhibiting T cell proliferation and CD3ζ expression, suggesting that arginase could be involved in a more general dampening of the immune response, perhaps by down-regulation of certain pro-inflammatory mediators. Global transcriptome analysis was performed on AGS gastric epithelial cells infected for 16 hours with a wild type Helicobacter pylori strain 26695, an arginase mutant (rocF-) or a rocF+ complemented strain. H. pylori infection triggered altered host gene expression in genes involved in cell movement, death/growth/proliferation, and cellular function and maintenance. While the wild type strain stimulates host inflammatory pathways, the rocF- mutant induced significantly more expression of IL-8. The results of the microarray were verified using real-time PCR, and the differential levels of protein expression were confirmed by ELISA and Bioplex analysis. MIP-1B was also significantly secreted by AGS cells after H. pylori rocF- mutant infection, as determined by Bioplex. Even though not explored in this manuscript, the impact that the results presented here may have on the development of gastritis, warrant further research to understand the underlying mechanisms of the relationship between H. pylori RocF and IL-8 induction. We conclude that H. pylori arginase modulates multiple host signaling and metabolic pathways of infected gastric epithelial cells. Arginase may play a critical role in anti-inflammatory host responses that could contribute to the ability of H. pylori to establish chronic infections.


Central administration of IL-1 alpha increases glucose uptake by muscle.
Intracerebroventricular (ICV) injection of interleukin (IL)-1 alpha has previously been demonstrated to enhance the rate of whole body glucose disposal. The purpose of the present study was to identify the specific tissue(s) responsible for the increased glucose uptake. All experiments were performed on fasted catheterized rats in which an ICV cannula had also been implanted. In vivo glucose uptake by individual tissues was determined, using tracer amounts of [14C]-2-deoxyglucose, 20-60 min after the ICV injection of recombinant human IL-1 alpha (100 ng/rat). IL-1 increased glucose uptake in skeletal muscle (117%), diaphragm (50%) and heart (110%), compared to time-matched control animals. Glucose uptake by other tissues, including the liver, spleen, lung, skin, ileum and whole brain, was not different from control values. As a result of these changes, the contribution of skeletal muscle to whole body glucose disposal increased from 29% to 48%, while that of skin and intestine decreased. The increased glucose uptake in various muscles was consistent with the increased (55%) plasma insulin levels in these animals. In rats pretreated with somatostatin, which produced severe insulinopenia, the IL-1 induced increases in glucose uptake were prevented in heart and diaphragm, and attenuated by more than 80% in skeletal muscle. These data indicate that the increased whole body glucose disposal produced by ICV injection of IL-1 alpha was due to an enhanced uptake of glucose by muscle via insulin-mediated pathways.(ABSTRACT TRUNCATED AT 250 WORDS)


Evidence for involvement of the insula in the psychotropic effects of THC in humans: a double-blind, randomized pharmacological MRI study.
The main reason for recreational use of cannabis is the 'high', the primary psychotropic effect of Δ9-tetrahydrocannabinol (THC). This psychoactive compound of cannabis induces a range of subjective, physical and mental reactions. The effect on heart rate is pronounced and complicates bloodflow-based neuroimaging of psychotropic effects of THC. In this study we investigated the effects of THC on baseline brain perfusion and activity in association with the induction of 'feeling high'. Twenty-three subjects participated in a pharmacological MRI study, where we applied arterial spin labelling (ASL) to measure perfusion, and resting-state functional MRI to assess blood oxygen level-dependent signal fluctuation as a measure of baseline brain activity. Feeling high was assessed with a visual analogue scale and was compared to the imaging measures. THC increased perfusion in the anterior cingulate cortex, superior frontal cortex, and insula, and reduced perfusion in the post-central and occipital gyrus. Baseline brain activity was altered, indicated by increased amplitude of fluctuations in resting-state functional MRI signal after THC administration in the insula, substantia nigra and cerebellum. Perfusion changes in frontal cortex were negatively correlated with ratings of feeling high, suggesting an interaction between cognitive control and subjective effects of THC. In conclusion, an acute THC challenge altered baseline brain perfusion and activity, especially in frontal brain areas involved in cognitive and emotional processes, and the insula, associated with interoceptive awareness. These changes may represent the THC-induced neurophysiological correlates of feeling high. The alterations in baseline brain perfusion and activity also have relevance for studies on task-related effects of THC on brain function.


Combination of rifapentine-moxifloxacin-minocycline (PMM) for the treatment of leprosy.
To further the development of a multidrug regimen for treatment of leprosy that is suitable for monthly administration and fully supervisable, the bactericidal activities against Mycobacterium leprae of HMR 3647 (HMR), moxifloxacin (MXFX) and rifapentine (RPT) were measured by the proportional bactericide technique in the mouse footpad system, and compared with those of the established antileprosy drugs clarithromycin (CLARI), ofloxacin (OFLO) and rifampicin (RMP). Administered in five daily doses of 100 mg per kg body weight, HMR appeared slightly more bactericidal than CLARI, but the difference did not attain statistical significance. Administered as single doses, MXFX in a dosage of 150 mg per kg was more active than OFLO in the same dosage, and displayed the same level of activity as RMP in a dosage of 10 mg per kg; the combination MXFX-minocycline (MINO) (MM) was more bactericidal than the combination OFLO-MINO (OM); RPT in a dosage of 10 mg per kg was more bactericidal than RMP administered in the same dosage, and even more active than the combination RMP-OFLO-MINO (ROM); the combination RPT-MXFX-MINO (PMM) killed 99.9% of viable M. leprae, and was slightly more bactericidal than was RPT alone, indicating that the combination PMM showed an additive effect against M. leprae. These promising results justify a clinical trial among lepromatous patients, in which MM is being compared with OM, and PMM with ROM, in terms of efficacy and tolerance.


Response to highly active antiretroviral therapy at 6 months and long-term disease progression in HIV-1 infection.
To compare the long-term prognostic significance of different definitions of immunologic and virologic responses to highly active antiretroviral therapy (HAART) at 6 months. This was a prospective study conducted in 68 French hospitals. HAART was initiated in 2236 protease inhibitor-naive patients included in the French Hospital Database on HIV. Multivariate Cox proportional hazard models measuring time from 6 months after starting HAART were used to compare the strength of the association between different definitions of immunologic and virologic responses at 6 months and subsequent progression to AIDS or death. The Akaike's Information Criteria were used to identify the most appropriate model. During a median follow-up of 58 months, 325 patients experienced an AIDS-defining event or died. The model that fitted best was the model in which the CD4 cell count and plasma HIV-1 RNA values attained at 6 months were considered. The risk of clinical progression at 5 years ranged from 7% (95% confidence interval [CI]: 4-10) in patients whose CD4 cell count at 6 months was >or=350 cells/microL and whose HIV-1 RNA concentration was <3 log10 copies/mL to 63% (95% CI: 52-75) in patients whose CD4 cell count at 6 months was <100 cells/microL and whose HIV-1 RNA concentration was >or=5 log10. Plasma HIV-1 RNA concentration and CD4 cell count should be taken into account independently when evaluating early response to treatment. The persistent impact of early response on clinical progression at 5 years emphasizes the major importance of the success of first-line HAART.


Cytokine Tuning of Intestinal Epithelial Function.
The intestine serves as both our largest single barrier to the external environment and the host of more immune cells than any other location in our bodies. Separating these potential combatants is a single layer of dynamic epithelium composed of heterogeneous epithelial subtypes, each uniquely adapted to carry out a subset of the intestine's diverse functions. In addition to its obvious role in digestion, the intestinal epithelium is responsible for a wide array of critical tasks, including maintaining barrier integrity, preventing invasion by microbial commensals and pathogens, and modulating the intestinal immune system. Communication between these epithelial cells and resident immune cells is crucial for maintaining homeostasis and coordinating appropriate responses to disease and can occur through cell-to-cell contact or by the release or recognition of soluble mediators. The objective of this review is to highlight recent literature illuminating how cytokines and chemokines, both those made by and acting on the intestinal epithelium, orchestrate many of the diverse functions of the intestinal epithelium and its interactions with immune cells in health and disease. Areas of focus include cytokine control of intestinal epithelial proliferation, cell death, and barrier permeability. In addition, the modulation of epithelial-derived cytokines and chemokines by factors such as interactions with stromal and immune cells, pathogen and commensal exposure, and diet will be discussed.


The internal cranial anatomy of Champsosaurus (Choristodera: Champsosauridae): Implications for neurosensory function.
Although isolated Champsosaurus remains are common in Upper Cretaceous sediments of North America, the braincase of these animals is enigmatic due to the fragility of their skulls. Here, two well-preserved specimens of Champsosaurus (CMN 8920 and CMN 8919) are CT scanned to describe their neurosensory structures and infer sensory capability. The anterior portion of the braincase was poorly ossified and thus does not permit visualization of a complete endocast; however, impressions of the olfactory stalks indicate that they were elongate and likely facilitated good olfaction. The posterior portion of the braincase is ossified and morphologically similar to that of other extinct diapsids. The absence of an otic notch and an expansion of the pars inferior of the inner ear suggests Champsosaurus was limited to detecting low frequency sounds. Comparison of the shapes of semicircular canals with lepidosaurs and archosauromorphs demonstrates that the semicircular canals of Champsosaurus are most similar to those of aquatic reptiles, suggesting that Champsosaurus was well adapted for sensing movement in an aquatic environment. This analysis also demonstrates that birds, non-avian archosauromorphs, and lepidosaurs possess significantly different canal morphologies, and represents the first morphometric analysis of semicircular canals across Diapsida.


Operating room waste: disposable supply utilization in neurosurgical procedures.
OBJECTIVE Disposable supplies constitute a large portion of operating room (OR) costs and are often left over at the end of a surgical case. Despite financial and environmental implications of such waste, there has been little evaluation of OR supply utilization. The goal of this study was to quantify the utilization of disposable supplies and the costs associated with opened but unused items (i.e., "waste") in neurosurgical procedures. METHODS Every disposable supply that was unused at the end of surgery was quantified through direct observation of 58 neurosurgical cases at the University of California, San Francisco, in August 2015. Item costs (in US dollars) were determined from the authors' supply catalog, and statistical analyses were performed. RESULTS Across 58 procedures (36 cranial, 22 spinal), the average cost of unused supplies was $653 (range $89-$3640, median $448, interquartile range $230-$810), or 13.1% of total surgical supply cost. Univariate analyses revealed that case type (cranial versus spinal), case category (vascular, tumor, functional, instrumented, and noninstrumented spine), and surgeon were important predictors of the percentage of unused surgical supply cost. Case length and years of surgical training did not affect the percentage of unused supply cost. Accounting for the different case distribution in the 58 selected cases, the authors estimate approximately $968 of OR waste per case, $242,968 per month, and $2.9 million per year, for their neurosurgical department. CONCLUSIONS This study shows a large variation and significant magnitude of OR waste in neurosurgical procedures. At the authors' institution, they recommend price transparency, education about OR waste to surgeons and nurses, preference card reviews, and clarification of supplies that should be opened versus available as needed to reduce waste.


Coffee acutely modifies gastrointestinal hormone secretion and glucose tolerance in humans: glycemic effects of chlorogenic acid and caffeine.
Accumulating evidence suggests that certain dietary polyphenols have biological effects in the small intestine that alter the pattern of glucose uptake. Their effects, however, on glucose tolerance in humans are unknown. The objective was to investigate whether chlorogenic acids in coffee modulate glucose uptake and gastrointestinal hormone and insulin secretion in humans. In a 3-way, randomized, crossover study, 9 healthy fasted volunteers consumed 25 g glucose in either 400 mL water (control) or 400 mL caffeinated or decaffeinated coffee (equivalent to 2.5 mmol chlorogenic acid/L). Blood samples were taken frequently over the following 3 h. Glucose and insulin concentrations tended to be higher in the first 30 min after caffeinated coffee consumption than after consumption of decaffeinated coffee or the control (P < 0.05 for total and incremental area under the curve for glucose and insulin). Glucose-dependent insulinotropic polypeptide secretion decreased throughout the experimental period (P < 0.005), and glucagon-like peptide 1 secretion increased 0-120 min postprandially (P < 0.01) after decaffeinated coffee consumption compared with the control. Glucose and insulin profiles were consistent with the known metabolic effects of caffeine. However, the gastrointestinal hormone profiles were consistent with delayed intestinal glucose absorption. Differences in plasma glucose, insulin, and gastrointestinal hormone profiles further confirm the potent biological action of caffeine and suggest that chlorogenic acid might have an antagonistic effect on glucose transport. Therefore, a novel function of some dietary phenols in humans may be to attenuate intestinal glucose absorption rates and shift the site of glucose absorption to more distal parts of the intestine.


A Nonheme Thiolate-Ligated Cobalt Superoxo Complex: Synthesis and Spectroscopic Characterization, Computational Studies, and Hydrogen Atom Abstraction Reactivity.
The synthesis and characterization of a Co(II) dithiolato complex Co(Me3TACN)(S2SiMe2) (1) are reported. Reaction of 1 with O2 generates a rare thiolate-ligated cobalt-superoxo species Co(O2)(Me3TACN)(S2SiMe2) (2) that was characterized spectroscopically and structurally by resonance Raman, EPR, and X-ray absorption spectroscopies as well as density functional theory. Metal-superoxo species are proposed to S-oxygenate metal-bound thiolate donors in nonheme thiol dioxygenases, but 2 does not lead to S-oxygenation of the intramolecular thiolate donors and does not react with exogenous sulfur donors. However, complex 2 is capable of oxidizing the O-H bonds of 2,2,6,6-tetramethylpiperidin-1-ol derivatives via H atom abstraction. Complementary proton-coupled electron-transfer reactivity is seen for 2 with separated proton/reductant pairs. The reactivity studies indicate that 2 can abstract H atoms from weak X-H bonds with bond dissociation free energy (BDFE) ≤ 70 kcal mol-1. DFT calculations predict that the putative Co(OOH) product has an O-H BDFE = 67 kcal mol-1, which matches the observed pattern of reactivity seen for 2. These data provide new information regarding the selectivity of S-oxygenation versus H atom abstraction in thiolate-ligated nonheme metalloenzymes that react with O2.


G-Protein Coupled Receptors (GPCRs): A Comprehensive Computational Perspective.
GPCRs are ubiquitous in most of the organs of the human body. These receptors were found to be the important targets to attenuate inflammation, cancer, cardiac dysfunction, diabetes, etc. The advanced technologies employed on GPCRs provided an opportunity to understand the physiological process of various diseases. Recently, GPCRs were viewed as viable therapeutic targets to deliver safer and more efficacious drug. In the literature, several computational studies were reported to describe the biological mechanism, function and three-dimensional structure of GPCRs. These studies revealed the multiple conserved transmembrane domains of GPCRs which were connected by intra and extracellular loops. In this review, we provide an updated overview on the computational tools and methodologies which were conducted to explore the structural and mechanistic features of GPCRs. The study also demonstrates the most recent computer-aided drug design approaches employed on GPCRs. This review provides the information that can be exploited toward the molecular understanding of GPCRs with an aim to design the novel ligands for GPCRs.


The Na(+) transporter, TaHKT1;5-D, limits shoot Na(+) accumulation in bread wheat.
Bread wheat (Triticum aestivum L.) has a major salt tolerance locus, Kna1, responsible for the maintenance of a high cytosolic K(+) /Na(+) ratio in the leaves of salt stressed plants. The Kna1 locus encompasses a large DNA fragment, the distal 14% of chromosome 4DL. Limited recombination has been observed at this locus making it difficult to map genetically and identify the causal gene. Here, we decipher the function of TaHKT1;5-D, a candidate gene underlying the Kna1 locus. Transport studies using the heterologous expression systems Saccharomyces cerevisiae and Xenopus laevis oocytes indicated that TaHKT1;5-D is a Na(+) -selective transporter. Transient expression in Arabidopsis thaliana mesophyll protoplasts and in situ polymerase chain reaction indicated that TaHKT1;5-D is localised on the plasma membrane in the wheat root stele. RNA interference-induced silencing decreased the expression of TaHKT1;5-D in transgenic bread wheat lines which led to an increase in the Na(+) concentration in the leaves. This indicates that TaHKT1;5-D retrieves Na(+) from the xylem vessels in the root and has an important role in restricting the transport of Na(+) from the root to the leaves in bread wheat. Thus, TaHKT1;5-D confers the essential salinity tolerance mechanism in bread wheat associated with the Kna1 locus via shoot Na(+) exclusion and is critical in maintaining a high K(+) /Na(+) ratio in the leaves. These findings show there is potential to increase the salinity tolerance of bread wheat by manipulation of HKT1;5 genes.


Genome-wide analysis of microsatellite repeats in humans: their abundance and density in specific genomic regions.
Simple sequence repeats (SSRs) are found in most organisms, and occupy about 3% of the human genome. Although it is becoming clear that such repeats are important in genomic organization and function and may be associated with disease conditions, their systematic analysis has not been reported. This is the first report examining the distribution and density of simple sequence repeats (1-6 base-pairs (bp)) in the entire human genome. The densities of SSRs across the human chromosomes were found to be relatively uniform. However, the overall density of SSR was found to be high in chromosome 19. Triplets and hexamers were more predominant in exonic regions compared to intronic and intergenic regions, except for chromosome Y. Comparison of densities of various SSRs revealed that whereas trimers and pentamers showed a similar pattern (500-1,000 bp/Mb) across the chromosomes, di- tetra- and hexa-nucleotide repeats showed patterns of higher (2,000-3,000 bp/Mb) density. Repeats of the same nucleotide were found to be higher than other repeat types. Repeats of A, AT, AC, AAT, AAC, AAG, AGC, AAAC, AAAT, AAAG, AAGG, AGAT predominate, whereas repeats of C, CG, ACT, ACG, AACC, AACG, AACT, AAGC, AAGT, ACCC, ACCG, ACCT, CCCG and CCGG are rare. The overall SSR density was comparable in all chromosomes. The density of different repeats, however, showed significant variation. Tri- and hexa-nucleotide repeats are more abundant in exons, whereas other repeats are more abundant in non-coding regions.


Peripheral hearing loss reduces the ability of children to direct selective attention during multi-talker listening.
Restoring normal hearing requires knowledge of how peripheral and central auditory processes are affected by hearing loss. Previous research has focussed primarily on peripheral changes following sensorineural hearing loss, whereas consequences for central auditory processing have received less attention. We examined the ability of hearing-impaired children to direct auditory attention to a voice of interest (based on the talker's spatial location or gender) in the presence of a common form of background noise: the voices of competing talkers (i.e. during multi-talker, or "Cocktail Party" listening). We measured brain activity using electro-encephalography (EEG) when children prepared to direct attention to the spatial location or gender of an upcoming target talker who spoke in a mixture of three talkers. Compared to normally-hearing children, hearing-impaired children showed significantly less evidence of preparatory brain activity when required to direct spatial attention. This finding is consistent with the idea that hearing-impaired children have a reduced ability to prepare spatial attention for an upcoming talker. Moreover, preparatory brain activity was not restored when hearing-impaired children listened with their acoustic hearing aids. An implication of these findings is that steps to improve auditory attention alongside acoustic hearing aids may be required to improve the ability of hearing-impaired children to understand speech in the presence of competing talkers.


Polycystic kidney disease in a patient with achondroplasia: case report.
Autosomal dominant polycystic kidney disease is a multisystem disease involving many organs. An association with other diseases such as tuberous sclerosis, von Hippel-Lindau disease and Marfan syndrome have been previously described. We describe a 35 year old female with achondroplasia who developed polycystic kidney disease involving both kidneys and progressing to end-stage renal disease. To the best of our knowledge this is the first such case described in the literature. We also delve, briefly, into the possibility of the genes and chromosomes involved in Marfan syndrome, polycystic kidney disease, tuberous sclerosis and achondroplasia playing a role in the co-occurrence of these entities.


Observational Learning in Octopus vulgaris.
Untrained Octopus vulgaris (observers) were allowed to watch conditioned Octopus(demonstrators) perform the task of selecting one of two objects that were presented simultaneously and differed only in color. After being placed in isolation, the observers, in a similar test, consistently selected the same object as did the demonstrators. This learning by observation occurred irrespective of the object chosen by the demonstrators as the positive choice and was more rapid than the learning that occurred during the conditioning of animals. The task was performed correctly without significant errors and further conditioning for 5 days. These results show that observational learning can occur in invertebrates.


Nurse behavioural psychotherapy and pathological gambling: an Australian perspective.
Nurses have been employed as behavioural psychotherapists for over 25 years. The first training in this field was established at The Maudsley Hospital (Marks et al. 1977). Since then there have been a number of courses producing many specialist nurse behavioural psychotherapists (NBTs) (Duggan et al. 1993). Nurse behavioural therapy is taken to mean nurses working as behavioural psychotherapists. This title does not mean they are practising a separate form of therapy from other professionals such as psychologists. In Australia there is no such training, with nurse behavioural psychotherapists working here having trained first in UK. Initially NBTs were trained to treat people with anxiety disorders. Over the past 25 years this emphasis has remained, but many NBTs have gone on to provide help to people with other problems. This paper will demonstrate the practical application of behavioural psychotherapy with problem gamblers, and how specialist trained nurses can provide such treatment. The paper will look briefly at nurse behavioural psychotherapy from its initial inception to its current status in Australia. The outcomes of the treatment programme carried out at Flinders Medical Centre for Problem Gamblers will be discussed with a view to nurses carrying out therapy. Finally, the future of nurse behavioural psychotherapy in Australia and how nurses can apply such skills across a wide range of problems, including gambling, will be reviewed. Aspects of this paper were first presented to the 7th NAGS conference, Adelaide 1996.


Development and Psychometric Properties of the Sussex-Oxford Compassion Scales (SOCS).
Compassion has received increasing societal and scientific interest in recent years. The science of compassion requires a tool that can offer valid and reliable measurement of the construct to allow examination of its causes, correlates, and consequences. The current studies developed and examined the psychometric properties of new self-report measures of compassion for others and for the self, the 20-item Sussex-Oxford Compassion for Others Scale (SOCS-O) and 20-item Sussex-Oxford Compassion for the Self Scale (SOCS-S). These were based on the theoretically and empirically supported definition of compassion as comprising five dimensions: (a) recognizing suffering, (b) understanding the universality of suffering, (c) feeling for the person suffering, (d) tolerating uncomfortable feelings, and (e) motivation to act/acting to alleviate suffering. Findings support the five-factor structure for both the SOCS-O and SOCS-S. Scores on both scales showed adequate internal consistency, interpretability, floor/ceiling effects, and convergent and discriminant validity.


Differences in the weighting and choice of evidence for plausible versus implausible causes.
Individuals have difficulty changing their causal beliefs in light of contradictory evidence. We hypothesized that this difficulty arises because people facing implausible causes give greater consideration to causal alternatives, which, because of their use of a positive test strategy, leads to differential weighting of contingency evidence. Across 4 experiments, participants learned about plausible or implausible causes of outcomes. Additionally, we assessed the effects of participants' ability to think of alternative causes of the outcomes. Participants either saw complete frequency information (Experiments 1 and 2) or chose what information to see (Experiments 3 and 4). Consistent with the positive test account, participants given implausible causes were more likely to inquire about the occurrence of the outcome in the absence of the cause (Experiments 3 and 4) than those given plausible causes. Furthermore, they gave less weight to Cells A and B in a 2 × 2 contingency table and gave either equal or less weight to Cells C and D (Experiments 1 and 2). These effects were inconsistently modified by participants' ability to consider alternative causes of the outcome. The total of the observed effects are not predicted by either dominant models of normative causal inference or by the particular positive test account proposed here, but they may be commensurate with a more broadly construed positive test account.


Diabetes: how to manage cardiovascular risk in secondary prevention patients.
Atherosclerotic cardiovascular disease (ASCVD) commonly affects people with type 2 diabetes (T2D). Historically, traditional cardiovascular (CV) risk-lowering therapies in patients with T2D and ASCVD have included antiplatelet agents, blood pressure-lowering therapies, lipid-lowering therapies and healthy lifestyle modifications. In the past decade, multiple antihyperglycaemic agents have emerged as CV risk-lowering therapies in this population as well. This article provides a narrative review on the current non-glycaemic and glycaemic treatment options for CV risk reduction in patients with T2D and ASCVD. The FDA requirement that all new antihyperglycaemic agents undergo cardiovascular outcomes trials has demonstrated increasing evidence to support the role of glucagon-like peptide 1 (GLP1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors as first-line agents for both glycaemic control and CV risk reduction in this population.


Different footprints of the Zika and dengue surface proteins on viral membranes.
The flavivirus Zika virus (ZV) became an international emergency within two years of its outbreak in the Americas. Dengue virus (DENV), which is also a flavivirus, causes significant clinical harm in equatorial regions. A common feature amongst flaviviruses like ZV and DENV is an icosahedral shell of exactly 180 copies of the envelope (E) and membrane (M) proteins anchored in a lipid membrane, which engulfs the viral RNA and capsid proteins. Host recognition by both ZV and DENV is linked to the presence of phosphatidylserine (PS) and phosphatidylethanolamine (PE) lipids in the viral lipidome. Glycosylation of Asn residues on the Zika E protein may be linked to ZV induced neuropathies. We carry out coarse grained molecular dynamics simulations of the E3M3 hexamer embedded in the ZV and DENV lipidomes, and we show that the proteins have a significantly different lipid footprint in the viral lipidome. PE lipids in DENV and PS lipids in ZV enrich near the protein hexamer. We attribute the difference to a higher number of cationic amino acids in the ZV M protein. We also show that the three glycosylation sites on ZV, but not on DENV, are conformationally variant. Our data shed new light on the lipid interactions, and thus the host recognition mechanisms of the two viruses, which may be molecular determinants of the neuropathies caused by the ZV.


Gastrointestinal tract disorder in natriuretic peptide receptor B gene mutant mice.
Natriuretic peptide receptor B (NPR-B), which has high affinity for C-type natriuretic peptide (CNP) and synthesizes intracellular cGMP, may be involved in gastrointestinal tract (GIT) regulation. A mutant allele of the NPR-B-encoding gene (Npr2) is responsible for the phenotype of the short-limb dwarfism (SLW) mouse. Homozygosity for this autosomal-recessive gene (slw/slw) leads to dwarfism and death before weaning because of milk retention in the stomach and intestinal distention. To elucidate the relationship between CNP/NPR-B signaling and GIT function, we investigated the association between Npr2 mutation and the GIT phenotype in slw/slw mice. The pylorus and large intestine of the mutants did not respond to CNP stimulation; further, they showed pyloric lumen narrowing with randomly aligned circular muscle cells. Comparison of the cGMP and neuronal marker distribution in GIT tissues confirmed cGMP expression in neuronal tissues. An Auerbach's plexus and submucosal tissues of the mutants didn't express cGMP and expressed Ca(2+). In contrast, those of normal mice (controls) expressed both cGMP and Ca(2+). Sequencing revealed that the causative Npr2 mutation was a 7-base deletion in exon 8, resulting in a frameshift and premature termination codon appearance. Therefore, the GIT phenotype of slw/slw mice is because of a CNP/NPR-B-signaling defect caused by an Npr2 mutation. These results facilitate better understanding of the role of CNP/NPR-B signaling in GIT motility.


Pupal habitat productivity of Anopheles gambiae complex mosquitoes in a rural village in western Kenya.
The productivity of larval habitats of the malaria vector Anopheles gambiae for pupae (the stage preceding adult metamorphosis) is poorly known, yet adult emergence from habitats is the primary determinant of vector density. To assess it, we used absolute sampling methods in four studies involving daily sampling for 25 days in 6 habitat types in a village in western Kenya. Anopheles gambiae s.s. comprised 82.5% of emergent adults and Anopheles arabiensis the remainder. Pupal production occurred from a subset of habitats, primarily soil burrow pits, and was discontinuous in time, even when larvae occupied all habitats continuously. Habitat stability was positively associated with pupal productivity. In a dry season, pupal productivity was distributed between burrow pits and pools in streambeds. Overall, these data support the notion that source reduction measures against recognizably productive habitats would be a useful component of an integrated management program for An. gambiae in villages.


Positron emission tomography and functional characterization of a complete PBR/TSPO knockout.
The evolutionarily conserved peripheral benzodiazepine receptor (PBR), or 18-kDa translocator protein (TSPO), is thought to be essential for cholesterol transport and steroidogenesis, and thus life. TSPO has been proposed as a biomarker of neuroinflammation and a new drug target in neurological diseases ranging from Alzheimer's disease to anxiety. Here we show that global C57BL/6-Tspo(tm1GuWu(GuwiyangWurra))-knockout mice are viable with normal growth, lifespan, cholesterol transport, blood pregnenolone concentration, protoporphyrin IX metabolism, fertility and behaviour. However, while the activation of microglia after neuronal injury appears to be unimpaired, microglia from (GuwiyangWurra)TSPO knockouts produce significantly less ATP, suggesting reduced metabolic activity. Using the isoquinoline PK11195, the ligand originally used for the pharmacological and structural characterization of the PBR/TSPO, and the imidazopyridines CLINDE and PBR111, we demonstrate the utility of (GuwiyangWurra)TSPO knockouts to provide robust data on drug specificity and selectivity, both in vitro and in vivo, as well as the mechanism of action of putative TSPO-targeting drugs.


Clinicopathologic features of frontotemporal dementia with progranulin sequence variation.
Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). Patients underwent a single clinical assessment, MRI, and [(18)F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A-->G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A-->G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.


Negative propagation effect in nonparaxial Airy beams.
Negative propagation is an unusual effect concerning the local sign change in the Poynting vector components of an optical beam under free propagation. We report this effect for finite-energy Airy beams in a subwavelength nonparaxial regime. This effect is due to a coupling process between propagating and evanescent plane waves forming the beam in the spectral domain and it is demonstrated for a single TE or TM mode. This is contrary to what happens for vector Bessel beams and vector X-waves, for which a complex superposition of TE and TM modes is mandatory. We also show that evanescent waves cannot contribute to the energy flux density by themselves such that a pure evanescent Airy beam is not physically realizable. The break of the shape-preserving and diffraction-free properties of Airy beams in a nonparaxial regime is exclusively caused by the propagating waves. The negative propagation effect in subwavelength nonparaxial Airy beams opens new capabilities in optical traps and tweezers, optical detection of invisibility cloacks and selective on-chip manipulation of nanoparticles.


Mikrocytos roughleyi taxonomic affiliation leads to the genus Bonamia (Haplosporidia).
Microcell-type parasites of oysters are associated with a complex of diseases in different oyster species around the world. The etiological agents are protists of very small size that are very difficult to characterize taxonomically. Associated lesions may vary according to the host species, and their occurrence may be related to variations in tissue structure. Lesion morphology cannot be used to distinguish the different agents involved. Ultrastructural observations on Mikrocytos roughleyi revealed similarities with Bonamia spp., particularly in regard to the presence of electron-dense haplosporosomes and mitochondria, whose absence from M. mackini also indicate that M. roughleyi and M. mackini are not congeneric. A partial small subunit (ssu) rRNA gene sequence of M. roughleyi was determined. This partial sequence, 951 nucleotides in length, has 95.2 and 98.4% sequence similarities with B. ostreae and B. exitiosus ssu rDNA sequences, respectively. Polymorphisms among the ssu rDNA sequences of B. ostreae, B. exitiosus and M. roughleyi allowed identification of restriction enzyme digestion patterns diagnostic for each species. Phylogenetic analysis based on the ssu rDNA data suggested that M. roughleyi belongs in the phylum Haplosporidia and that it is closely related to Bonamia spp. On the basis of ultrastructural and molecular considerations, M. roughleyi should be considered a putative member of the genus Bonamia.


Neurological disease or intellectual disability among sons of female Swedish dental personnel.
Prenatal exposure to elemental mercury may be a potential hazard for the offspring of female dental personnel working with dental amalgam. The aim of this study was to investigate whether potential in utero exposure to mercury might have affected the development of nervous system of the sons of Swedish female dental personnel leading to an increased risk of neurological disease or intellectual disability. We used national Swedish registers to investigate risks for diseases potentially related to adverse effects on neurodevelopment. Sons of female dentists (n=1690) and dental nurses (n=10,420) were compared with cohorts consisting of sons of other female healthcare personnel. Due to changes in mercury exposure in dentistry during the study period, analyses were stratified by decade of birth. Hazard ratios (HRs) were calculated using Cox proportional hazard models. We found no elevated risk for neurological disease, epilepsy or intellectual disability among the sons of dental personnel during any of the decades studied. HRs for neurological disease among the dental nurse cohort were even below 1.00 during the 1970s and 1980s. A low number of events resulted in uncertainty regarding results in the dentist cohort. We did not find any support for the hypothesis that mercury exposure in Swedish dentistry during the 1960s, 1970s or 1980s had any effect on the incidence of neurological disease or intellectual disability among the sons of female dental personnel. Our results imply that current use of dental amalgam should not represent an elevated risk for neurological disease or intellectual disability among the offspring of dental personnel.


Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/mitogen-activated protein kinase and c-Jun terminal kinase.
Alzheimer's disease (AD) is a disorder of two pathologies: amyloid plaques, the core of which is a peptide derived from the amyloid precursor protein (APP), and neurofibrillary tangles composed of highly phosphorylated tau. Protein kinase C (PKC) is known to increase non-amyloidogenic alpha-secretase cleavage of APP, producing secreted APP (sAPPalpha), and glycogen synthase kinase (GSK)-3beta is known to increase tau phosphorylation. Both PKC and GSK-3beta are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increases sAPPalpha production. The dishevelled action on APP is mediated via both c-jun terminal kinase (JNK) and protein kinase C (PKC)/mitogen-activated protein (MAP) kinase but not via p38 MAP kinase. These data position dvl-1 upstream of both PKC and JNK, thereby explaining the previously observed dual signaling action of dvl-1. Furthermore, we show that human dvl-1 and wnt-1 also reduce the phosphorylation of tau by GSK-3beta. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling.


Fourteen-month-old infants use interpersonal synchrony as a cue to direct helpfulness.
Musical behaviours such as dancing, singing and music production, which require the ability to entrain to a rhythmic beat, encourage high levels of interpersonal coordination. Such coordination has been associated with increased group cohesion and social bonding between group members. Previously, we demonstrated that this association influences even the social behaviour of 14-month-old infants. Infants were significantly more likely to display helpfulness towards an adult experimenter following synchronous bouncing compared with asynchronous bouncing to music. The present experiment was designed to determine whether interpersonal synchrony acts as a cue for 14-month-olds to direct their prosocial behaviours to specific individuals with whom they have experienced synchronous movement, or whether it acts as a social prime, increasing prosocial behaviour in general. Consistent with the previous results, infants were significantly more likely to help an experimenter following synchronous versus asynchronous movement with this person. Furthermore, this manipulation did not affect infant's behaviour towards a neutral stranger, who was not involved in any movement experience. This indicates that synchronous bouncing acts as a social cue for directing prosociality. These results have implications for how musical engagement and rhythmic synchrony affect social behaviour very early in development.


CD3+ WT31- peripheral T lymphocytes lack T44 (CD28), a surface molecule involved in activation of T cells bearing the alpha/beta heterodimer.
We have applied two-color fluorescence cytofluorometric techniques to the analysis of the distribution of T44 and CD3 antigens in peripheral blood human lymphocytes. While most CD3+ cells co-expressed T44 antigen, a small distinct subset was CD3+ T44- (2-10% of CD3+ cells). This cell subset also did not react with the WT31 monoclonal antibody (mAb), specific for an alpha/beta framework determinant of the T cell receptor (TCR). Lack of T44 antigen expression was also observed in purified CD3+ WT31- polyclonal populations that had been cultured in medium containing interleukin 2 (IL2) and as well as greater than 30 clones expressing the CD3+4-8-WT31- surface phenotype. Immunoprecipitation experiments confirmed that expression of T44 molecules was confined to CD3+ WT31+ peripheral blood T cells. While conventional CD3+ WT31+ cells produced IL2 in response to mAb directed to CD2, CD3 or T44 surface molecules, CD3+ WT31- cells did not respond to anti-T44 mAb but released IL2 following stimulation with anti-CD2 or anti-CD3 mAb. Therefore, assuming that anti-T44 mimicks the effect of a still undefined natural ligand our data suggest that T cells expressing the gamma-gene surface product may be signalled by stimuli which differ, at least in part, from those acting on CD3+ WT31+ T lymphocytes.


Ontogenetic shifts in trait-mediated mechanisms of plant community assembly.
Identifying the processes that maintain highly diverse plant communities remains a central goal in ecology. Species variation in growth and survival rates across ontogeny, represented by tree size classes and life history stage-specific niche partitioning, are potentially important mechanisms for promoting forest diversity. However, the role of ontogeny in mediating competitive dynamics and promoting functional diversity is not well understood, particular in high-diversity systems such as tropical forests. The interaction between interspecific functional trait variation and ontogenetic shifts in competitive dynamics may yield insights into the ecophysiological mechanisms promoting community diversity. We investigated how functional trait (seed size, maximum height, SLA, leaf N, and wood density) associations with growth, survival, and response to competing neighbors differ among seedlings and two size classes of trees in a subtropical rain forest in Puerto Rico. We used a hierarchical Bayes model of diameter growth and survival to infer trait relationships with ontogenetic change in competitive dynamics. Traits were more strongly associated with average growth and survival than with neighborhood interactions, and were highly consistent across ontogeny for most traits. The associations between trait values and tree responses to crowding by neighbors showed significant shifts as trees grew. Large trees exhibited greater growth as the difference in species trait values among neighbors increased, suggesting trait-associated niche partitioning was important for the largest size class. Our results identify potential axes of niche partitioning and performance-equalizing functional trade-offs across ontogeny, promoting species coexistence in this diverse forest community.


Peg-interferon improves liver histology in patients with HBeAg-positive chronic hepatitis B: no additional benefit of combination with lamivudine.
The effect of pegylated interferon or its combination with lamivudine on liver histology of patients with chronic hepatitis B (CHB) is unknown. In a double-blinded, randomized, multi-center study we assessed histological changes in 110 hepatitis B e-antigen (HBeAg)-positive CHB patients treated for 52 weeks with Pegylated interferon alpha-2b (PEG-IFN) in combination with either lamivudine or placebo. Liver biopsies were taken before and at the end of treatment. All biopsies were blinded and scored according to the Ishak system. Necroinflammatory score improved (defined as a decrease of at least two points) in 25 patients (48%) of the PEG-IFN/lamivudine combination therapy group and in 31 patients (53%) of the PEG-IFN monotherapy group. The fibrosis score improved (decrease of at least 1 point) in 17 patients (33%) of the combination therapy group vs. 13 patients (22%) of the PEG-IFN monotherapy group (P=0.23). Responders (n=42), defined as serum HBeAg negative at the end of therapy, showed a larger decline in necroinflammatory score than non-responders (mean decline 2.3 and 1.2 points, respectively, P=0.02). Among patients receiving PEG-IFN monotherapy necroinflammation improved more frequently in responders (78% of responders vs. 43% of non-responders, P=0.01) and in patients who showed normalization of ALT (76% of patients with normal ALT vs. 40% of patients with abnormal ALT, P=0.01). Fibrosis score in the PEG-IFN monotherapy group improved more often in responders (39%) than in non-responders (15%, P=0.04). In the PEG-IFN/lamivudine combination therapy group, we found no significant association between virological and biochemical endpoints and histological improvement. Treatment with PEG-IFN therapy improves liver necroinflammation in HBeAg-positive CHB patients, particularly in responders to therapy. PEG-IFN also improves fibrosis in responders. Addition of lamivudine to PEG-IFN did not further improve the histological outcome.


Controlled hypotension versus normotensive resuscitation strategy for people with ruptured abdominal aortic aneurysm.
An abdominal aortic aneurysm (AAA) is the pathological enlargement of the aorta and can develop in both men and women. Progressive aneurysm enlargement can lead to rupture. The rupture of an AAA is frequently fatal and accounts for the death from haemorrhagic shock of at least 45 people per 100,000 population. The outcome of people with ruptured AAA varies among countries and healthcare systems, with mortality ranging from 53% to 90%. Definitive treatment for ruptured AAA includes open surgery or endovascular repair. The management of haemorrhagic shock is crucial for the person's outcome and aims to restore organ perfusion and systolic blood pressure above 100 mmHg through immediate and aggressive fluid replacement. This rapid fluid replacement is known as the normotensive resuscitation strategy. However, evidence suggests that infusing large volumes of cold fluid causes dilutional and hypothermic coagulopathy. The association of these factors may exacerbate bleeding, resulting in a 'lethal triad' of hypothermia, acidaemia, and coagulopathy. An alternative to the normotensive resuscitation strategy is the controlled (permissive) hypotension resuscitation strategy, with a target systolic blood pressure of 50 mmHg to 100 mmHg. The principle of controlled or hypotensive resuscitation has been used in some management protocols for endovascular repair of ruptured AAA. It may be beneficial in preventing blood loss by avoiding the clot disruption caused by the rapid increase in systolic blood pressure; avoiding dilution of clotting factors, platelets and fibrinogen; and by avoiding the temperature decrease that inhibits enzyme activity involved in platelet and clotting factor function. This is an update of a review first published in 2016. To compare the effects of controlled (permissive) hypotension resuscitation and normotensive resuscitation strategies for people with ruptured AAA. The Cochrane Vascular Information Specialist searched the Specialised Register (August 2017), the Cochrane Register of Studies (CENTRAL (2017, Issue 7)) and EMBASE (August 2017). The Cochrane Vascular Information Specialist also searched clinical trials databases (August 2017) for details of ongoing or unpublished studies. We sought all published and unpublished randomised controlled trial (RCTs) that compared controlled hypotension and normotensive resuscitation strategies for the management of shock in patients with ruptured abdominal aortic aneurysms. Two review authors independently assessed identified studies for potential inclusion in the review. We used standard methodological procedures in accordance with the Cochrane Handbook for Systematic Review of Interventions. We identified no RCTs that met the inclusion criteria. We found no RCTs that compared controlled hypotension and normotensive resuscitation strategies in the management of haemorrhagic shock in patients with ruptured abdominal aortic aneurysm that assessed mortality, presence of coagulopathy, intensive care unit length of stay, and the presence of myocardial infarct and renal failure. High quality studies that evaluate the best strategy for managing haemorrhagic shock in ruptured abdominal aortic aneurysms are required.


Optimized theory for simple and molecular fluids.
An optimized closure approximation for both simple and molecular fluids is presented. A smooth interpolation between Perkus-Yevick and hypernetted chain closures is optimized by minimizing the free energy self-consistently with respect to the interpolation parameter(s). The molecular version is derived from a refinement of the method for simple fluids. In doing so, a method is proposed which appropriately couples an optimized closure with the variant of the diagrammatically proper integral equation recently introduced by this laboratory [K. M. Dyer et al., J. Chem. Phys. 123, 204512 (2005)]. The simplicity of the expressions involved in this proposed theory has allowed the authors to obtain an analytic expression for the approximate excess chemical potential. This is shown to be an efficient tool to estimate, from first principles, the numerical value of the interpolation parameters defining the aforementioned closure. As a preliminary test, representative models for simple fluids and homonuclear diatomic Lennard-Jones fluids were analyzed, obtaining site-site correlation functions in excellent agreement with simulation data.


The respiratory pyramid: From symptoms to disease in World Trade Center exposed firefighters.
This study utilizes a four-level pyramid framework to understand the relationship between symptom reports and/or abnormal pulmonary function and diagnoses of airway diseases (AD), including asthma, recurrent bronchitis and COPD/emphysema in WTC-exposed firefighters. We compare the distribution of pyramid levels at two time-points: by 9/11/2005 and by 9/11/2010. We studied 6,931 WTC-exposed FDNY firefighters who completed a monitoring exam during the early period and at least two additional follow-up exams 9/11/2005-9/11/2010. By 9/11/2005 the pyramid structure was as follows: 4,039 (58.3%) in Level 1, no respiratory evaluation or treatment; 1,608 (23.2%) in Level 2, evaluation or treatment without AD diagnosis; 1,005 (14.5%) in Level 3, a single AD diagnosis (asthma, emphysema/COPD, or recurrent bronchitis); 279 (4.0%) in Level 4, asthma and another AD. By 9/11/2010, the pyramid distribution changed considerably, with Level 1 decreasing to 2,612 (37.7% of the cohort), and Levels 3 (N = 1,530) and 4 (N = 796) increasing to 22.1% and 11.5% of the cohort, respectively. Symptoms, spirometry measurements and healthcare utilization were associated with higher pyramid levels. Respiratory diagnoses, even four years after a major inhalation event, are not the only drivers of future healthcare utilization. Symptoms and abnormal FEV-1 values must also be considered if clinicians and healthcare administrators are to accurately anticipate future treatment needs, years after initial exposure.