Pheochromocytoma in rats with multiple endocrine neoplasia (MENX) shares gene expression patterns with human pheochromocytoma

Pheochromocytomas are rare neoplasias of neural crest origin arising from chromaffin cells of the adrenal medulla and sympathetic ganglia (extra-adrenal pheochromocytoma). Pheochromocytoma that develop in rats homozygous for a loss-of-function mutation in p27Kip1 (MENX syndrome) show a clear progression from hyperplasia to tumor, offering the possibility to gain insight into tumor pathobiology. We compared the gene-expression signatures of both adrenomedullary hyperplasia and pheochromocytoma with normal rat adrenal medulla. Hyperplasia and tumor show very similar transcriptome profiles, indicating early determination of the tumorigenic signature. Overrepresentation of developmentally regulated neural genes was a feature of the rat lesions. Quantitative RT-PCR validated the up-regulation of 11 genes, including some involved in neural development: Cdkn2a, Cdkn2c, Neurod1, Gal, Bmp7, and Phox2a. Overexpression of these genes precedes histological changes in affected adrenal glands. Their presence at early stages of tumorigenesis indicates they are not acquired during progression and may be a result of the lack of functional p27Kip1. Adrenal and extra-adrenal pheochromocytoma development clearly follows diverged molecular pathways in MENX rats. To correlate these findings to human pheochromocytoma, we studied nine genes overexpressed in the rat lesions in 46 sporadic and familial human pheochromocytomas. The expression of GAL, DGKH, BMP7, PHOX2A, L1CAM, TCTE1, EBF3, SOX4, and HASH1 was up-regulated, although with different frequencies. Immunohistochemical staining detected high L1CAM expression selectively in 27 human pheochromocytomas but not in 140 nonchromaffin neuroendocrine tumors. These studies reveal clues to the molecular pathways involved in rat and human pheochromocytoma and identify previously unexplored biomarkers for clinical use.

Osteoporosis and periodontitis in older subjects participating in the Swedish National Survey on Aging and Care (SNAC-Blekinge)

Abstract Objective. We assessed the relationships between (I) ultrasonography calcaneus T-scores (PIXI) and mandibular cortex characteristics on oral panoramic radiographs in older subjects; and (II) osteoporosis and periodontitis. Material and methods. We examined 778 subjects (53% women) aged 59-96 years. Periodontitis was defined by alveolar bone loss assessed from panoramic radiographs. Results. PIXI calcaneus T-values ?-2.5 (osteoporosis) were found in 16.3% of women and in 8.1% of men. PIXI calcaneus T-values <-1.6 (osteoporosis, adjusted) were found in 34.2% of women and in 21.4% of men. The age of the subjects and PIXI T-values were significantly correlated in women (Pearson's r = 0.37, P < 0.001) and men (Pearson's r = 0.19, P < 0.001). Periodontitis was found in 18.7% of subjects defined by alveolar bone level ?5 mm. Subjects with osteoporosis defined by adjusted PIXI T-values had fewer remaining teeth [mean difference 4.1, 95% confidence interval (CI) -1.1 to -6.5, P < 0.001]. The crude odds ratio (OR) of an association between the panoramic assessment of mandibular cortex erosions as a sign of osteoporosis and the adjusted T-value (T-value cut-off <-1.6) was 4.8 (95% CI 3.1-7.2, P < 0.001; Pearson ?(2) = 60.1, P < 0.001). A significant OR between osteoporosis and periodontitis was only found in women for the T-value cut-off ?-2.5 (crude OR 1.8, 95% CI 1.1-3.3, P < 0.03). Conclusions. An association between osteoporosis and periodontitis was only confirmed in women. The likelihood that the mandibular cortex index agrees with adjusted PIXI T-values is significant.

Choice of Initial Combination Antiretroviral Therapy in Individuals With HIV Infection: Determinants and Outcomes

BACKGROUND Current guidelines give recommendations for preferred combination antiretroviral therapy (cART). We investigated factors influencing the choice of initial cART in clinical practice and its outcome. METHODS We analyzed treatment-naive adults with human immunodeficiency virus (HIV) infection participating in the Swiss HIV Cohort Study and starting cART from January 1, 2005, through December 31, 2009. The primary end point was the choice of the initial antiretroviral regimen. Secondary end points were virologic suppression, the increase in CD4 cell counts from baseline, and treatment modification within 12 months after starting treatment. RESULTS A total of 1957 patients were analyzed. Tenofovir-emtricitabine (TDF-FTC)-efavirenz was the most frequently prescribed cART (29.9%), followed by TDF-FTC-lopinavir/r (16.9%), TDF-FTC-atazanavir/r (12.9%), zidovudine-lamivudine (ZDV-3TC)-lopinavir/r (12.8%), and abacavir/lamivudine (ABC-3TC)-efavirenz (5.7%). Differences in prescription were noted among different Swiss HIV Cohort Study sites (P < .001). In multivariate analysis, compared with TDF-FTC-efavirenz, starting TDF-FTC-lopinavir/r was associated with prior AIDS (relative risk ratio, 2.78; 95% CI, 1.78-4.35), HIV-RNA greater than 100 000 copies/mL (1.53; 1.07-2.18), and CD4 greater than 350 cells/μL (1.67; 1.04-2.70); TDF-FTC-atazanavir/r with a depressive disorder (1.77; 1.04-3.01), HIV-RNA greater than 100 000 copies/mL (1.54; 1.05-2.25), and an opiate substitution program (2.76; 1.09-7.00); and ZDV-3TC-lopinavir/r with female sex (3.89; 2.39-6.31) and CD4 cell counts greater than 350 cells/μL (4.50; 2.58-7.86). At 12 months, 1715 patients (87.6%) achieved viral load less than 50 copies/mL and CD4 cell counts increased by a median (interquartile range) of 173 (89-269) cells/μL. Virologic suppression was more likely with TDF-FTC-efavirenz, and CD4 increase was higher with ZDV-3TC-lopinavir/r. No differences in outcome were observed among Swiss HIV Cohort Study sites. CONCLUSIONS Large differences in prescription but not in outcome were observed among study sites. A trend toward individualized cART was noted suggesting that initial cART is significantly influenced by physician's preference and patient characteristics. Our study highlights the need for evidence-based data for determining the best initial regimen for different HIV-infected persons.

Participatory on-farm appraisal of improved pearl millet varieties in Eritrea

Pearl millet is Eritrea’s second most important cereal crop. Embedded in Eritrea’s millet improvement programme, this study summarizes the results of an on-farm appraisal of millet varieties at 3 study sites in western Eritrea. The participating communities were asked to rank improved and traditional varieties. Men generally preferred the improved varieties for their higher yields, while women preferred the traditional landraces owing to taste and food quality.

Predictors of satisfaction with treatment decision, decision-making preferences, and main treatment goals in patients with advanced cancer

Purpose This study investigated satisfaction with treatment decision (SWTD), decision-making preferences (DMP), and main treatment goals, as well as evaluated factors that predict SWTD, in patients receiving palliative cancer treatment at a Swiss oncology network. Patients and methods Patients receiving a new line of palliative treatment completed a questionnaire 4–6 weeks after the treatment decision. Patient questionnaires were used to collect data on sociodemographics, SWTD (primary outcome measure), main treatment goal, DMP, health locus of control (HLoC), and several quality of life (QoL) domains. Predictors of SWTD (6 = worst; 30 = best) were evaluated by uni- and multivariate regression models. Results Of 480 participating patients in eight hospitals and two private practices, 445 completed all questions regarding the primary outcome measure. Forty-five percent of patients preferred shared, while 44 % preferred doctor-directed, decision-making. Median duration of consultation was 30 (range: 10–200) minutes. Overall, 73 % of patients reported high SWTD (≥24 points). In the univariate analyses, global and physical QoL, performance status, treatment goal, HLoC, prognosis, and duration of consultation were significant predictors of SWTD. In the multivariate analysis, the only significant predictor of SWTD was duration of consultation (p = 0.01). Most patients indicated hope for improvement (46 %), followed by hope for longer life (26 %) and better quality of life (23 %), as their main treatment goal. Conclusion Our results indicate that high SWTD can be achieved in most patients with a 30-min consultation. Determining the patient’s main treatment goal and DMP adds important information that should be considered before discussing a new line of palliative treatment.

Abacavir induced T cell reactivity from drug naïve individuals shares features of allo-immune responses.

Abacavir hypersensitivity is a severe hypersensitivity reaction which occurs exclusively in carriers of the HLA-B*57∶01 allele. In vitro culture of PBMC with abacavir results in the outgrowth of abacavir-reacting CD8+ T cells, which release IFNγ and are cytotoxic. How this immune response is induced and what is recognized by these T cells is still a matter of debate. We analyzed the conditions required to develop an abacavir-dependent T cell response in vitro. The abacavir reactivity was independent of co-stimulatory signals, as neither DC maturation nor release of inflammatory cytokines were observed upon abacavir exposure. Abacavir induced T cells arose in the absence of professional APC and stemmed from naïve and memory compartments. These features are reminiscent of allo-reactivity. Screening for allo-reactivity revealed that about 5% of generated T cell clones (n = 136) from three donors were allo-reactive exclusively to the related HLA-B*58∶01. The addition of peptides which can bind to the HLA-B*57∶01-abacavir complex and to HLA-B*58∶01 during the induction phase increased the proportion of HLA-B*58∶01 allo-reactive T cell clones from 5% to 42%. In conclusion, abacavir can alter the HLA-B*57∶01-peptide complex in a way that mimics an allo-allele ('altered self-allele') and create the potential for robust T cell responses.

First results from a Swiss level I trauma centre participating in the UK Trauma Audit and Research Network (TARN): Prospective cohort study

QUESTIONS UNDER STUDY: Patient characteristics and risk factors for death of Swiss trauma patients in the Trauma Audit and Research Network (TARN). METHODS: Descriptive analysis of trauma patients (≥16 years) admitted to a level I trauma centre in Switzerland (September 1, 2009 to August 31, 2010) and entered into TARN. Multivariable logistic regression analysis was used to identify predictors of 30-day mortality. RESULTS: Of 458 patients 71% were male. The median age was 50.5 years (inter-quartile range [IQR] 32.2-67.7), median Injury Severity Score (ISS) was 14 (IQR 9-20) and median Glasgow Coma Score (GCS) was 15 (IQR 14-15). The ISS was >15 for 47%, and 14% had an ISS >25. A total of 17 patients (3.7%) died within 30 days of trauma. All deaths were in patients with ISS >15. Most injuries were due to falls <2 m (35%) or road traffic accidents (29%). Injuries to the head (39%) were followed by injuries to the lower limbs (33%), spine (28%) and chest (27%). The time of admission peaked between 12:00 and 22:00, with a second peak between 00:00 and 02:00. A total of 64% of patients were admitted directly to our trauma centre. The median time to CT was 30 min (IQR 18-54 min). Using multivariable regression analysis, the predictors of mortality were older age, higher ISS and lower GCS. CONCLUSIONS: Characteristics of Swiss trauma patients derived from TARN were described for the first time, providing a detailed overview of the institutional trauma population. Based on these results, patient management and hospital resources (e.g. triage of patients, time to CT, staffing during night shifts) could be evaluated as a further step.

Spatial-temporal clustering of companion animal enteric syndrome: detection and investigation through the use of electronic medical records from participating private practices

SUMMARY There is interest in the potential of companion animal surveillance to provide data to improve pet health and to provide early warning of environmental hazards to people. We implemented a companion animal surveillance system in Calgary, Alberta and the surrounding communities. Informatics technologies automatically extracted electronic medical records from participating veterinary practices and identified cases of enteric syndrome in the warehoused records. The data were analysed using time-series analyses and a retrospective space-time permutation scan statistic. We identified a seasonal pattern of reports of occurrences of enteric syndromes in companion animals and four statistically significant clusters of enteric syndrome cases. The cases within each cluster were examined and information about the animals involved (species, age, sex), their vaccination history, possible exposure or risk behaviour history, information about disease severity, and the aetiological diagnosis was collected. We then assessed whether the cases within the cluster were unusual and if they represented an animal or public health threat. There was often insufficient information recorded in the medical record to characterize the clusters by aetiology or exposures. Space-time analysis of companion animal enteric syndrome cases found evidence of clustering. Collection of more epidemiologically relevant data would enhance the utility of practice-based companion animal surveillance.

Three-year outcomes of Straumann Bone Level SLActive dental implants in daily dental practice: a prospective non-interventional study

OBJECTIVE The aim of this investigation was to evaluate the performance of Straumann Bone Level SLActive implants in various clinical situations in daily dental practice for up to 3 years. METHOD AND MATERIALS This was a prospective, multicenter, non-interventional study in which implants were placed within approved indications in any situation deemed suitable by the treating clinician. No implant placement or loading protocol was specified, and implants were placed according to the routine treatment protocols at each participating center. RESULTS In this analysis, data were available from 342 implants in 233 patients in three countries (USA, Canada, and Switzerland). One or two implants were placed in the majority of patients (70.8% and 19.3%, respectively), mostly in the maxilla (71.3%); almost half (47.7%) were placed in the esthetic zone. Implant placement after 4 to > 16 weeks of healing was preferred in Switzerland (92.0%), while 42.0% of implants were placed immediately in the USA and Canada. A flapless procedure was performed in 25.2% of cases in the USA and Canada, compared to 0.5% in Switzerland. Cumulative implant survival and success rates after 3 years were 97.5% and 93.5%, respectively. CONCLUSION Straumann Bone Level Implants can achieve favorable outcomes and high survival rates after 3 years in daily dental practice. The survival and success rates were comparable with those achieved in formal controlled clinical trials.

PSHARE: Stata module to compute and graph percentile shares

-pshare- computes and graphs percentile shares from individual level data. Percentile shares are often used in inequality research to study the distribution of income or wealth. They are defined as differences between Lorenz ordinates of the outcome variable. Technically, the observations are sorted in increasing order of the outcome variable and the specified percentiles are computed from the running sum of the outcomes. Percentile shares are then computed as differences between percentiles, divided by total outcome. pshare requires moremata to be installed on the system; see ssc describe moremata.