Assessing the diagnostic accuracy and interobserver agreement of MRI perfusion in differentiating disease progression and pseudoprogression following treatment for glioblastoma in a tertiary UK centre.

AIM: To assess the local diagnostic accuracy and interobserver agreement of dynamic susceptibility contrast-enhanced magnetic resonance perfusion (DSC MRP) reporting in differentiating between disease progression and pseudoprogression (PP) at a tertiary UK centre. MATERIALS AND METHODS: This retrospective study included adults with histology-proven glioblastoma who underwent an index DSC MRP examination following treatment. Each index examination was evaluated by three reporters independently, including qualitative assessment and measurement of mean regional cerebral blood volume (rCBVmean) ratios. Consensus opinion was used as the reference standard and considered clinical, radiological and histological follow-up information. Examination reports were compared to each other and to the consensus opinion. RESULTS: Thirty-two cases were included (19 progression, 13 pseudoprogression). Interobserver agreement was fair for qualitative opinion (κ=0.58, 95% confidence interval [CI] 0.40-0.76) and good for rCBVmean ratio measurement (intraclass correlation coefficient [ICC, two-way random effects model] 0.63, 95% CI=0.43-0.78). Qualitative opinion showed diagnostic accuracies of 77.1% (95% CI=67.4-85.1) for progression and 75% (95% CI=65.1-83.3) for pseudoprogression. rCBVmean ratios were higher for progression (6.85 ± 3.98) than pseudoprogression (3.71 ± 3.40); a 3.0 threshold value maximised the sum of sensitivity (91.1%) and specificity (69.7%) on receiver operating characteristic analysis. CONCLUSIONS: DSC MRP and rCBVmean ratio measurement aid differentiation between progression and pseudoprogression following treatment for glioblastoma. Measurement of the rCBVmean ratio shows good interobserver agreement and can change opinion and improve confidence in DSC MRP reporting. Individual centres should validate their own threshold rCBVmean ratio values to optimise diagnostic accuracy.

Correction to: Adipokines and the insulin resistance syndrome in familial partial lipodystrophy caused by a mutation in lamin A/C.

The authors regret that Alexandra Bargiota's name was spelt incorrectly in the author list. The details given in this correction are correct.

From Crowdsourcing to Extreme Citizen Science: Participatory Research for Environmental Health.

Environmental health issues are becoming more challenging, and addressing them requires new approaches to research design and decision-making processes. Participatory research approaches, in which researchers and communities are involved in all aspects of a research study, can improve study outcomes and foster greater data accessibility and utility as well as increase public transparency. Here we review varied concepts of participatory research, describe how it complements and overlaps with community engagement and environmental justice, examine its intersection with emerging environmental sensor technologies, and discuss the strengths and limitations of participatory research. Although participatory research includes methodological challenges, such as biases in data collection and data quality, it has been found to increase the relevance of research questions, result in better knowledge production, and impact health policies. Improved research partnerships among government agencies, academia, and communities can increase scientific rigor, build community capacity, and produce sustainable outcomes.

Phase I study of PF-03446962, a fully human monoclonal antibody against activin receptor-like kinase-1, in patients with hepatocellular carcinoma.

BACKGROUND: This expansion cohort of a multicenter, dose-escalation, phase I study (NCT00557856) evaluated safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamic effects of the anti-activin receptor-like kinase-1 (ALK-1) monoclonal antibody PF-03446962 in advanced hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with HCC and disease progression after prior antiangiogenic therapy or intolerance to treatment received PF-03446962 7 mg/kg intravenously biweekly, as recommended in the dose-escalation part of the study. RESULTS: Twenty-four patients received PF-03446962. The most frequent treatment-related adverse events (AEs) were thrombocytopenia (33.3%), asthenia (29.2), and chills (16.7%). Two patients experienced treatment-related telangiectasia, suggesting an in vivo knockout of ALK-1 function through ALK-1 pathway inhibition. Overall, treatment-related grade 3-4 AEs were reported in eight patients (33.3%). Treatment-related grade 3-4 thrombocytopenia was noted in four patients. No complete or partial responses were reported. Twelve (50%) patients achieved stable disease, which lasted ≥12 weeks in seven (29.2%) patients. The median time to progression was 3 months. Biomarker analyses showed higher mean tumor expression of c-tumor mesenchymal-epithelial transition factor and higher mean serum levels of bone morphogenetic protein-9 in patients with disease control (DC) for ≥12 weeks versus patients with disease progression. Conversely, lower mean serum transforming growth factor-ß and vascular endothelial growth factor receptor-3 levels were detected in patients with DC versus patients with progression. CONCLUSIONS: The observed safety, tolerability, pharmacokinetic profile, and clinical activity support further evaluation of PF-03446962 in patients with HCC and other solid malignancies, as single agent or in combination with other antiangiogenic, chemotherapeutic, or immunotherapeutic agents. TRIAL REGISTRATION NUMBER: NCT00557856.

Immunological and C-peptide studies of patients with diabetes in northern Ethiopia: existence of an unusual subgroup possibly related to malnutrition.

AIMS/HYPOTHESIS: Surveys in northern Ethiopia have demonstrated that apparent type 1 diabetes occurs more frequently than elsewhere in Africa and, indeed, in other parts of the world. We therefore investigated in detail a cohort of diabetic patients from this region to clarify the nature of this type of diabetes. METHODS: All patients attending the diabetic clinic at Mekelle Hospital in the Tigray region of northern Ethiopia were investigated over a 6 week period. Clinical, demographic and anthropometric data were collected, as well as measurements of HbA(1c), fasting lipid profile, fasting serum C-peptide and serum markers of beta cell autoimmunity, i.e. islet antigen-2 and GAD antibodies (GADA). RESULTS: Of 105 patients seen, 69 (66%) were on insulin treatment and had been from or close to diagnosis. Their median age and diabetes duration were 30 and 5 years, respectively, with a male excess of 2:1. Median BMI was 20.6 kg/m². Despite these clinical characteristics suggestive of type 1 diabetes, only 42 of 69 (61%) patients were C-peptide-negative and 35% GADA-positive. Overall, 38 (36%) of the total group (n = 105) had immunological or C-peptide characteristics inconsistent with typical type 1 or type 2 diabetes. The clinical characteristics, local prevalence of undernutrition, and GADA and C-peptide heterogeneity suggest a malnutrition-related form of diabetes. CONCLUSIONS/INTERPRETATION: Not all patients in northern Ethiopia with apparent type 1 diabetes appear to have the form of disease seen in Europids; their disease may, in fact, be related to malnutrition.

Diabetes management of elective hospital admissions.

AIMS: At any given time, people with diabetes occupy approximately 10-20% of acute hospital beds. In addition, diabetes is associated with a greater length of stay. Patients undergoing elective procedures occupy approximately 50% of hospital beds. The aim of this 12-month project was to improve the quality of diabetes care for elective inpatients. The primary outcome measure was length of stay. METHODS: A team was established to improve the quality of care and reduce the length of stay of all patients admitted electively with diabetes. Specific areas of focus were surgical pre-assessment, planning the admission, post-operative care and planning a safe discharge. A retrospective audit of all elective patients with a coded diagnosis of diabetes admitted between June 2008 and June 2009 was performed. RESULTS: Comparing the year of the project with the preceding year day-case rates for patients with diabetes increased by 34.8% for diabetes vs. 13.7% for the total hospital population (P for difference=0.048). There was a significant fall in diabetes length of stay of 0.34 days comparing 2008 and 2009 (P=0.040). Over the same period, we have shown a smaller reduction in length of stay for all other admissions of 0.08 days (p=0.039). CONCLUSION: A team specifically employed to focus on elective inpatient diabetes care have a significant impact on length of stay of this patient group with potential cost savings.

Combination peroxisome proliferator-activated receptor gamma and alpha agonist treatment in Type 2 diabetes prevents the beneficial pioglitazone effect on liver fat content.

AIMS: Peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-alpha agonists individually reduce intra-organ triglyceride content and improve insulin sensitivity. However, the precise effects of combined PPAR-gamma and PPAR-alpha therapy on intra-organ triglyceride content and insulin sensitivity in subjects with Type 2 diabetes have not yet been determined. METHODS: Diet-controlled Type 2 subjects (n = 9) were studied before and after 16 weeks of combined PPAR-gamma [pioglitazone (PIO), 45 mg daily] and PPAR-alpha [bezafibrate (BEZA), modified release 400 mg daily] agonist therapy. Glucose metabolism and endogenous glucose production were measured following a standard liquid test meal. Liver and muscle triglyceride levels were measured by (1)H magnetic resonance spectroscopy. RESULTS: Combined PIO and BEZA therapy reduced mean fasting (7.5 +/- 0.5 vs. 6.5 +/- 0.2 mmol/l, P = 0.04) and peak postprandial plasma glucose (15.3 +/- 1.1 vs. 11.7 +/- 0.6 mmol/l, P = 0.007). No significant change in hepatic or muscle triglyceride content was observed. Postprandial suppression of endogenous glucose production remained similar on both study days. Both subcutaneous and visceral fat content increased following therapy. CONCLUSIONS: Combined PIO and BEZA therapy in Type 2 diabetes does not decrease intrahepatic triglyceride content or postprandial endogenous glucose production. This study demonstrates an unexpected adverse interaction of PPAR-alpha with PPAR-gamma agonist therapy.

Ghrelin restores 'lean-type' hunger and energy expenditure profiles in morbidly obese subjects but has no effect on postgastrectomy subjects.

OBJECTIVE: To examine the effects of ghrelin on appetite and energy expenditure in lean, obese and postgastrectomy subjects. DESIGN: A randomized, double-blind, placebo-controlled study. PATIENTS: Nine lean subjects (mean body mass index (BMI) 23.5+/-3 kg/m(2)) and nine morbidly obese subjects (mean BMI 51.4+/-10 kg/m(2)) and eight postgastrectomy subjects (mean BMI 22.4+/-1.0 kg/m(2)). INTERVENTIONS: Subjects were infused with either intravenous ghrelin (5 pmol kg(-1) min(-1)) or saline over 270 min. They were given a fixed energy breakfast followed by a free buffet lunch towards the end of the infusion. MAIN OUTCOME MEASURES: Visual analogue scales were used to record hunger and energy expenditure was measured by indirect calorimetry. RESULTS: Ghrelin increased energy intake at the buffet lunch in lean subjects (a 41% increase, P<0.01) and obese subjects (35% increase, P=0.04) but not in postgastrectomy subjects. Lean subjects showed a characteristic preprandial rise and postprandial fall in hunger scores, which was exaggerated by ghrelin infusion. Obese subjects showed little variation in hunger scores, but a 'lean-type' pattern was restored when given exogenous ghrelin. Ghrelin had no effect on resting metabolic rate but did increase respiratory quotient (RQ) in obese subjects. Ghrelin also increased RQ variability over time in all three groups (ANOVA, P<0.001). CONCLUSIONS: Hunger scores are abnormal in the obese, perhaps because of impaired ghrelin secretion. The effect of ghrelin in restoring normal hunger profiles in the obese suggests causality, confirming an important role in eating behaviour. Ghrelin also increases RQ in obese humans and increased RQ variability in all groups. This suggests that ghrelin regulates substrate utilization and may promote metabolic flexibility.

Myoinositol kinase: partial purification and identification of product.

Myoinositol kinase found in plant, animal, and microbial extracts has been partially purified by densitygradient centrifugation. The product of the enzymic reaction has been tentatively identified by paper chromatography. as myoinositol-1-phosphate.

Proton magnetic resonance spectroscopy in frontotemporal dementia.

This study of frontotemporal dementia (FTD) was carried out to determine whether MR spectroscopy can provide an in vivo marker for the neuronal loss and gliosis that occur in this condition. We compared spectra in frontal and temporal regions known to be affected early in the course of the disease with spectra in the parietal lobe that is spared until late stages of FTD. We were interested in the relative concentrations of two compounds, NAA (a marker of neuronal integrity) and mI (a marker of gliosis), expressed as ratios to creatine (a relatively stable brain constituent). MR spectroscopy was performed on the temporal, parietal, and anterior cingulate cortices of five patients with the established semantic dementia form of FTD, two patients with the frontal form of FTD and 13 age matched controls. Structural MRI and neuropsychometry were also performed. Patients with FTD had reduced NAA/Cr in frontal and temporal, but not parietal lobes. The two patients with the frontal form of FTD had increased mI/Cr in their cingulate cortices. These data show for the first time that MR spectroscopy can reveal regionally selective abnormalities in patients with FTD. This opens up the possibility of using MR spectroscopy as a clinical tool to identify earlier presentations of the condition.

Diabetic ketoacidosis complicated by axillary vein thrombosis.

A case is presented of a 39-year-old male with Down's Syndrome, who also had type 1 diabetes of 22 years duration. He presented with diabetic ketoacidosis (DKA)-arterial blood pH 7.17, plasma bicarbonate 13.6mmol/l, plasma glucose 26.4mmol/l and urine heavily positive for ketones. He recovered with standard intravenous fluid and insulin treatment, but on the third day of admission developed a swollen left arm (which had not been used for intravenous cannulation). Doppler ultrasound confirmed a left axillary vein thrombosis. This slowly resolved with anticoagulation. Review of the available literature revealed that though arterial thrombosis is a common complication of DKA, venous thromboembolism is surprisingly rare, and there appear to be no previous specific reports of axillary vein thrombosis complicating DKA.

Comparison of image quality, diagnostic confidence and interobserver variability in contrast enhanced MR angiography and 2D time of flight angiography in evaluation of carotid stenosis.

The aim of this study was to compare image quality, level of diagnostic confidence and interobserver agreement in assessment of carotid stenosis with contrast enhanced MR angiography (CE MRA) in comparison with 2D time of flight MR angiography (2D TOF MRA). 60 carotid arteries in 30 patients were examined by three observers. Image quality and diagnostic confidence were assessed on the basis of a visual analogue scale. Interobserver variability was assessed with the help of intraclass correlation coefficient. Median values on the visual analogue scale for image quality and diagnostic confidence were higher for CE MRA compared with 2D TOF MRA for all three observers. Higher intraclass correlation values were recorded for interobserver variability for CE MRA compared with 2D TOF MRA both for visual estimation of carotid stenosis as well as for measurement of carotid stenosis on the basis of North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) criteria. CE MRA provides better image quality, higher level of diagnostic confidence and more interobserver agreement compared with 2D TOF MRA.

Components of Population Vulnerability and Their Relationship With Climate-Sensitive Health Threats.

Climate change is increasingly being framed as risks that will impact the poorest and most vulnerable communities among us. This has led to more efforts to estimate climate change risks across populations and in the context of human health and health equity. We describe the public health dimensions of climate vulnerability-exposure, population sensitivity, and adaptive capacity-and explore how these dimensions can modify population health impacts and their distribution. An overview of health disparities associated with specific climate risks is presented, and we offer potential solutions grounded in equitable urban development and improved characterization of climate vulnerabilities.

Increased 1-Aminocyclopropane-1-Carboxylic Acid Oxidase Activity in Shoots of Flooded Tomato Plants Raises Ethylene Production to Physiologically Active Levels.

Soil flooding increased 1-aminocyclopropane-1-carboxylic (ACC) acid oxidase activity in petioles of wild-type tomato (Lycopersicon esculentum L.) plants within 6 to 12 h in association with faster rates of ethylene production. Petioles of flooded plants transformed with an antisense construct to one isoform of an ACC oxidase gene (ACO1) produced less ethylene and had lower ACC oxidase activity than those of the wild type. Flooding promoted epinastic curvature but did so less strongly in plants transformed with the antisense construct than in the wild type. Exogenous ethylene, supplied to well-drained plants, also promoted epinastic curvature, but transformed and wild-type plants responded similarly. Flooding increased the specific delivery (flux) of ACC to the shoots (picomoles per second per square meter of leaf) in xylem sap flowing from the roots. The amounts were similar in both transformed and wild-type plants. These observations demonstrate that changes in ACC oxidase activity in shoot tissue resulting from either soil flooding or introducing ACC oxidase antisense constructs can influence rates of ethylene production to a physiologically significant extent. They also implicate systemic root to shoot signals in regulating the activity of ACC oxidase in the shoot.

Food fails to suppress ghrelin levels in obese humans.

UNLABELLED: Ghrelin is the first circulating hormone shown to stimulate feeding in humans following systemic administration. Food consumption decreases circulating ghrelin concentrations in lean subjects but the effects of feeding have not been studied in the obese. METHODS: We investigated the effects of a test meal on plasma ghrelin and leptin concentrations in 13 lean and 10 obese subjects. RESULTS: Fasting ghrelin was significantly higher in lean than in obese subjects (857 pmol/1 vs. 325 pmol/l, (p = 0.002) and fell by 39.5% thirty minutes after eating in the lean group before returning rapidly towards baseline values: (p = 0.003). There was no change in circulating ghrelin in the obese group. Circulating leptin concentration also fell acutely 15 minutes following food intake in lean but not obese subjects (p < 0.0001). CONCLUSIONS: Obese subjects do not exhibit the decline in plasma ghrelin and leptin seen after a meal in the lean. The role of the decline in leptin is unclear but given the orexigenic properties of ghrelin, the lack of suppression following a meal in obese subjects could lead to increased food consumption and suggest that ghrelin may be involved in the pathophysiology of obesity.

Seroconversion, sexual activity, and condom use among 2915 HIV seronegative men followed for up to 2 years.

A cohort of 2915 HIV-1-seronegative men from the four centers of the Multicenter AIDS Cohort Study (MACS) was followed at 6 month intervals for 24 months to identify men who developed antibodies to HIV-1. Two hundred thirty-two men (8%) seroconverted. The highest attack rate was among men who reported practicing both receptive and insertive anal-genital intercourse. The attack rate among men who reported practicing receptive but not insertive intercourse was 3.6 times higher than among men practicing insertive intercourse although those practicing insertive only reported 38% more different partners. Only two men seroconverted who reported not practicing analgenital intercourse in the 12 month prior to the first antibody-positive visit. Because men were followed every 6 months, one of these men could have been infected within 6 months of the actual development of HIV-1 antibodies. The seroconversion rate was significantly lower among men who reported using condoms with all their partners. The results of this study (a) reaffirm that receptive anal-genital intercourse is the major route of infection among homosexual men of HIV-1, (b) suggest that there is a low risk of HIV-1 infection to the insertive partner in anal-genital intercourse, (c) suggest that infection may rarely occur through sexual activities other than anal-genital intercourse, (d) provide evidence that condoms as currently used by men in the MACS provide significant but not complete protection against HIV-1 infection, and (e) suggest that the number of men in the homosexual community engaging in high-risk behavior is declining.

The relationship between T-cell levels and CMV infection in asymptomatic HIV-1 antibody-positive homosexual men.

To investigate the relationship between cytomegalovirus (CMV) infection and progression of HIV-1 disease, a group of 234 asymptomatic, HIV-1 antibody-positive homosexual men were examined for CMV isolation and levels of CMV IgM antibodies, CMV IgG antibodies, and CD4+ and CD8+ T-lymphocytes. CMV IgG antibodies were present in 100% and CMV IgM antibodies in 22% of the men. CMV was isolated from the semen of 45% of the men. No relationship was observed between CMV IgM antibodies and CMV in semen or CD4+ levels. CD4+ cell levels were significantly lower in those from whose semen CMV was isolated. In addition, an inverse relationship was observed between the concentration of CMV in semen and CD4+ levels. We postulate that the seminal tract may be a reservoir for systemic CMV infection in HIV-infected homosexual men. Reinfection from this or other sources may result in recurrent stimulation of HIV-1 replication and lead to a further decline in CD4+ cells. Clarification of whether persistent CMV infection is secondary to HIV-1-induced immunodeficiency or, conversely, promotes a more rapid decline in immunocompetency will require follow-up studies.

Patterns of CD4+ cell changes after HIV-1 infection indicate the existence of a codeterminant of AIDS.

Successive interval slopes of CD4+ cells each constructed from levels at three consecutive 6 month visits were compared over 3 years of follow-up among 565 persistently HIV-1 antibody-positive, 326 persistently antibody-negative, and 51 seroconverting homosexual men who had at least 500 CD4+ cells/mm3 at baseline and completed the first three 6 month visits. "Change" was defined as a difference between two successive interval slopes. Sixty-two percent of seroconverters meeting these criteria experienced a shift in one or more of their successive CD4+ interval slopes, the majority (56%) from a level slope to a negative slope (decreasing numbers of CD4+ cells), a significantly greater proportion than that observed among seronegatives (30%, p less than 0.0001). Fifty-eight percent of the seropositives maintained level interval slopes over the 3 years of follow-up. The majority (59%) of those men experiencing a shift went from a level to a negative interval slope, a significantly greater proportion than observed among seronegatives (30%, p less than 0.0001). The observed patterns of change in interval slopes are consistent with the laboratory observation that CD4+ cells must be activated to replicate HIV-1. The use of the interval slope strategy provides a method to identify a temporal focal point at which to examine possible codeterminants that trigger the production of HIV-1 and the subsequent decline in CD4+ cells.

Inhibitors of blood platelet aggregation. Effects of some 1,2-benzisothiazol-3-ones on platelet responsiveness to adenosine diphosphate and collagen.

A series of substituted 1,2-benzisothiazol-3-ones was synthesized, and the compounds were tested for ability to inhibit platelet aggregation induced by adenosine diphosphate and collagen in rats and guinea pigs ex vivo. Alkyl substituents at the 2-position bearing a basic group were necessary for ex vivo activity. Several of the compounds were potent inhibitors of adenosine diphosphate induced first-phase aggregation, but adverse toxicological findings terminated their further development. Preliminary studies suggested that inhibition of aggregation was not attributable to inhibition of prostanoid synthesis or to raised levels of cyclic 3',5'-adenosine monophosphate.