Characterization and localization of a peripheral neural 5-hydroxytryptamine receptor subtype (5-HT1P) with a selective agonist, 3H-5-hydroxyindalpine.
Peripheral neural 5-hydroxytryptamine (5-HT) receptors are different from both classes 5-HT1 and 5-HT2, which have been described from studies of 5-HT receptors in the brain. Recently, it has been shown that, as in the CNS, there is more than a single type of neural receptor for 5-HT in the enteric nervous system. One of these, called 5-HT1P, has a high affinity for 3H-5-HT, initiates a long-lasting depolarization of enteric neurons associated with an increase in membrane resistance, and is the physiological receptor through which enteric serotoninergic neurons mediate slow EPSPs. The other receptor, called 5-HT3 (5-HT2P), does not bind 3H-5-HT with high affinity, and initiates a brief depolarization of enteric neurons with decreased input resistance, but a physiological action of 5-HT mediated by these receptors has not yet been identified. Hydroxylated indalpines have been found to be agonists at 5-HT1P receptors. We have now examined 5-HT1P receptors using 5-hydroxyindalpine (5-OHIP) as a probe. The action of 5-OHIP on enteric neurons was determined electrophysiologically and compared with that of 5-HT; the binding of 3H-5-OHIP to isolated enteric membranes was studied by rapid filtration, and to frozen sections of tissue by radioautography. 3H-5-OHIP binding was compared with that of 3H-5-HT. 5-OHIP, like 5-HT, induced a triphasic response in most enteric neurons: an initial short-lived depolarization, during which input resistance fell, followed by recovery, and then a long-lasting depolarization, during which the input resistance increased. 5-OHIP bound saturably, reversibly, and with high affinity to enteric membranes (Kd = 7.6 +/- 0.7 nM; Bmax = 76 +/- 14 fmol/mg protein). Binding of 3H-5-OHIP was not inhibited by agents that bind to alpha- or beta-adrenoceptors, nicotinic or muscarinic receptors, histamine H1 or H2 receptors, or 5-HT1(A,B,C, or D), 5-HT2, or 5-HT3 receptors, but was displaced by substances, such as hydroxylated indoles and a dipeptide of 5-hydroxytryptophan (5-HTP-DP), that antagonize the binding of 3H-5-HT to enteric membranes or tissue sections. It is concluded that 5-OHIP is an agonist at peripheral neural 5-HT1P receptors and can be used to label these receptors selectively outside the brain. Radioautographs demonstrated enteric 5-HT1P receptors in the lamina propria of the intestinal mucosa and in the submucosal and myenteric plexuses. Extraenteric 5-HT1P receptors were also found in the skin and heart. It is suggested that 5-HT1P receptors may be found on subtypes of primary afferent nerve fibers.


Purification and characterization of two isoforms of Acanthamoeba profilin.
Acanthamoeba profilin purified according to E. Reichstein and E.D. Korn (1979, J. Biol. Chem. 254:6174-6179) consists of two isoforms (profilin-I and-II) with approximately the same molecular weight and reactivity to a monoclonal antibody but different isoelectric points and different mobilities on carboxymethyl-agarose chromatography and reversed-phase high-performance liquid chromatography. The isoelectric points of profilin-I is approximately 5.5 and that of profilin-II is greater than or equal to 9.0. Tryptic peptides from the two proteins are substantially different, which suggests that there are major differences in their sequences. At similar concentrations, both profilins prolong the lag phase at the outset of spontaneous polymerization and inhibit the extent of polymerization. Both forms also inhibit elongation weakly at the barbed end and strongly at the pointed end of actin filaments.


Cell-specific type I IFN signatures in autoimmunity and viral infection: what makes the difference?
Gene expression profiling of peripheral blood mononuclear cells (PBMCs) has revealed a crucial role for type I interferon (IFN) in the pathogenesis of systemic lupus erythematosus (SLE). However, it is unclear how particular leucocyte subsets contribute to the overall type I IFN signature of PBMCs and whole blood samples.Furthermore, a detailed analysis describing the differences in the IFN signature in autoimmune diseases from that observed after viral infection has not been performed to date. Therefore, in this study, the transcriptional responses in peripheral T helper cells (CD4(+)) and monocyte subsets (CD16(-) inflammatory and CD16(+) resident monocytes) isolated from patients with SLE, healthy donors (ND) immunised with the yellow fever vaccine YFV-17Dand untreated controls were compared by global gene expression profiling.It was striking that all of the transcripts that were regulated in response to viral exposure were also found to be differentially regulated in SLE, albeit with markedly lower fold-change values. In addition to this common IFN signature, a pathogenic IFN-associated gene signature was detected in the CD4(+) T cells and monocytes from the lupus patients. IL-10, IL-9 and IL-15-mediated JAK/STAT signalling was shown to be involved in the pathological amplification of IFN responses observed in SLE. Type I IFN signatures identified were successfully applied for the monitoring of interferon responses in PBMCs of an independent cohort of SLE patients and virus-infected individuals. Moreover, these cell-type specific gene signatures allowed a correct classification of PBMCs independent from their heterogenic cellular composition. In conclusion, our data show for the first time that monocytes and CD4 cells are sensitive biosensors to monitor type I interferon response signatures in autoimmunity and viral infection and how these transriptional responses are modulated in a cell- and disease-specific manner.


Which family members use the best nets? An analysis of the condition of mosquito nets and their distribution within households in Tanzania.
Household ownership of insecticide-treated mosquito nets (ITNs) is increasing, and coverage targets have been revised to address universal coverage with ITNs. However, many households do not have enough nets to cover everyone, and the nets available vary in physical condition and insecticide treatment status. Since 2004, the Government of Tanzania has been implementing the Tanzania National Voucher Scheme (TNVS), which distributes vouchers for ITNs through antenatal clinics to target pregnant women and their infants. This analysis aimed to determine the following: (1) coverage patterns of bed nets within households according to physical condition and treatment status; (2) who might be at risk if mosquitoes were diverted from occupants of untreated nets to those not using nets? (3) the degree to which those at highest risk of malaria use the most protective nets. Data from the 2006 TNVS household survey were analysed to assess within-household distribution of net use. The associations between net characteristics and net user were also evaluated. Multivariate analysis was applied to the relationship between the number of holes per net and user characteristics while adjusting for confounders. In households with a net:person ratio better than 1:4 (one net for every four household members), more than 80% of the people in such households reported using a net the previous night. ITNs were most likely to be used by infants, young children (1-4 y), and women of childbearing age; they were least likely to be used by older women (>or=50 y), older children (5-14 y), and adult men. The nets used by infants and women of childbearing age were in better-than-average physical condition; the nets used by older women and older children were in worse-than-average condition; while young children and adult men used nets in intermediate (average) condition. When adjusted for confounders, the nets used by young and older children had more holes than nets used by infants. Infants and other vulnerable groups were most likely to sleep under the most protective nets. Nevertheless, more communication efforts are needed to increase use of intact ITNs within households for children. Further research is necessary to fully understand motivations influencing within-household net distribution.


Ready to Care? Student Nurse Perceptions of Spiritual Care Education.
This research investigated the spiritual care educational preparation that nursing students perceive they have received as they transition to practice. A survey using the Spirituality and Spiritual Care Rating Scale and interviews with senior BSN students at a Christian university demonstrated students' perceptions that their spiritual care education focused primarily on the practice of presence, emphasis on prayer, and the integration of faith in the curricula. Survey results showed a strong perception of readiness to provide spiritual care as graduate nurses.


Increasing certification through unit-based education
Certification has been identified by multiple organizations as an important component and means of elevating the level of nursing care provided to patients and demonstrating to the public that the nursing staff has subspecialty knowledge. Certification may lead to improved patient satisfaction and outcomes as well as increased nurse satisfaction and retention. Despite the known potential benefits associated with certification, institutions struggle to improve certification rates. One possible method to overcome system barriers to certification is the implementation of a unit-based study course to prepare nurses for the Certified Breast Care Nurse (CBCN) examination. Data collected by an author-developed tool as one institution created and executed a unit-based study course suggest that such an approach increased certification rates and improved disease-specific knowledge and confidence among the staff, despite no official data existing on the tool's reliability and validity. Implementation of similar programs may be successful in improving certification at other institutions seeking to raise certification rates.


Ontogeny of cell-mediated immunity. I. Early development of alloantigen-specific cytotoxic T-cell precursors in postnatal mice.
Cytotoxic T-cell precursors have been shown to occur in spleens of 2-3-day-old mice. By 12 days after birth, the cytotoxic T-cell response of spleen cells to alloantigens has reached 23-32% of adult levels. Addition of extra T-helper cells did not permit cytotoxic T-cell development in spleen cells from newborn to 2-day-old mice suggesting either a lack of precursors or suppression of precursors. The ontogeny of cell-mediated immune functions has thus been shown to correlate well with other work on the development of humoral immunity, accessory cells, and graft versus host reactivity.


Learning Multiparametric Biomarkers for Assessing MR-Guided Focused Ultrasound Treatment of Malignant Tumors.
Noninvasive MR-guided focused ultrasound (MRgFUS) treatments are promising alternatives to the surgical removal of malignant tumors. A significant challenge is assessing the viability of treated tissue during and immediately after MRgFUS procedures. Current clinical assessment uses the nonperfused volume (NPV) biomarker immediately after treatment from contrast-enhanced MRI. The NPV has variable accuracy, and the use of contrast agent prevents continuing MRgFUS treatment if tumor coverage is inadequate. This work presents a novel, noncontrast, learned multiparametric MR biomarker that can be used during treatment for intratreatment assessment, validated in a VX2 rabbit tumor model. A deep convolutional neural network was trained on noncontrast multiparametric MR images using the NPV biomarker from follow-up MR imaging (3-5 days after MRgFUS treatment) as the accurate label of nonviable tissue. A novel volume-conserving registration algorithm yielded a voxel-wise correlation between treatment and follow-up NPV, providing a rigorous validation of the biomarker. The learned noncontrast multiparametric MR biomarker predicted the follow-up NPV with an average DICE coefficient of 0.71, substantially outperforming the current clinical standard (DICE coefficient = 0.53). Noncontrast multiparametric MR imaging integrated with a deep convolutional neural network provides a more accurate prediction of MRgFUS treatment outcome than current contrast-based techniques.


Silver against Pseudomonas aeruginosa biofilms.
Silver has been recognized for its antimicrobial properties for centuries. Most studies on the antibacterial efficacy of silver, with particular emphasis on wound healing, have been performed on planktonic bacteria. Our recent studies, however, strongly suggest that colonization of wounds involves bacteria in both the planktonic and biofilm modes of growth. The action of silver on mature in vitro biofilms of Pseudomonas aeruginosa, a primary pathogen of chronic infected wounds, was investigated. The results show that silver is very effective against mature biofilms of P. aeruginosa, but that the silver concentration is important. A concentration of 5-10 mug/mL silver sulfadiazine eradicated the biofilm whereas a lower concentration (1 mug/mL) had no effect. The bactericidal concentration of silver required to eradicate the bacterial biofilm was 10-100 times higher than that used to eradicate planktonic bacteria. These observations strongly indicate that the concentration of silver in currently available wound dressings is much too low for treatment of chronic biofilm wounds. It is suggested that clinicians and manufacturers of the said wound dressings consider whether they are treating wounds primarily colonized either by biofilm-forming or planktonic bacteria.


Vanishing testes: a literature review.
Vanishing testes syndrome is often referred to as testicular regression syndrome (TRS) in the recent medical literature. The most characteristic histological findings are presence of a fibrovascular nodule with associated hemosiderin-laden macrophages and dystrophic calcification. Residual testicular tubules are found in less than 10% of cases, with prevalence being unrelated to age at surgery. Presence of seminiferous tubules and viable germ cells in testicular remnant tissue has been reported in some series. TRS theoretically carries a potential for malignant degeneration in the long term and therefore removal of any remnant is a common practice to eliminate this risk. However, no case series has reported germinal dysplasia or intratubular germ cell neoplasia in any of the specimens taken from these patients.


Craniovertebral junction melanocytoma: a case report.
Melanocytomas are rare melanocytic tumors of the central nervous system and its presence at the foramen magnum is extremely rare. We report a case of a 55-year-old male presenting with progressive quadriparesis over one year. Imaging showed a well-defined intradural extramedullary lobulated mass at craniovertebral junction towards the left side and extending to left C2-3 neural foramina. Patient was operated through foramen magnum approach with near total excision of tumor. On a ten-month follow up, he was ambulatory with normal motor power on right side of body and left lower limb and with motor power of 4-/5 in left upper limb. Histopathology and immunohistochemistry confirmed the lesion to be a melanocytoma.


BCG Vaccination in Early Childhood and Risk of Atopic Disease: A Systematic Review and Meta-Analysis.
Several large-scale studies suggest that Bacille Calmette-Guerin (BCG) vaccination in early childhood may reduce the risk of atopic diseases, but the findings remain controversial. Here, we aimed to investigate the potential correlation between early childhood BCG vaccination and the risk of developing atopic diseases. Eligible studies published on PubMed, EMBASE, and Cochrane CENTRAL were systematically sourced from 1950 to July 2021. Studies with over 100 participants and focusing on the association between BCG vaccine and atopic diseases including eczema, asthma, and rhinitis were included. Preliminary assessment of methods, interventions, outcomes, and study quality was performed by two independent investigators. Odds ratio (OR) with 95% confidence interval (CI) was calculated. Random effects of the meta-analysis were performed to define pooled estimates of the effects. Twenty studies with a total of 222,928 participants were selected. The quantitative analysis revealed that administering BCG vaccine in early childhood reduced the risk of developing asthma significantly (OR 0.77, 95% CI 0.63 to 0.93), indicating a protective efficacy of 23% against asthma development among vaccinated children. However, early administration of BCG vaccine did not significantly reduce the risk of developing eczema (OR 0.94, 95% CI 0.76 to 1.16) and rhinitis (OR 0.99, 95% CI 0.81 to 1.21). Further analysis revealed that the effect of BCG vaccination on asthma prevalence was significant especially in developed countries (OR 0.73, 95% CI 0.58 to 0.92). BCG vaccination in early childhood is associated with reduced risk of atopic disease, especially in developed countries.


First Report of Seiridium unicorne Causing Bark Cankers on a Monterey Cypress in California.
In June 2009, dieback of distal branches and resin exudation associated with bark lesions were observed in an adult Cupressus macrocarpa tree in Sonoma County, California (Glenn Ellen; 38°21'N, 122°31'W, elevation 233 m). The fungal pathogen, Seiridium unicorne (Cooke and Ellis) Sutton, was obtained by plating fragments of necrotic bark from the margins of branch cankers on potato dextrose agar (PDA). Identification was based on cultural, morphological, and molecular traits (2,3). Colonies on PDA were dense, cottony, off-white at first and then turning pale gray-green, and 2.3 and 4.3 cm in diameter after 1 and 2 weeks of growth at 20°C, respectively. Colonies of the fungus showed a faster radial growth at 20°C than at 25°C. Acervuli were abundantly produced on water agar amended with autoclaved cypress seeds after 2 to 3 weeks at 18°C under a mixture of fluorescent and near UV light. Conidia were six celled (five euseptate), fusiform, 20.9 to 35.2 × 7.11 to 10.57 μm, straight or slightly curved, with four, brown median cells, and with end cells bearing unbranched appendages 2 to 5 μm long. The DNA sequence of a portion of the β-tubulin locus (GenBank Accession No. HQ678171) revealed a 100% homology with sequences of S. unicorne isolates from Portugal and South Africa, while being clearly distinct from sequences of S. cupressi and S. cardinale isolates (2). Greenhouse stem inoculations were performed by underbark placement of a 3-mm plug taken from the margins of a colony of the fungus grown on PDA. Inoculations were repeated twice in the spring and fall of 2010 on 10 C. macrocarpa saplings grown in pots for 3 years. Three months postinoculation, the pathogen could be successfully reisolated from the edges of 15 to 30 mm long elliptical lesions, present on each one of the inoculated saplings. The observed S. unicorne isolate is atypical because of its shorter appendages compared with the form reported in the literature (2,3). Because of its shorter conidial appendages and in vitro temperature optimum of 18 to 20°C, the fungus described here is similar to an unnamed Coryneum sp. observed by Wagener on C. macrocarpa (4). S. unicorne is a pathogen of many Cupressaceae in Africa, New Zealand, Japan, and some U.S. states (Georgia, South Carolina, Kansas, and Texas) (3), and although it was mentioned in a USDA Plant Quarantine Division report from 1963 as found on cypress in San Francisco (1), it has never been officially reported from California. Since similar disease symptoms were observed on many Cupressaceae in the course of an extensive survey performed in 2009 in California, it may be important to evaluate the relative incidence of S. unicorne compared with that of S. cardinale, a pathogen more commonly reported in association with the disease (4). References: (1) D. F. Farr and A. Y. Rossman. Fungal Databases. Systematic Mycology and Microbiology Laboratory, ARS, USDA. Retrieved from http://nt.ars-grin.gov/fungaldatabases/fungushost/fungushost.cfm , 1/19/2011. (2) P. Krokene et al. Mycologia 96:1352, 2004. (3) N. A. Tisserat. Plant Dis. 75:138, 1991. (4) W. W. Wagener. J. Agric. Res. 58:1, 1939.


Antibiotic therapy for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in non surgical wounds.
Non surgical wounds include chronic ulcers (pressure or decubitus ulcers, venous ulcers, diabetic ulcers, ischaemic ulcers), burns and traumatic wounds. The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) colonisation (i.e. presence of MRSA in the absence of clinical features of infection such as redness or pus discharge) or infection in chronic ulcers varies between 7% and 30%. MRSA colonisation or infection of non surgical wounds can result in MRSA bacteraemia (infection of the blood) which is associated with a 30-day mortality of about 28% to 38% and a one-year mortality of about 55%. People with non surgical wounds colonised or infected with MRSA may be reservoirs of MRSA, so it is important to treat them, however, we do not know the optimal antibiotic regimen to use in these cases. To compare the benefits (such as decreased mortality and improved quality of life) and harms (such as adverse events related to antibiotic use) of all antibiotic treatments in people with non surgical wounds with established colonisation or infection caused by MRSA. We searched the following databases: The Cochrane Wounds Group Specialised Register (searched 13 March 2013); The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2); Database of Abstracts of Reviews of Effects (2013, Issue 2); NHS Economic Evaluation Database (2013, Issue 2); Ovid MEDLINE (1946 to February Week 4 2013); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, March 12, 2013); Ovid EMBASE (1974 to 2013 Week 10); EBSCO CINAHL (1982 to 8 March 2013). We included only randomised controlled trials (RCTs) comparing antibiotic treatment with no antibiotic treatment or with another antibiotic regimen for the treatment of MRSA-infected non surgical wounds. We included all relevant RCTs in the analysis, irrespective of language, publication status, publication year, or sample size. Two review authors independently identified the trials, and extracted data from the trial reports. We calculated the risk ratio (RR) with 95% confidence intervals (CI) for comparing the binary outcomes between the groups and planned to calculate the mean difference (MD) with 95% CI for comparing the continuous outcomes. We planned to perform the meta-analysis using both fixed-effect and random-effects models. We performed intention-to-treat analysis whenever possible. We identified three trials that met the inclusion criteria for this review. In these, a total of 47 people with MRSA-positive diabetic foot infections were randomised to six different antibiotic regimens. While these trials included 925 people with multiple pathogens, they reported the information on outcomes for people with MRSA infections separately (MRSA prevalence: 5.1%). The only outcome reported for people with MRSA infection in these trials was the eradication of MRSA. The three trials did not report the review's primary outcomes (death and quality of life) and secondary outcomes (length of hospital stay, use of healthcare resources and time to complete wound healing). Two trials reported serious adverse events in people with infection due to any type of bacteria (i.e. not just MRSA infections), so the proportion of patients with serious adverse events was not available for MRSA-infected wounds. Overall, MRSA was eradicated in 31/47 (66%) of the people included in the three trials, but there were no significant differences in the proportion of people in whom MRSA was eradicated in any of the comparisons, as shown below.1. Daptomycin compared with vancomycin or semisynthetic penicillin: RR of MRSA eradication 1.13; 95% CI 0.56 to 2.25 (14 people).2. Ertapenem compared with piperacillin/tazobactam: RR of MRSA eradication 0.71; 95% CI 0.06 to 9.10 (10 people).3. Moxifloxacin compared with piperacillin/tazobactam followed by amoxycillin/clavulanate: RR of MRSA eradication 0.87; 95% CI 0.56 to 1.36 (23 people). We found no trials comparing the use of antibiotics with no antibiotic for treating MRSA-colonised non-surgical wounds and therefore can draw no conclusions for this population. In the trials that compared different antibiotics for treating MRSA-infected non surgical wounds, there was no evidence that any one antibiotic was better than the others. Further well-designed RCTs are necessary.


Growth factors are released by mechanically wounded endothelial cells.
Growth factors may be required at sites of mechanical injury and normal wear and tear in vivo, suggesting that the direct action of mechanical forces on cells could lead to growth factor release. Scraping of cells from the tissue culture substratum at 37 degrees C was used to test this possibility. We show that scraping closely mimics in vitro both the transient plasma membrane wounds observed in cells subject to mechanical forces in vivo (McNeil, P. L., and S. Ito. 1989. Gastroenterology. 96:1238-1248) and the transient plasma membrane wounds shown here to occur in endothelial cells under normal culturing conditions. Scraping of endothelial cells from the culturing substratum released into the culture medium a potent growth-promoting activity for Swiss 3T3 fibroblasts. Growth-promoting activity was released rapidly (within 5 min) after scraping but was not subsequently degraded by the endothelial cells for at least 24 h thereafter. A greater quantity of growth-promoting activity was released by cells scraped 4 h after plating than by those scraped 4 or 7 d afterwards. Thus release is not due to scraping-induced disruption of extracellular matrix. Release was only partially cold inhibitable, was poorly correlated with the level of cell death induced by scraping, and did not occur when cells were killed with metabolic poisons. These results suggest that mechanical disruption of plasma membrane, either transient or permanent, is the essential event leading to release. A basic fibroblast growth factor-like molecule and not platelet-derived growth factor appears to be partially responsible for the growth-promoting activity. We conclude that one biologically relevant route of release of basic fibroblast growth factor, a molecule which lacks the signal peptide sequence for transport into the endoplasmic reticulum, could be directly through mechanically induced membrane disruptions of endothelial cells growing in vivo and in vitro.


Bradykinin-induced venodilation is not impaired with aging in humans.
The aim of this study was to determine whether there is an age-related decline in vascular responsiveness to bradykinin, whose vasodilatory action is mediated chiefly through endothelium-derived relaxing factor (EDRF). Dose-response curves for bradykinin were constructed using the dorsal hand vein compliance technique in veins preconstricted with phenylephrine in 27 volunteers (16 male, 11 female) aged 18 to 81 years. At the end of the bradykinin study, 12 subjects had a single infusion of a high dose of isoproterenol. There was no correlation between age and the EMAX or the log ED50 for bradykinin, although the same subjects showed a correlation between age and EMAX for isoproterenol, as previously found. There was no significant difference in either the EMAX or the log ED50 between male and female subjects. The results suggest that bradykinin-induced vasodilation is independent of age or gender.


Chemical analysis of Greek pollen - Antioxidant, antimicrobial and proteasome activation properties.
Pollen is a bee-product known for its medical properties from ancient times. In our days is increasingly used as health food supplement and especially as a tonic primarily with appeal to the elderly to ameliorate the effects of ageing. In order to evaluate the chemical composition and the biological activity of Greek pollen which has never been studied before, one sample with identified botanical origin from sixteen different common plant taxa of Greece has been evaluated. Three different extracts of the studied sample of Greek pollen, have been tested, in whether could induce proteasome activities in human fibroblasts. The water extract was found to induce a highly proteasome activity, showing interesting antioxidant properties. Due to this activity the aqueous extract was further subjected to chemical analysis and seven flavonoids have been isolated and identified by modern spectral means. From the methanolic extract, sugars, lipid acids, phenolic acids and their esters have been also identified, which mainly participate to the biosynthetic pathway of pollen phenolics. The total phenolics were estimated with the Folin-Ciocalteau reagent and the total antioxidant activity was determined by the DPPH method while the extracts and the isolated compounds were also tested for their antimicrobial activity by the dilution technique. The Greek pollen is rich in flavonoids and phenolic acids which indicate the observed free radical scavenging activity, the effects of pollen on human fibroblasts and the interesting antimicrobial profile.


Yawn contagion in humans and bonobos: emotional affinity matters more than species.
In humans and apes, yawn contagion echoes emotional contagion, the basal layer of empathy. Hence, yawn contagion is a unique tool to compare empathy across species. If humans are the most empathic animal species, they should show the highest empathic response also at the level of emotional contagion. We gathered data on yawn contagion in humans (Homo sapiens) and bonobos (Pan paniscus) by applying the same observational paradigm and identical operational definitions. We selected a naturalistic approach because experimental management practices can produce different psychological and behavioural biases in the two species, and differential attention to artificial stimuli. Within species, yawn contagion was highest between strongly bonded subjects. Between species, sensitivity to others' yawns was higher in humans than in bonobos when involving kin and friends but was similar when considering weakly-bonded subjects. Thus, emotional contagion is not always highest in humans. The cognitive components concur in empowering emotional affinity between individuals. Yet, when they are not in play, humans climb down from the empathic podium to return to the "understory", which our species shares with apes.


Millisecond time-resolved changes occurring in Ca2+-regulated myosin filaments upon relaxation.
Contraction of many muscles is activated in part by the binding of Ca(2+) to, or phosphorylation of, the myosin heads on the surface of the thick filaments. In relaxed muscle, the myosin heads are helically ordered and undergo minimal interaction with actin. On Ca(2+) binding or phosphorylation, the head array becomes disordered, reflecting breakage of the head-head and other interactions that underlie the ordered structure. Loosening of the heads from the filament surface enables them to interact with actin filaments, bringing about contraction. On relaxation, the heads return to their ordered positions on the filament backbone. In scallop striated adductor muscle, the disordering that takes place on Ca(2+) binding occurs on the millisecond time scale, suggesting that it is a key element of muscle activation. Here we have studied the reverse process. Using time-resolved negative staining electron microscopy, we show that the rate of reordering on removal of Ca(2+) also occurs on the same physiological time scale. Direct observation of images together with analysis of their Fourier transforms shows that activated heads regain their axial ordering within 20 ms and become ordered in their final helical positions within 50 ms. This rapid reordering suggests that reformation of the ordered structure, and the head-head and other interactions that underlie it, is a critical element of the relaxation process.


Influence of acylpeptide hydrolase polymorphisms on valproic acid level in Chinese epilepsy patients.
Concomitant use of meropenem (MEPM) can dramatically decrease valproic acid (VPA) plasma level. It is accepted that inhibition in acylpeptide hydrolase (APEH) activity by MEPM coadministration was the trigger of this drug-drug interaction. To investigate the influence of APEH genetic polymorphisms on VPA plasma concentration in Chinese epilepsy patients. Urinary VPA-d6 β-D-glucuronide concentration was determined in 19 patients with VPA treatment alone (n = 10) or concomitant use with MEPM (n = 9). A retrospective study was performed on 149 epilepsy patients to investigate the influence of APEH polymorphisms rs3816877 and rs1131095 on adjusted plasma VPA concentration (CVPA) at steady-state. Urinary VPA-d6 β-D-glucuronide (VPA-G) concentration was increased significantly in patients with MEPM coadministration. The CVPA of patients carrying the APEH rs3816877 C/C genotype was significantly higher than that of C/T carriers, and the difference was still obvious when stratified by UGT2B7 rs7668258 polymorphism. APEH polymorphism has significant influence on VPA pharmacokinetics in Chinese population.


Effects of In Utero Thyroxine Exposure on Murine Cranial Suture Growth.
Large scale surveillance studies, case studies, as well as cohort studies have identified the influence of thyroid hormones on calvarial growth and development. Surveillance data suggests maternal thyroid disorders (hyperthyroidism, hypothyroidism with pharmacological replacement, and Maternal Graves Disease) are linked to as much as a 2.5 fold increased risk for craniosynostosis. Craniosynostosis is the premature fusion of one or more calvarial growth sites (sutures) prior to the completion of brain expansion. Thyroid hormones maintain proper bone mineral densities by interacting with growth hormone and aiding in the regulation of insulin like growth factors (IGFs). Disruption of this hormonal control of bone physiology may lead to altered bone dynamics thereby increasing the risk for craniosynostosis. In order to elucidate the effect of exogenous thyroxine exposure on cranial suture growth and morphology, wild type C57BL6 mouse litters were exposed to thyroxine in utero (control = no treatment; low ~167 ng per day; high ~667 ng per day). Thyroxine exposed mice demonstrated craniofacial dysmorphology (brachycranic). High dose exposed mice showed diminished area of the coronal and widening of the sagittal sutures indicative of premature fusion and compensatory growth. Presence of thyroid receptors was confirmed for the murine cranial suture and markers of proliferation and osteogenesis were increased in sutures from exposed mice. Increased Htra1 and Igf1 gene expression were found in sutures from high dose exposed individuals. Pathways related to the HTRA1/IGF axis, specifically Akt and Wnt, demonstrated evidence of increased activity. Overall our data suggest that maternal exogenous thyroxine exposure can drive calvarial growth alterations and altered suture morphology.


Decoding the massive genome of loblolly pine using haploid DNA and novel assembly strategies.
The size and complexity of conifer genomes has, until now, prevented full genome sequencing and assembly. The large research community and economic importance of loblolly pine, Pinus taeda L., made it an early candidate for reference sequence determination. We develop a novel strategy to sequence the genome of loblolly pine that combines unique aspects of pine reproductive biology and genome assembly methodology. We use a whole genome shotgun approach relying primarily on next generation sequence generated from a single haploid seed megagametophyte from a loblolly pine tree, 20-1010, that has been used in industrial forest tree breeding. The resulting sequence and assembly was used to generate a draft genome spanning 23.2 Gbp and containing 20.1 Gbp with an N50 scaffold size of 66.9 kbp, making it a significant improvement over available conifer genomes. The long scaffold lengths allow the annotation of 50,172 gene models with intron lengths averaging over 2.7 kbp and sometimes exceeding 100 kbp in length. Analysis of orthologous gene sets identifies gene families that may be unique to conifers. We further characterize and expand the existing repeat library based on the de novo analysis of the repetitive content, estimated to encompass 82% of the genome. In addition to its value as a resource for researchers and breeders, the loblolly pine genome sequence and assembly reported here demonstrates a novel approach to sequencing the large and complex genomes of this important group of plants that can now be widely applied.


Incidence of venous thromboembolism in care homes: a prospective cohort study.
Care home residents have venous thromboembolism (VTE) risk profiles similar to medical inpatients; however, the epidemiology of VTE in care homes is unclear. To determine the incidence of VTE in care homes. Observational cohort study of 45 care homes in Birmingham and Oxford, UK. A consecutive sample of care home residents was enrolled and followed up for 12 months. Data were collected via case note reviews of care home and GP records; mortality information was supplemented with Health and Social Care Information Centre (now called NHS Digital) cause of death data. All potential VTE events were adjudicated by an independent committee according to three measures of diagnostic certainty: definite VTE (radiological evidence), probable VTE (high clinical indication but no radiological evidence), or possible VTE (VTE cannot be ruled out). (Study registration number: ISTCTN80889792.) RESULTS: There were 1011 participants enrolled, and the mean follow-up period was 312 days (standard deviation 98 days). The incidence rate was 0.71 per 100 person years of observation (95% confidence interval [CI] = 0.26 to 1.54) for definite VTE, 0.83 per 100 person years (95% CI = 0.33 to 1.70) for definite and probable VTE, and 2.48 per 100 person years (95% CI = 1.53 to 3.79) for definite, probable, and possible VTE. The incidence of VTE in care homes in this study (0.71-2.48 per 100 person years) is substantial compared with that in the community (0.117 per 100 person years) and in people aged ≥70 years (0.44 per 100 person years). Further research regarding risk stratification and VTE prophylaxis in this population is needed.


Association of Environmental Toxins With Amyotrophic Lateral Sclerosis.
Persistent environmental pollutants may represent a modifiable risk factor involved in the gene-time-environment hypothesis in amyotrophic lateral sclerosis (ALS). To evaluate the association of occupational exposures and environmental toxins on the odds of developing ALS in Michigan. Case-control study conducted between 2011 and 2014 at a tertiary referral center for ALS. Cases were patients diagnosed as having definitive, probable, probable with laboratory support, or possible ALS by revised El Escorial criteria; controls were excluded if they were diagnosed as having ALS or another neurodegenerative condition or if they had a family history of ALS in a first- or second-degree blood relative. Participants completed a survey assessing occupational and residential exposures. Blood concentrations of 122 persistent environmental pollutants, including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and brominated flame retardants (BFRs), were measured using gas chromatography-mass spectrometry. Multivariable models with self-reported occupational exposures in various exposure time windows and environmental toxin blood concentrations were separately fit by logistic regression models. Concordance between the survey data and pollutant measurements was assessed using the nonparametric Kendall τ correlation coefficient. Occupational and residential exposures to environmental toxins, and blood concentrations of 122 persistent environmental pollutants, including OCPs, PCBs, and BFRs. Participants included 156 cases (mean [SD] age, 60.5 [11.1] years; 61.5% male) and 128 controls (mean [SD] age, 60.4 [9.4] years; 57.8% male); among them, 101 cases and 110 controls had complete demographic and pollutant data. Survey data revealed that reported pesticide exposure in the cumulative exposure windows was significantly associated with ALS (odds ratio [OR] = 5.09; 95% CI, 1.85-13.99; P = .002). Military service was also associated with ALS in 2 time windows (exposure ever happened in entire occupational history: OR = 2.31; 95% CI, 1.02-5.25; P = .046; exposure ever happened 10-30 years ago: OR = 2.18; 95% CI, 1.01-4.73; P = .049). A multivariable model of measured persistent environmental pollutants in the blood, representing cumulative occupational and residential exposure, showed increased odds of ALS for 2 OCPs (pentachlorobenzene: OR = 2.21; 95% CI, 1.06-4.60; P = .04; and cis-chlordane: OR = 5.74; 95% CI, 1.80-18.20; P = .005), 2 PCBs (PCB 175: OR = 1.81; 95% CI, 1.20-2.72; P = .005; and PCB 202: OR = 2.11; 95% CI, 1.36-3.27; P = .001), and 1 BFR (polybrominated diphenyl ether 47: OR = 2.69; 95% CI, 1.49-4.85; P = .001). There was modest concordance between survey data and the measurements of persistent environmental pollutants in blood; significant Kendall τ correlation coefficients ranged from -0.18 (Dacthal and "use pesticides to treat home or yard") to 0.24 (trans-nonachlor and "store lawn care products in garage"). In this study, persistent environmental pollutants measured in blood were significantly associated with ALS and may represent modifiable ALS disease risk factors.


A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes.
Acute elevations in free fatty acids (FFAs) stimulate insulin secretion, but prolonged lipid exposure impairs beta-cell function in both in vitro studies and in vivo animal studies. In humans data are limited to short-term (< or =48 h) lipid infusion studies and have led to conflicting results. We examined insulin secretion and action during a 4-day lipid infusion in healthy normal glucose tolerant subjects with (FH+ group, n = 13) and without (control subjects, n = 8) a family history of type 2 diabetes. Volunteers were admitted twice to the clinical research center and received, in random order, a lipid or saline infusion. On days 1 and 2, insulin and C-peptide concentration were measured as part of a metabolic profile after standardized mixed meals. Insulin secretion in response to glucose was assessed with a +125 mg/dl hyperglycemic clamp on day 3. On day 4, glucose turnover was measured with a euglycemic insulin clamp with [3-3H]glucose. Day-long plasma FFA concentrations with lipid infusion were increased within the physiological range, to levels seen in type 2 diabetes (approximately 500-800 micromol/l). Lipid infusion had strikingly opposite effects on insulin secretion in the two groups. After mixed meals, day-long plasma C-peptide levels increased with lipid infusion in control subjects but decreased in the FH+ group (+28 vs. -30%, respectively, P < 0.01). During the hyperglycemic clamp, lipid infusion enhanced the insulin secretion rate (ISR) in control subjects but decreased it in the FH+ group (first phase: +75 vs. -60%, P < 0.001; second phase: +25 vs. -35%, P < 0.04). When the ISR was adjusted for insulin resistance (ISRRd = ISR / [1/Rd], where Rd is the rate of insulin-stimulated glucose disposal), the inadequate beta-cell response in the FH+ group was even more evident. Although ISRRd was not different between the two groups before lipid infusion, in the FH+ group, lipid infusion reduced first- and second-phase ISR(Rd) to 25 and 42% of that in control subjects, respectively (both P < 0.001 vs. control subjects). Lipid infusion in the FH+ group (but not in control subjects) also caused severe hepatic insulin resistance with an increase in basal endogenous glucose production (EGP), despite an elevation in fasting insulin levels, and impaired suppression of EGP to insulin. In summary, in individuals who are genetically predisposed to type 2 diabetes, a sustained physiological increase in plasma FFA impairs insulin secretion in response to mixed meals and to intravenous glucose, suggesting that in subjects at high risk of developing type 2 diabetes, beta-cell lipotoxicity may play an important role in the progression from normal glucose tolerance to overt hyperglycemia.


Analysis of the mechanism of asymmetric amplification by chiral auxiliary trans-1,2-diaminocyclohexane bistriflamide.
Asymmetric amplification is a phenomenon in which the enantiomeric excess (ee) of a product is higher than that of a chiral auxiliary for a catalyst. We analyzed the mechanism of asymmetric amplification observed in the addition of diethylzinc (Et(2)Zn) to benzaldehyde (PhCHO) to synthesize 1-phenyl-1-propanol in the presence of trans-1,2-diaminocyclohexane bistriflamide (DCBF) and titanium tetraisopropoxide (TIOP). In a manner similar to the reaction in which 1-piperidino-3,3-dimethyl-2-butanol is a chiral auxiliary for the catalyst, when asymmetric amplification was observed, the ee of the product varied as the reaction progressed. The mechanisms of variation in ee in the two reactions, however, were different. No asymmetric amplification was observed when TIOP and PhCHO were added to a mixture of DCBF and Et(2)Zn, while the ee of the product was always higher than that of DCBF when PhCHO and Et(2)Zn were added to a mixture of DCBF and TIOP. In the latter case, the product ee decreased as the reaction progressed. The results indicate that DCBF forms inactive heterochiral complex causing an increase in the ee of DCBF in the solution, which is the chiral auxiliary for the catalyst. But the complex is not very stable and gradually dissociates due to the reaction with Et(2)Zn. As a result, the asymmetric amplification decreases as the reaction progresses.


Reliability assessment of tissue classification algorithms for multi-center and multi-scanner data.
Gray and white matter volume difference and change are important imaging markers of pathology and disease progression in neurology and psychiatry. Such measures are usually estimated from tissue segmentation maps produced by publicly available image processing pipelines. However, the reliability of the produced segmentations when using multi-center and multi-scanner data remains understudied. Here, we assess the robustness of six publicly available tissue classification pipelines across images acquired from different MR scanners and sites. We used 90 T1-weighted images of a single individual, scanned in 73 sessions across 27 different sites to assess the robustness of the tissue classification tools. Variability in Dice similarity index values and tissue volumes was assessed for Atropos, BISON, Classify_Clean, FAST, FreeSurfer, and SPM12. BISON had the highest overall Dice coefficient for GM, followed by SPM12 and Atropos; while Atropos had the highest overall Dice coefficient for WM, followed by BISON and SPM12. BISON had the lowest overall variability in its volumetric estimates, followed by FreeSurfer, and SPM12. All methods also had significant differences between some of their estimates across different scanner manufacturers (e.g. BISON had significantly higher GM estimates and correspondingly lower WM estimates for GE scans compared to Philips and Siemens), and different signal-to-noise ratio (SNR) levels (e.g. FAST and FreeSurfer had significantly higher WM volume estimates for high versus medium and low SNR tertiles as well as correspondingly lower GM volume estimates). Our comparisons provide a benchmark on the reliability of the publicly used tissue classification techniques and the amount of variability that can be expected when using large multi-center and multi-scanner databases.


Evaluation of hospital room assignment and acquisition of Clostridium difficile infection.
Clostridium difficile spores persist in hospital environments for an extended period. We evaluated whether admission to a room previously occupied by a patient with C. difficile infection (CDI) increased the risk of acquiring CDI. Retrospective cohort study. Medical intensive care unit (ICU) at a tertiary care hospital. Patients admitted from January 1, 2005, through June 30, 2006, were evaluated for a diagnosis of CDI 48 hours after ICU admission and within 30 days after ICU discharge. Medical, ICU, and pharmacy records were reviewed for other CDI risk factors. Admitted patients who did develop CDI were compared with admitted patients who did not. Among 1,844 patients admitted to the ICU, 134 CDI cases were identified. After exclusions, 1,770 admitted patients remained for analysis. Of the patients who acquired CDI after admission to the ICU, 4.6% had a prior occupant without CDI, whereas 11.0% had a prior occupant with CDI (P = .002). The effect of room on CDI acquisition remained a significant risk factor (P = .008) when Kaplan-Meier curves were used. The prior occupant's CDI status remained significant (p = .01; hazard ratio, 2.35) when controlling for the current patient's age, Acute Physiology and Chronic Health Evaluation III score, exposure to proton pump inhibitors, and antibiotic use. A prior room occupant with CDI is a significant risk factor for CDI acquisition, independent of established CDI risk factors. These findings have implications for room placement and hospital design.


Peritoneal drainage versus laparotomy as initial surgical treatment for perforated necrotizing enterocolitis or spontaneous intestinal perforation in preterm low birth weight infants.
Standard surgical management of infants with perforated necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) is laparotomy with the resection of the necrotic or perforated segments of the intestine. Peritoneal drainage is an alternative approach to the management of such infants. To evaluate the benefits and risks of peritoneal drainage compared to laparotomy as the initial surgical treatment for perforated NEC or SIP in preterm infants. Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library 2010, Issue 3), MEDLINE (1966 to July 2010), EMBASE (1980 to July 2010), CINAHL (1982 to July 2010), previous reviews and cross-references were searched. Abstracts of paediatric academic society meetings were also searched (online: 2000 to 2009; handsearching Pediatric Research: 1995 to 2000). All randomised or quasi-randomised controlled trials in preterm (< 37 weeks gestation), low birth weight (< 2500 g) infants with perforated NEC or SIP allocated to peritoneal drainage or laparotomy as initial surgical treatment. Data were excerpted from the trial reports and analysed according to the standards of the Cochrane Neonatal Review Group. Only two randomised controlled trials (RCT) met the eligibility criteria. Overall, no significant differences were seen between the peritoneal drainage and laparotomy groups regarding the incidence of mortality within 28 days of the primary procedure (28/90 versus 30/95; typical relative risk (RR) 0.99, 95% CI 0.64 to 1.52; N = 185, two trials); mortality by 90 days after the primary procedure (typical RR 1.05, 95% CI 0.71 to 1.55; N = 185, two trials) and the number of infants needing total parenteral nutrition for more than 90 days (typical RR 1.18, 95% CI 0.72 to 1.95; N = 116, two trials). Nearly 50% of the infants in the peritoneal drainage group could avoid the need for laparotomy during the study period (44/90 versus 95/96; typical RR 0.49, 95% CI 0.39 to 0.61; N = 186, two trials). One study found that the time to attain full enteral feeds in infants ≤ 1000 g was prolonged in the peritoneal drainage group (mean difference (MD) 20.77, 95% CI 3.62 to 37.92). Evidence from two RCTs suggests no significant benefits or harms of peritoneal drainage over laparotomy. However, due to the very small sample size, clinically significant differences may have easily been missed. No firm recommendations can be made for clinicians. Large multicentre randomised controlled trials are needed to address this question definitively.


Making DNA without iron - induction of a manganese-dependent ribonucleotide reductase in response to iron starvation.
Ribonucleotide reductases supply cells with their deoxyribonucleotides. Three enzyme types are known, classes I, II and III. Class II enzymes are anaerobic whereas class I enzymes are aerobic, and so class I and II enzymes are often produced by the same organism under opposing oxygen regimes. Escherichia coli contains two types of class I enzyme (Ia and Ib) with the Fe-dependent Ia enzyme (NrdAB) performing the major role aerobically, leaving the purpose of the Ib enzyme (NrdEF) unclear. Several papers have recently focused on the class Ib enzymes showing that they are Mn (rather than Fe) dependent and suggesting that the E. coli NrdEF may function under redox-stress conditions. A paper published in this issue of Molecular Microbiology from James Imlay's group confirms that this unexplained NrdEF Ib enzyme is Mn-dependent, but shows that it does not substitute for NrdAB during redox stress. Instead, a role during iron restriction is demonstrated. Thus, the purpose of NrdEF (and possibly other class Ib enzymes) is to enhance growth under aerobic, low-iron conditions, and to functionally replace the Fe-dependent NrdAB when iron is unavailable. This finding reveals a new mechanism by which bacteria adjust to life under iron deprivation.


A stratospheric pathway linking a colder Siberia to Barents-Kara Sea sea ice loss.
Previous studies have extensively investigated the impact of Arctic sea ice anomalies on the midlatitude circulation and associated surface climate in winter. However, there is an ongoing scientific debate regarding whether and how sea ice retreat results in the observed cold anomaly over the adjacent continents. We present a robust "cold Siberia" pattern in the winter following sea ice loss over the Barents-Kara seas in late autumn in an advanced atmospheric general circulation model, with a well-resolved stratosphere. Additional targeted experiments reveal that the stratospheric response to sea ice forcing is crucial in the development of cold conditions over Siberia, indicating the dominant role of the stratospheric pathway compared with the direct response within the troposphere. In particular, the downward influence of the stratospheric circulation anomaly significantly intensifies the ridge near the Ural Mountains and the trough over East Asia. The persistently intensified ridge and trough favor more frequent cold air outbreaks and colder winters over Siberia. This finding has important implications for improving seasonal climate prediction of midlatitude cold events. The results also suggest that the model performance in representing the stratosphere-troposphere coupling could be an important source of the discrepancy between recent studies.


The physiological effects of IGF-1 (class 1:Ea transgene) over-expression on exercise-induced damage and adaptation in dystrophic muscles of mdx mice.
Duchenne muscular dystrophy (DMD) is a genetic disorder in which muscle weakness and fragility contribute to ongoing muscle degeneration. Although exercise-induced muscle damage is associated with adaptation that protects normal muscle from further damage, exploiting this process to protect dystrophic muscle has been avoided for fear of inducing excessive muscle degeneration. However, muscle-specific over-expression of the class 1:Ea isoform of insulin-like growth factor-1 (IGF-1) reduces myofibre necrosis in dystrophic mdx mice (a model for DMD) and, therefore, may enhance the adaptation process in response to eccentric exercise. To test this hypothesis, we evaluated the effect of transgenic class 1:Ea IGF-1 over-expression on the susceptibility to muscle damage and subsequent adaptation in 12-week-old dystrophic mdx and non-dystrophic control mice. Experiments were conducted in vivo using a custom-built isokinetic mouse dynamometer to measure the deficit in joint torque (indicating muscle damage) after 20 maximal lengthening (eccentric) contractions. Adaptation to this damaging exercise was evaluated by repeating the protocol 7 days after the initial exercise. The over-expression of IGF-1 significantly increased the normalised joint torque in non-dystrophic mice and appeared to ameliorate the muscle weakness in dystrophic mice. All mice displayed a marked reduction in the susceptibility to muscle damage on day 7; however, this adaptation was unaffected by IGF-1, showing that IGF-1 does not protect the dystrophic muscles of adult mdx mice against damage resulting from maximal lengthening contractions.


Elevational variation in body-temperature response to immune challenge in a lizard.
Immunocompetence benefits animal fitness by combating pathogens, but also entails some costs. One of its main components is fever, which in ectotherms involves two main types of costs: energy expenditure and predation risk. Whenever those costs of fever outweigh its benefits, ectotherms are expected not to develop fever, or even to show hypothermia, reducing costs of thermoregulation and diverting the energy saved to other components of the immune system. Environmental thermal quality, and therefore the thermoregulation cost/benefit balance, varies geographically. Hence, we hypothesize that, in alpine habitats, immune-challenged ectotherms should show no thermal response, given that (1) hypothermia would be very costly, as the temporal window for reproduction is extremely small, and (2) fever would have a prohibitive cost, as heat acquisition is limited in such habitat. However, in temperate habitats, immune-challenged ectotherms might show a febrile response, due to lower cost/benefit balance as a consequence of a more suitable thermal environment. We tested this hypothesis in Psammodromus algirus lizards from Sierra Nevada (SE Spain), by testing body temperature preferred by alpine and non-alpine lizards, before and after activating their immune system with a typical innocuous pyrogen. Surprisingly, non-alpine lizards responded to immune challenge by decreasing preferential body-temperature, presumably allowing them to save energy and reduce exposure to predators. On the contrary, as predicted, immune-challenged alpine lizards maintained their body-temperature preferences. These results match with increased costs of no thermoregulation with elevation, due to the reduced window of time for reproduction in alpine environment.


Identification of people with autosomal dominant polycystic kidney disease using routine data: a cross sectional study.
Autosomal dominant polycystic kidney disease (ADPKD) causes progressive renal damage and is a leading cause of end-stage renal failure. With emerging therapies it is important to devise a method for early detection. We aimed to identify factors from routine clinical data which can be used to distinguish people with a high likelihood of having ADPKD in a primary health care setting. A cross-sectional study was undertaken using data from the Quality Intervention in Chronic Kidney Disease trial extracted from 127 primary care practices in England. The health records of 255 people with ADPKD were compared to the general population. Logistic regression was used to identify clinical features which distinguish ADPKD. These clinical features were used to stratify individual risk using a risk score tool. Renal impairment, proteinuria, haematuria, a diastolic blood pressure over 90 mmHg and multiple antihypertensive medications were more common in ADPKD than the general population and were used to build a regression model (area under the receiver operating characteristic curve; 0.79). Age, gender, haemoglobin and urinary tract infections were not associated with ADPKD. A risk score (range -3 to +10) of ≥0 gave a sensitivity of 70.2% and specificity 74.9% of for detection. Stratification of ADPKD likelihood from routine data may be possible. This approach could be a valuable component of future screening programs although further longitudinal analyses are needed.


Grading quality of evidence and strength of recommendations.
Users of clinical practice guidelines and other recommendations need to know how much confidence they can place in the recommendations. Systematic and explicit methods of making judgments can reduce errors and improve communication. We have developed a system for grading the quality of evidence and the strength of recommendations that can be applied across a wide range of interventions and contexts. In this article we present a summary of our approach from the perspective of a guideline user. Judgments about the strength of a recommendation require consideration of the balance between benefits and harms, the quality of the evidence, translation of the evidence into specific circumstances, and the certainty of the baseline risk. It is also important to consider costs (resource utilisation) before making a recommendation. Inconsistencies among systems for grading the quality of evidence and the strength of recommendations reduce their potential to facilitate critical appraisal and improve communication of these judgments. Our system for guiding these complex judgments balances the need for simplicity with the need for full and transparent consideration of all important issues.


Sampling errors create bias in Markov models for community dynamics: the problem and a method for its solution.
Repeated, spatially explicit sampling is widely used to characterize the dynamics of sessile communities in both terrestrial and aquatic systems, yet our understanding of the consequences of errors made in such sampling is limited. In particular, when Markov transition probabilities are calculated by tracking individual points over time, misidentification of the same spatial locations will result in biased estimates of transition probabilities, successional rates, and community trajectories. Nonetheless, to date, all published studies that use such data have implicitly assumed that resampling occurs without error when making estimates of transition rates. Here, we develop and test a straightforward maximum likelihood approach, based on simple field estimates of resampling errors, to arrive at corrected estimates of transition rates between species in a rocky intertidal community. We compare community Markov models based on raw and corrected transition estimates using data from Endocladia muricata-dominated plots in a California intertidal assemblage, finding that uncorrected predictions of succession consistently overestimate recovery time. We tested the precision and accuracy of the approach using simulated datasets and found good performance of our estimation method over a range of realistic sample sizes and error rates.


Circadian rhythm profiles in women with night eating syndrome.
Night eating syndrome (NES) is characterized by evening hyperphagia and frequent awakenings accompanied by food intake. Patients with NES display a delayed circadian pattern of food intake but retain a normal sleep-wake cycle. These characteristics initiated the current study, in which the phase and amplitude of behavioral and neuroendocrine circadian rhythms in patients with NES were evaluated. Fifteen women with NES (mean age +/- SD, 40.8 +/- 8.7 y) and 14 control subjects (38.6 +/- 9.5 y) were studied in the laboratory for 3 nights, with food intake measured daily. Blood also was collected for 25 h (every 2 h from 0800 to 2000 h, and then hourly from 2100 to 0900 h) and assayed for glucose and 7 hormones (insulin, ghrelin, leptin, melatonin, cortisol, thyroid-stimulating hormone [TSH] and prolactin). Statistical analyses utilized linear mixed-effects cosinor analysis. Control subjects displayed normal phases and amplitudes for all circadian rhythms. In contrast, patients with NES showed a phase delay in the timing of meals, and delayed circadian rhythms for total caloric, fat, and carbohydrate intake. In addition, phase delays of 1.0 to 2.8 h were found in 2 food-regulatory rhythms-leptin and insulin-and in the circadian melatonin rhythm (with a trend for a delay in the circadian cortisol rhythm). In contrast, circulating levels of ghrelin, the primary hormone that stimulates food intake, were phase advanced by 5.2 h. The glucose rhythm showed an inverted circadian pattern. Patients with NES also showed reduced amplitudes in the circadian rhythms of food intake, cortisol, ghrelin, and insulin, but increased TSH amplitude. Thus, patients with NES demonstrated significant changes in the timing and amplitude of various behavioral and physiological circadian markers involved in appetite and neuroendocrine regulation. As such, NES may result from dissociations between central (suprachiasmatic nucleus) timing mechanisms and putative oscillators elsewhere in the central nervous system or periphery, such as the stomach or liver. Considering these results, chronobiologic treatments for NES such as bright light therapy may be useful. Indeed, bright light therapy has shown efficacy in reducing night eating in case studies and should be evaluated in controlled clinical trials.


ETO-2 associates with SCL in erythroid cells and megakaryocytes and provides repressor functions in erythropoiesis.
Lineage specification and cellular maturation require coordinated regulation of gene expression programs. In large part, this is dependent on the activator and repressor functions of protein complexes associated with tissue-specific transcriptional regulators. In this study, we have used a proteomic approach to characterize multiprotein complexes containing the key hematopoietic regulator SCL in erythroid and megakaryocytic cell lines. One of the novel SCL-interacting proteins identified in both cell types is the transcriptional corepressor ETO-2. Interaction between endogenous proteins was confirmed in primary cells. We then showed that SCL complexes are shared but also significantly differ in the two cell types. Importantly, SCL/ETO-2 interacts with another corepressor, Gfi-1b, in red cells but not megakaryocytes. The SCL/ETO-2/Gfi-1b association is lost during erythroid differentiation of primary fetal liver cells. Genetic studies of erythroid cells show that ETO-2 exerts a repressor effect on SCL target genes. We suggest that, through its association with SCL, ETO-2 represses gene expression in the early stages of erythroid differentiation and that alleviation/modulation of the repressive state is then required for expression of genes necessary for terminal erythroid maturation to proceed.


Benchmarking framework for myocardial tracking and deformation algorithms: an open access database.
In this paper we present a benchmarking framework for the validation of cardiac motion analysis algorithms. The reported methods are the response to an open challenge that was issued to the medical imaging community through a MICCAI workshop. The database included magnetic resonance (MR) and 3D ultrasound (3DUS) datasets from a dynamic phantom and 15 healthy volunteers. Participants processed 3D tagged MR datasets (3DTAG), cine steady state free precession MR datasets (SSFP) and 3DUS datasets, amounting to 1158 image volumes. Ground-truth for motion tracking was based on 12 landmarks (4 walls at 3 ventricular levels). They were manually tracked by two observers in the 3DTAG data over the whole cardiac cycle, using an in-house application with 4D visualization capabilities. The median of the inter-observer variability was computed for the phantom dataset (0.77 mm) and for the volunteer datasets (0.84 mm). The ground-truth was registered to 3DUS coordinates using a point based similarity transform. Four institutions responded to the challenge by providing motion estimates for the data: Fraunhofer MEVIS (MEVIS), Bremen, Germany; Imperial College London - University College London (IUCL), UK; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Inria-Asclepios project (INRIA), France. Details on the implementation and evaluation of the four methodologies are presented in this manuscript. The manually tracked landmarks were used to evaluate tracking accuracy of all methodologies. For 3DTAG, median values were computed over all time frames for the phantom dataset (MEVIS=1.20mm, IUCL=0.73 mm, UPF=1.10mm, INRIA=1.09 mm) and for the volunteer datasets (MEVIS=1.33 mm, IUCL=1.52 mm, UPF=1.09 mm, INRIA=1.32 mm). For 3DUS, median values were computed at end diastole and end systole for the phantom dataset (MEVIS=4.40 mm, UPF=3.48 mm, INRIA=4.78 mm) and for the volunteer datasets (MEVIS=3.51 mm, UPF=3.71 mm, INRIA=4.07 mm). For SSFP, median values were computed at end diastole and end systole for the phantom dataset(UPF=6.18 mm, INRIA=3.93 mm) and for the volunteer datasets (UPF=3.09 mm, INRIA=4.78 mm). Finally, strain curves were generated and qualitatively compared. Good agreement was found between the different modalities and methodologies, except for radial strain that showed a high variability in cases of lower image quality.


Metabonomic Profiling Reveals Difference in Altered Metabolic Pathways Between Chronic Kidney Disease and High-Fat-Induced Insulin Resistance in Rats.
Chronic kidney disease (CKD) is closely correlated with the development of insulin resistance (IR). Until now, the underlying molecular mechanisms remain to be elucidated. This study aimed to identify metabolites and molecular pathways unique to CKD-induced IR. Ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS) analysis coupled with orthogonal partial least square discriminant analysis (OPLS-DA) were performed to profile metabolites in the serum, liver, and muscle tissues and to analyze molecular pathways in relation to CKD- and high fat diet (HFD)-induced IR in the rats. At 18 weeks after the 5/6 Nx operation, CKD induction was demonstrated by renal histology and biochemical tests. Furthermore, both CKD-induced IR and HFD-induced IR rats showed significantly greater levels of fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR). In the UPLC-MS in combination with OPLS-DA analysis, we identified 101, 59, and 41 differential metabolites in the serum, liver, and muscle, which were associated with the CKD-induced IR, while 58, 38, and 17 differential metabolites in the serum, liver, and muscle were revealed in the HFD-induced rats compared to controls. Moreover, compared to HFD-induced IR rats, those with CKD-induced IR exhibited abnormal pathways primarily in the tryptophan metabolism, arginine metabolism, and trimethylamine oxide metabolite. Interestingly, altered metabolites in the CKD-induced IR and HFD-induced IR displayed an opposite direction. Alterations in metabolites and relevant pathways were significantly different between the CKD- and HFD-induced IR rats. These findings may offer important information regarding the pathogenesis specific to IR caused by the decline in the renal function.


Expecting the best and being prepared for the worst: structure, profiles, and 2-year temporal stability of dispositional optimism in women with breast cancer.
Dispositional optimism is viewed as a key personality resource for resiliency and has been linked to adjustment among women with breast cancer. The aim was to examine (a) the psychometric proprieties of Life Orientation Test-Revised (LOT-R), (b) the potential independence and co-occurrence of positive and negative dimensions of future outcome expectancies, (c) the longitudinal invariance of LOT-R and the temporal stability of dispositional optimism over 2 years following surgery, and (d) the predictive impact of optimism and pessimism on emotional distress among women with breast cancer. Data from a prospective study (n = 750) of women with breast cancer were acquired shortly after surgery, and the women were followed up for 2 years. Assessments of LOT-R, Hospital Anxiety and Depression Scale, treatment-related, and demographic variables were subjected to structural equation modeling analysis. A bidimensional and temporarily invariant structure of LOT-R displayed acceptable fit indices. Three profiles of future expectancies consisting of optimists, pessimists, and ambiguous were identified. Temporal stability in optimism and pessimism over 2 years was established. Women with higher education displayed higher degrees of pessimism. Baseline dispositional optimism inversely predicted emotional distress at 2 years. The LOT-R should be approached as a bidimensional measure. Co-occurrence of optimism and pessimism may indicate a cautious defensive coping effort in women with breast cancer. The importance of systematic efforts to enhance optimism as well as the capacity to acknowledge both positive and negative future expectancies is emphasized.Copyright © 2015 John Wiley & Sons, Ltd.


Fuel ethanol production from lignocellulose: a challenge for metabolic engineering and process integration.
With industrial development growing rapidly, there is a need for environmentally sustainable energy sources. Bioethanol (ethanol from biomass) is an attractive, sustainable energy source to fuel transportation. Based on the premise that fuel bioethanol can contribute to a cleaner environment and with the implementation of environmental protection laws in many countries, demand for this fuel is increasing. Efficient ethanol production processes and cheap substrates are needed. Current ethanol production processes using crops such as sugar cane and corn are well-established; however, utilization of a cheaper substrate such as lignocellulose could make bioethanol more competitive with fossil fuel. The processing and utilization of this substrate is complex, differing in many aspects from crop-based ethanol production. One important requirement is an efficient microorganism able to ferment a variety of sugars (pentoses, and hexoses) as well as to tolerate stress conditions. Through metabolic engineering, bacterial and yeast strains have been constructed which feature traits that are advantageous for ethanol production using lignocellulose sugars. After several rounds of modification/evaluation/modification, three main microbial platforms, Saccharomyces cerevisiae, Zymomonas mobilis, and Escherichia coli, have emerged and they have performed well in pilot studies. While there are ongoing efforts to further enhance their properties, improvement of the fermentation process is just one of several factors-that needs to be fully optimized and integrated to generate a competitive lignocellulose ethanol plant.


Insect glutathione transferases and insecticide resistance.
Glutathione transferases (GSTs) are a diverse family of enzymes found ubiquitously in aerobic organisms. They play a central role in the detoxification of both endogenous and xenobiotic compounds and are also involved in intracellular transport, biosynthesis of hormones and protection against oxidative stress. Interest in insect GSTs has primarily focused on their role in insecticide resistance. GSTs can metabolize insecticides by facilitating their reductive dehydrochlorination or by conjugation reactions with reduced glutathione, to produce water-soluble metabolites that are more readily excreted. In addition, they contribute to the removal of toxic oxygen free radical species produced through the action of pesticides. Annotation of the Anopheles gambiae and Drosophila melanogaster genomes has revealed the full extent of this enzyme family in insects. This mini review describes the insect GST enzyme family, focusing specifically on their role in conferring insecticide resistance.


Invasion of epithelial cells and proteolysis of cellular focal adhesion components by distinct types of Porphyromonas gingivalis fimbriae.
Porphyromonas gingivalis fimbriae are classified into six types (types I to V and Ib) based on the fimA genes encoding FimA (a subunit of fimbriae), and they play a critical role in bacterial interactions with host tissues. In this study, we compared the efficiencies of P. gingivalis strains with distinct types of fimbriae for invasion of epithelial cells and for degradation of cellular focal adhesion components, paxillin, and focal adhesion kinase (FAK). Six representative strains with the different types of fimbriae were tested, and P. gingivalis with type II fimbriae (type II P. gingivalis) adhered to and invaded epithelial cells at significantly greater levels than the other strains. There were negligible differences in gingipain activities among the six strains; however, type II P. gingivalis apparently degraded intracellular paxillin in association with a loss of phosphorylation 30 min after infection. Degradation was blocked with cytochalasin D or in mutants with fimA disrupted. Paxillin was degraded by the mutant with Lys-gingipain disrupted, and this degradation was prevented by inhibition of Arg-gingipain activity by Nalpha-p-tosyl-l-lysine chloromethyl ketone. FAK was also degraded by type II P. gingivalis. Cellular focal adhesions with green fluorescent protein-paxillin macroaggregates were clearly destroyed, and this was associated with cellular morphological changes and microtubule disassembly. In an in vitro wound closure assay, type II P. gingivalis significantly inhibited cellular migration and proliferation compared to the cellular migration and proliferation observed with the other types. These results suggest that type II P. gingivalis efficiently invades epithelial cells and degrades focal adhesion components with Arg-gingipain, which results in cellular impairment during wound healing and periodontal tissue regeneration.


The relationship between viscoelasticity and elasticity.
Soft materials that are subjected to large deformations exhibit an extremely rich phenomenology, with properties lying in between those of simple fluids and those of elastic solids. In the continuum description of these systems, one typically follows either the route of solid mechanics (Lagrangian description) or the route of fluid mechanics (Eulerian description). The purpose of this review is to highlight the relationship between the theories of viscoelasticity and of elasticity, and to leverage this connection in contemporary soft matter problems. We review the principles governing models for viscoelastic liquids, for example solutions of flexible polymers. Such materials are characterized by a relaxation time λ, over which stresses relax. We recall the kinematics and elastic response of large deformations, and show which polymer models do (and which do not) correspond to a nonlinear elastic solid in the limit λ → ∞. With this insight, we split the work done by elastic stresses into reversible and dissipative parts, and establish the general form of the conservation law for the total energy. The elastic correspondence can offer an insightful tool for a broad class of problems; as an illustration, we show how the presence or absence of an elastic limit determines the fate of an elastic thread during capillary instability.


What we know about leadership. Effectiveness and personality.
Although psychologists know a great deal about leadership, persons who make decisions about real leaders seem largely to ignore their accumulated wisdom. In an effort to make past research more accessible, interpretable, and relevant to decision makers, this article defines leadership and then answers nine questions that routinely come up when practical decisions are made about leadership (e.g., whom to appoint, how to evaluate them, when to terminate them.


Use of interventions to minimise perioperative allogeneic blood transfusion in Australia. A survey by the International Study of Perioperative Transfusion (ISPOT) Study Group.
To investigate use of interventions to minimise need for perioperative transfusion of allogeneic blood in surgical units in Australia. Two questionnaire-based surveys of practice. All hospitals in Australia, 1996-1997. Survey 1: all Australian hospitals that have at least 50 beds and undertake surgery; Survey 2: surgical units identified as using the interventions. Reported rates of use of the various interventions (preoperative autologous donation, acute normovolaemic haemodilution [ANH], cell salvage, and drugs); use of guidelines; and perceptions about the appropriateness of current levels of use. Survey 1 was returned by 349 of 400 hospitals (87%) and Survey 2 by 324 of 578 surgical units (56%). Preoperative autologous donation was most widely used (70% of hospitals), most commonly in units performing orthopaedic or vascular surgery (65% and 37%, respectively). Cell salvage and ANH were used by 27% and 24% of hospitals, respectively, most often in units performing cardiothoracic (40% and 44%, respectively) and vascular surgery (29% and 15%, respectively). These three interventions were used significantly more in private than in public hospitals (P < 0.05). Use of printed guidelines was uncommon. Respondents considered that autologous transfusion techniques should be used more widely because of their perceived efficacy and concerns about safety of allogeneic blood. Perceived barriers to greater use included lack of surgeon or physician interest, uncertain scheduling of surgery in public hospitals and cost (cell salvage). Drugs to minimise blood loss were used by fewer than 10% of hospitals. Interventions to minimise the need for perioperative allogeneic blood transfusion (apart from drugs) are widely used in Australia. However, enthusiasm for intraoperative techniques of re-infusing autologous blood needs to be assessed against the evidence of their efficacy and cost-effectiveness.


Fluoride-induced disruption of reproductive hormones in men.
Fluoride-induced reproductive effects have been reported in experimental models and in humans. However, these effects were found in heavily exposed scenarios. Therefore, in this work our objective was to study reproductive parameters in a population exposed to fluoride at doses of 3-27 mg/day (high-fluoride-exposed group-HFEG). Urinary fluoride levels, semen parameters, and reproductive hormones in serum (LH, FSH, estradiol, prolactin, inhibin-B, free and total testosterone) were measured. Results were compared with a group of individuals exposed to fluoride at lower doses: 2-13 mg/day (low-fluoride-exposed group-LFEG). A significant increase in FSH (P<0.05) and a reduction of inhibin-B, free testosterone, and prolactin in serum (P<0.05) were noticed in the HFEG. When HFEG was compared to LFEG, a decreased sensitivity was found in the FSH response to inhibin-B (P<0.05). A significant negative partial correlation was observed between urinary fluoride and serum levels of inhibin-B (r=-0.333, P=0.028) in LFEG. Furthermore, a significant partial correlation was observed between a chronic exposure index for fluoride and the serum concentrations of inhibin-B (r=-0.163, P=0.037) in HFEG. No abnormalities were found in the semen parameters studied in the present work, neither in the HFEG, nor in the LFEG. The results obtained indicate that a fluoride exposure of 3-27 mg/day induces a subclinical reproductive effect that can be explained by a fluoride-induced toxic effect in both Sertoli cells and gonadotrophs.


Familial clustering of latent class and DSM-IV defined attention-deficit/hyperactivity disorder (ADHD) subtypes.
Findings from family and twin-based studies of Attention Deficit/Hyperactivity Disorder (ADHD) have indicated that inattentive and combined subtypes cluster together among sibling pairs who both express ADHD symptoms. The current report examines the familial clustering of ADHD subtypes, defined according to latent class and DSM-IV criteria, in a general population sample of 2,848 Australian twins, 1,013 of their non-twin siblings and 4,036 female twins from Missouri, USA. Significant clustering of DSM-IV inattentive and combined subtypes, and significant clustering of the same latent classes among siblings was predicted. Logistic regression was used to assess 1) the clustering of same and different subtype combinations among twin and twin-sibling pairs and 2) whether genetic influences contribute significantly to the observed patterns of subtype combinations among siblings. With the exception of the DSM-IV hyperactive-impulsive subtype and the severe hyperactive-impulsive latent class, all other sibling DSM-IV and latent class ADHD subtypes consistently exhibited significant same-subtype clustering with MZ probands, DZ probands and their siblings in both samples. Furthermore, a significant genetic influence contributing to subtype concordance was detected for every DSM-IV subtype excluding hyperactive-impulsive, and for all eight latent classes. While some instances of significant different-subtype clustering among siblings was observed across both classification systems and samples, the particular subtype combinations involved were largely inconsistent across samples and no significant genetic influences contributing towards these discordant subtype combinations were detected. For both DSM-IV and latent class subtypes, the overall pattern of findings in both samples indicated significant familial clustering of same-subtype combinations and significant genetic influences contributing to these patterns of subtype concordance, despite important sample differences. These findings further extend previous work and are most consistent with the presence of multiple independent forms of ADHD.


Severe acute respiratory syndrome-coronavirus 2 in domesticated animals and its potential of transmission: A meta-analysis.
The coronavirus diseases-2019 (COVID-19) pandemic has caused a global lockdown, which has limited the mobility of the public, and thus, more time is spent with their pets. Unfortunately, many social media have blamed pet animals as a reservoir of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, triggering a panic abandonment of pets. However, no article has summarized the information regarding the role of pets as SARS-CoV-2 reservoirs. This study aimed to evaluate the role of pets as a reservoir of SARS-CoV-2 on the basis of research papers (i.e., animal model, surveillance, and case report) published in 2020. The review was conducted using articles from the PubMed database in 2020, using the keywords "COVID-19 in domesticated animals," which were screened and analyzed. Only the data from research articles were mimicked and transformed to conduct a meta-analysis. The meta-analysis was conducted regarding the effects of inhabitation and viral shedding in pets. In this study, we used 95% confidence intervals. A total of 132 papers in PubMed were related to the keywords, whereas only 12 papers were appropriate to answer the dynamics of the role of pets as the reservoir for SARS-CoV-2. Seven studies indicated the potential of cat-cat (4/7), human-cat (2/7), and human-dog (1/7) SARS-CoV-2 transmission. No study proved the presence of cat-human transmission. Another study showed that comingling did not affect SARS-CoV-2 viral shedding among a cat and dog. Furthermore, the viral shedding of cats and dogs caused asymptomatic manifestations and generated neutralizing antibodies within a short period of time. SARS-CoV-2 transmission is present in domesticated animals, especially in pet cats and dogs, and transmission occurs between animals of the same species (cat-cat). The reverse zoonosis (zooanthroponosis) was found from human to cat/dog (comingled) with asymptomatic clinical signs due to the representation of neutralizing antibodies.


Barcoding and microcoding using "identiprimers" with Leptographium species.
Leptographium species provide an ideal model to test the applications of a PCR microcoding system for differentiating species of other genera of ascomycetes. Leptographium species are closely related and share similar gross morphology. Probes designed for a PhyloChip for Leptographium have been transferred and tested as primers for PCR diagnostic against Leptographium species. The primers were combined with complementary universal primers to identify known and suspected undescribed species of Leptographium. The primer set was optimized for 56 species, including the three varieties of L. wageneri, then blind-tested against 10 random DNA samples. The protocols established in this study successfully identified species from the blind test as well as eight previously undescribed isolates of Leptographium. The undescribed isolates were identified as new species of Leptographium with the aid of the microcoding PCR identification system established in this study. The primers that were positive for each undescribed isolate were used to determine close relatives of these species and some of their biological characteristics. The transfer of oligonucleotides from a micro-array platform to a PCR diagnostic was successful, and the identification system is robust for both known and unknown species of Leptographium.


The molecular chaperone Hsp90 is required for cell cycle exit in Drosophila melanogaster.
The coordination of cell proliferation and differentiation is crucial for proper development. In particular, robust mechanisms exist to ensure that cells permanently exit the cell cycle upon terminal differentiation, and these include restraining the activities of both the E2F/DP transcription factor and Cyclin/Cdk kinases. However, the full complement of mechanisms necessary to restrain E2F/DP and Cyclin/Cdk activities in differentiating cells are not known. Here, we have performed a genetic screen in Drosophila melanogaster, designed to identify genes required for cell cycle exit. This screen utilized a PCNA-miniwhite(+) reporter that is highly E2F-responsive and results in a darker red eye color when crossed into genetic backgrounds that delay cell cycle exit. Mutation of Hsp83, the Drosophila homolog of mammalian Hsp90, results in increased E2F-dependent transcription and ectopic cell proliferation in pupal tissues at a time when neighboring wild-type cells are postmitotic. Further, these Hsp83 mutant cells have increased Cyclin/Cdk activity and accumulate proteins normally targeted for proteolysis by the anaphase-promoting complex/cyclosome (APC/C), suggesting that APC/C function is inhibited. Indeed, reducing the gene dosage of an inhibitor of Cdh1/Fzr, an activating subunit of the APC/C that is required for timely cell cycle exit, can genetically suppress the Hsp83 cell cycle exit phenotype. Based on these data, we propose that Cdh1/Fzr is a client protein of Hsp83. Our results reveal that Hsp83 plays a heretofore unappreciated role in promoting APC/C function during cell cycle exit and suggest a mechanism by which Hsp90 inhibition could promote genomic instability and carcinogenesis.


Lack of evidence for an association between Iridovirus and colony collapse disorder.
Colony collapse disorder (CCD) is characterized by the unexplained losses of large numbers of adult worker bees (Apis mellifera) from apparently healthy colonies. Although infections, toxins, and other stressors have been associated with the onset of CCD, the pathogenesis of this disorder remains obscure. Recently, a proteomics study implicated a double-stranded DNA virus, invertebrate iridescent virus (Family Iridoviridae) along with a microsporidium (Nosema sp.) as the cause of CCD. We tested the validity of this relationship using two independent methods: (i) we surveyed healthy and CCD colonies from the United States and Israel for the presence of members of the Iridovirus genus and (ii) we reanalyzed metagenomics data previously generated from RNA pools of CCD colonies for the presence of Iridovirus-like sequences. Neither analysis revealed any evidence to suggest the presence of an Iridovirus in healthy or CCD colonies.


Interleukin-2-dependent transcriptional and post-transcriptional regulation of transferrin receptor mRNA.
Interleukin-2 (IL-2) controls the proliferation of the murine T cell line B6.1 and induces transferrin receptor (TfR) mRNA steady-state levels 50-fold when added to arrested, IL-2-deprived cells. In addition, TfR mRNA is post-transcriptionally regulated by intracellular iron. Low iron levels activate a cytoplasmic RNA-binding protein, called iron regulatory factor (IRF) or iron-responsive element-binding protein, which coordinately stabilizes TfR mRNA and inhibits ferritin mRNA translation. Since ferritin expression is known to be modulated by cytokines, we decided to investigate the mechanism by which IL-2 activates TfR gene expression in B6.1 cells. Induction by IL-2 of both nuclear and cytoplasmic TfR RNA was compared with run-on transcription rates in isolated nuclei. The results revealed a 3-fold increase in TfR gene transcription and a 6-fold rise in nuclear TfR RNA reaching its steady-state level within 2 h. The main accumulation of mature mRNA in the cytoplasm occurred after 6 h in parallel with the activation of IRF. However, stimulation of IRF binding activity by the iron chelator desferrioxamine, in the absence of IL-2, failed to induce TfR mRNA. Moreover, deprivation of growing B6.1 cells of IL-2 resulted in cell arrest and a rapid decay of TfR mRNA, which was not prevented by the activation of IRF with desferrioxamine. TfR mRNA stabilization appears, therefore, to depend on IL-2. We conclude that TfR mRNA expression is controlled by at least three steps at the onset of cell proliferation: (i) the growth factor-dependent activation of transcription; (ii) mRNA stabilization by IRF in the cytoplasm; and (iii) an additional IL-2-dependent activity which prevents TfR mRNA degradation. Our results indicate that expression of TfR, like ferritin, is controlled by both iron and cytokines.


[Squamous cell carcinoma of the lip survival rate].
Squamous Cell Carcinoma (SCC) of the lip represents about 20% of all oral carcinomas. It is more common in men, peaking during their sixth and seventh decade, and is more prevalent in the lower lip. To determine the five years survival rate of Chilean patients with lip SCC. The registry of the Chilean National Cancer Institute was reviewed to retrieve the clinical records of patients with lip SCC. Information about age, sex, alcohol consumption, smoking, degree of pathological differentiation, lip location, type of treatment and metastases was recorded. Survival was determined with death certificates from the National Identification Service. Seventy four patients were identified. Their 5-year survival was 73%. The survival rate of this group of patients is lower than that of patients from Unites States who have an 89.5% survival, according to the Surveillance, Epidemiology, and End Results Program of the North American National Cancer Institute.


Avoiding acyclovir neurotoxicity in patients with chronic renal failure undergoing haemodialysis.
Acute neurotoxicity following the administration of the recommended oral dose of acyclovir (800 mg twice daily) to dialysis-dependent patients is increasingly recognised. This suggests that the recommended dose is too high. Little is known of the pharmacokinetics of oral acyclovir in dialysis patients. We studied 7 patients with oliguric end stage renal failure receiving haemodialysis. Following haemodialysis, each patient received a single 800-mg tablet of acyclovir. Plasma acyclovir levels were monitored over the next 48 h as well as before and after the next routine dialysis. Peak plasma levels were achieved at 3 h (12.54 +/- 1.76 microM, range 8.5-17.5 microM) with the half-life calculated to be 20.2 +/- 4.6 h. Mean plasma level of 6.29 +/- 0.94 microM were within the quoted range to inhibit herpes zoster virus (4-8 microM) at 18 h. Haemodialysis (4-5 h) eliminated 51 +/- 11.5% of the acyclovir which remained at 48 h. Computer modelling of various dose modifications suggests that a loading dose of 400 mg and a maintenance dose of 200 mg twice daily is sufficient to maintain a mean plasma acyclovir level of 6.4 +/- 0.8 microM. A further loading dose (400 mg) after dialysis would raise the residual acyclovir concentration by 6.1 +/- 1.0 microM. Such a dose modification should prevent neurotoxicity, whilst the rapid elimination of acyclovir by a single haemodialysis treatment provides both a diagnostic and therapeutic tool when toxicity is suspected.


Prevention in general practice: the views of doctors in the Oxford region.
A postal questionnaire was sent to all 1291 general practitioners in the Oxford region to determine the pattern of preventive care and their beliefs about its effectiveness. Replies were received from 1014 doctors (79%). Doctors' attitudes to their role in prevention and health promotion were very positive and a large majority claimed to discuss health related topics with their patients when indicated. Fewer respondents said they made a point of discussing smoking habits (64%), alcohol intake (26%), diet (12%), or exercise (11%) as a matter of routine with all their adult patients. Most general practitioners said they usually offered simple advice, leaflets, or other aids when they had identified a problem, but few said they would refer these patients to the practice nurse. With the exception of cervical screening (45%), few respondents said they maintained statistics on the distribution of risk factors in their practice population. Despite considerable enthusiasm for their role in preventive health care, before the imposition of the new contact most general practitioners in the Oxford region had not yet embraced the model of prevention which the contract aims to encourage: systematic screening for risk factors and lifestyle advice for all patients.


Recent Transmission of Tuberculosis - United States, 2011-2014.
Tuberculosis is an infectious disease that may result from recent transmission or from an infection acquired many years in the past; there is no diagnostic test to distinguish the two causes. Cases resulting from recent transmission are particularly concerning from a public health standpoint. To describe recent tuberculosis transmission in the United States, we used a field-validated plausible source-case method to estimate cases likely resulting from recent transmission during January 2011-September 2014. We classified cases as resulting from either limited or extensive recent transmission based on transmission cluster size. We used logistic regression to analyze patient characteristics associated with recent transmission. Of 26,586 genotyped cases, 14% were attributable to recent transmission, 39% of which were attributable to extensive recent transmission. The burden of cases attributed to recent transmission was geographically heterogeneous and poorly predicted by tuberculosis incidence. Extensive recent transmission was positively associated with American Indian/Alaska Native (adjusted prevalence ratio [aPR] = 3.6 (95% confidence interval [CI] 2.9-4.4), Native Hawaiian/Pacific Islander (aPR = 3.2, 95% CI 2.3-4.5), and black (aPR = 3.0, 95% CI 2.6-3.5) race, and homelessness (aPR = 2.3, 95% CI 2.0-2.5). Extensive recent transmission was negatively associated with foreign birth (aPR = 0.2, 95% CI 0.2-0.2). Tuberculosis control efforts should prioritize reducing transmission among higher-risk populations.