Chad Miller

Genetic clamping of renin gene expression induces hypertension and elevation of intrarenal ang II levels of graded severity in Cyp1a1-Ren2 transgenic rats

Introduction. Transgenic rats with inducible angiotensin II (Ang II)-dependent hypertension (strain name: TGR[Cyp1a1-Ren2]) were generated by inserting the mouse Ren2 renin gene, fused to the cytochrome P450 1a1 (Cyp1a1) promoter, into the genome of the rat. The present study was performed to characterise the changes in plasma and kidney tissue Ang II levels and in renal haemodynamic function in Cyp1a1-Ren2 rats following induction of either slowly developing or malignant hypertension in these transgenic rats. Materials and Methods. Arterial blood pressure (BP) and renal haemodynamics and excretory function were measured in pentobarbital sodium-anaesthetised Cyp1a1Ren2 rats fed a normal diet containing either a low dose (0.15%, w/w for 14—15 days) or high dose (0.3%, w/w for 11—12 days) of the aryl hydrocarbon indole-3-carbinol (I3C) to induce slowly developing and malignant hypertension, respectively. In parallel experiments, arterial blood samples and kidneys were harvested for measurement of Ang II levels by radioimmunoassay. Results. Dietary I3C increased plasma renin activity (PRA), plasma Ang II levels, and arterial BP in a dose-dependent manner. Induction of different fixed levels of renin gene expression and PRA produced hypertensive phenotypes of varying severity with rats developing either mild or malignant forms of hypertensive disease. Administration of I3C, at a dose of 0.15% (w/w), induced a slowly developing form of hypertension whereas administration of a higher dose (0.3%) induced a more rapidly developing hypertension and the clinical manifestations of malignant hypertension including severe weight loss. Both hypertensive phenotypes were characterised by reduced renal plasma flow, increased filtration fraction, elevated PRA, and increased plasma and intrarenal Ang II levels. These I3C-induced changes in renal haemodynamics, PRA and kidney Ang II levels were more pronounced in Cyp1a1-Ren2 rats with malignant hypertension. Chronic administration of the AT1-receptor antagonist, candesartan, prevented the development of hypertension, the associated changes in renal haemodynamics, and the augmentation of intrarenal Ang II levels. Conclusions. Activation of AT1-receptors by Ang II generated as a consequence of induction of the Cyp1a1-Ren2 transgene mediates the increased arterial pressure and the associated reduction of renal haemodynamics and enhancement of intrarenal Ang II levels in hypertensive Cyp1a1-Ren2 B transgenic rats.

Circulating Adipocytokines and Chronic Kidney Disease

Background Adipokines have been associated with atherosclerotic heart disease, which shares many common risk factors with chronic kidney disease (CKD), but their relationship with CKD has not been well characterized. Methods We investigated the association of plasma leptin, resistin and adiponectin with CKD in 201 patients with CKD and 201 controls without. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or presence of albuminuria. Quantile regression and logistic regression models were used to examine the association between adipokines and CKD adjusting for multiple confounding factors. Results Compared to controls, adjusted median leptin (38.2 vs. 17.2 ng/mL, p<0.0001) and adjusted mean resistin (16.2 vs 9.0 ng/mL, p<0.0001) were significantly higher in CKD cases. The multiple-adjusted odds ratio (95% confidence interval) of CKD comparing the highest tertile to the lower two tertiles was 2.3 (1.1, 4.9) for leptin and 12.7 (6.5, 24.6) for resistin. Median adiponectin was not significantly different in cases and controls, but the odds ratio comparing the highest tertile to the lower two tertiles was significant (1.9; 95% CI, 1.1, 3.6). In addition, higher leptin, resistin, and adiponectin were independently associated with lower eGFR and higher urinary albumin levels. Conclusions These findings suggest that adipocytokines are independently and significantly associated with the risk and severity of CKD. Longitudinal studies are warranted to evaluate the prospective relationship of adipocytokines to the development and progression of CKD.

Preparing to take the USMLE Step 1: a survey on medical students’ self-reported study habits

Background The USA Medical Licensing Examination Step 1 is a computerised multiple-choice examination that tests the basic biomedical sciences. It is administered after the second year in a traditional four-year MD programme. Most Step 1 scores fall between 140 and 260, with a mean (SD) of 227 (22). Step 1 scores are an important selection criterion for residency choice. Little is known about which study habits are associated with a higher score. Objective To identify which self-reported study habits correlate with a higher Step 1 score. Methods A survey regarding Step 1 study habits was sent to third year medical students at Tulane University School of Medicine every year between 2009 and 2011. The survey was sent approximately 3 months after the examination. Results 256 out of 475 students (54%) responded. The mean (SD) Step 1 score was 229.5 (22.1). Students who estimated studying more than 8–11 h per day had higher scores (p<0.05), but there was no added benefit with additional study time. Those who reported studying <40 days achieved higher scores (p<0.05). Those who estimated completing >2000 practice questions also obtained higher scores (p<0.01). Students who reported studying in a group, spending the majority of study time on practice questions or taking >40 preparation days did not achieve higher scores. Conclusions Certain self-reported study habits may correlate with a higher Step 1 score compared with others. Given the importance of achieving a high Step 1 score on residency choice, it is important to further identify which characteristics may lead to a higher score.

Formerly Obese, Now Thin and Confused: The Utility of Mnemonics in the Approach to Altered Mental Status

Altered mental status represents a common cause for admission to general medicine services. Often a significant workup ensues to define an underlying etiology. When a history of bariatric surgery with small bowel resection precedes the presentation, the differential diagnosis expands. We review a patient, having prior bariatric surgery and small bowel resection, who presents with altered mental status. After an extensive workup, she was diagnosed with a rare clinical problem, D-lactic acidosis. In presenting this case, we examine the use of mnemonics in medicine and how this can assist in solving clinical problems.

Skin-Deep Diagnosis: Affective Bias and Zebra Retreat Complicating the Diagnosis of Systemic Sclerosis

Abstract:Nearly half of medical errors can be attributed to an error of clinical reasoning or decision making. It is estimated that the correct diagnosis is missed or delayed in between 5% and 14% of acute hospital admissions. Through understanding why and how physicians make these errors, it is hoped that strategies can be developed to decrease the number of these errors. In the present case, a patient presented with dyspnea, gastrointestinal symptoms and weight loss; the diagnosis was initially missed when the treating physicians took mental short cuts and used heuristics as in this case. Heuristics have an inherent bias that can lead to faulty reasoning or conclusions, especially in complex or difficult cases. Affective bias, which is the overinvolvement of emotion in clinical decision making, limited the available information for diagnosis because of the hesitancy to acquire a full history and perform a complete physical examination in this patient. Zebra retreat, another type of bias, is when a rare diagnosis figures prominently on the differential diagnosis but the physician retreats for various reasons. Zebra retreat also factored in the delayed diagnosis. Through the description of these clinical reasoning errors in an actual case, it is hoped that future errors can be prevented or inspiration for additional research in this area will develop.

Student perceptions of high-value care education in internal medicine clerkships

1Division of General Internal Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; 2Division of Geriatric Medicine and Gerontology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; 3Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana; 4Division of Infectious Disease, University of Alabama School of Medicine, Birmingham, Alabama; 5Department of Medical Education, Icahn School of Medicine at Mount Sinai, New York, New York.