Prenatal Programming of Metabolic Syndrome in the Common Marmoset Is Associated With Increased Expression of 11��-Hydroxysteroid Dehydrogenase Type 1

OBJECTIVE

Recent studies in humans and animal models of obesity have shown increased adipose tissue activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which amplifies local tissue glucocorticoid concentrations. The reasons for this 11β-HSD1 dysregulation are unknown. Here, we tested whether 11β-HSD1 expression, like the metabolic syndrome, is “programmed” by prenatal environmental events in a nonhuman primate model, the common marmoset monkey.

RESEARCH DESIGN AND METHODS

We used a “fetal programming” paradigm where brief antenatal exposure to glucocorticoids leads to the metabolic syndrome in the offspring. Pregnant marmosets were given the synthetic glucocorticoid dexamethasone orally for 1 week in either early or late gestation, or they were given vehicle. Tissue 11β-HSD1 and glucocorticoid receptor mRNA expression were examined in the offspring at 4 and 24 months of age.

RESULTS

Prenatal dexamethasone administration, selectively during late gestation, resulted in early and persistent elevations in 11β-HSD1 mRNA expression and activity in the liver, pancreas, and subcutaneous—but not visceral—fat. The increase in 11β-HSD1 occurred before animals developed obesity or overt features of the metabolic syndrome. In contrast to rodents, in utero dexamethasone exposure did not alter glucocorticoid receptor expression in metabolic tissues in marmosets.

CONCLUSIONS

These data suggest that long-term upregulation of 11β-HSD1 in metabolically active tissues may follow prenatal “stress” hormone exposure and indicates a novel mechanism for fetal origins of adult obesity and the metabolic syndrome.The metabolic syndrome and its component features (central obesity, insulin resistance/type 2 diabetes, hypertension, dyslipidemia) have been causally linked to early life events as marked by low birth weight and other features of an adverse intrauterine environment (1,2). Two major etiological hypotheses of the “developmental origins” effects have been proposed: malnutrition and glucocorticoid overexposure (3,4). These mechanisms of “programming” may be linked because maternal undernutrition increases maternal glucocorticoid concentrations and reduces the placental enzymatic barrier to maternal glucocorticoids in rats, thus increasing fetal glucocorticoid exposure (5). Moreover, maternal glucocorticoid administration reduces food intake in rodents (6).The processes that link intrauterine insults and later risk of the metabolic syndrome are not yet understood. The metabolic syndrome resembles the rare Cushing''s syndrome of circulating glucocorticoid excess, but in uncomplicated metabolic syndrome, plasma cortisol levels are not raised, spawning the suggestion that increased tissue sensitivity to glucocorticoid action may be important in its pathogenesis (7). In the major metabolic organs, tissue sensitivity and exposure to glucocorticoids are determined by the density of intracellular glucocorticoid receptors and the activity of the microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyzes the regeneration of active cortisol (corticosterone in rodents) from inert cortisone (11-dehydrocorticosterone) (7). 11β-HSD1 is highly expressed in liver and adipose tissue, where glucocorticoids reduce insulin sensitivity and action (7).In obese humans and in monogenic obesity in rodents, there is a selective increase in 11β-HSD1 mRNA and activity in adipose tissues (8–10). Increased 11β-HSD1 in liver is found in other causes of metabolic syndrome, such as myotonic dystrophy (11). Transgenic overexpression of 11β-HSD1 selectively in adipose tissue in mice recapitulates all the major features of metabolic syndrome without changes in circulating steroid levels (12), whereas overexpression of 11β-HSD1 in liver alone produces an attenuated syndrome with insulin resistance, dyslipidemia, and hypertension, but not hyperglycemia or obesity (13). Conversely, 11β-HSD1 knockout mice are insulin sensitized and resist metabolic syndrome with dietary obesity (14).However, genetic variation in the HSD1B1 gene does not associate with obesity (15), suggesting the cause of increased 11β-HSD1 in adipose tissue in obesity is environmentally determined. Although many factors may upregulate 11β-HSD1 in the short term, attempts to chronically induce 11β-HSD1 in adipose tissue by nongenetic approaches have been unsuccessful. In particular, high-fat diets in rodents downregulate 11β-HSD1 in adipose tissue (16), although this does not appear to occur in humans (17), underlining the importance of relevant models of the human situation.Here, we have explored the early life antecedents of metabolic syndrome and especially 11β-HSD1 expression in metabolic tissues in a nonhuman primate model (the common marmoset monkey) of fetal programming.     

The use of the Ki-67 marker in the pathological diagnosis of the epithelioid variant of renal angiomyolipoma

Objective:  Epithelioid angiomyolipoma (EAML) is a rare malignant variant of renal angiomyolipoma (AML). There were 34 cases of EAML reported in 25 studies (including this present study) over the past decade. About 68% were females and 32% males. The mean age was 40.1 years, 53% developed metastatic disease after nephrectomy, and eight patients had TSC. All cases are reported positive when stained with HMB-45 which also labels all classical AML. This study evaluates the use of Ki-67 (proliferation marker) in the pathological diagnosis of EAML and distinction from classical AML. Method:  Immunohistochemical reactions for Ki-67 were generated on multiple representative blocks of tissue obtained from two cases of HMB-45 positive EAML and four cases of classic AML and the percentage of positively staining cells estimated. Results:  Both cases of EAML were strongly positive for Ki-67 while all four classic AML were completely negative. Conclusion:  The Ki67 is a useful marker in which distinguishes the malignant epithelioid variant of AML from classic AML.     

Antibiotic prophylaxis for total joint replacement surgery: results of a survey of Canadian orthopedic surgeons

Background

The role of perioperative antibiotic prophylaxis in total joint replacement (TJR) surgery is well established. Whereas guidelines have been published in some countries, in Canada controversy persists concerning the best clinical practice for perioperative antibiotic prophylaxis in TJR.

Methods

We conducted a survey of 590 practising orthopedic surgeons performing TJR in Canada to assess current antibiotic prophylaxis practice. The survey included questions pertaining to antibiotic prophylaxis indications, antibiotic choice, dosing, route and timing of administration in the primary and revision arthroplasty setting, as well as postoperative wound drainage evaluation and management.

Results

The response rate after 2 mail-outs was 410 of 590 (69.5%). Current antibiotic prophylaxis regimens varied widely among surgeons, underscoring the controversy that exists regarding what constitutes best clinical practice.

Conclusion

Opinions regarding use of perioperative antibiotic prophylaxis in TJR vary widely among orthopedic surgeons in Canada, illustrating the controversy as to what constitutes best clinical practice. This survey also points to a lack of consensus about the current management of postoperative wound drainage.     

Solid cervical ectopic thymus in an infant

Cervical ectopic thymus presenting as a neck mass is rare in a neonate. Just more than 100 cases have been reported in the literature with less than 10% occurring in infants. We report a case of solid cervical ectopic thymus in an asymptomatic 2-month-old boy. We review the literature and discuss the embryology, pathophysiology, diagnosis, and management of an infantile ectopic thymus.     

The OpenMRS Implementers Network

Objective

OpenMRS (www.openmrs.org) is a configurable open source electronic medical record application developed and maintained by a large network of open source developers coordinated by the Regenstrief Institute and Partners in Health and mainly used for HIV patient and treatment information management in Africa. Our objective is to develop an open Implementers Network for OpenMRS to provide regional support for the growing number of OpenMRS implementations in Africa and to include African developers and implementers in the future growth of OpenMRS.

Methods

We have developed the OpenMRS Implementers Network using a dedicated Wiki site and e-mail server. We have also organized annual meetings in South Africa and regional training courses at African locations where OpenMRS is being implemented. An OpenMRS Internship program has been initiated and we have started collaborating with similar networks and projects working in Africa. To evaluate its potential, OpenMRS was implemented initially at one site in South Africa by a single implementer using a downloadable OpenMRS application and only the OpenMRS Implementers Network for support.

Results

The OpenMRS Implementers Network Wiki and list server have grown into effective means of providing implementation support and forums for exchange of implementation experiences. The annual OpenMRS Implementers meeting has been held in South Africa for the past three years and is attracting successively larger numbers of participants with almost 200 implementers and developers attending the 2008 meeting in Durban, South Africa. Six African developers are presently registered on the first intake of the OpenMRS Internship program. Successful collaborations have been started with several African developer groups and projects initiated to develop interoperability between OpenMRS and various applications. The South African OpenMRS Implementer group successfully configured, installed and maintained an integrated HIV/TB OpenMRS application without significant programming support. Since then, this model has been replicated in several other African sites.

Conclusions

The OpenMRS Implementers Network has contributed substantially to the growth and sustainability of OpenMRS in Africa and has become a useful way of including Africans in the development and implementation of OpenMRS in developing countries. The Network provides valuable support and enables a basic OpenMRS application to be implemented in the absence of onsite programmers.     

Failed DBS for palliation of visual problems in a case of oculopalatal tremor

ObjectiveTo report the results of attempted bilateral red nucleus (RN) deep brain stimulation (DBS) for the palliative treatment of visual problems associated with oculopalatal tremor (OPT).BackgroundIt is hypothesized that OPT results from a defect in the Guillain–Mollaret triangle, a circuit that includes connections with the dentate nucleus, the contralateral red nucleus, and the inferior olive. We present a high functioning patient (an accountant) who underwent a palliative trial of RN region DBS in an approach targeted through the subthalamic nucleus region. The aim was to reduce eye tremor and improve vision through interruption of the pathologically oscillating circuit in the Guillain–Mollaret triangle.MethodsFollowing informed consent, a patient with OPT (and failure of multiple classes of medication and botulinum toxin therapy) underwent placement of bilateral DBS electrodes within the region of the RN. He underwent preoperative testing and testing after 12 months of continuous stimulation with the device in monopolar, bipolar, low frequency, and high frequency settings.ResultsThe patient did not demonstrate significant changes in the neurological examination following the procedure and postoperative programming sessions. Eye tremor was monitored pre- and postoperatively by ocular EMG and did not change in frequency. Following the one-year trial, stimulation was discontinued as there were no improvements in vision.ConclusionDBS for OPT was not clinically effective. There were many potential reasons for failed efficacy including a failure to implant the electrodes deep and medial enough into the target region because of stimulation induced side effects. Other targets within the Guillain–Mollaret circuit (and outside of the circuit) may be more useful, though they may prove to be less safe and even more difficult to access. Better custom designed DBS leads may be needed for such small targets in critical brain regions.     

Reference ranges for exhaled nitric oxide derived from a random community survey of adults

RATIONALE: Measurement of the fraction of nitric oxide in exhaled breath (Fe(NO)) has been proposed as a noninvasive marker of airway inflammation. Before the widespread use of this test, there is a need to develop reference ranges to allow clinicians to interpret Fe(NO) measurements. OBJECTIVES: To derive reference ranges for Fe(NO) and to determine which factors in health and disease influence Fe(NO) levels. Methods: Subjects aged between 25 and 75 years were drawn from a random sample of the predominantly white population of Wellington, New Zealand. MEASUREMENTS AND MAIN RESULTS: Fe(NO) was measured using an online nitric oxide monitor in accordance with international guidelines. A detailed respiratory questionnaire and pulmonary function tests were performed. The geometric mean Fe(NO) was 17.9 parts per billion (ppb) with a 90% confidence interval for an individual prediction (reference range) for normal subjects of 7.8 to 41.1 ppb. Sex, atopy, and smoking status significantly affected Fe(NO) levels, and several reference ranges are presented adjusting for these factors. Asthma and allergic rhinitis were associated with higher Fe(NO). Measurement of Fe(NO) had poor discriminant ability to identify steroid-naive subjects with asthma. CONCLUSIONS: The reference ranges presented may be used to assist in the interpretation of Fe(NO) measurements in white adults.