Effects of hormones on the synthesis of alpha 1 (acute-phase) glycoprotein in isolated rat hepatocytes.
Hormone effects on the synthesis of alpha(1) (acute-phase) glycoprotein and of albumin by isolated rat hepatocytes in suspension were examined. Insulin, glucagon, cortisol, somatotropin (bovine growth hormone) and tri-iodothyronine were added to achieve physiological concentrations in the medium [Jeejeebhoy, Ho, Greenberg, Phillips, Bruce-Robertson & Sodtke (1975) Biochem. J.146, 141-155]. After periodic additions, there were increases (compared with values for non-hormone-treated suspensions) in the concurrent absolute syntheses of alpha(1) (acute-phase) glycoprotein and of albumin. Trends were detectable after 24h, and significant increases were demonstrated after 48h of incubation (219 and 119% respectively of control values). Manipulation of hormones, by omission from the mixture or by addition of only one or two hormones in various combinations, indicated that for alpha(1) (acute-phase) glycoprotein (which may be representative of some other acute-phase proteins), cortisol was one of the most important hormones involved in the stimulation of synthesis, with glucagon enhancing the effect of cortisol but not being stimulatory by itself. Addition of actinomycin D inhibited this stimulation, suggesting that cortisol might have acted through promotion of RNA synthesis. For albumin, cortisol alone did not stimulate synthesis, but its absence from a hormone mixture significantly decreased synthesis compared with that observed with the complete hormone mixture. Our findings support the possibility that following tissue injury, synthesis of alpha(1) (acute-phase) glycoprotein may be stimulated by the hormonal response to this injury (which response includes elevated blood concentrations of cortisol and glucagon).


Retrieval of water vapor mixing ratio from a multiple channel Raman-scatter lidar using an optimal estimation method.
Lidar measurements of the atmospheric water vapor mixing ratio provide an excellent complement to radiosoundings and passive, ground-based remote sensors. Lidars are now routinely used that can make high spatial-temporal resolution measurements of water vapor from the surface to the stratosphere. Many of these systems can operate during the day and night, with operation only limited by clouds thick enough to significantly attenuate the laser beam. To enhance the value of these measurements for weather and climate studies, this paper presents an optimal estimation method (OEM) to retrieve the water vapor mixing ratio, aerosol optical depth profile, Ångstrom exponent, lidar constants, detector dead times, and measurement backgrounds from multichannel vibrational Raman-scatter lidars. The OEM retrieval provides the systematic uncertainties due to the overlap function, calibration factor, air density and Rayleigh-scatter cross sections, in addition to the random uncertainties of the retrieval due to measurement noise. The OEM also gives the vertical resolution of the retrieval as a function of height, as well as the height to which the contribution of the a priori is small. The OEM is applied to measurements made by the Meteoswiss Raman Lidar for Meteorological Observations (RALMO) in the day and night for clear and cloudy conditions. The retrieved water vapor mixing ratio is in excellent agreement with both the traditional lidar retrieval method and coincident radiosoundings.


World Endoscopy Organization Consensus Statements on Post-Colonoscopy and Post-Imaging Colorectal Cancer.
Colonoscopy examination does not always detect colorectal cancer (CRC)- some patients develop CRC after negative findings from an examination. When this occurs before the next recommended examination, it is called interval cancer. From a colonoscopy quality assurance perspective, that term is too restrictive, so the term post-colonoscopy colorectal cancer (PCCRC) was created in 2010. However, PCCRC definitions and methods for calculating rates vary among studies, making it impossible to compare results. We aimed to standardize the terminology, identification, analysis, and reporting of PCCRCs and CRCs detected after other whole-colon imaging evaluations (post-imaging colorectal cancers [PICRCs]). A 20-member international team of gastroenterologists, pathologists, and epidemiologists; a radiologist; and a non-medical professional met to formulate a series of recommendations, standardize definitions and categories (to align with interval cancer terminology), develop an algorithm to determine most-plausible etiologies, and develop standardized methodology to calculate rates of PCCRC and PICRC. The team followed the Appraisal of Guidelines for Research and Evaluation II tool. A literature review provided 401 articles to support proposed statements; evidence was rated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The statements were voted on anonymously by team members, using a modified Delphi approach. The team produced 21 statements that provide comprehensive guidance on PCCRCs and PICRCs. The statements present standardized definitions and terms, as well as methods for qualitative review, determination of etiology, calculation of PCCRC rates, and non-colonoscopic imaging of the colon. A 20-member international team has provided standardized methods for analysis of etiologies of PCCRCs and PICRCs and defines its use as a quality indicator. The team provides recommendations for clinicians, organizations, researchers, policy makers, and patients.


Exercise effects on cognitive functioning in young adults with first-episode psychosis: FitForLife.
Exercise has mood-enhancing effects and can improve cognitive functioning, but the effects in first-episode psychosis (FEP) remain understudied. We examined the feasibility and cognitive effects of exercise in FEP. Multi-center, open-label intervention study. Ninety-one outpatients with FEP (mean age = 30 years, 65% male) received usual care plus a 12-week supervised circuit-training program, consisting of high-volume resistance exercises, aerobic training, and stretching. Primary study outcome was cognitive functioning assessed by Cogstate Brief Battery (processing speed, attention, visual learning, working memory) and Trailmaking A and B tasks (visual attention and task shifting). Within-group changes in cognition were assessed using paired sample t tests with effect sizes (Hedges' g) reported for significant values. Relationships between exercise frequency and cognitive improvement were assessed using analysis of covariance. Moderating effects of gender were explored with stratified analyses. Participants exercised on average 13.5 (s.d. = 11.7) times. Forty-eight percent completed 12 or more sessions. Significant post-intervention improvements were seen for processing speed, visual learning, and visual attention; all with moderate effect sizes (g = 0.47-0.49, p < 0.05). Exercise participation was also associated with a positive non-significant trend for working memory (p < 0.07). Stratified analyses indicated a moderating effect of gender. Positive changes were seen among females only for processing speed, visual learning, working memory, and visual attention (g = 0.43-0.69). A significant bivariate correlation was found between total training frequency and improvements in visual attention among males (r = 0.40, p < 0.05). Supported physical exercise is a feasible and safe adjunct treatment for FEP with potential cognitive benefits, especially among females.


PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways.
The phosphoinositide 3-kinase (PI3-kinase) signalling pathway plays a key role in the regulation of cell survival and proliferation. We show that the PI3-kinase/Akt pathway is constitutively active in primary acute myeloid leukaemia (AML) cells and that blockade by the selective inhibitor LY294002 reduces survival of the total blast population (mean 52%). The ERK/MAPK module is also constitutively active and treatment with the MAPKK inhibitor U0126 reduces cell survival by 22%. In 10 of 18 samples, PI3-kinase contributes to MAPK activation as incubation with LY294002 leads to a marked reduction in its phosphorylation. PI3-kinase inhibition reduces survival of the CD34+38- AML progenitor subset by 44%, whereas MAPKK inhibition has little effect. Reporter assays in primary AML cells show that blocking PI3-kinase leads to a marked reduction of constitutive NF-kappaB activity and promotes p53-mediated transcription. This is associated with a synergistic interaction between LY294002 and Ara-C. An inducible activated form of Akt protects normal myeloid cells from Ara-C and etoposide-mediated apoptosis. These results show that blocking PI3-kinase has direct antileukaemic effects and potentiates the response to conventional cytotoxics via a number of targets including NF-kappaB, p53 and MAPK. Inhibitors of PI3-kinase and Akt may be useful in the treatment of AML.


The effect of a secondary patient on the family practice visit.
This study describes how the provision of care to a family member other than the identified patient affects the outpatient family practice visit. Research nurses directly observed consecutive patient visits on 2 separate days in the offices of 138 practicing family physicians. Patient visits during which another family member's problem was addressed were identified. Differences in patient and visit characteristics, patient satisfaction, delivery of preventive services, and time use, measured with the Davis Observation Code, were compared for visits with and without the provision of care to a family member. Care was provided to a secondary patient during 18% of observed outpatient visits. The secondary patient was present during only half of these visits. When another family member's problem was discussed, patients were more likely to report that their expectations for the visit were met. There was no difference in patient report of satisfaction with the visit, the delivery of preventive services, or the level of billing for visits at which another family member's problem was addressed. Visits during which another family member's problem was discussed were an average of 1.3 minutes longer; with less time spent chatting, providing feedback, and conducting physical examinations, and more time spent counseling, taking history, gathering family information, and delivering preventive services. The provision of care to a second family member is relatively common in family practice, and affects the care of the index patient in identifiable ways. This care of another family member represents an important added value of family practice.


Impact of organizational leadership on physician burnout and satisfaction.
To evaluate the impact of organizational leadership on the professional satisfaction and burnout of individual physicians working for a large health care organization. We surveyed physicians and scientists working for a large health care organization in October 2013. Validated tools were used to assess burnout. Physicians also rated the leadership qualities of their immediate supervisor in 12 specific dimensions on a 5-point Likert scale. All supervisors were themselves physicians/scientists. A composite leadership score was calculated by summing scores for the 12 individual items (range, 12-60; higher scores indicate more effective leadership). Of the 3896 physicians surveyed, 2813 (72.2%) responded. Supervisor scores in each of the 12 leadership dimensions and composite leadership score strongly correlated with the burnout and satisfaction scores of individual physicians (all P<.001). On multivariate analysis adjusting for age, sex, duration of employment at Mayo Clinic, and specialty, each 1-point increase in composite leadership score was associated with a 3.3% decrease in the likelihood of burnout (P<.001) and a 9.0% increase in the likelihood of satisfaction (P<.001) of the physicians supervised. The mean composite leadership rating of each division/department chair (n=128) also correlated with the prevalence of burnout (correlation=-0.330; r(2)=0.11; P<.001) and satisfaction (correlation=0.684; r(2)=0.47; P<.001) at the division/department level. The leadership qualities of physician supervisors appear to impact the well-being and satisfaction of individual physicians working in health care organizations. These findings have important implications for the selection and training of physician leaders and provide new insights into organizational factors that affect physician well-being.


Effect of urease on HeLa cell vacuolation induced by Helicobacter pylori cytotoxin.
Concentrated broth culture supernatants from 50 to 60% of Helicobacter pylori strains induce eukaryotic cell vacuolation in vitro. A quantitative assay for cell vacuolation was developed on the basis of the rapid uptake of visibly vacuolated HeLa cells was significantly greater than that of nonvacuolated cells. By using the rapid NRU assay, we sought to determine the roles of H. pylori cytotoxin, urease, and ammonia in the vacuolation of HeLa cells. The NRU of HeLa cells incubated in medium containing ammonium chloride or ammonium sulfate was significantly greater than that of cells incubated in medium alone. In addition, ammonium salts augmented the NRU induced by H. pylori supernatants. The NRU induced by jack bean urease was augmented by the addition of urea to cell culture medium; this suggests that urease-mediated NRU occurs via the generation of ammonia. Acetohydroxamic acid blocked the NRU induced by jack bean urease and urea but failed to block the uptake induced by H. pylori supernatants. Supernatant from a non-urease-producing H. pylori mutant strain induced NRU identical to that of the urease-positive parental strain. These observations indicate that the vacuolating activity in H. pylori supernatants is not mediated solely by urease activity but that it may be potentiated by urease-mediated ammonia production.


Disorder-specific grey matter deficits in attention deficit hyperactivity disorder relative to autism spectrum disorder.
Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are two common childhood disorders that exhibit genetic and behavioural overlap and have abnormalities in similar brain systems, in particular in frontal and cerebellar regions. This study compared the two neurodevelopmental disorders to investigate shared and disorder-specific structural brain abnormalities. Forty-four predominantly medication-naïve male adolescents with ADHD, 19 medication-naïve male adolescents with ASD and 33 age-matched healthy male controls were scanned using high-resolution T1-weighted volumetric imaging in a 3-T magnetic resonance imaging (MRI) scanner. Voxel-based morphometry (VBM) was used to test for group-level differences in structural grey matter (GM) and white matter (WM) volumes. There was a significant group difference in the GM of the right posterior cerebellum and left middle/superior temporal gyrus (MTG/STG). Post-hoc analyses revealed that this was due to ADHD boys having a significantly smaller right posterior cerebellar GM volume compared to healthy controls and ASD boys, who did not differ from each other. ASD boys had a larger left MTG/STG GM volume relative to healthy controls and at a more lenient threshold relative to ADHD boys. The study shows for the first time that the GM reduction in the cerebellum in ADHD is disorder specific relative to ASD whereas GM enlargement in the MTG/STG in ASD may be disorder specific relative to ADHD. This study is a first step towards elucidating disorder-specific structural biomarkers for these two related childhood disorders.


A convergent synthesis of 1,3,4-oxadiazoles from acyl hydrazides under semiaqueous conditions.
The 1,3,4-oxadiazole is an aromatic heterocycle valued for its low-lipophilicity in drug development. Substituents at the 2- and/or 5-positions can modulate the heterocycle's electronic and hydrogen bond-accepting capability, while exploiting its use as a carbonyl bioisostere. A new approach to 1,3,4-oxadiazoles is described wherein α-bromo nitroalkanes are coupled to acyl hydrazides to deliver the 2,5-disubstituted oxadiazole directly, avoiding a 1,2-diacyl hydrazide intermediate. Access to new building blocks of oxadiazole-substituted secondary amines is improved by leveraging chiral α-bromo nitroalkane or amino acid hydrazide substrates. The non-dehydrative conditions for oxadiazole synthesis are particularly notable, in contrast to alternatives reliant on highly oxophilic reagents to effect cyclization of unsymmetrical 1,2-diacyl hydrazides. The mild conditions are punctuated by the straightforward removal of co-products by a standard aqueous wash.


Aspergillus to Zygomycetes: causes, risk factors, prevention, and treatment of invasive fungal infections.
Invasive fungal infections (IFIs) are an important cause of morbidity and mortality, particularly in patients with underlying risk factors (e.g., neutropenia, cancer chemotherapy, transplantation, AIDS). Although Candida species remain a relevant cause of IFI, other organisms (particularly moulds) have become increasingly prevalent. In particular, Aspergillus species are the leading cause of mould infections although other moulds including Fusarium species and Zygomycetes are increasing in frequency, and are associated with a high mortality rate. Options available for the prevention and treatment of these infections include standard and liposomal formulations of amphotericin B, but toxicity concerns limit their use; fluconazole is effective for the prevention and treatment of candidiasis but its inactivity against moulds and increasing resistance are limiting factors. Newer azoles, particularly voriconazole and posaconazole, have an enhanced spectrum of activity that includes Candida species, Aspergillus species, Cryptococcus species, dimorphic fungi, Fusarium species, and, for posaconazole, Zygomycetes. Recent data suggest that these agents are highly effective in a variety of clinical settings. Echinocandins have good activity against Candida species and Aspergillus species but their spectrum generally does not include Fusarium species, Cryptococcus species, Trichosporon species, Zygomycetes, and dematiaceous moulds. While these agents are unlikely to exhibit crossresistance with polyenes or azoles, they must be administered intravenously. Knowledge of the pathogenesis of IFIs and the activity, efficacy, and limitations of available treatment options will allow the selection of an appropriate antifungal agent for individual patients.


Transfer of tilt after-effects between second-order cues.
Second-order cues are visual stimuli that are detectable by human observers, without eliciting a peak in Fourier energy that corresponds to their perceptual properties. The most commonly studied exemplars of second-order cues are those defined by modulation of local contrast (CM). It is widely accepted that such cues are initially detected separately from first-order, luminance modulated (LM), cues. However, after-effects have been shown to transfer between first- and second-order cues (LM and CM, respectively). This suggests the existence of a late link in the mechanisms that subserve their processing. To extend the investigation of the mechanisms for processing second-order cues we consider cues defined by modulations in local orientation (OM). Using a tilt-after-effect (TAE) paradigm, we found partial transfer of adaptation between LM and OM cues, confirming the presence of a link between first and second-order cues. Furthermore, we found a partial transfer of TAE between OM and CM cues. These results suggest that, at or before the site of adaptation, information from all visual cues is combined. However, as transfer of adaptation is below 100% in all cases, this is only a partial integration of information.


Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors.
Radiotherapy kills cancer cells by causing DNA damage, and stimulates a systemic antitumor immune response by releasing tumor antigen and endogenous adjuvant within the tumor microenvironment. However, radiotherapy also induces the recruitment of immunosuppressive myeloid cells, which can interfere with the antitumor immune responses elicited by apoptotic tumor cells. We hypothesized that local delivery of vaccine following radiotherapy will lead to the priming of antigen-specific CTL immune responses and render immunosuppressive myeloid cells susceptible to killing by the activated CTLs. Using several antigenic systems, we tested whether intratumoral injection of antigenic peptide/protein in irradiated tumors would be able to prime CTLs as well as load myeloid cells with antigen, rendering them susceptible to antigen-specific CTL killing. We show that by combining radiotherapy and targeted antigenic peptide delivery to the tumor, the adjuvant effect generated by radiotherapy itself was sufficient to elicit the priming and expansion of antigen-specific CTLs, through the type I IFN-dependent pathway, leading to synergistic therapeutic antitumor effects compared with either treatment alone. In addition, using two different types of transgenic mice, we demonstrated that CTL-mediated killing of stromal cells in tumors by our approach is important for tumor control. Finally, we confirmed the efficacy of this approach in our preclinical model using two clinically tested therapeutic human papilloma virus (HPV) vaccines. These data serve as an important foundation for the future clinical translation of radiotherapy combined with a clinically tested therapeutic HPV vaccine for the control of HPV-associated cancers.


Strategy and effect of repeat bypass surgery for anterior/posterior circulation in refractory moyamoya disease.
In this study the authors aimed to describe clinical features, surgical techniques, and long-term outcomes of repeat bypass surgery required for a certain subset of patients with moyamoya disease. The authors retrospectively reviewed a total of 22 repeat bypass surgeries for 20 patients (age range 1-69 years) performed during the last 20 years at their institutions. The patients were classified into 2 groups. Group A included 10 patients who underwent repeat bypass surgery for anterior circulation due to insufficient revascularization on the ipsilateral side. Group B included 10 patients who underwent repeat bypass surgery for posterior circulation due to the involvement of the posterior cerebral artery (PCA) after successful initial surgery for anterior circulation. Preoperative symptoms included headache in 3 patients, transient ischemic attack in 10, cerebral infarction in 3, and intracranial hemorrhage in 4 patients. Intervals between the initial bypass surgery and repeat bypass surgery were 0.3-30 years (median 3 years). In group A, superficial temporal artery to middle cerebral artery (MCA) anastomosis and indirect bypass were performed on 7 hemispheres. Only indirect bypass was performed on 3 hemispheres because of the lack of suitable donor or recipient arteries. In group B, occipital artery (OA) to PCA anastomosis and indirect bypass were conducted on 4 hemispheres, and OA-MCA anastomosis and indirect bypass on 1 hemisphere. Only indirect bypass was conducted on 7 hemispheres because of the lack of suitable recipient arteries. All 22 repeat bypass surgeries were successfully conducted. During follow-up periods (median 4 years), none of the patients suffered repeat stroke except 1 patient who died of recurrent intracerebral hemorrhage 3 years after repeat bypass surgery for anterior circulation. Repeat bypass surgery was feasible and effective to reduce further incidence of headache attack, transient ischemic attack, and ischemic/hemorrhagic stroke in moyamoya disease patients. Through precise radiological analysis, surgical procedures should be planned to yield maximal therapeutic effects.


Evaluation of Retinal Function in Streptozotocin-induced Diabetic Rats by Using the Electroretinography and Immunohistochemistry Methods.
Streptozotocin-induced diabetic rat (STZ rat) was used in many studies for the diabetic mellitus. In this study, we demonstrated whether the electroretinograms (ERG) was changed in the retina of STZ rats. In addition, we investigated the histopathological alteration in the retina of STZ rats by using the immunological method. The 100 mg/kg of STZ was injected continuously for 2 d (100 mg/kg×2). The insulin level was decreased, and the glucose level was enhanced 14 d after the injection of STZ. Moreover, the levels of a-wave, b-wave and OP amplitude were decreased in the rat at 14 d after the injection of STZ. Although, the damage and apoptosis was not observed in the retinal ganglion cell of STZ rats by the immunological experiment using the phospho-H2A.X and cleaved caspase-3, the distance between cell and cell was increased in both of outer- and inner- nuclear (granule) layer in retina of STZ rats. In conclusion, we showed that the enhanced thickening in retina was caused by the injection of excessive STZ. The thickening in retina of STZ rats may lead to the dysfunction of retina, resulting in the decrease in ERG. These findings provide significant information that can be used in the design of a model of diabetic retinopathy.


Imaging biochemistry inside cells.
Proteins provide the building blocks for multicomponent molecular units, or pathways, from which higher cellular functions emerge. These units consist of either assemblies of physically interacting proteins or dispersed biochemical activities connected by rapidly diffusing second messengers, metabolic intermediates, ions or other proteins. It will probably remain within the realm of genetics to identify the ensemble of proteins that constitute these functional units and to establish the first-order connectivity. The dynamics of interactions within these protein machines can be assessed in living cells by the application of fluorescence spectroscopy on a microscopic level, using fluorescent proteins that are introduced within these functional units. Fluorescence is sensitive, specific and non-invasive, and the spectroscopic properties of a fluorescent probe can be analysed to obtain information on its molecular environment. The development and use of sensors based on the genetically encoded variants of green-fluorescent proteins has facilitated the observation of 'live' biochemistry on a microscopic level, with the advantage of preserving the cellular context of biochemical connectivity, compartmentalization and spatial organization. Protein activities and interactions can be imaged and localized within a single cell, allowing correlation with phenomena such as the cell cycle, migration and morphogenesis.


Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004.
As of December 31, 2004, more than 23,000 pancreas transplant had been reported to the IPTR, >17,000 in the US and almost 6000 from outside the US. An analysis of US pancreas transplants performed between 1988 and 2003 showed a progressive improvement in outcome, with pancreas transplant graft survival rates (GSRs) going from 75% at 1 yr for 1988/1989 to 85% for 2002/2003 simultaneous pancreas-kidney (SPK) cases, from 55 to 78% for pancreas after kidney (PAK) cases, and from 45 to 77% for pancreas transplants alone (PTA) cases. The improvements were due both to decreases in technical failure (TF) rates (from 12 to 6% in SPK, 13-8% in PAK, and 24-7% in PTA) and immunological failure rates (going from 7 to 2% for SPK, from 28 to 7% for PAK, and from 38 to 8% for PTA cases). These results are even more impressive under the aspect that during the same time the rate of potential risk factors increased and the duct management techniques changed from bladder to enteric drainage. The improvement in outcome allowed also an increase in the number of solitary pancreas transplants from initially 12% to now 35%. Contemporary primary deceased donor pancreas transplant outcomes were calculated separately for 2000-2004 US and non-US cases. The US patient survival rates at 1 yr were >95% in each recipient category, with 1 yr primary pancreas GSRs of 85% for SPK, 78% for PAK, and 76% for PTA (p < 0.0001). The immunological graft failure rates for 2000-2004 technically successful (TS) SPK, PAK, and PTA cases were 2, 8, and 10% at 1 yr (p = 0.0001). In the majority of all transplants ED was used for duct management (81% of SPK, 67% of PAK, and 56% for PTA cases). Of the ED transplants, venous drainage via the portal system was used for 20% of SPK, 23% of PAK, and 35% of PTA cases. Duct management technique did not have a significant impact on overall pancreas graft function in the univariate or the multivariate model. The outcomes of ED and BD transplants are comparable with 85 vs. 87% at 1 yr for SPK, 77 vs. 80% for PAK, and 72 vs. 79% for PTA. The overall TF rate was higher in ED pancreas transplants but this difference did reach significance only in SPK. In addition, in technically successful PTA the immunological graft loss rate was higher in ED vs. BD transplants (15 vs. 5% at 1 yr). The different vascular management techniques did not seem to have an impact on the outcome of the pancreas transplants. Kidney GSRs were not significantly different for ED vs. BD SPK cases, 93 and 91% at 1 yr (p = 0.24). The overall conversion rate from BD to ED was 9% at 1 yr and 17% at 3 yr post-transplant. The most influential factor for patient survival in SPK and PAK in the multivariate and the univariate models was the status of the transplanted organ. The hazard ratio (HR) for a failed kidney was 14.99 in SPK and 9.17 in PAK (p = 0.0001). The HR for a failed pancreas graft was 3.51 in SPK and 4.17 for PAK (p = 0.0001). In PTA a failed pancreas graft did not have a direct impact on patient survival. SPK and PAK patients older than 44 yr at the time of transplants also showed an increased mortality risk, but at the same time the risk of immunological graft loss was significantly decreased for those patients. TAC&MMF remained the dominant maintenance immunosuppressant for 2000-2004 US cases (approximately two-third) in all three categories and with this regime 1-year GSRs were > or =80% in all three recipient categories. The results were comparable (> or =83% 1-year GSR) for patients (approximately 10%) treated with Sirolimus (SIR) under various protocols. In regard to non-US pancreas transplants, even for 2000-2004 the overwhelming majority continued to be in the SPK category (91%), with 1-year patient, kidney and pancreas survival rates of 94, 92, and 87%. Solitary transplants are still very rarely done outside the US. Non-US PAK GSR at 1 yr was 85%, non-US PTA GSR at 1 yr was 76%. In summary, with the new advancements in immunosuppression and changes in surgical techniques the outcomes in patient survival and pancreas transplant graft function continue to improve even with an increasing proportion of high risk patients in all three categories.


Systems analysis of bacterial glycomes.
Bacteria produce an array of glycan-based structures including capsules, lipo-oligosaccharide and glycosylated proteins, which are invariably cell-surface-located. For pathogenic bacteria, such structures are involved in diverse roles in the life cycle of the bacterium, including adhesion, colonization, avoidance of predation and interactions with the immune system. Compared with eukaryotes, bacteria produce huge combinatorial variations of glycan structures, which, coupled to the lack of genetic data, has previously hampered studies on bacterial glycans and their role in survival and pathogenesis. The advent of genomics in tandem with rapid technological improvements in MS analysis has opened a new era in bacterial glycomics. This has resulted in a rich source of novel glycan structures and new possibilities for glycoprospecting and glycoengineering. However, assigning genetic information in predicted glycan biosynthetic pathways to the overall structural information is complex. Bioinformatic analysis is required, linked to systematic mutagenesis and functional analysis of individual genes, often from diverse biosynthetic pathways. This must then be related back to structural analysis from MS or NMR spectroscopy. To aid in this process, systems level analysis of the multiple datasets can be used to make predictions of gene function that can then be confirmed experimentally. The present paper exemplifies these advances with reference to the major gastrointestinal pathogen Campylobacter jejuni.


Personalised Medicine: The Promise, the Hype and the Pitfalls.
In engaging critically with personalised medicine and mapping pitfalls which mark its progress this project aims to stimulate conversations which deal intelligently with controversies for the sake of consensus. We aim to ask the ethical questions which will lead to the improvement of healthcare and we take an open-minded approach to finding answers to them over time. What is or should be meant by 'personalised medicine' is a major theme of this issue. It is a debate bound up with question of both values in the sense of ethical reflection and value in the sense of economic return. This editorial discusses and interrelates the articles of the issue under four headings: the promise and the hype of personalised medicine; the human person and the communication of risk; data sharing and participation; value, equity and power. A key intention throughout is to provoke discourse and debate, to identify aspirations which are more grounded in myth or hype than reality and to challenge them; and to identify focussed, practical questions which need further examination.


The American College of Gastroenterology Bleeding Registry: preliminary findings.
The American College of Gastroenterology (ACG) Institute for Clinical Research and Education conducted a survey study to assess demographics, management strategies, and outcome for patients with gastrointestinal bleeding. This pilot project was intended to determine the feasibility of surveying the ACG membership about common clinical issues. Color-coded survey forms were sent to all ACG members and Fellows, with instructions to supply information about demographics, presenting symptoms, management, and outcome for bleeding patients and procedure-matched controls. Forms returned between June 1 and August 31, 1995, were tabulated and analyzed for differences between the bleeding group and procedure-matched controls. A total of 1235 forms were returned by respondents, 60% of whom were in private practice. Patient demographics indicated that bleeding patients were significantly older, more likely to be male, and more likely to use alcohol, tobacco, and prescription or over-the-counter aspirin or nonsteroidal anti-inflammatory drugs and anticoagulants than were controls. Upper GI bleeding accounted for 76% of bleeding events, with duodenal and gastric ulcers being the source in more than 50% of the upper GI bleeders. Diverticula was the most common bleeding source identified in lower GI bleeders. In the bleeding group, 78.8% were anemic, with 60.9% having hemoglobin of <10 g/dl; 31% presented with orthostatic changes in blood pressure or shock. Most bleeding subjects, regardless of source, were hospitalized, 58.2% received blood transfusions, and 45.5% received endoscopic therapy. Rebleeding (11.2%), need for surgery (7.1%), and fatalities (2.1%) were uncommon. Over-the-counter aspirin and nonsteroidal anti-inflammatory drugs were used significantly more often in the bleeding population (47.6%) than in controls (19.4%). The success of the GI Bleeding Registry supports the feasibility of surveying ACG members about common clinical problems. Data suggest that ACG members manage sick patients with severe gastrointestinal bleeding who require hospitalization, transfusions, and endoscopic treatment. These preliminary results will serve as an impetus to conduct further survey studies of gastrointestinal bleeding and other common digestive disease conditions.


A highly X-ray sensitive iridium prodrug for visualized tumor radiochemotherapy.
Concomitant treatment of radiotherapy and chemotherapy is widely used in cancer therapy. The search for highly efficient radiochemotherapy drugs for tumor targeting therapy under image-guiding is of considerable interest. Herein we report an Ir-based prodrug Ir-NB with high sensitization efficiency for in vivo tumor microenvironment responsive cancer-targeted bioimaging radiochemotherapy. To the best of our knowledge, the sensitivity enhancement ratio (SER) of the Ir-NB prodrug is the highest among those reported for radiotherapy metal complex drugs. From detailed action mechanism study, we provide evidence that the prodrug is effectively suppresses the tumor growth through inducing mitochondrial dysfunction, and eventually amplifies the apoptotic signal pathway. This study provides an approach for the development of cancer theranostic agents for tumor radiotherapy.


Socioeconomic and environmental determinants of dengue transmission in an urban setting: An ecological study in Nouméa, New Caledonia.
Dengue is a mosquito-borne virus that causes extensive morbidity and economic loss in many tropical and subtropical regions of the world. Often present in cities, dengue virus is rapidly spreading due to urbanization, climate change and increased human movements. Dengue cases are often heterogeneously distributed throughout cities, suggesting that small-scale determinants influence dengue urban transmission. A better understanding of these determinants is crucial to efficiently target prevention measures such as vector control and education. The aim of this study was to determine which socioeconomic and environmental determinants were associated with dengue incidence in an urban setting in the Pacific. An ecological study was performed using data summarized by neighborhood (i.e. the neighborhood is the unit of analysis) from two dengue epidemics (2008-2009 and 2012-2013) in the city of Nouméa, the capital of New Caledonia. Spatial patterns and hotspots of dengue transmission were assessed using global and local Moran's I statistics. Multivariable negative binomial regression models were used to investigate the association between dengue incidence and various socioeconomic and environmental factors throughout the city. The 2008-2009 epidemic was spatially structured, with clusters of high and low incidence neighborhoods. In 2012-2013, dengue incidence rates were more homogeneous throughout the city. In all models tested, higher dengue incidence rates were consistently associated with lower socioeconomic status (higher unemployment, lower revenue or higher percentage of population born in the Pacific, which are interrelated). A higher percentage of apartments was associated with lower dengue incidence rates during both epidemics in all models but one. A link between vegetation coverage and dengue incidence rates was also detected, but the link varied depending on the model used. This study demonstrates a robust spatial association between dengue incidence rates and socioeconomic status across the different neighborhoods of the city of Nouméa. Our findings provide useful information to guide policy and help target dengue prevention efforts where they are needed most.


The effect of indomethacin and prostaglandin (PGE2) on renal failure due to glycerol in saline-loaded rats.
1. Acute renal failure was induced in conscious rate by subcutaneous injection of glycerol. 2. Expansion of the extracellular space by infusion of 150 mmol/l sodium chloride (saline) partly protected the animals against acute renal failure. 3. This protective effect of saline infusion disappeared when the animals were treated with indomethacin. This effect could be reversed by the addition of prostaglandin (PGE2) to the saline infusion. 4. We suggest that prostaglandins may be involved in mediating the protection afforded by saline infusion against acute renal failure due to glycerol.


Music Training Increases Phonological Awareness and Reading Skills in Developmental Dyslexia: A Randomized Control Trial.
There is some evidence for a role of music training in boosting phonological awareness, word segmentation, working memory, as well as reading abilities in children with typical development. Poor performance in tasks requiring temporal processing, rhythm perception and sensorimotor synchronization seems to be a crucial factor underlying dyslexia in children. Interestingly, children with dyslexia show deficits in temporal processing, both in language and in music. Within this framework, we test the hypothesis that music training, by improving temporal processing and rhythm abilities, improves phonological awareness and reading skills in children with dyslexia. The study is a prospective, multicenter, open randomized controlled trial, consisting of test, rehabilitation and re-test (ID NCT02316873). After rehabilitation, the music group (N = 24) performed better than the control group (N = 22) in tasks assessing rhythmic abilities, phonological awareness and reading skills. This is the first randomized control trial testing the effect of music training in enhancing phonological and reading abilities in children with dyslexia. The findings show that music training can modify reading and phonological abilities even when these skills are severely impaired. Through the enhancement of temporal processing and rhythmic skills, music might become an important tool in both remediation and early intervention programs.Trial Registration: ClinicalTrials.gov NCT02316873


MicroRNA-302 increases reprogramming efficiency via repression of NR2F2.
MicroRNAs (miRNAs) have emerged as critical regulators of gene expression through translational inhibition and RNA decay and have been implicated in the regulation of cellular differentiation, proliferation, angiogenesis, and apoptosis. In this study, we analyzed global miRNA and mRNA microarrays to predict novel miRNA-mRNA interactions in human embryonic stem cells and induced pluripotent stem cells (iPSCs). In particular, we demonstrate a regulatory feedback loop between the miR-302 cluster and two transcription factors, NR2F2 and OCT4. Our data show high expression of miR-302 and OCT4 in pluripotent cells, while NR2F2 is expressed exclusively in differentiated cells. Target analysis predicts that NR2F2 is a direct target of miR-302, which we experimentally confirm by reporter luciferase assays and real-time polymerase chain reaction. We also demonstrate that NR2F2 directly inhibits the activity of the OCT4 promoter and thus diminishes the positive feedback loop between OCT4 and miR-302. Importantly, higher reprogramming efficiencies were obtained when we reprogrammed human adipose-derived stem cells into iPSCs using four factors (KLF4, C-MYC, OCT4, and SOX2) plus miR-302 (this reprogramming cocktail is hereafter referred to as "KMOS3") when compared to using four factors ("KMOS"). Furthermore, shRNA knockdown of NR2F2 mimics the over-expression of miR-302 by also enhancing reprogramming efficiency. Interestingly, we were unable to generate iPSCs from miR-302a/b/c/d alone, which is in contrast to previous publications that have reported that miR-302 by itself can reprogram human skin cancer cells and human hair follicle cells. Taken together, these findings demonstrate that miR-302 inhibits NR2F2 and promotes pluripotency through indirect positive regulation of OCT4. This feedback loop represents an important new mechanism for understanding and inducing pluripotency in somatic cells.


Preoperative left ventricular peak systolic pressure/end-systolic volume ratio and functional status following valve surgery in patients with mitral regurgitation and enlarged end-systolic volumes.
This study was done to determine if the left ventricular (LV) peak systolic pressure/end-systolic volume (PSP/ ESV) ratio predicts symptomatic improvement with valve replacement or repair in patients with mitral regurgitation (MR) and an enlarged LV ESV. Patients with MR and LV ESV <30 ml/m2 consistently improve symptomatically with valve surgery, whereas the response of those with an ESV >30 ml/m2 is heterogeneous. The LV PSP/ESV ratio, an easily acquired measure of LV performance, may discriminate those who improve with valve surgery from those who do not. Accordingly, in 40 patients (15 men and 25 women, aged 14 to 74 years) with moderate or severe MR, no other cardiovascular abnormalities, and a LV ESV >30 ml/m2, we assessed the utility of clinical, hemodynamic, and angiographic variables routinely measured preoperatively to predict symptomatic improvement with valve replacement or repair. Of the 40 subjects, 3 died during or within 6 months of surgery. Six months after valve surgery, symptoms had improved in 34 patients, were unchanged in 1, and had worsened in 2. By univariate analysis, only the preoperative pulmonary capillary wedge pressure was predictive of a change in functional class (p = 0.05). The PSP/ESV ratio was not predictive of a change in functional class after valve surgery. Thus, the PSP/ESV ratio does not identify which patients with MR and an enlarged LV ESV will manifest symptomatic improvement with valve surgery.


A typology of collaboration efforts in environmental management.
Collaboration involves stakeholders and the public in a process of consensus building to address some of the most difficult environmental management problems facing society today. Collaborative groups vary widely, ranging from small watershed councils to regional ecosystem collaboratives to groups addressing large-scale policy issues. While these collaboratives all match the common principles of collaboration, a closer examination reveals many differences. Using institutional theories about levels of decision making provides a way of classifying collaboratives along a spectrum from action level to organizational level to policy level. This typology is applied to thirty-six collaboration case studies in Australia and the United States that were investigated over a series of years through interviews, observation, document analysis, and surveys. The application reveals different tendencies among the case types in terms of population, size, problem significance, institutional setting, and focus of activities. The typology also reveals functional differences in the types of stakeholders involved, the management arrangements for implementation, and the approaches to implementing change. This typology can help practitioners better understand the challenges and appropriate types of collaborations for different settings. It helps highlight differences in the role of government and decentralization of power. It distinguishes the different theoretical foundations for different types of collaboratives. Finally, it elucidates the different evaluation approaches for different types of collaboratives.


Elucidating Unique Axonal Dysfunction Between Nitrous Oxide Abuse and Vitamin B12 Deficiency.
Introduction: Abuse of nitrous oxide (N2O) has an unusually high lifetime prevalence in developed countries and represents a serious concern worldwide. Myeloneuropathy following the inhalant abuse is commonly attributed to the disturbance of vitamin B12 metabolism, with severe motor deficits are often noted. The present study aims to elucidate its underlying pathophysiology. Methods: Eighteen patients with N2O abuse or vitamin B12 deficiency were recruited. Comprehensive central and peripheral neuro-diagnostic tests were performed, including whole spine MRI, and thermal quantitative sensory testing (QST). Specifically, paired motor and sensory nerve excitability tests were performed in order to obtain a complete picture of the sensorimotor axonal damage. Results: The mean duration of N2O exposure for the N2O abuse patients was 17.13 ± 7.23 months. MRI revealed T2 hyperintensity in 87.5% of the N2O abuse patients and 50% of the vitamin B12 deficiency patients. In N2O abuse patients, the motor nerve excitability test showed decreased in peak response (7.08 ± 0.87 mV, P = 0.05), increased latency (7.09 ± 0.28 ms, P < 0.01), increased superexcitability (-32.95 ± 1.74%, P < 0.05), and decreased accommodation to depolarizing current [TEd (40-60 ms) 56.53 ± 0.70%, P < 0.05]; the sensory test showed only decreased peak response (30.54 ± 5.98 μV, P < 0.05). Meanwhile, motor test in vitamin B12 deficiency patients showed only decreased accommodation to depolarizing current [TEd (40-60 ms) 55.72 ± 1.60%, P < 0.01]; the sensory test showed decreased peak response (25.86 ± 3.44 μV, P < 0.05) increased superexcitability (-28.58 ± 3.71%, P < 0.001), increased subexcitability (8.31 ± 1.64%, P < 0.05), and decreased accommodation to depolarizing current [TEd (peak) 67.31 ± 3.35%, P < 0.001]. Conclusion: Compared to vitamin B12 deficiency, N2O abuse patients showed prominent motor superexcitability changes and less prominent sensory superexcitability changes, hinting a unique pathological process different from that of vitamin B12 deficiency. N2O abuse might cause axonal dysfunction not only by blocking methionine metabolism but also by toxicity affecting the paranodal region.


Reaction Wood Anatomical Traits and Hormonal Profiles in Poplar Bent Stem and Root.
Reaction wood (RW) formation is an innate physiological response of woody plants to counteract mechanical constraints in nature, reinforce structure and redirect growth toward the vertical direction. Differences and/or similarities between stem and root response to mechanical constraints remain almost unknown especially in relation to phytohormones distribution and RW characteristics. Thus, Populus nigra stem and root subjected to static non-destructive mid-term bending treatment were analyzed. The distribution of tension and compression forces was firstly modeled along the main bent stem and root axis; then, anatomical features, chemical composition, and a complete auxin and cytokinin metabolite profiles of the stretched convex and compressed concave side of three different bent stem and root sectors were analyzed. The results showed that in bent stems RW was produced on the upper stretched convex side whereas in bent roots it was produced on the lower compressed concave side. Anatomical features and chemical analysis showed that bent stem RW was characterized by a low number of vessel, poor lignification, and high carbohydrate, and thus gelatinous layer in fiber cell wall. Conversely, in bent root, RW was characterized by high vessel number and area, without any significant variation in carbohydrate and lignin content. An antagonistic interaction of auxins and different cytokinin forms/conjugates seems to regulate critical aspects of RW formation/development in stem and root to facilitate upward/downward organ bending. The observed differences between the response stem and root to bending highlight how hormonal signaling is highly organ-dependent.


Outcomes Related to the Use of Frozen Plasma or Pooled Solvent/Detergent-Treated Plasma in Critically Ill Children.
To determine if the use of fresh frozen plasma/frozen plasma 24 hours compared to solvent detergent plasma is associated with international normalized ratio reduction or ICU mortality in critically ill children. This is an a priori secondary analysis of a prospective, observational study. Study groups were defined as those transfused with either fresh frozen plasma/frozen plasma 24 hours or solvent detergent plasma. Outcomes were international normalized ratio reduction and ICU mortality. Multivariable logistic regression was used to determine independent associations. One hundred one PICUs in 21 countries. All critically ill children admitted to a participating unit were included if they received at least one plasma unit during six predefined 1-week (Monday to Friday) periods. All children were exclusively transfused with either fresh frozen plasma/frozen plasma 24 hours or solvent detergent plasma. None. There were 443 patients enrolled in the study. Twenty-four patients (5%) were excluded because no plasma type was recorded; the remaining 419 patients were analyzed. Fresh frozen plasma/frozen plasma 24 hours group included 357 patients, and the solvent detergent plasma group included 62 patients. The median (interquartile range) age and weight were 1 year (0.2-6.4) and 9.4 kg (4.0-21.1), respectively. There was no difference in reason for admission, severity of illness score, pretransfusion international normalized ratio, or lactate values; however, there was a difference in primary indication for plasma transfusion (p < 0.001). There was no difference in median (interquartile range) international normalized ratio reduction, between fresh frozen plasma/frozen plasma 24 hours and solvent detergent plasma study groups, -0.2 (-0.4 to 0) and -0.2 (-0.3 to 0), respectively (p = 0.80). ICU mortality was lower in the solvent detergent plasma versus fresh frozen plasma/frozen plasma 24 hours groups, 14.5% versus 29.1%%, respectively (p = 0.02). Upon adjusted analysis, solvent detergent plasma transfusion was independently associated with reduced ICU mortality (odds ratio, 0.40; 95% CI, 0.16-0.99; p = 0.05). Solvent detergent plasma use in critically ill children may be associated with improved survival. This hypothesis-generating data support a randomized controlled trial comparing solvent detergent plasma to fresh frozen plasma/frozen plasma 24 hours.


Nuclear and mitochondrial tRNA-lookalikes in the human genome.
We are interested in identifying and characterizing loci of the human genome that harbor sequences resembling known mitochondrial and nuclear tRNAs. To this end, we used the known nuclear and mitochondrial tRNA genes (the "tRNA-Reference" set) to search for "tRNA-lookalikes" and found many such loci at different levels of sequence conservation. We find that the large majority of these tRNA-lookalikes resemble mitochondrial tRNAs and exhibit a skewed over-representation in favor of some mitochondrial anticodons. Our analysis shows that the tRNA-lookalikes have infiltrated specific chromosomes and are preferentially located in close proximity to known nuclear tRNAs (z-score ≤ -2.54, P-value ≤ 0.00394). Examination of the transcriptional potential of these tRNA-lookalike loci using public transcript annotations revealed that more than 20% of the lookalikes are transcribed as part of either known protein-coding pre-mRNAs, known lncRNAs, or known non-protein-coding RNAs, while public RNA-seq data perfectly agreed with the endpoints of tRNA-lookalikes. Interestingly, we found that tRNA-lookalikes are significantly depleted in known genetic variations associated with human health and disease whereas the known tRNAs are enriched in such variations. Lastly, a manual comparative analysis of the cloverleaf structure of several of the transcribed tRNA-lookalikes revealed no disruptive mutations suggesting the possibility that these loci give rise to functioning tRNA molecules.


Endophthalmitis Associated With Glaucoma Drainage Implants.
To identify the clinical features, organisms, and treatment outcomes in patients with endophthalmitis associated with glaucoma drainage implants. A retrospective noncomparative case series. Of the 13 patients, exposure occurred in eight eyes, including exposure of the tube in four eyes, exposure of the patch graft in three eyes, and exposure of the plate in one eye. In the remaining five eyes, either recent implant placement or conjunctival revision occurred. The most common organism was Staphylococcus epidermidis (five eyes). Intravitreal antibiotics were administered in all eyes, with the exception of one eye (primary evisceration). Removal of the implant was performed in six eyes and evisceration or enucleation was performed in three eyes. Median pre-infection visual acuity was 20/80 (range: 20/30 to hand motion). Visual acuity at last follow-up was no light perception (five eyes), light perception (two eyes), hand motion (one eye), and better than or equal to 20/200 (five eyes). Clinical features associated with endophthalmitis include implant exposure and a history of recent surgery. Staphylococcus epidermidis was the most common isolate. Although removal of the implant was performed in many patients, successful treatment was accomplished in some patients without removal. Visual outcomes were generally poor. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:563-569.].


Quantitative analysis of collagen lamellae in the normal and keratoconic human cornea by second harmonic generation imaging microscopy.
To characterize the structural properties of collagen lamellae in the normal and keratoconic human corneal stroma, we measured their width and angle relative to Bowman's layer (BL). Thirteen normal and four keratoconic corneas were examined. Collagen lamellae in tissue blocks from the central cornea were visualized by second harmonic generation imaging microscopy. Images obtained in 1-μm steps from BL to Descemet's membrane (DM) were subjected to three-dimensional reconstruction. The reconstructed data sets were divided into 10 layers of equal depth (L1-L10) for analysis. The width of lamellae adherent to BL (L0) was also determined. For the normal cornea, the width (mean ± SD) of collagen lamellae was 6.5 ± 1.7 μm at L0, decreased to 4.3 ± 1.3 μm at L1, and then increased gradually with progression toward DM to 122.2 ± 34.5 μm at L10, whereas the angle of lamellae was 20.9° ± 5.4° at L1 and decreased initially to 10.6° ± 3.2° at L2 before declining gradually to 2.7° ± 2.2° at L10. The width and angle of collagen lamellae in the keratoconic cornea were significantly larger and smaller, respectively, relative to those in the normal cornea. In the normal human cornea, collagen lamellae adjacent to BL are narrow and form a steep angle with BL, whereas they increase in width and their angle relative to BL flattens with progression toward DM. These properties of collagen lamellae are altered in keratoconus and are likely related to abnormalities of corneal shape.


Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children.
Antibodies targeting Plasmodium falciparum sporozoites play a key role in human immunity to malaria. However, antibody mechanisms that neutralize sporozoites are poorly understood. This has been a major constraint in developing highly efficacious vaccines, as we lack strong correlates of protective immunity. We quantified the ability of human antibodies from malaria-exposed populations to interact with human complement, examined the functional effects of complement activity against P. falciparum sporozoites in vitro, and identified targets of functional antibodies. In children and adults from malaria-endemic regions, we determined the acquisition of complement-fixing antibodies to sporozoites and their relationship with antibody isotypes and subclasses. We also investigated associations with protective immunity in a longitudinal cohort of children (n = 206) residing in a malaria-endemic region. We found that antibodies to the major sporozoite surface antigen, circumsporozoite protein (CSP), were predominately IgG1, IgG3, and IgM, and could interact with complement through recruitment of C1q and activation of the classical pathway. The central repeat region of CSP, included in leading vaccines, was a key target of complement-fixing antibodies. We show that antibodies activate human complement on P. falciparum sporozoites, which consequently inhibited hepatocyte cell traversal that is essential for establishing liver-stage infection, and led to sporozoite death in vitro. The natural acquisition of complement-fixing antibodies in malaria-exposed populations was age-dependent, and was acquired more slowly to sporozoite antigens than to merozoite antigens. In a longitudinal cohort of children, high levels of complement-fixing antibodies were significantly associated with protection against clinical malaria. These novel findings point to complement activation by antibodies as an important mechanism of anti-sporozoite human immunity, thereby enabling new strategies for developing highly efficacious malaria vaccines. We also present evidence that complement-fixing antibodies may be a valuable correlate of protective immunity in humans.


Deregulation of STAT-5 isoforms in the development of HPV-mediated cervical carcinogenesis.
Cervical cancer is the second most common cancer and is leading cause of cancer related deaths in women worldwide. High Risk-Human papillomavirus (HPV) types play an important role in cervical carcinogenesis. Considering the important role of signal transducer and activator of transcription-5 (STAT-5), an important member of JAK/STAT family which plays a crucial role in various cancers and HPV as a key mediator in the development of cervical carcinogenesis, the purpose of the current study was to examine the possible relationship between HPV infection and expression of STAT-5 gene isoforms in cervical cancer. A total of 120 fresh cervical tissue specimens comprising precancer (n = 12), cancer (n = 78) and normal controls (n = 30) were analyzed for HPV infection and expression pattern of STAT-5 mRNA (both isoforms STAT-5a and STAT-5b) and protein in different stages of cervical carcinoma biopsies by reverse-transcriptase-PCR, western blotting and immunohistochemistry. A significantly increased expression of STAT-5 was detected in most of the cervical tumors (P < 0.001), whereas it was almost undetectable in normal controls. Also the study of relative contribution of STAT-5 isoforms revealed a higher expression pattern of STAT-5b and was associated with severity of the disease. On the contrary, STAT-5a was found to be significantly downregulated in cervical tumor tissues (P < 0.001). HPV infection was found in 90% of the cervical cancer cases and was significantly associated with STAT-5 overexpression (P = 0.001). We observed for the first time the differential expression pattern of STAT-5 isoforms in cervical cancer and that STAT-5 may play an important role in the progression of HPV-mediated cervical cancer.


Gall stone disease without gall stones--bile acid and bile lipid metabolism after complete gall stone dissolution.
Although bile acid and bile lipid metabolism have been studied in established cholelithiasis, little is known about them in patients destined to develop gall stones, but in whom the stones have not yet appeared (prestone gall stone disease). After confirmed complete gall stone dissolution and withdrawal of treatment, gall stones recur frequently. Before the stones reappear, these patients have 'poststone gall stone disease'. In 13 such patients we confirmed complete gall stone dissolution with two normal cholecystograms and in 11 of the 13 by normal ultrasonography, measured bile acid and bile lipid composition in fasting duodenal bile, bile acid synthesis from marker corrected three day faecal bile acid excretion, bile acid pool size using an abbreviated isotope dilution technique, 'steady-state' bile lipid secretion using a duodenal amino acid perfusion system and then calculated the enterohepatic cycling frequency of the bile acid pool and the relationship between pool size and body weight. The results confirm that after withdrawal of treatment the biliary cholesterol saturation index reverts to levels (1.6 +/- SEM 0.4) comparable with those before dissolution therapy first began (1.6 +/- 0.2; NS). The mean bile acid pool size in the 13 patients of 4.4 +/- 0.5 mmol was comparable with that in untreated gall stone patients. Pool size was significantly smaller in the nine non-obese patients (3.5 +/- 0.3), than in the four obese (6.0 +/- 0.8; p less than 0.05). It also correlated significantly with body weight (r = 0.72) and with %IBW (r = 0.79). The coefficients of variation for biliary bile acid, phospholipid and cholesterol secretion were high, but the mean hourly secretion rates were of the same order as those seen in untreated gall stone patients studied with the amino acid duodenal perfusion stimulus. These results provide a baseline for assessing the response to postdissolution treatment and may indicate metabolic events leading to gall stone formation.


Physician response to financial incentives when choosing drugs to treat breast cancer.
This paper considers physician agency in choosing drugs to treat metastatic breast cancer, a clinical setting in which patients have few protections from physicians' rent seeking. Physicians have explicit financial incentives attached to each potential drug treatment, with profit margins ranging more than a hundred fold. SEER-Medicare claims and Medispan pricing data were formed into a panel of 4,503 patients who were diagnosed with metastatic breast cancer and treated with anti-cancer drugs from 1992 to 2002. We analyzed the effects of product attributes, including profit margin, randomized controlled trial citations, FDA label, generic status, and other covariates on therapy choice. Instruments and drug fixed effects were used to control for omitted variables and possible measurement error associated with margin. We find that increasing physician margin by 10% yields between an 11 and 177% increase in the likelihood of drug choice on average across drugs. Physicians were more likely to use drugs with which they had experience, had more citations, and were FDA-approved to treat breast cancer. Oncologists are susceptible to financial incentives when choosing drugs, though other factors play a large role in their choice of drug.


Children's head motion during fMRI tasks is heritable and stable over time.
Head motion during fMRI scans negatively impacts data quality, and as post-acquisition techniques for addressing motion become increasingly stringent, data retention decreases. Studies conducted with adult participants suggest that movement acts as a relatively stable, heritable phenotype that serves as a marker for other genetically influenced phenotypes. Whether these patterns extend downward to childhood has critical implications for the interpretation and generalizability of fMRI data acquired from children. We examined factors affecting scanner motion in two samples: a population-based twin sample of 73 participants (ages 7-12 years) and a case-control sample of 32 non-struggling and 78 struggling readers (ages 8-11 years), 30 of whom were scanned multiple times. Age, but not ADHD symptoms, was significantly related to scanner movement. Movement also varied as a function of task type, run length, and session length. Twin pair concordance for head motion was high for monozygotic twins and moderate for dizygotic twins. Cross-session test-retest reliability was high. Together, these findings suggest that children's head motion is a genetically influenced trait that has the potential to systematically affect individual differences in BOLD changes within and across groups. We discuss recommendations for future work and best practices for pediatric neuroimaging.


A human axillary odorant is carried by apolipoprotein D.
The characterization of the source of the odor in the human axillary region is not only of commercial interest but is also important biologically because axillary extracts can alter the length and timing of the female menstrual cycle. In males, the most abundant odor component is known to be E-3-methyl-2-hexenoic acid (E-3M2H), which is liberated from nonodorous apocrine secretions by axillary microorganisms. Recently, it was found that in the apocrine gland secretions, 3M2H is carried to the skin surface bound to two proteins, apocrine secretion odor-binding proteins 1 and 2 (ASOB1 and ASOB2) with apparent molecular masses of 45 kDa and 26 kDa, respectively. To better understand the formation of axillary odors and the structural relationship between 3M2H and its carrier protein, the amino acid sequence and glycosylation pattern of ASOB2 were determined by mass spectrometry. The ASOB2 protein was identified as apolipoprotein D (apoD), a known member of the alpha2mu-microglobulin superfamily of carrier proteins also known as lipocalins. The pattern of glycosylation for axillary apoD differs from that reported for plasma apoD, suggesting different sites of expression for the two glycoproteins. In situ hybridization of an oligonucleotide probe against apoD mRNA with axillary tissue demonstrates that the message for synthesis of this protein is specific to the apocrine glands. These results suggest a remarkable similarity between human axillary secretions and nonhuman mammalian odor sources, where lipocalins have been shown to carry the odoriferous signals used in pheromonal communication.


Molecular landscapes of human hematopoietic stem cells in health and leukemia.
Blood cells are organized as a hierarchy with hematopoietic stem cells (HSCs) at the root. The advent of genomic technologies has opened the way for global characterization of the molecular landscape of HSCs and their progeny, both in mouse and human models, at the genetic, transcriptomic, epigenetic, and proteomics levels. Here, we outline our current understanding of the molecular programs that govern human HSCs and how dynamic changes occurring during HSC differentiation are necessary for well-regulated blood formation under homeostasis and upon injury. A large body of evidence is accumulating on how the programs of normal hematopoiesis are modified in acute myeloid leukemia, an aggressive adult malignancy driven by leukemic stem cells. We summarize these findings and their clinical implications.


The Relative Functionality of Freshly Isolated and Cryopreserved Human Adipose-Derived Stromal/Stem Cells.
The capability of multipotent mesenchymal stem cells to maintain cell viability, phenotype and differentiation ability upon thawing is critical if they are to be banked and used for future therapeutic purposes. In the present study, we examined the effect of 9-10 months of cryostorage on the morphology, immunophenotype, colony-forming unit (CFU) and differentiation capacity of fresh and cryopreserved human adipose-derived stromal/stem cells (ASCs) from the same donors. Cryopreservation did not reduce the CFU frequency and the expression levels of CD29, CD73, CD90 and CD105 remained unchanged with the exception of CD34 and CD45; however, the differentiation capacity of cryopreserved ASCs relative to fresh cells was significantly reduced. While our findings suggest that future studies are warranted to improve cryopreservation methods and agents, cryopreserved ASCs retain sufficient features to ensure their practical utility for both research and clinical applications.


Surgonomics as a health care financing policy for hospitalized surgical patients.
The Medicare system of prospective payment to hospitals based on diagnostic related groups (DRG) has been severely criticized at a number of levels. Many states are using DRG prospective "All Payor Systems" for reimbursement to hospitals with the federal DRG system as a model. In All Payor Systems, Medicare, Medicaid, Blue Cross and other commercial insurers pay by the DRG mode; the state of New York has been All Payor since 1 January 1988. This study simulated DRG All Payor methods on a large sample (N = 17,560) of surgical patients for a two year period, using both federal and New York DRG reimbursement methods currently in effect. Both Medicare and Medicaid patients had, on average, a longer length of stay in the hospital and higher total cost of hospitalization compared with patients from Blue Cross and other commercial payors. Medicare and Medicaid patients also had a greater severity of illness compared with patients from Blue Cross or other payors. All except commercial insurors (that is, Medicaid, Blue Cross and Medicare) had greater financial risk under the DRG All Payor scheme. Results from our study suggest that federal, state and private payors may not be adequately reimbursing health care providers for the care of the hospitalized surgical patient under the DRG prospective scheme of hospital payment. It appears that the financing policy for health care, especially at the federal and state level, could limit both the access and quality of care for surgical patients.


Tunable reflectance of an inverse opal-chiral nematic liquid crystal multilayer device by electric- or thermal-control.
A new type of electric- or thermal-responsive multilayer device composed of SiO2 bilayer inverse opal (IOP) and chiral nematic liquid crystals (N*LCs) was developed. Bilayer IOP was fabricated by layer-by-layer assembly of polystyrene (PS) spheres with two different sizes and showed a reflectance in an extended range of the near-infrared region. Furthermore, the electrically or thermally tunable reflectance of the bilayer-IOP-N*LC device was investigated. The device exhibited the photonic bandgap (PBG) of the N*LC-IOP composite structure with the application of an electric field (voltage-on), while it presented the reflectance of N*LCs without an electric field (voltage-off) and the electrically-responsive behaviour could be reversibly switched. Besides, the device exhibited a gradient redshift of reflectance as temperature increased below the clearing point (TC) while it showed the PBG of the N*LC-IOP composite structure when the temperature was above TC.


Expression profiling stratifies mesothelioma tumors and signifies deregulation of spindle checkpoint pathway and microtubule network with therapeutic implications.
Malignant pleural mesothelioma (MPM) is a lethal neoplasm exhibiting resistance to most treatment regimens and requires effective therapeutic options. Though an effective strategy in many cancer, targeted therapy is relatively unexplored in MPM because the therapeutically important oncogenic pathways and networks in MPM are largely unknown. We carried out gene expression microarray profiling of 53 surgically resected MPMs tumors along with paired normal tissue. We also carried out whole transcriptomic sequence (RNA-seq) analysis on eight tumor specimens. Taqman-based quantitative Reverse-transcription polymerase chain reaction (qRT-PCR), western analysis and immunohistochemistry (IHC) analysis of mitotic arrest deficient-like 1 (MAD2L1) was carried out on tissue specimens. Cell viability assays of MPM cell lines were carried out to assess sensitivity to specific small molecule inhibitors. Bioinformatics analysis of the microarray data followed by pathway analysis revealed that the mitotic spindle assembly checkpoint (MSAC) pathway was most significantly altered in MPM tumors with upregulation of 18 component genes, including MAD2L1 gene. We validated the microarray data for MAD2L1 expression using quantitative qRT-PCR and western blot analysis on tissue lysates. Additionally, we analyzed expression of the MAD2L1 protein by IHC using an independent tissue microarray set of 80 MPM tissue samples. Robust clustering of gene expression data revealed three novel subgroups of tumors, with unique expression profiles, and showed differential expression of MSAC pathway genes. Network analysis of the microarray data showed the cytoskeleton/spindle microtubules network was the second-most significantly affected network. We also demonstrate that a nontaxane small molecule inhibitor, epothilone B, targeting the microtubules have great efficacy in decreasing viability of 14 MPM cell lines. Overall, our findings show that MPM tumors have significant deregulation of the MSAC pathway and the microtubule network, it can be classified into three novel molecular subgroups of potential therapeutic importance and epothilone B is a promising therapeutic agent for MPM.


Histopathology of the conduction system in sudden death from coronary heart disease.
Sudden cardiac death (SCD) has been attributed to the development of lethal dysrhythmias in coronary heart disease victims, and several recent autopsy surveys showed that 10 to 50% of SCD patients had unsuspected acute myocardial infarction (AMI). The present study concerned histopathological findings of the conduction system in 49 SCD (within six hours of the onset of acute symptoms) patients; 39 with established AMI (group A) and ten without (group B). Both groups showed high incidence of cardiomegaly, significant coronary artery disease affecting one or more vessels, and acute myocardial ischemia detectable by specific histological criteria. Stenosis of nutrient vessels of the conduction system was present in about 50% of the atrioventricular (A-V) node arteries and about 25% of the sinoatrial (SA) node arteries in both groups of SCD patients. Nonspecific "degenerative" changes (fibrosis, fatty infiltration, or both) of the conduction tissue, which might or might not represent results of old ischemic injury, also occurred with similar frequencies. Acute changes (infarction, hemorrhage) of the A-V node and bundle branches were found only in two group A patients, both had massive septal infarction. Thus, the conduction tissue appeared more resistant to ischemic injury and was overtly damaged only on rare occasions in fatal AMI. The scarcity of acute lesions in the conduction system itself suggested that lethal dysrhythmia in SCD was probably due to electrical instability of the acutely ischemic contractile myocardium rather than a direct injury to the specialized tissue of the heart.


Is there a "Scottish effect" for self reports of health? Individual level analysis of the 2001 UK census.
Scotland's overall health record is comparatively poor for a Western European country, particularly amongst people of working age. A number of previous studies have explored why this might be the case by comparing mortality in Scotland with England and Wales. A study in the 1980s showed that the higher prevalence of deprivation in Scotland accounted for Scotland's excess mortality risk. However, more recent studies suggest that deprivation now explains less of this excess. This has led to the suggestion that there is a yet unidentified "Scottish effect" contributing to Scotland's mortality excess. Recent research has also suggested that there could be an unidentified effect influencing Scotland's higher rate of heart disease. This paper explores whether there is also an unexplained Scottish excess, relative to England, in self reports of poor health. Data came from the individual Sample of Anonymised Records, a 3% random sample of the 2001 UK census. Using logistic regression models, self reports of health (limiting illness and general health) from the working age populations (aged 25 to 64) of Scotland and England were compared. Account was taken of people's country of birth. Stratified analysis by employment status allowed further exploration of Scotland's excess. People born and living in Scotland reported higher levels of poor general health and limiting illness compared to people born and living in England. Adjustment for socioeconomic position and employment status largely explained the higher rates. In the stratified analysis a Scottish excess was seen only amongst the economically inactive born and living in Scotland. For those in employment, people born and living in Scotland actually had slightly lower odds of reporting poor general health and limiting illness than people born and living in England. This analysis suggests that higher rates of poor self reported health in Scotland can be explained by differences in employment and socioeconomic position and so there is unlikely to be an unidentified "Scottish effect" for self reports of health. Scotland's excess of poor general health and limiting illness amongst the economically inactive is probably attributable to its economic and employment history.


Functional bias in molecular evolution rate of Arabidopsis thaliana.
Characteristics derived from mutation and other mechanisms that are advantageous for survival are often preserved during evolution by natural selection. Some genes are conserved in many organisms because they are responsible for fundamental biological function, others are conserved for their unique functional characteristics. Therefore one would expect the rate of molecular evolution for individual genes to be dependent on their biological function. Whether this expectation holds for genes duplicated by whole genome duplication is not known. We empirically demonstrate here, using duplicated genes generated from the Arabidopsis thaliana alpha-duplication event, that the rate of molecular evolution of genes duplicated in this event depend on biological function. Using functional clustering based on gene ontology annotation of gene pairs, we show that some duplicated genes, such as defense response genes, are under weaker purifying selection or under stronger diversifying selection than other duplicated genes, such as protein translation genes, as measured by the ratio of nonsynonymous to synonymous divergence (dN/dS). These results provide empirical evidence indicating that molecular evolution rate for genes duplicated in whole genome duplication, as measured by dN/dS, may depend on biological function, which we characterize using gene ontology annotation. Furthermore, the general approach used here provides a framework for comparative analysis of molecular evolution rate for genes based on their biological function.


A wirelessly controlled implantable LED system for deep brain optogenetic stimulation.
In recent years optogenetics has rapidly become an essential technique in neuroscience. Its temporal and spatial specificity, combined with efficacy in manipulating neuronal activity, are especially useful in studying the behavior of awake behaving animals. Conventional optogenetics, however, requires the use of lasers and optic fibers, which can place considerable restrictions on behavior. Here we combined a wirelessly controlled interface and small implantable light-emitting diode (LED) that allows flexible and precise placement of light source to illuminate any brain area. We tested this wireless LED system in vivo, in transgenic mice expressing channelrhodopsin-2 in striatonigral neurons expressing D1-like dopamine receptors. In all mice tested, we were able to elicit movements reliably. The frequency of twitches induced by high power stimulation is proportional to the frequency of stimulation. At lower power, contraversive turning was observed. Moreover, the implanted LED remains effective over 50 days after surgery, demonstrating the long-term stability of the light source. Our results show that the wireless LED system can be used to manipulate neural activity chronically in behaving mice without impeding natural movements.


Production of chemotactic factor and lymphotoxin by human leukocytes stimulated with Herpes simplex virus.
Peripheral blood leukocytes (PBL) of 41 subjects were tested for their ability to be stimulated by herpes simplex virus antigens as measured by [(3)H]thymidine incorporation and lymphokine production (i.e., lymphocyte-derived chemotactic factor and lymphotoxin). The PBL of seronegative subjects failed to respond to viral antigens as measured by stimulation or lymphokine production. In contrast, PBL from seropositive subjects without clinical lesions of herpes labialis were stimulated by herpes simplex virus antigens and produced lymphokines. PBL from seropositive patients with clinical lesions of herpes labialis also produced lymphokines, but [(3)H]thymidine incorporation was slightly depressed. These findings suggest that lymphocytes from patients with a recent herpes simplex virus infection may respond less vigorously to in vitro stimulation by herpes antigens, but our study fails to show any basic defect in the responsiveness of the lymphocytes to account for recurrent herpetic episodes.


["Let these things speak for themselves". Experiment kits, instruction manuals, and narratives between 1870 and 1930].
Experiment kits, such as physical cabinets, chemistry sets, and electricity kits designed for amateurs and children, gained huge popularity in Germany around 1900. These home laboratories connected themselves to the things of everyday life as objects of investigation and everyday knowledge as their framework of reference. In the previous centuries, portable laboratories had already accompanied travelling scientists and intellectuals. Experiment kits however, while still portable, were designed to serve as extensions of classrooms and lecture halls. The kits--available through teaching materials catalogues and early forms of mail-order catalogues--illustrate the increased attention that was given to experimental practices in general education between 1870 and 1930. An examination of these objects, which consisted of instruments, substances, and supplementary contents arranged in wooden, metal, or paper boxes, together with an analysis of their instruction manuals, shows how the miniature laboratories structured the spaces within which experiments were supposed to take place.


Validation of the updated ArthroS simulator: face and construct validity of a passive haptic virtual reality simulator with novel performance metrics.
To assess the construct and face validity of ArthroS, a passive haptic VR simulator. A secondary aim was to evaluate the novel performance metrics produced by this simulator. Two groups of 30 participants, each divided into novice, intermediate or expert based on arthroscopic experience, completed three separate tasks on either the knee or shoulder module of the simulator. Performance was recorded using 12 automatically generated performance metrics and video footage of the arthroscopic procedures. The videos were blindly assessed using a validated global rating scale (GRS). Participants completed a survey about the simulator's realism and training utility. This new simulator demonstrated construct validity of its tasks when evaluated against a GRS (p ≤ 0.003 in all cases). Regarding it's automatically generated performance metrics, established outputs such as time taken (p ≤ 0.001) and instrument path length (p ≤ 0.007) also demonstrated good construct validity. However, two-thirds of the proposed 'novel metrics' the simulator reports could not distinguish participants based on arthroscopic experience. Face validity assessment rated the simulator as a realistic and useful tool for trainees, but the passive haptic feedback (a key feature of this simulator) is rated as less realistic. The ArthroS simulator has good task construct validity based on established objective outputs, but some of the novel performance metrics could not distinguish between surgical experience. The passive haptic feedback of the simulator also needs improvement. If simulators could offer automated and validated performance feedback, this would facilitate improvements in the delivery of training by allowing trainees to practise and self-assess.


Follow-up of a self-resolving renal pseudoaneurysm using contrast-enhanced power Doppler ultrasonography.
It has been standard practice to embolise a pseudoaneurysm caused by penetrating trauma whenever it is found, even in the absence of overt symptoms. This is a case report of a renal pseudoaneurysm (RPA) caused by a stab wound, which was safely monitored and followed using colour Doppler ultrasonography. On day 1, angiography showed a pseudoaneurysm of the renal artery in the parenchyma and ultrasonography showed blood flow into the pseudoaneurysm. Although abnormal blood flow into the kidney was seen, there appeared to be no leakage of blood from the pseudoaneurysm. The abnormal flow disappeared on day 12 and the area of the pseudoaneurysm became unclear from day 13. This report suggests the possibility that RPA caused by a stab wound could be an indication for conservative therapy under the following conditions: the RPA is detected initially; close monitoring using a colour Doppler ultrasound is possible; there is no leakage of blood from the right subclavian artery and there is a 2-week period of observation.


Pre-pregnancy community-based intervention for couples in Malaysia: application of intervention mapping.
Malaysia is experiencing a nutrition transition with burgeoning obesity, particularly in women, and a growing prevalence of non-communicable disease. These health burdens have severe implications not only for adult health but also across generations. Pre-conception health promotion could address the intergenerational risk of metabolic disease. This paper describes the development of the "Jom Mama" intervention using Intervention Mapping (IM). The Jom Mama intervention aims to improve the health of young adult couples in Malaysia prior to conception. IM comprises of five steps prior to the last one, which involves the evaluation of the intervention. We used the five steps to develop the Jom Mama intervention. Both the process and evidence is documented providing the rationale to the selection of the key objectives of the intervention: (i) increasing healthy dietary practice; (ii) increasing physical activity levels, (iii) reducing sedentary activity; and (iv) improving social support to offset stressful lifestyles. From the IM process, Jom Mama will be health-system centred approach that uniquely combines both community health promoters and an electronic-health platform to deliver the complex intervention. IM is an iterative process that systematically gathers "best" evidence, selects appropriate theories of behaviour change, and facilitates formative research so as to develop a complex intervention. Though the IM process is time consuming, complex, and costly, it has enriched the Jom Mama intervention with a number of notable advantages: (i) intervention fashioned on formative work with stakeholders and in the target group; (ii) intervention combines research evidence with theory; (iii) intervention acknowledges multiple dynamics of influence; and (iv) intervention is embedded within health service priorities in Malaysia for greater scale-up possibility.


Cannabinoid and cholinergic systems interact during performance of a short-term memory task in the rat.
It is now well established that cannabinoid agonists such as Δ(9)-tetrahydrocannabinol (THC), anandamide, and WIN 55,212-2 (WIN-2) produce potent and specific deficits in working memory (WM)/short-term memory (STM) tasks in rodents. Although mediated through activation of CB1 receptors located in memory-related brain regions such as the hippocampus and prefrontal cortex, these may, in part, be due to a reduction in acetylcholine release (i.e., cholinergic hypofunction). To determine the interaction between cannabinoid and cholinergic systems, we exposed rats treated with WIN-2 or cholinergic drugs to a hippocampal-dependent delayed nonmatch to sample (DNMS) task to study STM, and recorded hippocampal single-unit activity in vivo. WIN-2 induced significant deficits in DNMS performance and reduced the average firing and bursting rates of hippocampal principal cells through a CB1 receptor-mediated mechanism. Rivastigmine, an acetylcholinesterase inhibitor, reversed these STM deficits and normalized hippocampal discharge rates. Effects were specific to 1 mg/kg WIN-2 as rivastigmine failed to reverse the behavioral and physiological deficits that were observed in the presence of MK-801, an NMDA receptor antagonist. This supports the notion that cannabinoid-modulated cholinergic activity is a mechanism underlying the performance deficits in DNMS. Whether deficits are due to reduced nicotinic or muscarinic receptor activation, or both, awaits further analysis.


Seasonal patterns of Asthma medication fills among diverse populations of the United States.
Nonadherence to controller and overuse of reliever asthma medications are associated with exacerbations. We aimed to determine patterns of seasonal asthma medication use and to identify time period(s) during which interventions to improve medication adherence could reduce asthma morbidity. We conducted a retrospective cohort study of asthmatics 4-50 years of age and enrolled in three diverse health insurance plans. Seasonal patterns of medications were reported by monthly prescription fill rates per 1000 individuals with asthma from 1998 to 2013, and stratified by healthcare plan, sex, and age. There was a distinct and consistent seasonal fill pattern for all asthma medications. The lowest fill rate was observed in the month of July. Fills increased in the autumn and remained high throughout the winter and spring. Compared with the month of May with high medication fills, July represented a relative decrease of fills ranging from 13% (rate ratio, RR: 0.87, 95% confidence interval, 95%CI: 0.72-1.04) for the combination of inhaled corticosteroids (ICS) + long acting beta agonists (LABA) to 45% (RR: 0.55, 95%CI: 0.49-0.61) for oral corticosteroids. Such a seasonal pattern was observed each year across the 16-year study period, among healthcare plans, sexes, and ages. LABA containing control medication (ICS+LABA and LABA) fill rates were more prevalent in older asthmatics, while leukotriene receptor antagonists were more prevalent in the younger population. A seasonal pattern of asthma medication fill rates likely represents a reactive response to a loss of disease control and increased symptoms. Adherence to and consistent use of asthma medications among individuals who use medications in reaction to seasonal exacerbations might be a key component in reducing the risk of asthma exacerbations.


Continuous in situ measurements of water stable isotopes in soils, tree trunk and root xylem: Field approval.
New methods to measure stable isotopes of soil and tree water directly in the field enable us to increase the temporal resolution of obtained data and advance our knowledge on the dynamics of soil and plant water fluxes. Only few field applications exist. However, these are needed to further improve novel methods and hence exploit their full potential. We tested the borehole equilibration method in the field and collected in situ and destructive samples of stable isotopes of soil, trunk and root xylem water over a 2.5-month experiment in a tropical dry forest under natural abundance conditions and following labelled irrigation. Water from destructive samples was extracted using cryogenic vacuum extraction. Isotope ratios were determined with IRIS instruments using cavity ring-down spectroscopy both in the field and in the laboratory. In general, timelines of both methods agreed well for both soil and xylem samples. Irrigation labelled with heavy hydrogen isotopes clearly impacted the isotope composition of soil water and one of the two studied tree species. Inter-method deviations increased in consequence of labelling, which revealed their different capabilities to cover spatial and temporal heterogeneities. We applied the novel borehole equilibration method in a remote field location. Our experiment reinforced the potential of this in situ method for measuring xylem water isotopes in both tree trunks and roots and confirmed the reliability of gas permeable soil probes. However, in situ xylem measurements should be further developed to reduce the uncertainty within the range of natural abundance and hence enable their full potential.


Searching for optimal sensory signals: iterative stimulus reconstruction in closed-loop experiments.
Shaped by evolutionary processes, sensory systems often represent behaviorally relevant stimuli with higher fidelity than other stimuli. The stimulus dependence of neural reliability could therefore provide an important clue in a search for relevant sensory signals. We explore this relation and introduce a novel iterative algorithm that allows one to find stimuli that are reliably represented by the sensory system under study. To assess the quality of a neural representation, we use stimulus reconstruction methods. The algorithm starts with the presentation of an initial stimulus (e.g. white noise). The evoked spike train is recorded and used to reconstruct the stimulus online. Within a closed-loop setup, this reconstruction is then played back to the sensory system. Iterating this procedure, the newly generated stimuli can be better and better reconstructed. We demonstrate the feasibility of this method by applying it to auditory receptor neurons in locusts. Our data show that the optimal stimuli often exhibit pronounced sub-threshold periods that are interrupted by short, yet intense pulses. Similar results are obtained for simple model neurons and suggest that these stimuli are encoded with high reliability by a large class of neurons.


Impact of tobacco use on the development of opportunistic respiratory infections in HIV seropositive patients on antiretroviral therapy.
The increased risk of developing lung diseases in cigarette smokers has been well recognized. The association between smoking and the risk of developing pulmonary infections in HIV-1-infected patients, however, which has not been established, was evaluated in the present study. Twenty-seven cases with lower respiratory infections (15 Pneumocystis carinii pneumonia (PCP), 12 TB cases) were compared with 27 age, gender, socio-economic and HIV status-matched patients, without history of respiratory diseases. Medical history and physical examinations were obtained every 6 months. Blood was drawn for CD4 and viral load measurements. A substantial number of HIV + smokers who developed PCP (one-third) had been on highly active retroviral therapy (HAART) for more than 6 months and prophylaxis had been discontinued. Multivariate analyses indicated that in HIV-infected people, after controlling for HIV status and antiretrovirals, cigarette smoking doubled the risk for developing PCP (p = 0.01). Multivariate analyses demonstrated that long-term smoking also increased the risk (2 x) of developing tuberculosis (p = 0.04). Moreover, daily tobacco use seemed to attenuate by 40% the immune and virological response to antiretroviral therapies. These findings indicate that tobacco use significantly increases the risk of pulmonary diseases in HIV infected subjects and has a potential deleterious impact on antiretroviral treatment.