Nephrin Localizes at the Podocyte Filtration Slit Area and Is Characteristically Spliced in the Human Kidney

Defects in the newly reported gene NPHS1 in chromosome 19 cause the massive proteinuria of Finnish type congenital nephrotic syndrome (CNF). Together with its gene product, nephrin, NPHS1 is providing new understanding of the pathophysiological mechanisms of glomerular filtration. Here we show the characteristic splicing of NPHS1 mRNA in the normal and CNF kidneys and localize nephrin exclusively in the glomerulus and to the filtration slit area by light and immunoelectron microscopy. These results indicate that nephrin is a new protein of the interpodocyte filtration slit area with a profound role in the pathophysiology of the filtration barrier.     

In vivo diagnostics of human knee cartilage lesions using delayed CBCT arthrography

The aim of this study was to investigate the feasibility of delayed cone beam (CBCT) arthrography for clinical diagnostics of knee cartilage lesions. Knee joints with cartilage lesions were imaged using native radiography, MRI, and delayed CBCT arthrography techniques in vivo. The joints were imaged three times with CBCT, just before, immediately after (arthrography) and 45 min after the intra‐articular injection of contrast agent. The arthrographic images enabled sensitive detection of the cartilage lesions. Use of arthrographic and delayed images together with their subtraction image enabled also detection of cartilage with inferior integrity. The contrast agent partition in intact cartilage (ICRS grade 0) was lower (p < 0.05) than that of cartilage surrounding the ICRS grade I–IV lesions. Delayed CBCT arthrography provides a novel method for diagnostics of cartilage lesions. Potentially, it can also be used in diagnostics of cartilage degeneration. Due to shorter imaging times, higher resolution, and lower costs of CT over MRI, this technique could provide an alternative for diagnostics of knee pathologies. However, for comprehensive evaluation of the clinical potential of the technique a further clinical study with a large pool of patients having a wide range of cartilage pathologies needs to be conducted. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:403–412, 2014.     

Endothelin-1-Independent and Angiotensin II-Independent Induction of Adrenomedullin Gene Expression

-Adrenomedullin (AM) may function as an autocrine and/or paracrine factor in the heart, but the exact mechanisms regulating cardiac AM gene expression are unknown. The aim of the present study was to characterize the precise time course of induction of atrial and ventricular AM gene expression during pressure overload and to study whether endothelin-1 or angiotensin II plays a causal role in the activation of cardiac AM gene expression. The pressure overload was produced by arginine-vasopressin (AVP, 0.05 μg/kg per minute IV) infusion for 15 minutes, 30 minutes, 1 hour, 2 hours, or 4 hours in conscious rats. A significant increase in left ventricular AM mRNA levels was seen after 2 hours of pressure overload in the left ventricle and after 30 minutes in the left atrium. The left atrial immunoreactive AM (ir-AM) levels decreased significantly after 2 hours of pressure overload. Plasma ir-AM levels increased slightly in response to 4 hours of AVP infusion. Bolus injections of bosentan (mixed ET(A)/ET(B) receptor antagonist, 10 mg/kg IV), losartan (AT(1) receptor antagonist, 10 mg/kg IV), and their combination had no effect on the increase of cardiac AM mRNA and ir-AM levels produced by 2 hours of pressure overload. In addition, losartan, bosentan, and their combination did not affect plasma ir-AM levels in the vehicle-infused and AVP-infused animals. The present study indicates that cardiac AM gene expression is rapidly upregulated in response to pressure. The induction of ventricular and atrial AM gene expression by pressure overload is angiotensin II-independent and endothelin-1-independent.     

Slow regional clearance of myocardial thallium-201 in the absence of perfusion defect: contribution to detection of individual coronary artery stenoses and mechanism for occurrence

As a result of the "spatially relative" nature of perfusion defect analysis of stress-redistribution thallium-201 (201Tl) scintigrams, hypoperfused myocardial segments may not appear as perfusion defects but they may demonstrate a slow washout rate of 201Tl that can be analyzed in a "spatially nonrelative" manner. Quantitative analysis of perfusion defects and slow washout rate of 201Tl was performed on scintigrams from 116 consecutive patients with adequate exercise tests, defined as achievement of 85% or more of age-predicted maximum heart rate or development of angina or ST segment depression. A total of 232 diseased and 116 nondiseased vessels were found in the patients. Additional analysis of slow washout rate significantly (p less than .05) improved sensitivity for detection of disease in the left anterior descending (from 74% to 82%), left circumflex (from 40% to 61%), and right coronary arteries (from 78% to 90%) without significant loss of specificity. This improvement resulted from the additional detection of 32 of 232 (14%) diseased vascular distributions when the isolated slow washout rate of 201Tl was also determined. In nine of these 32, isolated slow washout rate was associated with another region with isolated slow washout rate in the contralateral myocardial segment. Coronary arteriography revealed similar degrees of stenosis in the vessels supplying these segment pairs. In 13 of 32 cases, a perfusion defect and a slow washout rate were found in the contralateral segment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenovirus-mediated expression of glucokinase in the liver as an adjuvant treatment for type 1 diabetes

Glucokinase (GK) plays a crucial role in hepatic glucose disposal. Its activity is decreased in patients with maturity-onset diabetes of the young and in some animal models of diabetes. We investigated the feasibility of manipulating GK expression as an adjuvant treatment for type 1 diabetes, using an E1/E3-deleted adenoviral vector (Ad.EF1(alpha)GK) delivered to the liver of streptozotocin-induced type 1 diabetic rats. First, we studied the metabolic impact of constitutive glucokinase expression in the absence of insulin. Normal blood glucose levels were observed after gene transfer, and glucose tolerance was substantially enhanced compared with diabetic control animals, suggesting that hepatic GK expression is a feasible mechanism to enhance glucose disposal. In a second study we administered Ad.EF1(alpha)GK together with subcutaneous insulin injections to determine whether the combined action of insulin plus GK activity would provide better glucose homeostasis than insulin treatment alone. This combination approach resulted in constant, near-normal glucose values under fed conditions. Furthermore, the animals stayed in the normoglycemic range after an overnight fast, indicating that the risk to develop hypoglycemia is not increased by expression of GK. Alterations of other metabolic routes were observed, suggesting that insulin-regulated expression of GK may be necessary to use the strategy as a treatment of type 1 diabetes.     

Pharmacokinetics of telbivudine in subjects with various degrees of renal impairment

This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CL(CR)), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CL(R)), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CL(R) and CL(CR). In ESRD subjects, a routine 3.5- to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of approximately 45%, representing a approximately 23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.     

Depression is associated with the long-term outcome of lumbar spinal stenosis surgery: a 10-year follow-up study

Background Context

Depression is associated with greater postoperative disability in patients with lumbar spinal stenosis (LSS). No previous studies have reported the association in a 10-year follow-up.