Marginal iodide deficiency and thyroid function: dose-response analysis for quantitative pharmacokinetic modeling

Severe iodine deficiency (ID) results in adverse health outcomes and remains a benchmark for understanding the effects of developmental hypothyroidism. The implications of marginal ID, however, remain less well known. The current study examined the relationship between graded levels of ID in rats and serum thyroid hormones, thyroid iodine content, and urinary iodide excretion. The goals of this study were to provide parametric and dose-response information for development of a quantitative model of the thyroid axis. Female Long Evans rats were fed casein-based diets containing varying iodine (I) concentrations for 8 weeks. Diets were created by adding 975, 200, 125, 25, or 0 μg/kg I to the base diet (∼25 μg I/kg chow) to produce 5 nominal I levels, ranging from excess (basal + added I, Treatment 1: 1000 μg I/kg chow) to deficient (Treatment 5: 25 μg I/kg chow). Food intake and body weight were monitored throughout and on 2 consecutive days each week over the 8-week exposure period, animals were placed in metabolism cages to capture urine. Food, water intake, and body weight gain did not differ among treatment groups. Serum T4 was dose-dependently reduced relative to Treatment 1 with significant declines (19 and 48%) at the two lowest I groups, and no significant changes in serum T3 or TSH were detected. Increases in thyroid weight and decreases in thyroidal and urinary iodide content were observed as a function of decreasing I in the diet. Data were compared with predictions from a recently published biologically based dose-response (BBDR) model for ID. Relative to model predictions, female Long Evans rats under the conditions of this study appeared more resilient to low I intake. These results challenge existing models and provide essential information for development of quantitative BBDR models for ID during pregnancy and lactation.     

Angiotensin‐converting enzyme inhibition increases glucose‐induced insulin secretion in response to acute restraint

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Safety of Laparoscopic Ventral Hernia Repair in Octogenarians

Background and Objectives:

The recurrence rate after laparoscopic ventral hernia repair is lower than the rate of recurrence via the open approach in many series. Studies have demonstrated the safety and efficacy of this procedure but have had relatively young patient populations. We present our experience in a significantly older population.

Methods:

A retrospective chart review of all patients 80 to 89 years of age undergoing a laparoscopic ventral hernia repair at our institution from May 2000 to June 2007 was performed. Data collected included demographics, number and type of previous abdominal operations, number of previous hernia repairs, defect and mesh size, postoperative complications, and follow-up.

Results:

Twenty octogenarian patients underwent laparoscopic ventral hernia repair. Nine were men and 11 were women. The mean age was 82 years. Thirteen patients (65%) had one or more associated comorbidities at the time of surgery. Eighteen patients (90%) had undergone a mean of 1.7 prior abdominal operations. Six (30%) patients had undergone a mean of 1.1 previous open hernia repairs; 5 (83%) with mesh. Eight patients (40%) had an additional operative procedure at the time of laparoscopic hernia repair. Ten minor complications occurred in 10 patients (50%). Four major complications occurred in 4 patients (20%). One patient required reoperation for evacuation of hematoma at a trocar site. No patients complained of pain at a transabdominal suture site or persistent seromas by 6 weeks of follow-up. At mean follow-up of 3.1 months, no recurrences occurred and no patients required mesh removal in this series. No deaths occurred.

Conclusion:

Laparoscopic ventral hernia repair is becoming an accepted technique for hernia repair in the United States, with a well-documented low recurrence rate. Our series demonstrates that this approach is equally safe and effective for a significantly older segment of the population.     

Epac Regulates UT-A1 to Increase Urea Transport in Inner Medullary Collecting Ducts

Urea plays a critical role in the concentration of urine, thereby regulating water balance. Vasopressin, acting through cAMP, stimulates urea transport across rat terminal inner medullary collecting ducts (IMCD) by increasing the phosphorylation and accumulation at the apical plasma membrane of UT-A1. In addition to acting through protein kinase A (PKA), cAMP also activates Epac (exchange protein activated by cAMP). In this study, we tested whether the regulation of urea transport and UT-A1 transporter activity involve Epac in rat IMCD. Functional analysis showed that an Epac activator significantly increased urea permeability in isolated, perfused rat terminal IMCD. Similarly, stimulating Epac by adding forskolin and an inhibitor of PKA significantly increased urea permeability. Incubation of rat IMCD suspensions with the Epac activator significantly increased UT-A1 phosphorylation and its accumulation in the plasma membrane. Furthermore, forskolin-stimulated cAMP significantly increased ERK 1/2 phosphorylation, which was not prevented by inhibiting PKA, indicating that Epac mediated this phosphorylation of ERK 1/2. Inhibition of MEK 1/2 phosphorylation decreased the forskolin-stimulated UT-A1 phosphorylation. Taken together, activation of Epac increases urea transport, accumulation of UT-A1 at the plasma membrane, and UT-A1 phosphorylation, the latter of which is mediated by the MEK–ERK pathway.Urea plays a crucial role in the urinary concentrating mechanism, and therefore, in the regulation of water balance. Urea''s importance to the generation of a concentrated urine has been appreciated since at least 1934.^1,2 Several studies have shown that maximal urine concentrating ability is decreased in protein-deprived mammals and is restored by urea infusion.³ More recently, a UT-A1/UT-A3 knock-out mouse,^4,5 a UT-A2 knock-out mouse,⁶ and a UT-B knock-out mouse^7–9 were each shown to have urine concentrating defects. Thus, any hypothesis regarding the mechanism by which the kidney concentrates urine needs to include some effect derived from urea.The UT-A1 urea transporter is expressed in the terminal inner medullary collecting duct (IMCD).¹⁰ Vasopressin stimulates urea transport across perfused rat terminal IMCDs by increasing UT-A1 phosphorylation and apical plasma membrane accumulation.^11–15 Vasopressin acts by binding to V₂ receptors in the basolateral plasma membrane, stimulating adenylyl cyclase, increasing cAMP production, and increasing urea transport.^11,16–18 Forskolin, which directly activates adenylyl cyclase,¹⁹ also increases urea transport in perfused rat terminal IMCDs.²⁰cAMP is traditionally thought to act through protein kinase A (PKA). However, when we stimulate the PKA activity by increasing cAMP with forskolin in MDCK cells that are stably transfected with UT-A1 (UT-A1-MDCK cells), only 50% of the forskolin-stimulated urea flux is inhibited by H-89, a PKA inhibitor.²¹ Vasopressin and forskolin work in a similar manner to increase the cAMP levels, so this partial inhibition by H-89 suggests that vasopressin may signal through two cAMP-dependent pathways: one involving PKA and one that is independent of PKA. Because the UT-A1-MDCK cells reproduce many of the properties of native rat IMCDs,^13,21,22 these findings raise the possibility that vasopressin may signal through a second cAMP-dependent, but non–PKA-dependent, pathway in rat IMCDs.In addition to PKA, cAMP can activate Epac (exchange protein activated by cAMP), which signals by activating Rap1, a Ras-related small molecular weight G protein, which in turn signals through mitogen-activated protein kinase kinase (MEK) and extracellular signal-related kinase (ERK)^23,24 (Figure 1). There are two closely related exchange proteins activated by cAMP (Epac) proteins, Epac1 and Epac2, and both have been detected in rat IMCDs, although one or the other predominates in different studies.^25–28 The purpose of this study was to determine whether activation of the Epac pathway resulted in a functional change in urea transport in perfused rat terminal IMCDs.Open in a separate windowFigure 1.Vasopressin signaling diagram.     

Cardiac CT and MRI guide surgery in impending left ventricular rupture after acute myocardial infarction

We report the case of a 67 year-old patient who presented with worsening chest pain and shortness of breath, four days post acute myocardial infarction. Contrast enhanced computed tomography of the chest ruled out a pulmonary embolus but revealed an unexpected small subepicardial aneurysm (SEA) in the lateral left ventricular wall which was confirmed on cardiac magnetic resonance imaging. Intraoperative palpation of the left lateral wall was guided by the cardiac MRI and CT findings and confirmed the presence of focally thinned and weakened myocardium, covered by epicardial fat. An aneurysmorrhaphy was subsequently performed in addition to coronary bypass surgery and a mitral valve repair. The patient was discharged home on post operative day eight in good condition and is feeling well 2 years after surgery.     

Acoustic monitoring (RFM) of total hip arthroplasty results of a cadaver study

Introduction

At present there are no reliable non-traumatic and non-invasive methods to analyse the healing process and loosening status after total hip replacement. Therefore early as well as late loosening of prosthesis and interface component problems are difficult to be found or diagnosed at any time.

Methods

In a cadaver study the potential application of Resonance Frequency Monitoring (RFM) will be evaluated as a non-invasive and non-traumatic method to monitor loosening and interface problems in hip replacement. In a 65 year old female cadaver different stability scenarios for a total hip replacement (shaft, head/modular head and cup, ESKA, Luebeck, Germany) are simulated in cemented and cement less prosthesis and then analysed with RFM. The types of stability vary from secure/press-fit to interface-shaft disruption.

Results

The RFM shows in cemented as well as cement less prosthesis significant intra-individual differences in the spectral measurements with a high dynamic (20 dB difference corresponding to the factor 100 (10000%)), regarding the simulated status of stability in the prosthesis system.

Conclusion

The results of the study demonstrate RFM as a highly sensitive non-invasive and non-traumatic method to support the application of RFM as a hip prosthesis monitoring procedure. The data obtained shows the possibility to use RFM for osteointegration surveillance and early detection of interface problems, but will require further evaluation in clinical and experimental studies.