Human adipocytes induce an ERK1/2 MAP kinases-mediated upregulation of steroidogenic acute regulatory protein (StAR) and an angiotensin II-sensitization in human adrenocortical cells

OBJECTIVES: Hypertension is a major complication of overweight with frequently elevated aldosterone levels in obese patients. Our previous work suggests a direct stimulation of adrenal aldosterone secretion by adipocytes. Owing to aldosterone's important role in maintaining blood pressure homeostasis, its regulation in obesity is of major importance. One objective was to determine the signaling mechanisms involved in adipocyte-induced aldosterone secretion. In addition to a direct stimulation, a sensitization toward angiotensin II (AngII) might be involved. The second objective was to determine a possible adipokines-induced sensitization of human adrenocortical cells to AngII. DESIGN: Human subcutaneous adipocytes and adrenocortical cells, and the adrenocortical cell line NCI-H295R were used. Adrenocortical cells were screened for signal transduction protein expression and phosphorylation. Subsequently, steroidogenic acute regulatory protein (StAR), cAMP response element-binding protein (CREB), cAMP and phosphorylated extracellular regulated kinase were analyzed by Western blot, enzyme-linked immunosorbent assay, quantitative PCR, reporter gene assay and confocal microscopy to investigate their role in adipocyte-mediated aldosterone secretion. RESULTS: AngII-mediated aldosterone secretion was largely increased by preincubating H295R cells with adipocyte secretory products. StAR mRNA and StAR protein were upregulated in a time-dependent way. This steroidogenic effect was independent of the cAMP-protein kinase A (PKA) pathway as cellular cAMP was unaltered and inhibition of PKA by H89 failed to reduce aldosterone secretion. However, CREB reporter gene activity was moderately elevated. Upregulation of StAR was accompanied by ERK1/2 MAP kinase activation and nuclear translocation of the kinases. Inhibition of MAP kinase by UO126 abolished adipokine-stimulated aldosterone secretion from primary human adrenocortical and H295R cells, and inhibited StAR gene activity. Adipokines stimulated steroidogenesis also in primary human adrenocortical cells, supporting a role in human physiology and/or pathology. CONCLUSIONS: Adipokines induce aldosterone secretion from human adrenocortical cells and sensitization of the cells to stimulation by AngII, possibly mediated via ERK1/2-dependent upregulation of StAR activity. This stimulation of aldosterone secretion could be one link between overweight and inappropriately elevated aldosterone levels.     

Is Patients’ Preferred Involvement in Health Decisions Related to Outcomes for Patients with HIV?

BACKGROUND Previous studies suggest that patients who are more involved in their medical care have better outcomes. OBJECTIVES We sought to compare health care processes and outcomes for patients with HIV based on their preferred level of involvement in health decisions. DESIGN Cross-sectional analysis of audio computer-assisted interviews with patients at an urban HIV clinic. PATIENTS One thousand and twenty-seven patients awaiting an appointment with their primary care provider. MEASURES Patients were asked how they preferred to be involved in decisions (doctor makes most or all decisions, doctor and patient share decisions, patient makes all decisions). We also asked patients to rate the quality of communication with their HIV provider, and their self-reported receipt of and adherence to HAART. RESULTS Overall, 23% patients preferred that their doctor make all or most decisions, 63% preferred to share decisions with their doctor, and 13% preferred to make all final decisions alone. Compared to patients who prefer to share decisions with their HIV provider, patients who prefer that their provider make all/most decisions were significantly less likely to adhere to HAART (OR [odds ratio] 0.57, 95% CI 0.38–0.86) and patients who preferred to make decisions alone were significantly less likely to receive HAART or to have undetectable HIV RNA in unadjusted analyses (OR 0.52, 95% CI 0.31–0.87 for receipt of HAART; OR 0.64, 95% CI 0.44–0.95 for undetectable HIV RNA). After controlling for potentially confounding patient characteristics and differences in patient ratings of communication quality, patients who preferred that their provider make all/most decisions remained significantly less likely to adhere to HAART (OR 0.58, 95% CI 0.38–0.89); however, the associations with receipt of HAART and undetectable HIV RNA were no longer significant (OR 0.60, 95% CI 0.34–1.05 for receipt of HAART; OR 0.80, 95% C.I 0.53–1.20 for undetectable HIV RNA). CONCLUSIONS Although previous research suggests that more patient involvement in health care decisions is better, this benefit may be reduced when the patient wants to make decisions alone. Future research should explore the extent to which this preference is modifiable so as to improve outcomes.     

Internal fixation in compound type III fractures presenting after golden period

Objective:

Patients often reach the hospital late after passage of golden hours (initial 6 hours) after sustaining high-velocity injuries. The decision of internal fixation in Gustilo''s Type IIIA and IIIB fractures becomes a formidable challenge in patients reaching late. The purpose of the present study was to find out if internal fixation could be safely undertaken in these patients.

Materials and Methods:

Sixty-three patients, having 70 compound fractures (46 Type IIIA and 24 IIIB), which were internally fixed after 6h but within 24h after injury, were included in the present analysis. Follow-up ranged from 18 to 48 months with mean of 28 months.

Result:

Overall infection rate noted was (n = 11) 15.71% (8.7% in IIIA, and 29.16% in IIIB). The difference in deep infection rate between Type IIIA and Type IIIB was found to be statistically significant (P value < 0.01). Nonunion was seen in five fractures. Functional evaluation using Katenjian''s criteria, showed 62.85% (44 fractures of 70) good to excellent results.

Conclusion:

Satisfactory results may be obtained in Gustilo''s Type IIIA and IIIB fractures even if fixed after the golden period, provided strict protocol such as aggressive debridement, prophylactic antibiotic coverage, early soft tissue reconstruction and timely bone grafting is followed. The primary coverage of the wound is discouraged.     

The IFN regulatory factor 7‐dependent type I IFN response is not essential for early resistance against murine cytomegalovirus infection

IFN regulatory factor 7 (IRF7) has been described as the master regulator of type I IFN responses and has been shown to be critical for innate antiviral immunity in vivo. In addition to type I IFN, NK cell responses are involved in the control of viral replication during acute viral infection. To investigate the role of IRF7 in the context of a viral infection that induces a strong NK cell response, the murine cytomegalovirus (MCMV) infection model was used. WT, IRF7‐deficient and IRF3/IRF7‐double deficient mice were infected with MCMV. The systemic IFN‐α response to MCMV was entirely dependent on IRF7, but independent of IRF3. However, peak IFN‐β production during MCMV infection was not affected by the lack of IRF7 or both IRF7 and IRF3. Despite the complete lack of IFN‐α production IRF7‐ and IRF3/IRF7‐deficient mice were surprisingly efficient in controlling MCMV replication and were only modestly more susceptible to MCMV infection than WT mice. NK cell cytotoxicity was unimpaired and NK cell IFN‐γ production was enhanced in IRF7‐deficient mice correlating with increased levels of bioactive IL‐12. Owing to these compensatory mechanisms IRF7‐dependent antiviral immune responses were not essential for resistance against acute MCMV infection in vivo.     

The effect of the COMT val<Superscript>158</Superscript>met polymorphism on neural correlates of semantic verbal fluency

Variation in the val¹⁵⁸met polymorphism of the COMT gene has been found to be associated with cognitive performance. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal areas. Given the complex modulation and functional heterogeneity of frontal lobe systems, further specification of COMT gene-related phenotypes differing in prefrontally mediated cognitive performance are of major interest. Eighty healthy individuals (54 men, 26 women; mean age 23.3 years) performed an overt semantic verbal fluency task while brain activation was measured with functional magnetic resonance imaging (fMRI). COMT val¹⁵⁸met genotype was determined and correlated with brain activation measured with fMRI during the task. Although there were no differences in performance, brain activation in the left inferior frontal gyrus [Brodmann area 10] was positively correlated with the number of val alleles in the COMT gene. COMT val¹⁵⁸met status modulates brain activation during the language production on a semantic level in an area related to executive functions.     

Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer

BACKGROUND: Preclinical studies have demonstrated that the inhibition of the PI3K/Akt/mTOR pathway restores gefitinib sensitivity in resistant cancer cell lines. A phase 1 study was conducted of the combination of everolimus, an mTOR inhibitor, and gefitinib to determine a daily dose of everolimus with gefitinib in patients with advanced nonsmall-cell lung cancer (NSCLC). METHODS: Oral everolimus and gefitinib were both administered daily to patients with progressive NSCLC. Patients were enrolled in 3-patient cohorts at everolimus dose levels of 5 and 10 mg daily. All patients received gefitinib 250 mg daily. RESULTS: Ten patients were enrolled. The maximum tolerated dose of everolimus was 5 mg when administered daily with gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus experienced dose-limiting toxicity, including grade 5 hypotension and grade 3 stomatitis. Pharmacokinetic studies demonstrated no consistent, significant interaction on the t(max), C(max), and AUC(0-8h) of either agent. Two partial radiographic responses were identified among the 8 response-evaluable patients. CONCLUSIONS: For further study, everolimus at a dose of 5 mg daily in combination with daily gefitinib 250 mg is recommended. The 2 radiographic responses identified are encouraging. A phase 2 trial in patients with NSCLC is under way.     

Expression of human neutrophil proteins in acne vulgaris

Background In acne vulgaris patients, the presence of a dysregulation of the production of innate and specific antimicrobial peptides has been postulated. Objective This study aims to determine whether human neutrophil proteins (HNP) 1–3 are expressed in acne patients. Materials and methods HNP 1–3 expression was investigated in 35 acne patients treated with isotretinoin and in 25 healthy subjects. At the beginning of the study, two skin biopsies were taken from acne patients; one biopsy was taken from an established pustule and one from uninvolved skin, and the biopsies were repeated after treatment. Only one biopsy was obtained from controls. Results The statistical analysis showed that pustular lesions of acne patients had significantly higher levels of perivascular and interstitial HNP 1–3 expression when compared with the biopsy of uninvolved skin of these patients (P = 0.003, P = 0.001, respectively) and with that of healthy controls (P = 0.007, P = 0.014, respectively). Isotretinoin treatment achieved a decrease in the perivascular and interstitial HNP 1–3 expression of pustular lesions (P = 0.01, P = 0.001, respectively). Conclusion Our current study demonstrates the novel observation that a recently identified antimicrobial peptide, HNP 1–3, is expressed in neutrophils of acne inflammation but not in uninvolved skin of these patients. These results suggest that HNP 1–3 may contribute to the development of inflammatory lesions of acne.     

Inadequacies of repeated radiological examinations in a university hospital

Purpose: To establish why 16% of 1,045 patients undergoing abdominal and/or vascular surgery referred to the University Department of Radiology for a B-image sonogram reported that a US of the same regions of the body had been conducted during the previous 6 weeks without any changes in the clinical status.Statement of the problem: Evaluation of the reasons for these superfluous examinations and analysis of the consequences that the US follow-up examinations implied for the patient.Material and Methods: One senior resident radiologist and one senior resident surgeon reviewed the medical records of the patients reporting previous examinations and examinations scheduled at the time of the questioning of the patients.Results: One hundred and eight (63%) of the 171 medical records were available. Data on previous examinations mentioned in the report forms were incorrect in 14 cases (13%). Therefore, further evaluations were based on 94 patients. Ten (8%) out of 121 sonograms, 4 (10%) out of 40 CT and 2 (20%) out of 10 MR investigations documented in the medical records had not been mentioned by the patients. As many as 41 (75%) of the 55 preliminary sonograms performed by general practitioners and specialists in private practice were not documented in the medical records. Even though records existed of clinically plausible findings, 36 (84%) of the 43 preliminary US investigations performed by doctors in the University Hospital were repeated to verify the diagnosis without any further diagnostic benefit.Conclusion: A cross-speciality consensus over the diagnostic value of B-image sonography and management of the findings obtained is of paramount importance.