Urinary Oxygenation as a Surrogate Measure of Medullary Oxygenation During Angiotensin II Therapy in Septic Acute Kidney Injury.
Angiotensin II is an emerging therapy for septic acute kidney injury, but it is unknown if its vasoconstrictor action induces renal hypoxia. We therefore examined the effects of angiotensin II on intrarenal PO2 in ovine sepsis. We also assessed the validity of urinary PO2 as a surrogate measure of medullary PO2. Interventional study. Research Institute. Sixteen adult Merino ewes (n = 8/group). Sheep were instrumented with fiber-optic probes in the renal cortex, medulla, and within a bladder catheter to measure PO2. Conscious sheep were infused with Escherichia coli for 32 hours. At 24-30 hours, angiotensin II (0.5-33.0 ng/kg/min) or saline vehicle was infused. Septic acute kidney injury was characterized by hypotension and a 60% ± 6% decrease in creatinine clearance. During sepsis, medullary PO2 decreased from 36 ± 1 to 30 ± 3 mm Hg after 1 hour and to 20 ± 2 mm Hg after 24 hours; at these times, urinary PO2 was 42 ± 2, 34 ± 2, and 23 ± 2 mm Hg. Increases in urinary neutrophil gelatinase-associated lipocalin (12% ± 3%) and serum creatinine (60% ± 23%) were only detected at 8 and 24 hours, respectively. IV infusion of angiotensin II, at 24 hours of sepsis, restored arterial pressure and improved creatinine clearance, while not exacerbating medullary or urinary hypoxia. In septic acute kidney injury, renal medullary and urinary hypoxia developed several hours before increases in currently used biomarkers. Angiotensin II transiently improved renal function without worsening medullary hypoxia. In septic acute kidney injury, angiotensin II appears to be a safe, effective therapy, and urinary PO2 may be used to detect medullary hypoxia.


Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial.
This study was conducted to compare the efficacy and safety profiles of exenatide and insulin glargine therapy in patients with type 2 diabetes who had not achieved glucose control with metformin or sulfonylurea monotherapy. This multinational, randomized, open-label, crossover noninferiority study compared the efficacy of exenatide 10 pg BID and insulin glargine QD (titrated targeting a fasting serum glucose (FSG) level < or =5.6 mmol/L) in patients with type 2 diabetes treated with a single oral antidiabetic agent. The study included two 16-week treatment periods. The primary a priori outcome variable was the change in glycosylated hemoglobin (HbA(lc)). Secondary outcomes included the proportion of patients achieving the American Diabetes Association (ADA) target HbA(lc) of < or =7% and the European Association for the Study of Diabetes target of < or =6.5%, the change in FSG, end-point values and change in the 7-point self-monitored glucose profile, and change in body weight. Adverse events were assessed based on standard laboratory tests and patient reports. One hundred thirty-eight patients were randomized to study treatment (52.9% female, 47.1% male; 79.7% white; mean [SEM] age, 54.9 [0.8] years; duration of diabetes, 7.4 [0.4] years; body mass index, 31.1 [0.4] kg/m(2); weight, 84.8 [1.4] kg) while continuing to receive metformin (55.1%) or a sulfonylurea (44.9%). The population had a baseline least squares (LS) mean (SEM) HbA(lc) of 8.95% (0.09%) and an LS mean FSG concentration of 12.0 (0.3) mmol/L. Both exenatide and titrated insulin glargine therapy were associated with similar significant changes from baseline in HbA(1c) (both, -1.36% [0.09%]; P < 0.001); the difference between groups was not statistically significant. The LS mean HbA(1c) at end point was above the ADA target with both treatments (exenatide, 7.57% [0.09%]; insulin glargine, 7.58% [0.09%]). Similar proportions of patients achieved an HbA(1c) < or =7% (37.5% and 39.8%, respectively; P = NS) or < or =6.5% (21.5% and 13.6%). Patients lost weight during exenatide treatment, whereas they gained weight during insulin glargine treatment; the between-group difference in weight change was statistically significant (LS mean difference, -2.2 [0.3] kg; 95% CI, -2.8 to-1.7; P < 0.001). Both exenatide and insulin glargine were associated with significant reductions from baseline in FSG (-2.9 [0.2] and -4.1 [0.2] mmol/L, respectively; both, P < 0.001), although the reduction was significantly greater with insulin glargine compared with exenatide (LS mean difference, 1.2 [0.3] mmol/L; 95% CI, 0.7 to 1.7; P < 0.001). Compared with insulin glargine, exenatide was associated with significantly lower 2-hour postprandial glucose (PPG) excursions (P < 0.016) and total daily mean glucose excursion (P < 0.001). The proportions of patients reporting nausea during exenatide and insulin glargine treatment were 42.6% and 3.1%, respectively; the proportions reporting vomiting were 9.6% and 3.1%. The incidence of hypoglycemia in the 2 groups was 14.7% and 25.2% (P = NS). In this open-label, crossover study, treatment with exenatide or insulin glargine for 16 weeks was associated with similar significant improvements from baseline in HbA(1c), independent of treatment order. The improvements in HbA(1c) from baseline did not differ significantly between treatment groups. Exenatide therapy was associated with significant reductions in body weight and PPG excursions compared with insulin glargine, whereas insulin glargine was associated with a significantly greater reduction in FSG compared with exenatide. These findings provide additional information to guide treatment decisions in patients with type 2 diabetes who are potential candidates for either therapy.


Adiponectin confers protection from acute colitis and restricts a B cell immune response.
Adiponectin demonstrates beneficial effects in various metabolic diseases, including diabetes, and in bowel cancer. Recent data also suggest a protective role in colitis. However, the precise molecular mechanisms by which adiponectin and its receptors modulate colitis and the nature of the adaptive immune response in murine models are yet to be elucidated. Adiponectin knock-out mice were orally administered dextran sulfate sodium for 7 days and were compared with wild-type mice. The severity of disease was analyzed histopathologically and through cytokine profiling. HCT116 colonic epithelial cells were employed to analyze the in vitro effects of adiponectin and AdipoR1 interactions in colonic injury following dextran sulfate sodium treatment. Adiponectin knock-out mice receiving dextran sulfate sodium exhibited severe colitis, had greater inflammatory cell infiltration, and an increased presence of activated B cells compared with controls. This was accompanied by an exaggerated proinflammatory cytokine profile and increased STAT3 signaling. Adiponectin knock-out mouse colons had markedly reduced proliferation and increased epithelial apoptosis and cellular stress. In vitro, adiponectin reduced apoptotic, anti-proliferative, and stress signals and restored STAT3 signaling. Following the abrogation of AdipoR1 in vitro, these protective effects of adiponectin were abolished. In summary, adiponectin maintains intestinal homeostasis and protects against murine colitis through interactions with its receptor AdipoR1 and by modulating adaptive immunity.


KITlow Cells Mediate Imatinib Resistance in Gastrointestinal Stromal Tumor.
Gastrointestinal stromal tumor (GIST) is commonly driven by oncogenic KIT mutations that are effectively targeted by imatinib (IM), a tyrosine kinase inhibitor (TKI). However, IM does not cure GIST, and adjuvant therapy only delays recurrence in high-risk tumors. We hypothesized that GIST contains cells with primary IM resistance that may represent a reservoir for disease persistence. Here, we report a subpopulation of CD34+KITlow human GIST cells that have intrinsic IM resistance. These cells possess cancer stem cell-like expression profiles and behavior, including self-renewal and differentiation into CD34+KIThigh progeny that are sensitive to IM treatment. We also found that TKI treatment of GIST cell lines led to induction of stem cell-associated transcription factors (OCT4 and NANOG) and concomitant enrichment of the CD34+KITlow cell population. Using a data-driven approach, we constructed a transcriptomic-oncogenic map (Onco-GPS) based on the gene expression of 134 GIST samples to define pathway activation during GIST tumorigenesis. Tumors with low KIT expression had overexpression of cancer stem cell gene signatures consistent with our in vitro findings. Additionally, these tumors had activation of the Gas6/AXL pathway and NF-κB signaling gene signatures. We evaluated these targets in vitro and found that primary IM-resistant GIST cells were effectively targeted with either single-agent bemcentinib (AXL inhibitor) or bardoxolone (NF-κB inhibitor), as well as with either agent in combination with IM. Collectively, these findings suggest that CD34+KITlow cells represent a distinct, but targetable, subpopulation in human GIST that may represent a novel mechanism of primary TKI resistance, as well as a target for overcoming disease persistence following TKI therapy.


Social support and antenatal depression in extended and nuclear family environments in Turkey: a cross-sectional survey.
Social support is strongly implicated in the aetiology of perinatal mental disorder: particularly the quality of the marital and family environment. Family structures are important under-researched potential modifiers. Turkey offers particular advantages for research in this area because of long-standing coexistence of Western and Middle Eastern family structures. We aimed to investigate associations between the quality of key relationships and depression in women in their third trimester of pregnancy, and the extent to which these associations were modified by family structure. Women attending antenatal clinics in their third trimester were recruited from urban and rural settings in Ankara. A nuclear family structure was defined as a wife and husband living alone or with their children in the same household, whereas a traditional/extended family structure was defined if another adult was living with the married couple in the same household. Depression was ascertained using the Edinburgh Postnatal Depression Scale (EPDS) and social support was assessed by the Close Person Questionnaire with respect to the husband, mother and mother-in-law. Social support was compared between participants with/without case-level depression on the EPDS in linear regression models adjusted for relevant covariates, then stratified by nuclear/traditional family structure. Of 772 women approached, 751 (97.3%) participated and 730 (94.6%) had sufficient data for this analysis. Prevalence of case-level depression was 33.1% and this was associated with lower social support from all three family members but not with traditional/nuclear family structure. The association between depression and lower emotional support from the husband was significantly stronger in traditional compared to nuclear family environments. Lower quality of relationships between key family members was strongly associated with third trimester depression. Family structure modified the association but, contrary to expectations, spousal emotional support was a stronger correlate of antenatal depression in traditional rather than nuclear family settings. Previous psychiatric history was not formally ascertained and the temporal relationship between mood state and social support needs to be clarified.


Clinical encounters in tactical medicine: a mission-specific analysis of the Maryland State Police experience.
The Maryland State Police (MSP) Tactical Medical Unit (TMU) provides tactical emergency medical support (TEMS) through the deployment of specially trained state trooper tactical paramedics. The MSP TMU maintains an operational database of all mission related medical activity. This information constitutes a robust dataset derived from real world operational medicine experiences. A retrospective analysis of de-identified entries from the MSP TMU operational response database was performed for the 5-year period of 2007?2013. A summative analysis of missions, as well as a subgroup analysis of types of patients encountered, was performed to further characterize patient encounters based on the type of law enforcement tactical mission. Analysis was performed on 1,042 tactical missions, of which there were 367 total patient encounters during the study period. The majority (67%; 246/367) of patients encountered were law enforcement tactical team personnel. The most frequently occurring mission, by type, was high-risk warrant service, accounting for 45% (470/1,042) of all missions in this series. Law enforcement training support missions comprised 25% (259/1,042), and 15% (157/1,042) of all missions in the database were medical standbys for law enforcement operations. The highest number of patient contacts were associated with training activities, resulting in 29% (108/367) of clinical encounters. The next most common mission associated with patient encounters was high-risk warrant service (24%; 88/367). The 5-year analysis conducted in this study represents the largest known retrospective assessment of a state police tactical medical program. Training activities resulted in the highest number of patient encounters by this program, with law enforcement/tactical team personnel comprising the majority of patient encounters. The majority of chief complaints encountered were non?life threatening and reinforce the need for expanded scope of practice training and enhanced treatment protocols for tactical medics.


Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation).
Haloperidol used alone is recommended to help calm situations of aggression or agitation for people with psychosis. It is widely accessible and may be the only antipsychotic medication available in limited-resource areas. To examine whether haloperidol alone is an effective treatment for psychosis-induced aggression or agitation, wherein clinicians are required to intervene to prevent harm to self and others. We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (26th May 2016). This register is compiled by systematic searches of major resources (including AMED, BIOSIS CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings, with no language, date, document type, or publication status limitations for inclusion of records into the register. Randomised controlled trials (RCTs) involving people exhibiting aggression and/or agitation thought to be due to psychosis, allocated rapid use of haloperidol alone (by any route), compared with any other treatment. Outcomes of interest included tranquillisation or asleep by 30 minutes, repeated need for rapid tranquillisation within 24 hours, specific behaviours (threat or injury to others/self), adverse effects. We included trials meeting our selection criteria and providing useable data. We independently inspected all citations from searches, identified relevant abstracts, and independently extracted data from all included studies. For binary data we calculated risk ratio (RR), for continuous data we calculated mean difference (MD), and for cognitive outcomes we derived standardised mean difference (SMD) effect sizes, all with 95% confidence intervals (CI) and using a fixed-effect model. We assessed risk of bias for the included studies and used the GRADE approach to produce 'Summary of findings' tables which included our pre-specified main outcomes of interest. We found nine new RCTs from the 2016 update search, giving a total of 41 included studies and 24 comparisons. Few studies were undertaken in circumstances that reflect real-world practice, and, with notable exceptions, most were small and carried considerable risk of bias. Due to the large number of comparisons, we can only present a summary of main results.Compared with placebo, more people in the haloperidol group were asleep at two hours (2 RCTs, n=220, RR 0.88, 95%CI 0.82 to 0.95, very low-quality evidence) and experienced dystonia (2 RCTs, n=207, RR 7.49, 95%CI 0.93 to 60.21, very low-quality evidence).Compared with aripiprazole, people in the haloperidol group required fewer injections than those in the aripiprazole group (2 RCTs, n=473, RR 0.78, 95%CI 0.62 to 0.99, low-quality evidence). More people in the haloperidol group experienced dystonia (2 RCTs, n=477, RR 6.63, 95%CI 1.52 to 28.86, very low-quality evidence).Four trials (n=207) compared haloperidol with lorazepam with no significant differences with regard to number of participants asleep at one hour (1 RCT, n=60, RR 1.05, 95%CI 0.76 to 1.44, very low-quality of evidence) or those requiring additional injections (1 RCT, n=66, RR 1.14, 95%CI 0.91 to 1.43, very low-quality of evidence).Haloperidol's adverse effects were not offset by addition of lorazepam (e.g. dystonia 1 RCT, n=67, RR 8.25, 95%CI 0.46 to 147.45, very low-quality of evidence).Addition of promethazine was investigated in two trials (n=376). More people in the haloperidol group were not tranquil or asleep by 20 minutes (1 RCT, n=316, RR 1.60, 95%CI 1.18 to 2.16, moderate-quality evidence). Acute dystonia was too common in the haloperidol alone group for the trial to continue beyond the interim analysis (1 RCT, n=316, RR 19.48, 95%CI 1.14 to 331.92, low-quality evidence). Additional data from new studies does not alter previous conclusions of this review. If no other alternative exists, sole use of intramuscular haloperidol could be life-saving. Where additional drugs are available, sole use of haloperidol for extreme emergency could be considered unethical. Addition of the sedating promethazine has support from better-grade evidence from within randomised trials. Use of an alternative antipsychotic drug is only partially supported by fragmented and poor-grade evidence. Adding a benzodiazepine to haloperidol does not have strong evidence of benefit and carries risk of additional harm.After six decades of use for emergency rapid tranquillisation, this is still an area in need of good independent trials relevant to real-world practice.


Ultrastructural biology of Leishmania (Viannia) panamensis (=Leishmania braziliensis panamensis) in Lutzomyia gomezi (Diptera: Psychodidae): a natural host-parasite association.
The development of Leishmania (Viannia) panamensis in a natural sand fly host, Lutzomyia gomezi, was studied by light and transmission electron microscopy. New aspects of peripylarian parasite behavior and morphology in the sand fly gut, early bloodmeal stages, and ultrastructural development in the anterior gut were documented. Eight distinct morphological forms were observed in the life cycle of the parasite within the insect. In the bloodmeal, amastigotes (1) transformed into stumpy promastigotes (2) which rapidly multiplied, resulting in spatulate-shaped nectomonad promastigotes (3) and elongate nectomonad promastigotes (4). These latter forms migrated primarily into the hindgut, where both were observed attached (=haptomonad phase) to the cuticular intima by hemidesmosomes within extremely shortened flagella. Spatulate haptomonad promastigotes predominated, colonizing the entire length of the hindgut, with the greatest density at 2 disjunct sites: the pylorus/ileum and the anterior rectum/rectal sac. Paramastigotes and dividing flagellates were rare. Some parasites migrated directly to the cardia/stomodeal valve region without a hindgut phase; however, major movement anteriorly was from the hindgut beginning at 6 days postinfection. In the cardia lumen, dividing short Type A promastigotes (5) predominated, intermixed with short Type B promastigotes with longer flagella (6). Paramastigotes (7) were free-swimming in the lumen as well as attached to the stomodeal valve. The primary colonizers of the valve were pear-shaped haptomonad promastigotes (8), with flagella of variable lengths and multi-segmented hemidesmosomal attachment points to the intima. Promastigotes and paramastigotes colonized the esophagus-pharynx region and attached to the foregut lining by flagellar hemidesmosomes. Both forms may represent infective stages of L. (V.) panamensis; however, no parasites were detected in the cibarium or proboscis. L. (V.) panamensis appeared well-adapted to the gut of Lu. gomezi, multiplying extensively at 2 sites, changing morphological form, and adhering to host surfaces by variously modified flagellar hemidesmosomes.


The distinction of positive and negative symptoms. The failure of a two-dimensional model.
The distinction of positive and negative symptoms in describing schizophrenic patients has become popular. It presupposes that symptoms cluster in two dimensions, fitting together not only theoretically but empirically. Factor analysis of three published studies of 93, 62 and 52 schizophrenic patients and a large pooled sample showed that more than two distinct dimensions are required to categorise symptoms in schizophrenia. This result is consistent across methods and samples, and with previous literature. The added dimensionality resulted from a splitting of the positive symptom domain into more distinct factors.


Effects of nicotinic dimethylaminoethyl esters on working memory performance of rats in the radial-arm maze.
Nicotine has been found to improve memory performance in a variety of tests, including the radial-arm maze. This improvement, together with the consistent finding of a decline in cortical nicotinic receptor concentration in Alzheimer's patients, has fueled the search for novel nicotinic ligands with therapeutic potential. In the current studies, a series of nicotinic compounds was tested for effects on working memory performance in the radial-arm maze. One of the three compounds tested, DMAE II (dimethylaminoethanol cyclohexyl carboxylate fumurate), produced significant improvements in working memory performance. In the first experiment, this drug produced a biphasic dose-response curve with improved performance at the 20-mg/kg dose but not at 10 or 40 mg/kg. In a second round of DMAE II administration, the same rats showed a significant improvement with the 40-mg/kg dose. In the second experiment, a new set of rats also showed a biphasic dose-response to DMAE II. The 20-mg/kg dose caused a significant improvement whereas the 40-mg/kg dose did not. Interactions of DMAE II with nicotine and mecamylamine were also studied. Nicotine (0.2 mg/kg) by itself caused a significant improvement in working memory performance. No additive effects of DMAE II with nicotine were seen. In fact, some attenuation of response was seen with the combination. Choice accuracy data for mecamylamine could not be analyzed because of excessive sedation and nonresponding. These studies show that, like nicotine, the nicotinic ligand DMAE II causes an improvement in radial-arm mace choice accuracy. The lack of additivity with nicotine may have been to the partial agonist effects of DMAE II.


Clinico-hematological and thromboelastographic profiles in glanzmann's thrombasthenia.
: Glanzmann's thrombasthenia is a rare inherited bleeding disorder characterized by the quantitative or qualitative defect of glycoprotein IIb/IIIa receptor on platelets which leads to ineffective aggregation. Light transmittance aggregometry is considered as the gold standard for diagnosis of Glanzmann's thrombasthenia. Thromboelastography (TEG) is a global hemostatic assay which measures clot formation, clot strengthening and fibrinolysis. This study evaluates the clinical, laboratory and TEG profiles in patients with Glanzmann's thrombasthenia. Bleeding score by (International Society on Thrombosis and Haemostasis) ISTH-bleeding assessment tool (bleeding score), laboratory tests to diagnose Glanzmann's thrombasthenia, and TEG parameters were correlated in 11 Glanzmann's thrombasthenia patients. Seventeen participants with normal bleeding score were included as controls. Bleeding score was increased in all patients. The highest bleeding score was in an adult female (26), whereas the lowest score (4) was in two children of less than 1 year. Majority of TEG parameters (except R-time) showed a statistically significant difference between Glanzmann's thrombasthenia patients and controls (K-time: P < 0.001, angle: P < 0.001, maximum amplitude: P < 0.001). The average time required to record the maximum amplitude was 23 min. Maximum amplitude was markedly reduced in all Glanzmann's thrombasthenia patients with an average of 20.9 mm (reference range 44-68 mm) having 100% sensitivity. The thromboelastographic profile of Glanzmann's thrombasthenia showed a consistently reduced maximum amplitude. Hence reduced maximum amplitude with a normal platelet count, significant bleeding score and prolonged bleeding time could potentially be used as a preliminary algorithm for the diagnosis of Glanzmann's thrombasthenia.


Effects of a post-weaning cafeteria diet in young rats: metabolic syndrome, reduced activity and low anxiety-like behaviour.
Among adolescents, overweight, obesity and metabolic syndrome are rapidly increasing in recent years as a consequence of unhealthy palatable diets. Animal models of diet-induced obesity have been developed, but little is known about the behavioural patterns produced by the consumption of such diets. The aim of the present study was to determine the behavioural and biochemical effects of a cafeteria diet fed to juvenile male and female rats, as well as to evaluate the possible recovery from these effects by administering standard feeding during the last week of the study. Two groups of male and female rats were fed with either a standard chow diet (ST) or a cafeteria (CAF) diet from weaning and for 8 weeks. A third group of males (CAF withdrawal) was fed with the CAF diet for 7 weeks and the ST in the 8th week. Both males and females developed metabolic syndrome as a consequence of the CAF feeding, showing overweight, higher adiposity and liver weight, increased plasma levels of glucose, insulin and triglycerides, as well as insulin resistance, in comparison with their respective controls. The CAF diet reduced motor activity in all behavioural tests, enhanced exploration, reduced anxiety-like behaviour and increased social interaction; this last effect was more pronounced in females than in males. When compared to animals only fed with a CAF diet, CAF withdrawal increased anxiety in the open field, slightly decreased body weight, and completely recovered the liver weight, insulin sensitivity and the standard levels of glucose, insulin and triglycerides in plasma. In conclusion, a CAF diet fed to young animals for 8 weeks induced obesity and metabolic syndrome, and produced robust behavioural changes in young adult rats, whereas CAF withdrawal in the last week modestly increased anxiety, reversed the metabolic alterations and partially reduced overweight.


Differential transcriptional effects of PTH and estrogen during anabolic bone formation.
The aim of this study was to compare transcriptional regulation in vivo during anabolic bone formation induced by either estradiol (E2) treatment or intermittent parathyroid hormone[1-34] (PTH) therapy. We utilized an ovariectomized (OVX) mouse model of osteoporosis and transcriptional profiling to identify genes upregulated by either high-dose E2 or PTH. Five weeks post-OVX, the mice were administered either E2 and/or PTH, or vehicle for 4 weeks. Femoral bones were analyzed by microCT and histomorphometry to confirm the anabolic effect of each treatment. OVX vehicle-treated control mice lost metaphyseal trabecular bone, with significant decrease in trabecular number, thickness, and connectivity. Both E2 and PTH treatments increased trabecular and cortical bone indices above the level of the sham operated controls, fully restoring both bone volume and bone mineral density (BMD). Moreover, PTH/E2 combination treatment led to significantly greater increase in cancellous bone and BMD than would be expected from the additive effects of the separate treatments. To determine whether PTH and E2 treatments were stimulating similar bone anabolic mechanisms, or were activating distinct signaling pathways, we compared patterns of gene expression using transcriptional profiling after either E2 or PTH treatment. After 4, 11, and 24 days of treatment, total RNA was collected from both the distal femoral metaphysis and diaphysis. Transcriptional profiling was performed using Affymetrix GeneChip probe arrays, comprised of approximately 36,000 full-length mouse genes and EST clusters from the UniGene database. Several markers of osteoblast activity, including c-fos, RANKL, PHEX, and PTHR1, were consistently upregulated by PTH in both skeletal sites. PTH treatment also increased expression of Cathespin K, consistent with the predicted increase in osteoclast activity. E2 treatment upregulated a largely distinct set of genes, including TGFbeta3, and BMP1, as well as several genes critical for cell cycle control, including Cyclin D1 and CDK inhibitor 1A. Overall, comparison of transcriptional profiles suggest that anabolic responses in bone to PTH and high-dose E2 treatment after OVX-induced osteoporosis involve largely distinct patterns of gene regulation, each resulting in restoration of bone mass.


Treatment of nonalcoholic fatty liver disease: role of AMPK.
Nonalcoholic fatty liver disease (NAFLD) is a growing worldwide epidemic and an important risk factor for the development of insulin resistance, type 2 diabetes, nonalcoholic steatohepatitis (NASH), and hepatic cellular carcinoma (HCC). Despite the prevalence of NAFLD, lifestyle interventions involving exercise and weight loss are the only accepted treatments for this disease. Over the last decade, numerous experimental compounds have been shown to improve NAFLD in preclinical animal models, and many of these therapeutics have been shown to increase the activity of the cellular energy sensor AMP-activated protein kinase (AMPK). Because AMPK activity is reduced by inflammation, obesity, and diabetes, increasing AMPK activity has been viewed as a viable therapeutic strategy to improve NAFLD. In this review, we propose three primary mechanisms by which AMPK activation may improve NAFLD. In addition, we examine the mechanisms by which AMPK is activated. Finally, we identify 27 studies that have used AMPK activators to reduce NAFLD. Future considerations for studies examining the relationship between AMPK and NAFLD are highlighted.


A safety analysis of different drug regimens used in human immunodeficiency virus-positive patients.
Long-term toxicity of antiretroviral agents is rarely addressed in initial clinical trials. Effective pharmacovigilance is essential for long-term safety of antiretroviral therapy (ART). All adverse drug reactions (ADRs) reported due to ART between January 2014 and September 2016 were analyzed as per different drug regimens used. ADRs were also analyzed for system organ classification, seriousness, time relationship of ADRs with drug therapy, causality (as per the World Health Organization-Uppsala Monitoring Centre scale and Naranjo algorithm), and severity (Hartwig and Siegel scale). Comparison was done between (tenofovir + lamivudine + efavirenz [TLE]) and (zidovudine + lamivudine + nevirapine [ZLN]) regimens. During a study period, 2983 patients were on ART. The most common drug regimen prescribed was TLE (1805) followed by ZLN (326). A total of 325 (10.89%) ADRs were reported in which 150 ADRs were reported in TLE regimens (46%) and 130 in ZLN regimens (40%). The mean age of patients with ADRs was 40 ± 12.56 years and men (58.1%) were more affected than women (41.8%). The most common system organ involved in ZLN regimen was blood (50, 39%) and skin (35, 27%), while it was neurological (63, 42%) and renal disorder (27, 18%) in TLE regimen. Most of ADRs were observed after 1 month of therapy (79.5%) and showed possible causal relation with drug therapy (78.15%). Majority of ADRs were mild in nature (86.7%). The serious ADRs were reported more in ZLN (18%) regimen as compared to TLE (9%) (P < 0.05). Both ART regimens are associated with ADRs affecting all body system; however, the frequency and severity of ADR are high with ZLN regimen.


Watch-n-Patch: Unsupervised Learning of Actions and Relations.
There is a large variation in the activities that humans perform in their everyday lives. We consider modeling these composite human activities which comprises multiple basic level actions in a completely unsupervised setting. Our model learns high-level co-occurrence and temporal relations between the actions. We consider the video as a sequence of short-term action clips, which contains human-words and object-words. An activity is about a set of action-topics and object-topics indicating which actions are present and which objects are interacting with. We then propose a new probabilistic model relating the words and the topics. It allows us to model long-range action relations that commonly exist in the composite activities, which is challenging in previous works. We apply our model to the unsupervised action segmentation and clustering, and to a novel application that detects forgotten actions, which we call action patching. For evaluation, we contribute a new challenging RGB-D activity video dataset recorded by the new Kinect v2, which contains several human daily activities as compositions of multiple actions interacting with different objects. Moreover, we develop a robotic system that watches and reminds people using our action patching algorithm. Our robotic setup can be easily deployed on any assistive robots.


How can quality of life researchers make their work more useful to health workers and their patients?
To make optimal use of data from randomized trials in clinical decision-making, clinicians require knowledge of the magnitude of treatment effects. Reports of trials including quality of life data often fail to report results that provide interpretable estimates of magnitude of effect. Strategies that investigators could use to remedy this problem include reporting mean differences between groups in relation to the minimal important difference and reporting the proportion of patients who benefit from treatment and the associated number needed to treat. Techniques are available that allow investigators to use the same strategies in reporting pooled estimates from meta-analyses, even when studies use different instruments to measure the same construct. These reporting approaches, as well as ensuring access to data from individual items, will also help those developing decision aids to use quality of life data.


Decreased hydrocortisone sensitivity of T cell function in multiple sclerosis-associated major depression.
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS with a high prevalence of depression. Both MS and depression have been linked to elevated cortisol levels and inflammation, indicating disturbed endocrine-immune regulation. An imbalance in mineralocorticoid versus glucocorticoid signaling in the CNS has been proposed as a pathogenetic mechanism of depression. Intriguingly, both receptors are also expressed in lymphocytes, but their role for 'escape' of the immune system from endocrine control is unknown. Using steroid sensitivity of T cell function as a read-out system, we here investigate a potential role of mineralocorticoid receptor (MR) versus glucocorticoid receptor (GR) regulation in the immune system as a biological mechanism underlying MS-associated major depression. Twelve female MS patients meeting diagnostic criteria for current major depressive disorder (MDD) were compared to twelve carefully matched MS patients without depression. We performed lymphocyte phenotyping by flow cytometry. In addition, steroid sensitivity of T cell proliferation was tested using hydrocortisone as well as MR (aldosterone) and GR (dexamethasone) agonists. Sensitivity to hydrocortisone was decreased in T cells from depressed MS patients. Experiments with agonists suggested disturbed MR regulation, but intact GR function. Importantly, there were no differences in lymphocyte composition and frequency of T cell subsets, indicating that the differences in steroid sensitivity are unlikely to be secondary to shifts in the immune compartment. To our knowledge, this study provides first evidence for altered steroid sensitivity of T cells from MS patients with comorbid MDD possibly due to MR dysregulation.


[Seminal obstructions of the inflammatory origin].
Presence of bacteria in the sperm is often associated to a reduction of fertility in relationship with a decrease in number and motility of spermatozoa and with an augmentation of the abnormal spermatic cells. In the most severe cases, chronic and complicated phlogosis may lead to obstruction of seminal pathways with consequent azoospermia. Clinical features of seminal phlogosis are extremely variable both in acute and chronic evolutions. In every case the first diagnostical step is sperm count and seminal complete analysis which can give evidence of phlogistic alteration in quantity and quality of spermatic cells with a typical presence of an excess in white blood cells (leukospermia) as consequence of infection. The great variety in clinical and bacteriological aspects and the particular biological features of the organs involved, as the prostate, makes treatment a difficult problem to solve with particular regard to the choice of an effective antibiotic which pharmacokinetic has to result suitable for the microorganism as well as for the tissue of the infection site. All those efforts are indispensable to reduce the too frequent therapeutical failures in the management of seminal phlogistic pathology with complications of organic but also physiological relevancy for the patient and the partner too, such as azoospermia.


Lymphocyte subsets associated with major depression and dysthymia: modification by antidepressant treatment.
Major depression and dysthymia (chronic, low grade depression) were associated with an increase in the number of CD16/56 (natural killer; NK) cells in blood, whereas other lymphocyte subsets (CD3, CD4, CD8, CD19, and the CD4/CD8 ratio) did not differ from control subjects. After treatment with a specific serotonin reuptake inhibitor, the symptoms of depression were alleviated in both the major depressive and dysthymic patients. Likewise, NK cell numbers declined to control values in these treated groups. Among the major depressive patients, the NK cell number reached control values within 4 weeks, whereas 6 months of treatment was required for such an effect to be achieved in the dysthymic patients. Although plasma levels of epinephrine, norepinephrine, cortisol, and ACTH were not different between groups, among the major depressive patients ACTH was inversely correlated with total lymphocytes, CD3, and CD19, and epinephrine was directly related to the CD4 and CD4/CD8 ratio. Among dysthymics, ACTH was unrelated to any of the lymphocyte subsets, but norepinephrine was directly related to total lymphocytes, CD3, CD4, and NK cells. The data are interpreted in terms of stress perception among major depressive and dysthymic patients and the potential impact of stressor experiences on immune processes.


High levels of X-linked Inhibitor-of-Apoptosis Protein (XIAP) are indicative of radio chemotherapy resistance in rectal cancer.
The mainstay of treatment in rectal cancer is neoadjuvant radio chemotherapy prior to surgery, in an attempt to downstage the tumour, allowing for more complete removal during surgery. In 40 % of cases however, this neoadjuvant radio chemotherapy fails to achieve tumour regression, partly due insufficient apoptosis signaling. X-linked Inhibitor of Apoptosis Protein (XIAP) is an anti-apoptotic protein that has been reported to contribute to disease progression and chemotherapy resistance. We obtained rectal biopsy normal and matched tumour tissue from 29 rectal cancer patients with varying degrees of tumour regression, and using Western blot, examined anti-apoptotic XIAP and pro-apoptotic Smac protein levels in these tissues, with the aim to examine whether disturbed XIAP/Smac levels may be an indicator of neoadjuvant radio chemotherapy resistance. Expression of inhibitor of apoptosis proteins cIAP-1 and cIAP-2 was also examined. We found that levels of XIAP increased in accordance with the degree of radio chemotherapy resistance of the tissue. Levels of this protein were also significantly higher in tumour tissue, compared to matched normal tissue in highly resistant tissue. In contrast, Smac protein levels did not increase with radio chemotherapy resistance, and the protein was similarly expressed in normal and tumour tissue, indicating a shift in the balance of these proteins. Post treatment surgical resection tissue was available for 8 patients. When we compared matched tissue pre- and post- radio chemotherapy we found that XIAP levels increased significantly during treatment in both normal and tumour tissue, while Smac levels did not change. cIAP-1 and cIAP-2 levels were not differentially expressed in varying degrees of radio chemotherapy resistance, and neoadjuvant therapy did not alter expression of these proteins. These data indicate that disturbance of the XIAP/Smac balance may be a driver of radio chemotherapy resistance, and hence high levels of XIAP may be a useful indicator of neoadjuvant radio chemotherapy resistance in rectal cancer. Moreover, as XIAP levels increase with radio chemotherapy it is possible that a subset of more resistant tumour cells survive this treatment and may be resistant to further adjuvant treatment. Patients with resistant tumours highly expressing XIAP may benefit from alternative treatment strategies, such as Smac mimetics post neoadjuvant radio chemotherapy.


JunB potentiates function of BRCA1 activation domain 1 (AD1) through a coiled-coil-mediated interaction.
BRCA1 is involved in the regulation of multiple nuclear events including transcription. AD1, one of the two trans-activation domains in BRCA1, stimulates transcription in a cell context-dependent manner. Here, it is shown that BRCA1 interacts with Jun proteins via a coiled-coil motif in AD1 and the basic leucine zipper (bZIP) region of the Jun proteins. The Jun-interacting domain in BRCA1 is critical for AD1-mediated transcriptional activation. In particular, the strength of AD1 in transcriptional activation is limited by the JunB level and ectopic expression of JunB potentiates the transcriptional activity of AD1. Furthermore, JunB mRNA expression is down-regulated in many ovarian tumor tissues examined. Thus, the coiled-coil-mediated cooperation between BRCA1 and JunB may facilitate the function of these proteins in tissue-specific transcriptional regulation and tumor suppression.


Heavy-atom derivatization.
Most of the standard methods of solving macromolecular structures involve producing a protein crystal that is derivatized by an anomalous scatterer or heavy atom (MIR, SIRAS, MAD, SAD etc.). The theoretical methodology which underpins the extraction of phase information from such derivatives is widely available in the literature. In addition, there are comprehensive sources of information on the chemistry of heavy-atom compounds and the ligands with which they are known to interact, as well as the Heavy Atom Databank accessible on the World Wide Web. This contribution therefore aims to provide some information on the less well documented practical problems of firstly deciding on an overall strategy for derivatization and secondly performing the physical manipulations involved in producing heavy-atom derivatives from native protein crystals and then cryocooling them. Ways to optimize the chances of isomorphous unit cells are suggested. Methods of determining whether or not the heavy atom is bound are outlined, including the powerful technique of PIXE (particle-induced X-ray emission).


Fetal esophageal ligation induces expression of vascular endothelial growth factor messenger ribonucleic acid in fetal membranes.
Obstruction of the fetal esophagus does not always produce the expected polyhydramnios. This is because of increased intramembranous absorption of amniotic fluid into the fetal circulation. A possible mediator for this increased absorption is vascular endothelial growth factor (VEGF). The present objective was to explore whether VEGF gene expression and action would be induced in fetal membranes and placentas of ovine fetuses after esophageal ligation. Five late-gestation fetal sheep underwent esophageal ligation and 5 served as control animals. On postoperative day 9, amnion, chorion, and placenta were collected for cellular localization and quantitation of VEGF messenger ribonucleic acid by in situ hybridization and Northern blot analysis. Reverse-transcription polymerase chain reaction was used to identify the VEGF molecular forms. Immunostaining with Ki-67 antibody was used to determine the proliferation of vascular endothelium in the fetal membranes and placentas. VEGF messenger ribonucleic acid was localized in amniotic epithelium, chorionic cytotrophoblast, and cytotrophoblast of the placenta. VEGF164 was the major transcript expressed in these tissues. The abundance of VEGF messenger ribonucleic acid in the amnion and chorion, but not in the placenta, was significantly increased in the ligated fetuses in comparison with the control fetuses. The proliferation of the intramembranous blood vessel endothelium was greater in the ligated fetuses than in the control fetuses. The levels of VEGF messenger ribonucleic acid and the proliferation of vascular endothelium in the amnion and chorion increased after fetal esophageal ligation. This provides a possible mechanism for the enhanced intramembranous absorption of amniotic fluid through increased vascularity and permeability of the fetal membranes, thus ameliorating the development of polyhydramnios. We speculate that the signal(s) that mediate the increase in VEGF expression is present in either the fetal urine or the fetal lung secretions, or both.


Cloning, purification, and properties of a phosphotyrosine protein phosphatase from Streptomyces coelicolor A3(2).
We describe the isolation and characterization of a gene (ptpA) from Streptomyces coelicolor A3(2) that codes for a protein with a deduced M(r) of 17,690 containing significant amino acid sequence identity with mammalian and prokaryotic small, acidic phosphotyrosine protein phosphatases (PTPases). After expression of S. coelicolor ptpA in Escherichia coli with a pT7-7-based vector system, PtpA was purified to homogeneity as a fusion protein containing five extra amino acids. The purified fusion enzyme catalyzed the removal of phosphate from p-nitrophenylphosphate (PNPP), phosphotyrosine (PY), and a commercial phosphopeptide containing a single phosphotyrosine residue but did not cleave phosphoserine or phosphothreonine. The pH optima for PNPP and PY hydrolysis by PtpA were 6.0 and 6.5, respectively. The Km values for hydrolysis of PNPP and PY by PtpA were 0.75 mM (pH 6.0, 37 degrees C) and 2.7 mM (pH 6.5, 37 degrees C), respectively. Hydrolysis of PNPP by S. coelicolor PtpA were 0.75 mM (pH 6.0, 37 degrees C) and 2.7 mM (pH 6.5, 37 degrees C), respectively. Hydrolysis of PNPP by S. coelicolor PtpA was competitively inhibited by dephostatin with a Ki of 1.64 microM; the known PTPase inhibitors phenylarsine oxide, sodium vanadate, and iodoacetate also inhibited enzyme activity. Apparent homologs of ptpA were detected in other streptomycetes by Southern hybridization; the biological functions of PtpA and its putative homologs in streptomycetes are not yet known.


Order Without Intellectual Property Law: Open Science in Influenza.
Today, intellectual property (IP) scholars accept that IP as an approach to information production has serious limits. But what lies beyond IP? A new literature on "intellectual production without IP" (or "IP without IP") has emerged to explore this question, but its examples and explanations have yet to convince skeptics. This Article reorients this new literature via a study of a hard case: a global influenza virus-sharing network that has for decades produced critically important information goods, at significant expense, and in a loose-knit group--all without recourse to IP. I analyze the Network as an example of "open science," a mode of information production that differs strikingly from conventional IP, and yet that successfully produces important scientific goods in response to social need. The theory and example developed here refute the most powerful criticisms of the emerging "IP without IP" literature, and provide a stronger foundation for this important new field. Even where capital costs are high, creation without IP can be reasonably effective in social terms, if it can link sources of funding to reputational and evaluative feedback loops like those that characterize open science. It can also be sustained over time, even by loose-knit groups and where the stakes are high, because organizations and other forms of law can help to stabilize cooperation. I also show that contract law is well suited to modes of information production that rely upon a "supply side" rather than "demand side" model. In its most important instances, "order without IP" is not order without governance, nor order without law. Recognizing this can help us better ground this new field, and better study and support forms of knowledge production that deserve our attention, and that sometimes sustain our very lives.


A 3D tunable and multi-frequency graphene plasmonic cloak.
We demonstrate the possibility of cloaking three-dimensional objects at multi-frequencies in the far-infrared part of the spectrum. The proposed cloaking mechanism exploits graphene layers wrapped around the object to be concealed. Graphene layers are doped via a variable external voltage difference permitting continuous tuning of the cloaking frequencies. Particularly, two configurations are investigated: (i) Only one graphene layer is used to suppress the scattering from a dielectric sphere. (ii) Several of these layers biased at different gate voltages are used to achieve a multi-frequency cloak. These frequencies can be set independently. The proposed cloak's functionality is verified by near- and far-field computations. By considering geometry and material parameters that are realizable by practical experiments, we contribute to the development of graphene based plasmonic applications that may find use in disruptive photonic technologies.


Analysis of allele-specific expression in mouse liver by RNA-Seq: a comparison with Cis-eQTL identified using genetic linkage.
We report an analysis of allele-specific expression (ASE) and parent-of-origin expression in adult mouse liver using next generation sequencing (RNA-Seq) of reciprocal crosses of heterozygous F1 mice from the parental strains C57BL/6J and DBA/2J. We found a 60% overlap between genes exhibiting ASE and putative cis-acting expression quantitative trait loci (cis-eQTL) identified in an intercross between the same strains. We discuss the various biological and technical factors that contribute to the differences. We also identify genes exhibiting parental imprinting and complex expression patterns. Our study demonstrates the importance of biological replicates to limit the number of false positives with RNA-Seq data.


Dynamic organization of splicing factors in adenovirus-infected cells.
Adenovirus infection affects the nuclear distribution of host splicing factors. Late phase-infected cells contain discrete clusters of small nuclear ribonucleoproteins (snRNPs) that are separate from centers containing the viral 72-kilodalton DNA-binding protein (72K protein). In the present study, we demonstrate that these snRNP clusters also contain splicing factors from the SR protein family. We show that a previously described monoclonal antibody, 3C5, detects SR proteins. Furthermore, we demonstrate that late region 3 transcription occurs at a maximal rate in infected cultures in which greater than 90% of the cells contain the snRNP clusters, indicating that such cells are actively transcribing their late genes. During the onset of the late phase, the intranuclear distribution of splicing factors is very different from that seen after the late phase is established. When late viral transcription commences, cells with snRNP clusters are less prevalent than in cultures that are maintaining maximum levels of late transcription. Instead, a cell type which shows snRNPs, concentrated in foci that also contain the viral 72K DNA-binding protein is detected. This cell type disappears from cultures by 18 to 20 h after a high-multiplicity infection. These results suggest a dynamic organization of splicing factors in infected cells that can be correlated to the status of viral gene expression. Our work also provides an explanation for the differing results that have been published concerning the organization of splicing factors in the adenovirus-infected cell nucleus (L. F. Jiménez-García and D. L. Spector, Cell 73:47-59, 1993). During the present study we observed that a monoclonal antibody against the SC-35 protein, which was used by Jiménez-García and Spector to study the localization of the SC-35 splicing factor in adenovirus-infected cells, cross-reacts with the adenovirus 72K DNA-binding protein and is thus unsuitable for this type of study.


Implication of the APP Gene in Intellectual Abilities.
Cognitive functions are highly heritable and polygenic, though the source of this genetic influence is unclear. On the neurobiological level, these functions rely on effective neuroplasticity, in which the activity-regulated cytoskeleton associated protein (ARC) plays an essential role. To examine whether the ARC gene complex may contribute to the genetic components of intellectual function given the crucial role of ARC in brain plasticity and memory formation. The ARC complex was tested for association with intelligence (IQ) in children from the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5,165). As Alzheimer's disease (AD) shares genetics with cognitive functioning, the association was followed up in an AD sample (17,008 cases, 37,154 controls). The ARC complex revealed association with verbal and total IQ (empirical p = 0.027 and 0.041, respectively) in the ALSPAC. The strongest single variant signal (rs2830077; empirical p = 0.018), within the APP gene, was confirmed in the AD sample (p = 2.76E-03). Functional analyses of this variant showed its preferential binding to the transcription factor CP2. This study implicates APP in childhood IQ. While follow-up studies are needed, this observation could help elucidate the etiology of disorders associated with cognitive dysfunction, such as AD.


Dental Pulp Response to RetroMTA after Partial Pulpotomy in Permanent Human Teeth.
A lack of information exists regarding the efficacy of RetroMTA (BioMTA, Seoul, Korea) directly applied on the pulp in vital pulp therapy. This study was designed to examine the clinical efficacy of RetroMTA compared with ProRoot mineral trioxide aggregate (MTA) (Dentsply Tulsa Dental, Tulsa, OK) for partial pulpotomy. Partial pulpotomy was performed in 22 healthy human maxillary and mandibular third molars planned for extraction. The teeth were randomly divided into 2 groups (n = 11) and underwent partial pulpotomy with RetroMTA and ProRoot MTA as the control. The teeth were then restored with glass ionomer cement. Clinical and electric pulp tests were performed after 1 and 8 weeks. The teeth were radiographed and extracted at 8 weeks. Histologic sections were prepared and analyzed for pulp inflammation and dentinal bridge formation. Data were analyzed using the Mann-Whitney U test. Clinical examination after 1 and 8 weeks showed no sensitivity to heat, cold, or palpation in the ProRoot MTA and RetroMTA groups. Periapical radiographs taken before the extraction of teeth showed no evidence of periapical pathology. Electric pulp testing revealed no sensitivity. Data comparisons using the Mann-Whitney U test showed no significant difference between the materials with regard to the pulp inflammation type, intensity and extension (P = .3), or bridge continuity (P = .12). However, these data revealed a significant difference between the 2 materials in pulp morphology (P < .05) and bridge thickness (P < .01). This is the first work to evaluate a RetroMTA histologic outcome in partial pulpotomy in human permanent teeth. It shows pulp disorganization, an absence of inflammation, and discontinuous mineralization, which may represent a potential drawback with RetroMTA in this indication.


F-TIMER: fast tensor image morphing for elastic registration.
We propose a novel diffusion tensor imaging (DTI) registration algorithm, called fast tensor image morphing for elastic registration (F-TIMER). F-TIMER leverages multiscale tensor regional distributions and local boundaries for hierarchically driving deformable matching of tensor image volumes. Registration is achieved by utilizing a set of automatically determined structural landmarks, via solving a soft correspondence problem. Based on the estimated correspondences, thin-plate splines are employed to generate a smooth, topology preserving, and dense transformation, and to avoid arbitrary mapping of nonlandmark voxels. To mitigate the problem of local minima, which is common in the estimation of high dimensional transformations, we employ a hierarchical strategy where a small subset of voxels with more distinctive attribute vectors are first deployed as landmarks to estimate a relatively robust low-degrees-of-freedom transformation. As the registration progresses, an increasing number of voxels are permitted to participate in refining the correspondence matching. A scheme as such allows less conservative progression of the correspondence matching towards the optimal solution, and hence results in a faster matching speed. Compared with its predecessor TIMER, which has been shown to outperform state-of-the-art algorithms, experimental results indicate that F-TIMER is capable of achieving comparable accuracy at only a fraction of the computation cost.


Calibration and precompensation of noncommon path aberrations for extreme adaptive optics.
Noncommon path aberrations (NCPAs) are one of the main limitations of an extreme adaptive optics (AO) system. NCPAs prevent extreme AO systems from achieving their ultimate performance. These static aberrations are unseen by the wavefront sensor and therefore are not corrected in closed loop. We present experimental results validating what we believe to be new procedures of measurement and precompensation of the NCPAs on the AO bench at ONERA (Office National d'Etudes et de Recherches Aérospatiales). The measurement procedure is based on refined algorithms of phase diversity. The precompensation procedure makes use of a pseudo-closed-loop scheme to overcome the AO wavefront-sensor-model uncertainties. Strehl ratio obtained in the images reaches 98.7% at 632.8 nm. This result allows us to be confident of achieving the challenging performance required for direct observation of extrasolar planets.


Utilization and costs for children who have special health care needs and are enrolled in a hospital-based comprehensive primary care clinic.
When deciding how much hospital resources should be allocated to comprehensive primary care clinics for children with multisystem disorders, it is important to consider all of the non-primary care revenue streams associated with these children as well as the effects of a comprehensive primary care program on access and quality. The objectives of this study were, first, to determine costs as well as the payments associated with hospital ambulatory and inpatient services for children with multisystem disorders followed by a comprehensive primary care clinic; and, second, to determine the effect of enrollment in a hospital-based comprehensive primary care clinic on ambulatory and inpatient utilization patterns and expenditures for children with multisystem disorders. The study population for the payment analysis consisted of 1012 children of all ages who were seen in the Special Primary Care Clinic (SPCC) in 2001. For these children, outcomes included direct costs, total (direct plus allocated overhead) costs, and payments per patient per 365 days after their first SPCC visit in 2001. A total of 175 of these patients were 4 years of age or older and had no SPCC visit before their first visit in 2001. We compared utilization and expenditures for the 175 children during the year before enrollment in SPCC with those in the year after enrollment. The Children's Hospital administrative database was used to document direct costs, total costs, and payments by type of service for 365 days after an index visit. Ambulatory services included medical and surgical ambulatory, inpatient, emergency department (ED), and ancillary services. We determined the proportion of children who had visits; the visit rates per 100 child-years; and the average total and direct costs per visit, per child with a visit, and per child-year. Inpatient services data included non-intensive care and intensive care hospitalization rates per 100 child-years; the proportion of children hospitalized; their average length of stay; and the average total and direct costs per hospitalization, per patient hospitalized, and per child-year of total patients in the cohort. For 1012 children who were seen in SPCC in 2001, the hospital overall loss per child-year was $956. The loss per child-year for outpatient services was $1554. This loss was partially offset by a gain from inpatient services of $598. For the 175 patients for whom data were available to compare costs before and after enrollment in the SPCC, there were no significant differences in hospitalization or in direct costs per patient for patients who were hospitalized. The average length of non-intensive care stay was lower after enrollment (4.8 vs 11.7). In the surgical specialty analysis, children were more likely to see a surgeon after enrollment (41% vs 21%) and had a higher rate of visits per 100 child-years (102.3 vs 51.4). Differences in medical subspecialty, ancillary, and ED services did not achieve statistical significance. This study suggests that children with multisystem disorders are medically fragile and require frequent hospitalizations and ED visits even with improved primary care. Enrollment in a comprehensive primary care program was associated with a decreased length of stay for non-intensive care hospitalizations and with increased use of surgical services.


Water-soluble compounds of lettuce inhibit DNA damage and lipid peroxidation induced by glucose/serum deprivation in N2a cells.
Oxidative stress, increase of lipid peroxidation and resultant DNA damage are associated with pathophysiology of many human diseases such as acute and chronic CNS injuries and diseases, cancer, and also aging. This work was done to investigate whether water fraction from the hydroalcoholic extract of green leaf lettuce (Lactuca sativa L.) can protect N2a cells against glucose/serum deprivation (GSD)-induced lipid peroxidation and DNA fragmentation. The cells were cultivated for 12 h in GSD condition in the absence or presence of the lettuce fraction. The total antioxidant ability of the lettuce water fraction was determined using ferric reducing antioxidant power (FRAP) assay. The intracellular lipid peroxidation was evaluated by malondialdehyde (MDA) level. DNA damage was determined using single cell gel electrophoresis. Using FRAP assay, the antioxidant activity of lettuce water fraction was found to be 574 micromol/g, which is equivalent to 64.1 mg of pure ascorbic acid. Exposure of the cells to GSD condition led to a significant increase of MDA level and DNA fragmentation. Lettuce extract at 400 microg/mL could decrease the elevated intracellular lipid peroxidation and DNA damage. The present study demonstrates that lettuce exerts genoprotective effect through inhibition of oxidative stress.


The evolution of the State Children's Health Insurance Program (SCHIP) in New York: changing program features and enrollee characteristics.
The State Children's Health Insurance Program (SCHIP) has been operating for >5 years. Policy makers are interested in the characteristics of children who have enrolled and changes in the health care needs of enrolled children as programs mature. New York State's SCHIP evolved from a similar statewide health insurance program that was developed in 1991 (Child Health Plus [CHPlus]). Understanding how current SCHIP enrollees differ from early CHPlus enrollees together with how program features changed during the period may shed light on how best to serve the evolving SCHIP population. To 1) describe changes in the characteristics of children enrolled in 1994 CHPlus and 2001 SCHIP; 2) determine if changes in the near-poor, age-eligible population during the time period could account for the evolution of enrollment; and 3) describe changes in the program during the period that could be responsible for the enrollment changes. New York State, stratified into 4 regions: New York City, New York City environs, upstate urban counties, and upstate rural counties. Retrospective telephone interviews of parents of 2 cohorts of CHPlus enrollees: 1) children who enrolled in CHPlus in 1993 to 1994 and 2) children who enrolled in New York's SCHIP in 2000 to 2001. The Current Population Survey (CPS) 1992 to 1994 and 1999 to 2001 were used to identify secular trends that could explain differences in the CHPlus and SCHIP enrollees. PROGRAM CHARACTERISTICS: 1994 CHPlus and 2001 SCHIP were similar in design, both limiting eligibility by age, family income, and insurance status. SCHIP 2001 included 1) expansion of eligibility to adolescents 13 to 19 years old; 2) expansion of benefits to include hospitalizations, mental health, and dental benefits; 3) changes in premium contributions; 4) more participating insurance plans, limited to managed care; 5) expansions in marketing and outreach; and 6) a combined enrollment application for SCHIP and several low-income programs including Medicaid. Cohort 1 included 2126 new CHPlus enrollees 0 to 13 years old who were enrolled for at least 9 months, stratified by geographic region. Cohort 2 included 1100 new SCHIP enrollees 0 to 13 years old who were enrolled for at least 9 months, stratified by geographic region, age, race, and ethnicity. Results were weighted to be representative of statewide CHPlus or SCHIP new enrollees who met the sampling criteria. Samples of age- and income-eligible children from New York State were drawn from the CPS and pooled and reweighted (1992-1994 and 1999-2001) to generate a comparison group of children targeted by CHPlus and SCHIP. Sociodemographic characteristics, race and ethnicity (white non-Hispanic, black non-Hispanic, and Hispanic), prior health insurance, health care access, and first source of information about the program. Weighted bivariate analyses (comparisons of means and rates) adjusted for the complex sampling design to compare measures between the 2 program cohorts and between the 2 CPS samples. We tested for equivalence by using chi2 statistics. As the program evolved from CHPlus to SCHIP, relatively more black and Hispanic children enrolled (9% to 30% black from 1994 to 2001, and 16% to 48% Hispanic), more New York City residents (46% to 69% from 1994 to 2001), more children with parents who had less than a high school education (10% to 25%), more children from lower income families (59% to 75% below 150% of the federal poverty level), and more children from families with parents not working (7% to 20%) enrolled. These socioeconomic and demographic changes were not reflected in the underlying age- and income-eligible population. A greater proportion of 2001 enrollees were uninsured for some time immediately before enrollment (57% to 76% had an uninsured gap), were insured by Medicaid during the year before enrollment (23% to 48%), and lacked a USC (5% to 14%). Although "word of mouth" was the most common means by which families heard about both programs, a greater proportion of 2001 enrollees learned about SCHIP from marketing or outreach sources. As New York programs for the uninsured evolved, more children from minority groups, with lower family incomes and education, and having less baseline access to health care were enrolled. Although changes in the underlying population were relatively small, progressively increased marketing and outreach, particularly in New York City, the introduction of a single application form for SCHIP and Medicaid, and expansions in the benefit package may have accounted, in part, for the large change in the characteristics of enrollees.


Transcriptome analysis of cyclic AMP-dependent protein kinase A-regulated genes reveals the production of the novel natural compound fumipyrrole by Aspergillus fumigatus.
Aspergillus fumigatus is an opportunistic human pathogenic fungus causing life-threatening infections in immunocompromised patients. Adaptation to different habitats and also virulence of the fungus depends on signal perception and transduction by modules such as the cyclic AMP-dependent protein kinase A (PKA) pathway. Here, by transcriptome analysis, 632 differentially regulated genes of this important signaling cascade were identified, including 23 putative transcriptional regulators. The highest upregulated transcription factor gene was located in a previously unknown secondary metabolite gene cluster, which we named fmp, encoding an incomplete non-ribosomal peptide synthetase, FmpE. Overexpression of the regulatory gene fmpR using the Tet(On) system led to the specific expression of the other six genes of the fmp cluster. Metabolic profiling of wild type and fmpR overexpressing strain by HPLC-DAD and HPLC-HRESI-MS and structure elucidation by NMR led to identification of 5-benzyl-1H-pyrrole-2-carboxylic acid, which we named fumipyrrole. Fumipyrrole was not described as natural product yet. Chemical synthesis of fumipyrrole confirmed its structure. Interestingly, deletion of fmpR or fmpE led to reduced growth and sporulation of the mutant strains. Although fmp cluster genes were transcribed in infected mouse lungs, deletion of fmpR resulted in wild-type virulence in a murine infection model.


How should Canada fund the blood system? An evaluation of the chargeback proposal.
The Canadian blood system is a critical interface between public health and the delivery of patient care. The organization of the blood system plays a vital role in ensuring that its functions are effectively fulfilled. Previous structural problems in the blood system led to serious health consequences by contributing to the blood transmission of hepatitis C and HIV in the 1980s. To address these problems, the Canadian blood system has recently undergone considerable organizational reform. However, policy-makers, particularly in Ontario, are considering further structural reform specifically focusing on how the blood system is financed. This move for reform is partially motivated by the rising cost of blood products and the perception that the current system has failed to provide incentives for the efficient use of these products. The suggested payment mechanism, a "chargeback system," involves the provincial ministries of health funding hospitals so that hospitals can directly purchase blood products from the Canadian Blood Services. This approach would replace the current system in which the provinces directly fund the Canadian Blood Services, which in turn provides blood products free of charge to hospitals. Based on a review of documents and stakeholder interviews, we report the potential advantages and disadvantages of a change to a new system of funding and make recommendations on how provinces should proceed.


A roadmap for fever of unknown origin in children.
Fever of unknown origin (FUO) in adults is conventionally defined by the occurrence of body temperatures above 38.3 degrees C (101 degrees F) for a period of 3 weeks without any identified etiology after a period of 1-week hospitalization. The issue of FUO in pediatrics is rather hazy and still represents a challenging diagnostic dilemma. Most of the available data are limited to nationwide cohorts of patients of any age. The major difficulty in establishing a diagnosis is that the characteristic features rendering specific disorders clinically recognizable are absent or subtle, hence only a painstaking questioning on family background may elicit the correct investigative path. No diagnostic algorithms are actually available and clinicians must rely on a very careful step-by-step evaluation of the single patient. The need for invasive diagnostic techniques should be closely taken into consideration when laboratory tests or simple imaging procedures fail to discern the origin of FUO. Fevers with no reasonable explanation and no localizing signs often conceal different common diseases in children, which tend to display an unusual or atypical pattern. The principal causes behind FUO in pediatric age remain infections, followed by collagen vascular diseases and neoplastic disorders, although most children with malignancies present other systemic signs or suggestive laboratory abnormalities. The possibility of autoinflammatory syndromes, drug fever, and factitious fever should also be taken into account.


[Malignant pleural mesothelioma: multidisciplinary experience in a public tertiary hospital].
To evaluate the experience in diagnosing and treating malignant pleural mesothelioma (MPM) accumulated over 5 years in a tertiary public hospital. The medical charts of the patients diagnosed with MPM between January of 2000 and February of 2005 were evaluated retrospectively. Of the 17 patients analyzed, 14 were male and 3 were female. The mean age was 54.1 years (range, 13-75 years). The biopsy specimens for histopathological examination were obtained through thoracoscopy in 9 patients (53%), Cope needle in 5 (29.5%), and open pleural biopsy in 3 (17.5%). The following histological types were identified: epithelial, in 14 patients (82%); sarcomatoid, in 1 (6%); and biphasic, in 2 (12%). The therapeutic approaches used were as follows: multimodal (pleuropneumonectomy and adjuvant radiotherapy and chemotherapy) in 6 patients (35%); chemotherapy and radiotherapy in 6 (35%); radiotherapy alone in 3 (17.5%); and chemotherapy alone in 2 (12%). The mean survival was 11 months (range, 1-26 months). In the cases studied, an integrated multidisciplinary approach was used, and a highly complex hospital infrastructure was available for the diagnosis and treatment of MPM, as recommended in the literature. However, the mean survival was only 11 months, reflecting the aggressiveness of the disease.


Intestinal intraepithelial lymphocyte-enterocyte crosstalk regulates production of bactericidal angiogenin 4 by Paneth cells upon microbial challenge.
Antimicrobial proteins influence intestinal microbial ecology and limit proliferation of pathogens, yet the regulation of their expression has only been partially elucidated. Here, we have identified a putative pathway involving epithelial cells and intestinal intraepithelial lymphocytes (iIELs) that leads to antimicrobial protein (AMP) production by Paneth cells. Mice lacking γδ iIELs (TCRδ(-/-)) express significantly reduced levels of the AMP angiogenin 4 (Ang4). These mice were also unable to up-regulate Ang4 production following oral challenge by Salmonella, leading to higher levels of mucosal invasion compared to their wild type counterparts during the first 2 hours post-challenge. The transfer of γδ iIELs from wild type (WT) mice to TCRδ(-/-) mice restored Ang4 production and Salmonella invasion levels were reduced to those obtained in WT mice. The ability to restore Ang4 production in TCRδ(-/-) mice was shown to be restricted to γδ iIELs expressing Vγ7-encoded TCRs. Using a novel intestinal crypt co-culture system we identified a putative pathway of Ang4 production initiated by exposure to Salmonella, intestinal commensals or microbial antigens that induced intestinal epithelial cells to produce cytokines including IL‑23 in a TLR-mediated manner. Exposure of TCR-Vγ7(+) γδ iIELs to IL-23 promoted IL‑22 production, which triggered Paneth cells to secrete Ang4. These findings identify a novel role for γδ iIELs in mucosal defence through sensing immediate epithelial cell cytokine responses and influencing AMP production. This in turn can contribute to the maintenance of intestinal microbial homeostasis and epithelial barrier function, and limit pathogen invasion.


Human guanylate kinase (GUK1): cDNA sequence, expression and chromosomal localisation.
Guanylate kinase (GK) catalyses the conversion of GMP to GTP as part of the cGMP cycle. In mammalian phototransduction, this cycle is essential for the regeneration of cGMP following its hydrolysis by phosphodiesterase. Mutations in different parts of this signalling cascade lead to retinal degeneration in humans. Protein studies have localized a locus for GK to a region of human chromosome 1 that also contains an autosomal recessive form of retinitis pigmentosa (RP12) and Usher's type 11a (USH2A). We report the sequence of this human GK (GUK1) and a further refinement of its localization to 1q32-41, placing it in the same interval as USH2A.


Implementation research for early childhood development programming in humanitarian contexts.
Young children living in conditions of war, disaster, and displacement are at high risk for developmental difficulties that can follow them throughout their lives. While there is robust evidence supporting the need for early childhood development (ECD) in humanitarian settings, implementation of ECD programming remains sparse, largely due to the lack of evidence of how and why these programs can improve outcomes in humanitarian settings. In order to build the evidence base for ECD in humanitarian settings, we review the current state of implementation research for ECD programming (targeting children 0-8) in humanitarian settings, through a literature review and a series of key informant interviews. Drawing from existing frameworks of implementation research and the findings from our analysis, we present a framework for ECD implementation research in humanitarian settings and propose an agenda for future research.


SCLERAL PITS IN CHOROIDEREMIA: Implications for Retinal Gene Therapy.
We report a novel finding on spectral domain optical coherence tomography in patients with choroideremia, which we describe as scleral pits (SCPs). Cross-sectional observational case series of 36 patients with choroideremia, who underwent ophthalmic examination and multimodal imaging, including optical coherence tomography of the macula. Optical coherence tomography images were reviewed for SCP, which were defined as discrete tracts of hyporeflectivity that traverse the sclera with or without the involvement of Bruch membrane, retinal pigment epithelium, and retina. Unpaired two-tailed t-test with Welch correction was used for statistical analysis. Of the 36 patients, 19 had SCP in at least one eye. Scleral pits were confined to areas of advanced chorioretinal degeneration and never involved the foveola. Type 1 SCP affected only the sclera, whereas Type 2 SCP also involved the Bruch membrane and the retinal pigment epithelium. Type 3 SCP additionally had a full-thickness retinal defect. Patients with SCP were significantly older (51 ± 2 vs. 33 ± 4 years; P < 0.05) and had lower best-corrected visual acuity (20/160 vs. 20/30 or 0.9 ± 0.2 vs. 0.2 ± 0.07 logarithm of the minimum angle of resolution; P < 0.05) than patients without SCP. Patients with SCP had a greater myopic refractive error compared with patients without SCP (-2.6 ± 0.5 vs. -0.3 ± 0.5D; P < 0.05), but there was no significant correlation between the number of SCPs with refraction. Short posterior ciliary arteries were observed to enter the eye through one Type 3 SCP. Scleral pits are, to the best of our knowledge, a novel optical coherence tomography finding in advanced choroideremia that likely represents the abnormal juxtaposition of penetrating short posterior ciliary arteries with the retina.


Inhibition of alpha7 nicotinic receptors in the ventral hippocampus selectively attenuates reinstatement of morphine-conditioned place preference and associated changes in AMPA receptor binding.
Recurrent relapse is a major problem in treating opiate addiction. Pavlovian conditioning plays a role in recurrent relapse whereby exposure to cues learned during drug intake can precipitate relapse to drug taking. α7 nicotinic acetylcholine receptors (nAChRs) have been implicated in attentional aspects of cognition and mechanisms of learning and memory. In this study we have investigated the role of α7 nAChRs in morphine-conditioned place preference (morphine-CPP). CPP provides a model of associative learning that is pertinent to associative aspects of drug dependence. The α7 nAChR antagonist methyllycaconitine (MLA; 4 mg/kg s.c.) had no effect on the acquisition, maintenance, reconsolidation or extinction of morphine-CPP but selectively attenuated morphine-primed reinstatement of CPP, in both mice and rats. Reinstatement of morphine-CPP in mice was accompanied by a selective increase in [3 H]-AMPA binding (but not in [3 H]-MK801 binding) in the ventral hippocampus that was prevented by prior treatment with MLA. Administration of MLA (6.7 μg) directly into the ventral hippocampus of rats prior to a systemic priming dose of morphine abolished reinstatement of morphine-CPP, whereas MLA delivered into the dorsal hippocampus or prefrontal cortex was without effect. These results suggest that α7 nAChRs in the ventral hippocampus play a specific role in the retrieval of associative drug memories following a period of extinction, making them potential targets for the prevention of relapse.


Identification of a plasma membrane glutamine transporter from the rat hepatoma cell line H4-IIE-C3.
Glutamine is taken up into the rat hepatoma cell line H4-IIE-C3 by a Na+-dependent transport system which is specific for glutamine, alanine, serine, cysteine and asparagine and does not tolerate substitution of Na+ by Li+. Glutamine transport was relatively weakly inhibited by a 50-fold excess of leucine and was not inhibited by phenylalanine or N -methyl aminoisobutyrate. These general properties are characteristic of the recently identified ASCT/B0 family of transporters. Using a reverse transcriptase PCR-based homology cloning approach, we have characterized a cDNA for a novel member of this transporter family (H4-ASCT2) from H4-IIE-C3 cells. The cDNA encodes a 551-amino acid protein which exhibits similarities of between 75 and 85% with ASCT/B0 transporters previously cloned from other sources. When expressed in Xenopus oocytes, this transporter catalyses Na+-dependent glutamine uptake with characteristics very similar to those of glutamine uptake into the H4-IIE-C3 cells. This newly characterized transporter possesses a number of amino acid sequence differences from ASCT2 clones recently isolated from rat astroglial cells and from normal rat liver. In particular, the loop region between transmembrane helices 3 and 4 from H4-ASCT2 shares less than 60% sequence similarity with ASCT2 from rat liver; furthermore, there are some 25 single amino acid substitutions elsewhere in the H4-ASCT2 sequence compared with that from rat liver. Thus enhanced glutamine uptake in rat hepatoma cells is mediated by the expression of a novel ASCT/B0 transporter isoform rather than by increased expression of the ASCT2 mRNA found in normal rat liver.


Risk management in HIV/AIDS: ethical and economic issues associated with restricting HAART access only to adherent patients.
Like many other developing nations, South Africa faces the challenge of mobilising resources in response to the HIV pandemic. There is a large budget gap between the ideal and the actual amount of funding needed to achieve universal access to highly active antiretroviral therapy (HAART). In addition to financial demands, new burdens are being placed on HAART programmes with the emergence of HIV drug resistance (HIVDR). Thus, a major threat to successful HAART rollout is HIVDR due to non-adherence to HAART. The use of HAART as a primary and secondary HIV-prevention strategy could be ineffective in situations characterised by high rates of non-adherence. In this context, the research looked at issues related to adherence and non-adherence to HAART from the perspective of the provider. Using the software TreeAge Pro 2009, we developed a Markov model to project economic outcomes for a hypothetical cohort of HIV/AIDS patients on HAART. The model compared two scenarios: adherence and non-adherence to HAART. Input data for the model was obtained from existing literature on HAART uptake in South Africa. Moral arguments were analysed and managed through moral reasoning and critical thinking. Discounted lifetime costs for adherent and non-adherent HAART patients in South Africa were estimated at US$9 771 and US$14 762, respectively. The model showed the loss of 4.55 quality-adjusted life years (QALYs) for non-adherent patients, which could be otherwise gained through improved adherence. The incremental cost-effectiveness ratio (ICER) indicated that restricting HAART access only to adherent patients was the dominant strategy. We suggest that, although not a panacea, the withholding or withdrawal of treatment from non-adherent individuals as a precautionary intervention has economic and moral merit.


R-spondin-3 induces secretory, antimicrobial Lgr5+ cells in the stomach.
Wnt signalling stimulated by binding of R-spondin (Rspo) to Lgr-family members is crucial for gastrointestinal stem cell renewal. Infection of the stomach with Helicobacter pylori stimulates increased secretion of Rspo by myofibroblasts, leading to an increase in proliferation of Wnt-responsive Axin2+Lgr5- stem cells in the isthmus of the gastric gland and finally gastric gland hyperplasia. Basal Lgr5+ cells are also exposed to Rspo3, but their response remains unclear. Here, we demonstrate that-in contrast to its known mitogenic activity-Rspo3 induces differentiation of basal Lgr5+ cells into secretory cells that express and secrete antimicrobial factors, such as intelectin-1, into the lumen. The depletion of Lgr5+ cells or the knockout of Rspo3 in myofibroblasts leads to hypercolonization of the gastric glands with H. pylori, including the stem cell compartment. By contrast, systemic administration or overexpression of Rspo3 in the stroma clears H. pylori from the gastric glands. Thus, the Rspo3-Lgr5 axis simultaneously regulates both antimicrobial defence and mucosal regeneration.


Real-time multimodal medical image processing: a dynamic volume-rendering application.
In the present research, a system for medical image processing has been proposed, which allows multimodal dynamic three-dimensional (3-D) visualization interactively and in real time. The system has been conceived to support medical specialists in the diagnosis of moving organs, such as the heart during the cardiac cycle, allowing them to compare information on perfusion/contraction match as a basis for diagnosis of important cardiovascular diseases. The 3-D volume-rendering algorithm runs on a SIMD machine because of the great amount of data to be manipulated by always using the same operations. One of the features of the algorithm is the possibility to change, interactively, image processing and visualization parameters at any step, and to perform simple and effective image manipulations. Performance studies have demonstrated a very high global efficiency in practical situations by using typical data-volume dimensions. The system has been tested in the medical environment, by using magnetic resonance (MR) and single-photon emission-computed tomographic (SPECT) images.


99mTc-antimyosin antibody imaging for the detection of acute myocardial infarction in human beings.
111In-antimyosin imaging is a highly sensitive and specific technique for the detection of myocardial necrosis. Two new methods of labeling antimyosin with 99mTc have been developed, and were compared with the standard 111In-antimyosin imaging technique in 29 patients with acute myocardial infarction. Fourteen patients (group I) received directly labeled 99mTc-antimyosin, and 15 (group II) were given RP-1 conjugated 99mTc-antimyosin. 99mTc-antimyosin imaging was performed at 6, 12, and 24 hours, and 111In-antimyosin imaging was done at 24 and 48 hours following injection. The images were interpreted by three blinded observers. In group I, 99mTc-antimyosin uptake could be detected in 3, 6, and 12 cases at 6, 12, and 24 hours, respectively, compared with only 8 cases at 24 hours with 111In-antimyosin. At 48 hours all patients showed 111In-antimyosin uptake. In group II, 99mTc-antimyosin uptake could be detected in 2, 3, and 6 cases at 6, 12, and 24 hours, respectively, compared with 8 and 12 cases at 24 and 48 hours, respectively, with 111In-antimyosin. Gated blood pool studies could be obtained in all patients following 99mTc-antimyosin injection and could be used to identify regional wall motion abnormalities. The plasma half-lives of 99mTc-antimyosin in group I and group II were 2.67 +/- 0.3 hours and 4.23 +/- 0.3 hours, respectively, and the plasma half-life of 111In-antimyosin was 6.3 +/- 0.4 hours.(ABSTRACT TRUNCATED AT 250 WORDS)


Secretion of a proteolytic anticoagulant by Ancylostoma hookworms.
Hookworms of the genus Ancylostoma secrete an anticoagulant that both inhibits the clotting of human plasma and promotes fibrin clot dissolution. This anticoagulant activity is attributable to a 36,000 dalton proteolytic enzyme. The protease can degrade fibrinogen into five smaller polypeptides that intrinsically have anticoagulating properties, covert plasminogen to a mini-plasminogen-like molecule, and hydrolyze a synthetic peptide substrate with specificity for elastolytic enzymes. It is hypothesized that the parasite uses this enzyme to prevent blood clotting while feeding on villous capillaries.


Tuberculosis associated chronic obstructive pulmonary disease.
Reviewed the epidemiology, clinical characteristics, mechanisms, and treatment of tuberculosis associated chronic obstructive pulmonary disease. We searched PubMed, EMBASE, and the CINAHL from inception to June 2016. We used the following search terms: Tuberculosis, COPD, Tuberculosis associated COPD, and so forth. All types of study were chosen. Chronic obstructive pulmonary disease (COPD) and tuberculosis are significant public health problems, particularly in developing countries. Although, smoking is the conventional risk factor for COPD, nonsmoking related risk factors such as biomass fuel exposure, childhood lower-respiratory tract infections, chronic asthma, outdoor air pollution, and prior history of pulmonary tuberculosis have become important risk factors of COPD, particularly in developing countries. Past history of tuberculosis as a risk factor of chronic airflow obstruction has been reported in several studies. It may develop during the course of tuberculosis or after completion of tuberculosis treatment. Developing countries with large burden of tuberculosis can contribute significantly to the burden of chronic airflow obstruction. Prompt diagnosis and treatment of tuberculosis should be emphasized to lessen the future burden of chronic airflow obstruction.


Ancient coexistence of norepinephrine, tyramine, and octopamine signaling in bilaterians.
Norepinephrine/noradrenaline is a neurotransmitter implicated in arousal and other aspects of vertebrate behavior and physiology. In invertebrates, adrenergic signaling is considered absent and analogous functions are performed by the biogenic amines octopamine and its precursor tyramine. These chemically similar transmitters signal by related families of G-protein-coupled receptors in vertebrates and invertebrates, suggesting that octopamine/tyramine are the invertebrate equivalents of vertebrate norepinephrine. However, the evolutionary relationships and origin of these transmitter systems remain unclear. Using phylogenetic analysis and receptor pharmacology, here we have established that norepinephrine, octopamine, and tyramine receptors coexist in some marine invertebrates. In the protostomes Platynereis dumerilii (an annelid) and Priapulus caudatus (a priapulid), we have identified and pharmacologically characterized adrenergic α1 and α2 receptors that coexist with octopamine α, octopamine β, tyramine type 1, and tyramine type 2 receptors. These receptors represent the first examples of adrenergic receptors in protostomes. In the deuterostome Saccoglossus kowalevskii (a hemichordate), we have identified and characterized octopamine α, octopamine β, tyramine type 1, and tyramine type 2 receptors, representing the first examples of these receptors in deuterostomes. S. kowalevskii also has adrenergic α1 and α2 receptors, indicating that all three signaling systems coexist in this animal. In phylogenetic analysis, we have also identified adrenergic and tyramine receptor orthologs in xenacoelomorphs. Our results clarify the history of monoamine signaling in bilaterians. Given that all six receptor families (two each for octopamine, tyramine, and norepinephrine) can be found in representatives of the two major clades of Bilateria, the protostomes and the deuterostomes, all six receptors must have coexisted in the last common ancestor of the protostomes and deuterostomes. Adrenergic receptors were lost from most insects and nematodes, and tyramine and octopamine receptors were lost from most deuterostomes. This complex scenario of differential losses cautions that octopamine signaling in protostomes is not a good model for adrenergic signaling in deuterostomes, and that studies of marine animals where all three transmitter systems coexist will be needed for a better understanding of the origin and ancestral functions of these transmitters.


Comparison of African and North American velvet ant mimicry complexes: Another example of Africa as the 'odd man out'.
Africa has the most tropical and subtropical land of any continent, yet has relatively low species richness in several taxa. This depauperate nature of the African tropical fauna and flora has led some to call Africa the "odd man out." One exception to this pattern is velvet ants (Hymenoptera: Mutillidae), wingless wasps that are known for Müllerian mimicry. While North American velvet ants form one of the world's largest mimicry complexes, mimicry in African species has not been investigated. Here we ask do African velvet ant Müllerian mimicry rings exist, and how do they compare to the North American complex. We then explore what factors might contribute to the differences in mimetic diversity between continents. To investigate this we compared the color patterns of 304 African velvet ant taxa using nonmetric multidimensional scaling (NMDS). We then investigated distributions of each distinct mimicry ring. Finally, we compared lizard diversity and ecoregion diversity on the two continents. We found that African female velvet ants form four Müllerian rings, which is half the number of North American rings. This lower mimetic diversity could be related to the relatively lower diversity of insectivorous lizard species or to the lower number of distinct ecoregions in Africa compared to North America.


Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors.
Cholangiocarcinoma is a heterogeneous disease with a poor outcome that accounts for 5%-10% of primary liver cancers. We characterized its genomic and genetic features and associated these with patient responses to therapy. We profiled the transcriptomes from 104 surgically resected cholangiocarcinoma samples collected from patients in Australia, Europe, and the United States; epithelial and stromal compartments from 23 tumors were laser capture microdissected. We analyzed mutations in KRAS, epidermal growth factor receptor (EGFR), and BRAF in samples from 69 tumors. Changes in gene expression were validated by immunoblotting and immunohistochemistry; integrative genomics combined data from the patients with data from 7 human cholangiocarcinoma cell lines, which were then exposed to trastuzumab and lapatinib. Patients were classified into 2 subclasses, based on 5-year survival rate (72% vs 30%; χ(2) = 11.61; P < .0007), time to recurrence (13.7 vs 22.7 months; P < .001), and the absence or presence of KRAS mutations (24.6%), respectively. Class comparison identified 4 survival subgroups (SGI-IV; χ(2) = 8.34; P < .03); SGIII was characterized by genes associated with proteasomal activity and the worst prognosis. The tumor epithelium was defined by deregulation of the HER2 network and frequent overexpression of EGFR, the hepatocyte growth factor receptor (MET), pRPS6, and Ki67, whereas stroma was enriched in inflammatory cytokines. Lapatinib, an inhibitor of HER2 and EGFR, was more effective in inhibiting growth of cholangiocarcinoma cell lines than trastuzumab. We provide insight into the pathogenesis of cholangiocarcinoma and identify previously unrecognized subclasses of patients, based on KRAS mutations and increased levels of EGFR and HER2 signaling, who might benefit from dual-target tyrosine kinase inhibitors. The group of patients with the worst prognosis was characterized by transcriptional enrichment of genes that regulate proteasome activity, indicating new therapeutic targets.