Urinary podocyte loss is a more specific marker of ongoing glomerular damage than proteinuria

Podocyte loss contributes to the development of glomerulosclerosis. Although podocyte detachment has been recognized as a new mechanism of podocyte loss in glomerular diseases, its time course and relationship to disease activity are not known. Urinary excretion of viable podocytes was quantified in two models of transient glomerular injury, i.e., rats with puromycin aminonucleoside-induced nephrosis (PAN) and mesangioproliferative nephropathy (anti-Thy 1.1 nephritis model), as well as in a model of continuous glomerular injury, i.e., hypertensive nephropathy (5/6-nephrectomy model), and in aging rats. The number of glomerular Wilm's tumor (WT)-1-positive podocytes and the glomerular expression of cell-cycle proteins in vivo were assessed. Urinary podocyte loss occurred in both primary (PAN) and secondary (anti-Thy 1.1 nephritis) in parallel to the onset of proteinuria. However, subsequently proteinuria persisted despite remission of podocyturia. In continuous glomerular injury, i.e., after 5/6-nephrectomy, podocyturia paralleled the course of proteinuria and of systemic hypertension, whereas no podocyturia became detectable during normal aging (up to 12 mo). Despite podocyte detachment of varying degrees, no decrease in glomerular podocyte counts (i.e., WT-1 positive nuclei) was noted in either disease model. Podocyturia in the PAN and anti-Thy 1.1 nephritis model was preceded by entry of glomerular podocytes into the cell cycle, i.e., cyclin D1, cdc2, and/or proliferating cell nuclear antigen (PCNA) expression. Podocyturia is a widespread phenomenon in glomerular disease and not simply a reflection of proteinuria because it is limited to phases of ongoing glomerular injury. The data suggest that podocyturia may become a more sensitive means to assess the activity of glomerular damage than proteinuria.     

U.S. and German case studies in chronic care management: an overview

In December 2004, the Bertelsmann Stiftung, The Commonwealth Fund, and AcademyHealth jointly sponsored a conference in Berlin, Germany on "Case Studies in Chronic Care Management." This conference assembled representatives from the U.S. and German Governments, several organizations that had developed chronic care management initiatives in the two countries, and other health care and policy experts to discuss clinical, organizational, and financing issues. The case studies discussed at the conference are presented in this issue of the Review; this article describes some relevant considerations that are common to the U.S. and German health systems.     

Polyadenosine diphosphate-ribose polymerase inhibition modulates skeletal muscle injury following ischemia reperfusion

HYPOTHESIS: Polyadenosine diphosphate-ribose polymerase (PARP) has been implicated as a mediator of inflammation and tissue necrosis in murine models of human stroke and myocardial infarction. This study was designed to determine whether PARP modulates skeletal muscle injury and cytokine-growth factor levels during ischemia-reperfusion. DESIGN: Prospective controlled animal study. SETTING: Medical school-affiliated university hospital. INTERVENTIONS: Mice were divided into 2 groups-treated (PJ) and untreated; all mice were subjected to unilateral hind limb tourniquet ischemia followed by 4 or 48 hours of reperfusion. In treated mice, PJ34, an ultrapotent-specific PARP inhibitor was given immediately before ischemia and prior to reperfusion. A group of PARP-1 knockout mice (PARP-/-) were also subjected to hind limb ischemia followed by 48 hours of reperfusion. MAIN OUTCOME MEASURES: After ischemia-reperfusion, muscle was harvested for measurement of edema, viability, cytokine, and vascular endothelial growth factor content. RESULTS: The PJ34-treated mice had increased skeletal muscle viability when compared with the untreated mice after 4 and 48 hours of reperfusion (P<.01). Viability between PARP-/- and PJ34-treated mice were similar at 48 hours of reperfusion (P>.05), and it exceeded that of untreated mice (P<.01). Tissue edema was unaltered by PARP inhibition. Tissue levels of cytokine were only different (P<.05) in PJ34-treated vs untreated mice at 48 hours of reperfusion. Vascular endothelial growth factor levels in PJ34-treated mice were markedly reduced when compared with untreated mice only after 4 hours of reperfusion (P<.01), and in PARP-/- mice (P<.01) at 48 hours of reperfusion. CONCLUSIONS: Polyadenosine diphosphate-ribose polymerase modulates skeletal muscle viability, cytokine and vascular endothelial growth factor synthesis during reperfusion. Polyadenosine diphosphate-ribose polymerase inhibition may represent a novel method to modulate skeletal muscle ischemia-reperfusion injury.     

Real-time in vivo imaging of the convective distribution of a low-molecular-weight tracer

OBJECT: Convection-enhanced delivery (CED) is increasingly used to distribute therapeutic agents to locations in the central nervous system. The optimal application of convective distribution of various agents requires the development of imaging tracers to monitor CED in vivo in real time. The authors examined the safety and utility of an iodine-based low-molecular-weight surrogate tracer for computerized tomography (CT) scanning during CED. METHODS: Various volumes (total volume range 90-150 microl) of iopamidol (MW 777 D) were delivered to the cerebral white matter of four primates (Macaca mulatta) by using CED. The distribution of this imaging tracer was determined by in vivo real-time and postinfusion CT scanning (< or = 5 days after infusion [one animal]) as well as by quantitative autoradiography (14C-sucrose [all animals] and 14C-dextran [one animal]), and compared with a mathematical model. Clinical observation (- 5 months) and histopathological analyses were used to evaluate the safety and toxicity of the tracer delivery. Real-time CT scanning of the tracer during infusion revealed a clearly definable region of perfusion. The volume of distribution (Vd) increased linearly (r2 = 0.97) with an increasing volume of infusion (V.). The overall Vd/Vi ratio was 4.1+/-0.7 (mean+/-standard deviation) and the distribution of infusate was homogeneous. Quantitative autoradiography confirmed the accuracy of the imaged distribution for a small (sucrose, MW 359 D) and a large (dextran, MW 70 kD) molecule. The distribution of the infusate was identifiable up to 72 hours after infusion. There was no clinical or histopathological evidence of toxicity in any animal. CONCLUSIONS: Real-time in vivo CT scanning of CED of iopamidol appears to be safe, feasible, and suitable for monitoring convective delivery of drugs with certain features and low infusion volumes.     

Dystrophic calcification as a cause for non healing leg ulcers

Despite advances in molecular biology and a repertoire of other therapeutic options, chronic venous leg ulcers remain a significant problem within our society. There are various reasons, both local and systemic, which contribute to the non healing nature of such wounds. Among them, dystrophic calcification (DC) or calcified deposits within the ulcer bed, although rare, is an overlooked and a seldom reported cause. In the presence of DC, wound healing cannot proceed through a timely and orderly manner resulting in a non healing ulcer. In this article, we discuss the aetiology, pathophysiology and the management options of this rarely reported condition. We also report their clinical prognosis using a series of patients with venous ulcers complicated by DC leading to difficulties in healing.     

Ensuring a broad and inclusive approach: a provincial perspective on pandemic preparedness

The SARS crisis revealed critical gaps in Ontario's health emergency response capacity, and identified, in the starkest terms possible, the need for improved emergency response planning. This article reviews the development of the Ontario Health Plan for an Influenza Pandemic (OHPIP), released in June 2005. Some key points arising from the provincial planning process include the necessity to: ensure a broad and inclusive development process; ensure the pandemic plan identifies: 1) clear roles and responsibilities of federal, provincial/territorial and municipal levels of government, 2) the approach to occupational health and safety issues and ethical decision-making, 3) a communications strategy linking all affected sectors and levels of government and health sector; 4) any commitments to antiviral stockpiling, vaccine and antiviral allocation and use, and an approach for drug delivery from provincial stockpiles to local public health units; 5) health human resource management and supplementation; and 6) key programs/services to be scaled back to maximize surge capacity; address best practices (e.g., involve all sectors of the health care system at the outset, acquire strategic expertise, coordinate/advocate with broader emergency response system, etc); and, outline future stages that include strengthening the delivery of clinical care to influenza cases; clarifying the role of primary care practitioners during a pandemic; leveraging Ontario's significant e-Health investments.     

Growth in adolescent hemodialysis patients: Data from the Centers for Medicare & Medicaid Services ESRD Clinical Performance Measures Project

The Centers for Medicare & Medicaid Services' (CMS) end-stage renal disease (ESRD) Clinical Performance Measures (CPM) Project has collected data on all adolescent hemodialysis patients since 2000. Thus, by 2002 data were available on all adolescents on hemodialysis in the USA for 3 consecutive years. Possible associations between clinical parameters and linear growth in this cohort were evaluated. Ninety-four adolescents were on hemodialysis for the 3 study years. The mean height standard deviation score (ht SDS) fell from -1.97 to -2.36 over the 3 study years. Compared with patients with ht SDS > or =-1.88, patients with ht SDS <-1.88 in the 2002 study year (n =53) were more likely to be male (66% vs 44%, p <0.05), on dialysis longer (6.9+/-4.5 years vs 4.1+/-2.3 years, p <0.001), and had lower height SDS in the 2000 study year (-2.90+/-1.31 vs -0.772+/-1.10, p <0.001). Patients with a ht SDS <-1.88 had a lower mean hemoglobin (11.4+/-1.6 g/dl vs 12.0+/-1.1 g/dl, p <0.05), but there were no differences in other clinical parameters. Among patients with ht SDS <-1.88, 38.8% (n =20) were prescribed recombinant human growth hormone (rhGH) in the 2002 study year. There were no differences in demographic or clinical parameters between rhGH treated and untreated patients. Many adolescents who remain on hemodialysis have poor linear growth. Further evaluation is needed to delineate contributory factors and the possible underutilization of rhGH.