Hypothalamus-pituitary-adrenal axis during Trypanosoma cruzi acute infection in mice

Functional interactions between neuroendocrine and immune systems are mediated by similar ligands and receptors, which establish a bi-directional communication that is relevant for homeostasis. We investigated herein the hypothalamus-pituitary-adrenal (HPA) axis in mice acutely infected by Trypanosoma cruzi, the causative agent of Chagas' disease. Parasites were seen in the adrenal gland, whereas T. cruzi specific PCR gene amplification product was found in both adrenal and pituitary glands of infected mice. Histological and immunohistochemical analyses of pituitary and adrenal glands of infected animals revealed several alterations including vascular stasis, upregulation of the extracellular matrix proteins fibronectin and laminin, as well as T cell and macrophage infiltration. Functionally, we detected a decrease in CRH and an increase in corticosterone contents, in hypothalamus and serum respectively. In contrast, we did not find significant changes in the amounts of ACTH in sera of infected animals, whereas the serum levels of the glucocorticoid-stimulating cytokine, IL-6 (interleukin-6), were increased as compared to controls. When we analyzed the effects of T. cruzi in ACTH-producing AtT-20 cell line, infected cultures presented lower levels of ACTH and pro-opiomelanocortin production when compared to controls. In these cells we observed a strong phosphorylation of STAT-3, together with an increased synthesis of IL-6, suppressor of cytokine signaling 3 (SOCS-3) and inhibitor of activated STAT-3 (PIAS-3), which could explain the partial blockage of ACTH production. In conclusion, our data reveal that the HPA axis is altered during acute T. cruzi infection, suggesting direct and indirect influences of the parasite in the endocrine homeostasis.     

Medical Readers' Theater: Relevance to Geriatrics Medical Education

Medical Readers' Theater (MRT) is an innovative and simple way of helping medical students to reflect on difficult-to-discuss topics in geriatrics medical education, such as aging stereotypes, disability and loss of independence, sexuality, assisted living, relationships with adult children, and end-of-life issues. The authors describe a required MRT experience involving third-year medical students on their Family Medicine clerkship and volunteer residents from a nearby continuing care retirement community. Evaluation of the program shows positive benefits to student and senior participants in terms of greater awareness of each other's perspectives and improved communication.     

Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors

Germline mutations in the fumarate hydratase (FH) gene at 1q43 predispose to dominantly inherited cutaneous and uterine leiomyomas, uterine leiomyosarcoma, and papillary renal cell cancer (HLRCC syndrome). To evaluate the role of FH inactivation in sporadic tumorigenesis, we analyzed a series of 299 malignant tumors representing 10 different malignant tumor types for FH mutations. Additionally, 153 uterine leiomyomas from 46 unselected individuals were subjected to and informative in loss of heterozygosity analysis at the FH locus, and the five (3.3%) tumors displaying loss of heterozygosity were subjected to FH mutation analysis. Although mutation search in the 299 malignant tumors was negative, somatic FH mutations were found in two nonsyndromic leiomyomas; a splice site change IVS4 + 3A>G, leading to deletion of exon four, and a missense mutation Ala196Thr. The occurrence of somatic mutations strongly suggests that FH is a true target of the 1q43 deletions. Although uterine leiomyomas are the most common tumors of women, specific inactivating somatic mutations contributing to the formation of nonsyndromic leiomyomas have not been reported previously. Taking into account the apparent risk of uterine leiomyosarcoma associated with FH germline mutations, the finding raises the possibility that also some nonsyndromic leiomyomas may have a genetic profile that is more prone to malignant degeneration. Our data also indicate that somatic FH mutations appear to be limited to tumor types observed in hereditary leiomyomatosis and renal cell cancer.     

Variation in the use of online clinical evidence: a qualitative analysis

OBJECTIVE: To investigate factors influencing variations in clinicians' use of an online evidence retrieval system. SETTING: Public hospitals in New South Wales, Australia. METHOD: Web log analysis demonstrated considerable variation in rates of evidence use by clinicians at different hospitals. Focus groups and interviews were held with 61 staff from three hospitals, two with high rates of use and one with a low rate of use, to explore variation in evidence use. RESULTS: Differences between hospitals' and professional groups' (doctors, nurses and allied health) use of online evidence could be explained by organizational, professional and cultural factors. These included the presence of champions, organizational cultures which supported evidence-based practice (EBP), and database searching skills of individual clinicians. Staff shortages, ease of access and time taken to use the online evidence system were cited as barriers to use at the low use site, but no objective differences in these measures were found between the high and low use sites. CONCLUSION: Social and cultural factors were found to be better discriminators of high and low evidence use than technical factors.     

Research and applications: The safety of electronic prescribing: manifestations,mechanisms, and rates of system-related errors associated with two commercial systems in hospitals

Objectives

To compare the manifestations, mechanisms, and rates of system-related errors associated with two electronic prescribing systems (e-PS). To determine if the rate of system-related prescribing errors is greater than the rate of errors prevented.

Methods

Audit of 629 inpatient admissions at two hospitals in Sydney, Australia using the CSC MedChart and Cerner Millennium e-PS. System related errors were classified by manifestation (eg, wrong dose), mechanism, and severity. A mechanism typology comprised errors made: selecting items from drop-down menus; constructing orders; editing orders; or failing to complete new e-PS tasks. Proportions and rates of errors by manifestation, mechanism, and e-PS were calculated.

Results

42.4% (n=493) of 1164 prescribing errors were system-related (78/100 admissions). This result did not differ by e-PS (MedChart 42.6% (95% CI 39.1 to 46.1); Cerner 41.9% (37.1 to 46.8)). For 13.4% (n=66) of system-related errors there was evidence that the error was detected prior to study audit. 27.4% (n=135) of system-related errors manifested as timing errors and 22.5% (n=111) wrong drug strength errors. Selection errors accounted for 43.4% (34.2/100 admissions), editing errors 21.1% (16.5/100 admissions), and failure to complete new e-PS tasks 32.0% (32.0/100 admissions). MedChart generated more selection errors (OR=4.17; p=0.00002) but fewer new task failures (OR=0.37; p=0.003) relative to the Cerner e-PS. The two systems prevented significantly more errors than they generated (220/100 admissions (95% CI 180 to 261) vs 78 (95% CI 66 to 91)).

Conclusions

System-related errors are frequent, yet few are detected. e-PS require new tasks of prescribers, creating additional cognitive load and error opportunities. Dual classification, by manifestation and mechanism, allowed identification of design features which increase risk and potential solutions. e-PS designs with fewer drop-down menu selections may reduce error risk.     

Interaction of ambrisentan with clarithromycin and its modulation by polymorphic SLCO1B1

Purpose

We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1*15 haplotype in healthy volunteers.

Methods

In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n?=?6), with CYP2C19*1/*1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n?=?4), with CYP2C19 EM and homozygous (n?=?3) or heterozygous for SLCO1B1*15 (n?=?1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3–14 and twice-daily oral doses of 500 mg clarithromycin on study days 11–14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady-state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin).

Results

Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (C_max) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and C_max by 27 % (n?=?10, both p?<?0.05). No contribution of SLCO1B1*15 to the extent of this interaction was observed.

Conclusions

Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant.