To examine the association of ambulatory blood pressure (ABP) and ambulatory pulse rate (APR) with diabetic retinopathy (DR) in persons with type 1 diabetes in the Renin-Angiotensin System Study ...(RASS), a multicenter primary diabetic nephropathy (DN) prevention trial.
Cross-sectional study.
One hundred ninety-four normotensive RASS participants in 3 centers who are 16 years of age or older with type 1 diabetes mellitus (DM) of 2 to 20 years' duration.
Ambulatory blood pressure and APR were monitored using standardized protocols. Patients were defined as nondippers if the night-to-day ratios for both systolic and diastolic blood pressures were >0.9. Diabetic retinopathy was determined by masked grading of 30 degrees color stereoscopic fundus photographs of 7 standard fields using the Early Treatment Diabetic Retinopathy Study severity scale.
Severity of DR.
No DR was present in 32%, mild nonproliferative DR (NPDR) was present in 55%, and moderate to severe NPDR or proliferative DR was present in 13% of the cohort. Neither 24-hour systolic ABP or diastolic ABP, daytime systolic or diastolic ABP, nor nighttime diastolic ABP were related to severity of DR. Statistically significant associations were found between nighttime systolic ABP and mean ABP and DR. Among those with no DR, 19% were nondippers; for those with mild NPDR, 28% were nondippers; and for those with severe NPDR or proliferative DR, 36% were nondippers (P = 0.08). The ratio of nighttime to daytime APR, but not the 24-hour APR or daytime or nighttime APR, was related positively to the severity of DR. In multivariable analyses, only the nighttime systolic ABP was related to severity of DR (P<0.05).
These data suggest that ABP, especially during the night, may provide a better measure than clinical BP regarding the relationship of BP to the severity of retinopathy in normotensive persons with type 1 DM without clinical DN.
The control of helminth diseases of people and livestock continues to rely on the widespread use of anti-helminthic drugs. However, concerns with the appearance of drug resistant parasites and the ...presence of pesticide residues in food and the environment, has given further incentive to the goal of discovering molecular vaccines against these pathogens. The exponential rate at which gene and protein sequence information is accruing for many helminth parasites requires new methods for the assimilation and analysis of the data and for the identification of molecules capable of inducing immunological protection. Some promising vaccine candidates have been discovered, in particular cathepsin L proteases from
Fasciola hepatica, aminopeptidases from
Haemonchus contortus, and aspartic proteases from schistosomes and hookworms, all of which are secreted into the host tissues or into the parasite intestine where they play important roles in host-parasite interactions. Since secreted proteins, in general, are exposed to the immune system of the host they represent obvious candidates at which vaccines could be targeted. Therefore, in this article, we consider the potential values and uses of algorithms for characterising cDNAs amongst the collated helminth genomic information that encode secreted proteins, and methods for their selective isolation and cloning. We also review the variety of prokaryotic and eukaryotic cell expression systems that have been employed for the production and downstream purification of recombinant proteins in functionally active form, and provide an overview of the parameters that must be considered if these recombinant proteins are to be commercialised as vaccine therapeutics in humans and/or animals.
Patients on conventional hemodialysis (HD) have elevated markers of oxidative stress and chronic inflammation, which may contribute to a high prevalence of cardiovascular disease. Glutathione (GSH), ...an important intracellular antioxidant, requires cysteine as a rate-limiting amino acid for its synthesis and riboflavin for its regeneration.
We aimed to examine whether erythrocyte GSH (eGSH) concentrations and riboflavin status are influenced by the increased dialysis dose provided to vitamin-supplemented patients receiving home nocturnal hemodialysis (HNHD) (6-8 hours/session, 5-7 nights/week) compared with patients on standard hemodialysis (SHD) (4 hours/session, 3 days/week).
This was a cross-sectional comparative study involving 30 patients undergoing SHD or HNHD regimens and a group of 15 healthy control subjects (HC). We measured eGSH concentration by liquid chromatography-tandem mass spectrometry, riboflavin status by eGSH reductase activity coefficient (EGRAC) as well as plasma total cysteine (Cys) and total homocysteine (Hcy), vitamin C by high-performance liquid chromatography, and C-reactive protein (CRP) by standard method. Estimated dietary protein and energy intakes were determined by 3-day food records, and nutritional status was assessed by subjective global assessment (SGA).
There were no significant differences among groups in eGSH concentration, EGRAC, dietary protein intake, and SGA score. SHD patients had significantly higher plasma Cys (P < .001) and Hcy compared with HNHD and HC groups (P = .048). Vitamin C was significantly lower (P = .01) and CRP significantly higher (P = .048) in both HD groups compared with HC.
eGSH concentration appears to be unaffected by dialysis dose in well-nourished HD patients.
Summary
The M2 subset of macrophages has a critical role to play in host tissue repair, tissue fibrosis and modulation of adaptive immunity during helminth infection. Infection with the helminth, ...Fasciola hepatica, is associated with M2 macrophages in its mammalian host, and this response is mimicked by its excretory‐secretory products (FhES). The tegumental coat of F. hepatica (FhTeg) is another major source of immune‐modulatory molecules; we have previously shown that FhTeg can modulate the activity of both dendritic cells and mast cells inhibiting their ability to prime a Th1 immune response. Here, we report that FhTeg does not induce Th2 immune responses but can induce M2‐like phenotype in vivo that modulates cytokine production from CD4+ cells in response to anti‐CD3 stimulation. FhTeg induces a RELMα expressing macrophage population in vitro, while in vivo, the expression of Arg1 and Ym‐1/2 but not RELMα in FhTeg‐stimulated macrophages was STAT6 dependent. To support this finding, FhTeg induces RELMα expression in vivo prior to the induction of IL‐13. FhTeg can induce IL‐13‐producing peritoneal macrophages following intraperitoneal injection This study highlights the important role of FhTeg as an immune‐modulatory source during F. hepatica infection and sheds further light on helminth–macrophage interactions.
ACE-I and ARBs in early diabetic nephropathy Mauer, Michael; Zinman, Bernard; Gardiner, Robert ...
Journal of the renin-angiotensin-aldosterone system,
12/2002, Letnik:
3, Številka:
4
Journal Article
Recenzirano
Introduction
Antihypertensive treatment of patients with clinical manifestations of diabetic nephropathy, and especially, renin-angiotensin system (RAS) inhibition, slows, but may not fully arrest ...progression towards end-stage renal disease. Studies using `hard' endpoints such as doubling of serum creatinine, dialysis, or death that are initiated before emergence of any renal functional abnormalities in diabetes, would be of impractical length and size. We therefore undertook a primary prevention study (The Renin-Angiotensin System Study or RASS) to determine if inhibition of the RAS could slow the development of a key diabetic glomerulopathy structural endpoint, increase in mesangial fractional volume (VvMes/glom).
Methods
This is a parallel group, double-blind, placebo-controlled trial with 285 patients with Type 1 diabetes mellitus (95 per group) randomised to receive the angiotensin-converting enzyme inhibitor, enalapril, the angiotensin II receptor blocker, losartan, or placebo. All patients are normotensive, normoalbuminuric and have normal or increased glomerular filtration rates at study entry. The study is based on primary endpoint of change in Vv(Mes/glom) from baseline to the five-year renal biopsy, with baseline and interval measures of albumin excretion rate, glomerular filtration rate, blood pressure, and glycaemia. Baseline, mid-point, and five-year retinal fundus photography are also performed.
Results
One thousand and sixty-five patients were interviewed, 707 refused participation and 73 were excluded. The target of 285 subjects were randomised and their clinical and demographic characteristics are described. Biopsy complications occurred in 17 (6%), only one of which required hospitalisation. There were no permanent biopsy-related sequelae.
Conclusions
Renal structural variables are reasonable surrogate endpoints for studies of progression of early diabetic nephropathy. Although requiring substantial recruitment effort, diabetic nephropathy primary prevention trials based on change in renal structure are feasible.
The Relationship of Diabetic Retinopathy to Preclinical Diabetic Glomerulopathy Lesions in Type 1 Diabetic Patients
The Renin-Angiotensin System Study
Ronald Klein 1 ,
Bernard Zinman 2 ,
Robert ...Gardiner 3 ,
Samy Suissa 4 ,
Sandra M. Donnelly 5 ,
Alan R. Sinaiko 6 ,
Michael S. Kramer 7 ,
Paul Goodyer 8 ,
Scot E. Moss 1 ,
Trudy Strand 6 and
Michael Mauer 6
1 Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin
2 Division of Medicine, University of Toronto, Toronto, Ontario, Canada
3 Division of Medicine, McGill University, Montreal, Quebec, Canada
4 Departments of Epidemiology and Biostatistics and Medicine, McGill University, Montreal, Quebec, Canada
5 Department of Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario,
Canada
6 Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
7 Departments of Pediatrics and Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada
8 Department of Pediatrics, McGill University, Montreal, Quebec, Canada
Address correspondence to Ronald Klein, MD, MPH, Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison,
610 North Walnut St., 460 WARF Madison, WI 53726. E-mail: kleinr{at}epi.ophth.wisc.edu
Abstract
Few epidemiological data exist regarding the correlation of anatomic measures of diabetic retinopathy and nephropathy, especially
early in the disease processes. The aim of this study was to examine the association of severity of diabetic retinopathy with
histological measures of diabetic nephropathy in normoalbuminuric patients with type 1 diabetes. The study included participants
( n = 285) in the Renin-Angiotensin System Study (RASS; a multicenter diabetic nephropathy primary prevention trial) who were
aged ≥16 years and had 2–20 years of type 1 diabetes with normal baseline renal function measures. Albumin excretion rate
(AER), blood pressure, serum creatinine, and glomerular filtration rate (GFR) were measured using standardized protocols.
Diabetic retinopathy was determined by masked grading of 30° color stereoscopic fundus photographs of seven standard fields
using the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale. Baseline renal structural parameters, e.g., fraction
of the glomerulus occupied by the mesangium or mesangial fractional volume Vv(Mes/glom) and glomerular basement membrane
width, were assessed by masked electron microscopic morphometric analyses of research percutaneous renal biopsies. No retinopathy
was present in 36%, mild nonproliferative diabetic retinopathy in 53%, moderate to severe nonproliferative diabetic retinopathy
in 9%, and proliferative diabetic retinopathy in 2% of the cohort. Retinopathy was not related to AER, blood pressure, serum
creatinine, or GFR. All renal anatomical end points were associated with increasing severity of diabetic retinopathy, while
controlling for other risk factors. These data demonstrate a significant association between diabetic retinopathy and preclinical
morphologic changes of diabetic nephropathy in type 1 diabetic patients.
AER, albumin excretion rate
ETDRS, Early Treatment Diabetic Retinopathy Study
GBM, glomerular basement membrane
GFR, glomerular filtration rate
RASS, Renin-Angiotensin System Study
Sv(PGBM), surface density of peripheral glomerular capillary GBM
Vv(MC/glom), fractional volume of the glomerulus occupied by mesangial cells
Footnotes
R.K. has received honoraria for serving on the steering committee for the DIRECT Program from Astra-Zeneca. R.G. holds stock
in and has received consulting fees from Merck. S.M.D. has received consulting fees from Merck.
Accepted October 19, 2004.
Received July 30, 2004.
DIABETES
The secretion and activation of the major cathepsin L1 cysteine protease involved in the virulence of the helminth pathogen Fasciola hepatica was investigated. Only the fully processed and active ...mature enzyme can be detected in medium in which adult F. hepatica are cultured. However, immunocytochemical studies revealed that the inactive procathepsin L1 is packaged in secretory vesicles of epithelial cells that line the parasite gut. These observations suggest that processing and activation of procathepsin L1 occurs following secretion from these cells into the acidic gut lumen. Expression of the 37-kDa procathepsin L1 in Pichia pastoris showed that an intermolecular processing event within a conserved GXNXFXD motif in the propeptide generates an active 30-kDa intermediate form. Further activation of the enzyme was initiated by decreasing the pH to 5.0 and involved the progressive processing of the 37 and 30-kDa forms to other intermediates and finally to a fully mature 24.5 kDa cathepsin L with an additional 1 or 2 amino acids. An active site mutant procathepsin L, constructed by replacing the Cys26 with Gly26, failed to autoprocess. However, Gly26procathepsin L was processed by exogenous wild-type cathepsin L to a mature enzyme plus 10 amino acids attached to the N terminus. This exogenous processing occurred without the formation of a 30-kDa intermediate form. The results indicate that activation of procathepsin L1 by removal of the propeptide can occur by different pathways, and that this takes place within the parasite gut where the protease functions in food digestion and from where it is liberated as an active enzyme for additional extracorporeal roles.
Erythropoietin (Epo) is distinct amongst haematopoietic hormones, in that it is produced remote from the bone marrow. The tissue oxygen pressure required to trigger the Epo gene under physiological ...conditions is uniquely sited at a restricted area in the kidney termed the critmeter. Angiotensin II (Ang II) increases sodium reabsorption and hence oxygen consumption at any given blood flow rate; therefore, it may affect the balance of renal oxygen supply vs. demand and hence Epo production. The purpose of this study was to determine whether Epo production is modulated by the renin-angiotensin system (RAS). Twenty normal subjects on a controlled sodium and protein diet had glomerular filtration rate (GFR) and renal plasma flow (RPF) assessed by standard methods of inulin and para-aminohippurate clearance, respectively, at baseline, hourly after the administration of losartan (25 mg) and after each 30 minute period of the infusion of Ang II at doses of 0.5, 1.5 and 2.5 ng/kg/minute. The baseline GFR was 115±4.0 ml/minute/1.73 m2, RPF 650±29 ml/minute/1.73 m2 and Epo 12.4±0.8 U/L. In spite of a marked increase in filtration fraction (FF) with Ang II, no changes in serum Epo levels were observed at two hours (11.7±1.3 U/L, p=n.s. compared with baseline). After the administration of losartan, there was a variable effect on FF, but a strong correlation of the change in serum Epo concentration and the change in FF (r=0.648, p=0.002), suggesting that the RAS may modulate Epo production.
Abstract
The creation of buttonhole tracks with
S
upercath
S
afety
C
lampcath is a novel and simple technique that allows dull fistula needle insertions with relative ease and diminished pain. As ...greater experience with this procedure develops, new issues arise for consideration. We report an unexpected complication of
S
upercath
S
afety
C
lampcath catheter breakage that may be due to physical distortions as a result of its location in the antecubital fossa just proximal to the elbow joint. We present a review of our experience and a framework for the safe ongoing use of this device for creation of buttonholes in fistula for hemodialysis.
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