Urinary biomarkers to detect significant effects of environmental and occupational exposure to nephrotoxins. V. Monitoring of individuals with elevated test patterns.
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Biomedical subjects
Publications and source records attributed to G A Porter.
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BACKGROUND: Intraoperative inadvertent perforation of the rectum is a potentially avoidable complication of abdominoperineal resection (APR). Although widely thought to be detrimental, the impact of inadvertent perforation on outcome has not been conclusively determined, especially after controlling for potential confounding variables. The objective of this study was to determine if inadvertent perforation of the rectum during APR for rectal cancer is an independent risk factor for the adverse outcomes of local recurrence and/or death. METHODS: This retrospective cohort study included all patients who underwent APR for primary adenocarcinoma of the rectum at a single teaching hospital from 1980 to 1990. Data were obtained regarding patient demographics, presence of inadvertent perforation, histopathological characteristics, adjuvant therapy, local recurrence, and survival. RESULTS: Of 178 patients included in the study, 42 (24%) had inadvertent perforation. By univariate analysis, local recurrence was significantly higher in the perforated group than the nonperforated group (54% vs 17%; P < 0.001). Similarly, 5-year survival was significantly decreased with inadvertent perforation (29% vs 59%; P = 0.003). Multivariate analysis controlling for stage, grade, age, sex, and adjuvant therapy showed inadvertent perforation to be an independent risk factor for both increased local recurrence and decreased 5-year survival (Hazard Ratio for each model). CONCLUSIONS: Inadvertent perforation of the rectum during APR is associated with increased local recurrence and decreased 5-year survival. The detrimental implications of inadvertent perforation during APR mandates meticulous avoidance.
The pertinent literature concerning the experimental induction of analgesic nephropathy is reviewed. Based on the accumulated data from animal experiments that induced a pathologic lesion resembling chronic analgesic nephropathy, of the limited number of analgesics tested, aspirin seems to be the most nephrotoxic of the commonly available analgesics. When aspirin is combined with other analgesics, the limited data available suggest at least an additive nephrotoxic effect, if not a synergism. The histologic presentation of acute intoxication is substantially different from that following chronic ingestion. With improvements in pathologic analysis of experimental results, future studies may well provide more insight as to the significance, relative contribution, and risk of combination analgesic products in inducing experimental analgesic nephrotoxicity.
PURPOSE: A study was undertaken to study the potential benefits for function and regional recurrence of preserving the sensory ventral branches of the cervical plexus in modified neck dissections. METHODS: Fifteen cases of squamous cell carcinoma or melanoma of the head and neck in which the sensory nerves were spared were matched to 15 cases in which the nerves were sacrificed. The subjects were examined for sensory loss, questioned regarding acute and chronic dysfunction, and followed for regional recurrence for a minimum of 2 years. RESULTS: The group whose nerves were preserved had significantly less sensory loss and a lower incidence of acute and chronic dysfunction. No subjects in either group had regional recurrence. CONCLUSION: The results of this initial study support a policy of routine preservation of the sensory ventral branches of the cervical plexus when there is no direct tumor involvement.
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Significant renal insufficiency defined as a stable SCr > 1.5 mg/dl is the single most important risk factor for RCIN. Based on the outcome data summarized, the occurrence of RCIN should be avoided, since significant deterioration of renal function occurs in one of every four patients. Clearly volume depletion should be corrected before administering RCM. In high-risk patients a hydration protocol should be initiated before the procedure and continued for at least 2 h after the procedure. At least one large cooperative study has reported a significant reduction in RCIN when LORCM are compared to HORCM. Limiting the total volume of RCM used for an individual study also reduces the incidence of RCIN. While indications for invasive studies with RCM continue to expand, especially for elderly and other high-risk groups, using the above recommendations as guidelines should minimize the risk of RCIN while still providing the critical information needed to develop a clinical management plan.
Biomarkers represent measurable changes in biologic systems or samples which correlate with an organism's altered biochemical or cellular function. For the kidney urine is the usual body fluid sampled. The principle processes which are evaluated are filtration/elimination and reabsorption/secretion. Proteins, either abnormal in type or amount, and enzymes have dominated interest in this field for many years. However, application of monoclonal antibody techniques, along with an understanding of the role of cytokiness, growth factors, collagen matrix and lipid mediators have rapidly expanded the field of new candidates for urinary biomarkers.
Contrast-associated nephropathy, a significant rise in serum creatinine 1-5 days following intervascular contrast injection, remains one of the most serious complications of contrast imaging. The reported incidence varies widely; in consecutive random cases ranges from 2 to 7%, but it can increase 5- to 10-fold in high risk patients with serum creatinine > 1.5 mg/dl. Postulated mechanisms of renal damage include vasoconstriction and direct tubular cell injury. The usual clinical presentation is an asymptomatic increase in serum creatinine without oliguria. Residual loss of renal function occurs in principle in patients with preexisting renal impairment. Aggressive prestudy hydration along with selective use of low osmolar contrast media can significantly reduce the risk of contrast nephropathy for patients with either chronic renal failure or diabetic nephropathy.
Assessing the rehabilitative/restorative process requires the definition of desired outcome. Traditionally, medicine has defined the desired outcome of treatment as curing disease. End-stage renal disease (ESRD) cannot be cured by applying current biotechnology. Thus, to assess treatment interventions in patients with ESRD, the desired outcome must be expanded to incorporate the broader components of health, which include physical, mental, and social well-being or quality of life. Based on this expanded definition of health, desirable treatment outcomes in patients with ESRD include employment of those able to work, individual control over the effects of kidney disease and dialysis, enhanced fitness, improved communications with caregivers and family, improved compliance with the dialysis regimen, and resumption of many activities enjoyed before the initiation of dialysis. Broadening the definition of desired outcome requires new measurement techniques. Measurement instruments for health status must evaluate fixed disease, which imposes certain limits on expected outcome; mutable health status, which represents the focus of intervention; and factors unrelated to healthcare, which will modify the scope of intervention that can be prescribed. Health-care status involves both self-reported evaluation and physical assessment. The reporting forms should be comprehensive, convenient, controlled, and valid. Such forms can be targeted to gain information about the natural evolution of a disease or disability process, to evaluate the effectiveness of treatment or other intervention on altering the disease or disability outcome, and to measure the quality of care. Two examples of the application of health status assessment will be reviewed.(ABSTRACT TRUNCATED AT 250 WORDS)
The single most important risk factor for the development of CAN is significant renal insufficiency, which correlates with a stable sCr greater than 1.5 mg/dL. Based on the outcome data summarized, avoidance of CAN should be our goal, as it causes significant deterioration of renal function in one of every four patients afflicted. Clearly, volume depletion should be eliminated before administering radiographic CM. In addition, high-risk patients should have a hydration protocol initiated before the procedure and continued for at least 2 hours postprocedure. At least one large cooperative study has reported a significant reduction in CAN when LOICM was compared with HOICM. Limiting the total volume of radiographic CM used for an individual study also seems to reduce the incidence of CAN. Although indications for invasive studies with radiographic RCM continue to expand, especially for elderly and other high-risk groups, using these suggestions as guidelines should minimize the risk of CAN while still obtaining the critical information needed to develop a clinical management plan.
RATIONALE AND OBJECTIVES: Contrast-induced changes produced in normal renal function are discussed, and possible mechanisms by which such changes may occur are described. Animal experiments are reviewed, with the dog model providing results most closely approximating observations in humans. METHODS: In the previous studies considered, standard clearance techniques were used to assess glomerulo-vascular changes, while urinary enzyme and protein excretions, along with changes in tubular reabsorption of electrolytes, were examined as indirect measures of contrast-induced tubular effects. The selection of papers for review was based primarily on studies conducted in large animals and humans. To be incorporated, traditional studies regarding accepted methods of analyzing renal function that did not involve extensive surgical preparation were reviewed. RESULTS: Renal vascular effects of contrast media induce a biphasic change in renal blood flow--a brief increase followed by a more prolonged decline--the magnitude of which varies by dose and route of administration. Tubular effects include increased excretion of cytosolic enzymes plus changes in tubular reabsorption of sodium, potassium, and chloride. A transient osmotic diuresis also occurs. CONCLUSIONS: Changes in renal blood flow, glomerular filtration rate, urinary electrolyte and solute excretion, and modification of the urinary concentrating-diluting mechanisms have yielded insights into the tubulo-glomerular actions of contrast media. The link between acute renal effects and subsequent contrast-associated nephropathy, while not absolutely defined, is becoming better understood as new information is gained using experimental models that more closely approximate high-risk states, including states of volume depletion, circulatory insufficiency, and pre-existing renal damage. Current attention is focused on the tubulo-glomerular feedback mechanism as accounting for the renal effects of contrast media.
Duchenne's muscular dystrophy (DMD) is caused by the absence or drastic decrease of the structural protein, dystrophin, and is characterized by sarcolemmal lesions in skeletal muscle due to the stress of contraction. Dystrophin has been localized to the sarcolemma, but its organization there is not known. We report immunofluorescence studies which show that dystrophin is concentrated, along with the major muscle isoform of beta-spectrin, in three distinct domains at the sarcolemma: in elements overlying both I bands and M lines, and in occasional strands running along the longitudinal axis of the myofiber. Vinculin, which has previously been found at the sarcolemma overlying the I bands and in longitudinal strands, was present in the same three structures as spectrin and dystrophin. Controls demonstrated that the labeling was intracellular. Comparison to labeling of the lipid bilayer and of the extracellular matrix showed that the labeling for spectrin and dystrophin is associated with the intact sarcolemma and is not a result of processing artifacts. Dystrophin is not required for this lattice-like organization, as similar domains containing spectrin but not dystrophin are present in muscle from the mdx mouse and from humans with Duchenne's muscular dystrophy. We discuss the possibility that dystrophin and spectrin, along with vinculin, may function to link the contractile apparatus to the sarcolemma of normal skeletal muscle.
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A number of recently developed localization techniques are beginning to be applied in the study of endothelial cells and their structural components. In this article we will review a number of these cytochemical approaches as well as their advantages and disadvantages and their applications. The methods will be presented for processing tissues for either L.R. White embedding or semi-thin and thin frozen sections followed by subsequent lectin and immunolabeling for fluorescence and electron microscopic examination. These techniques are easily applied in the localization of perfused exogenous proteins and of endogenous endothelial-associated proteins. The results that can be obtained from such studies are presented and discussed.
In the rat lung, we found that the Lycopersicon esculentum (LEA) lectin specifically binds to the epithelium of bronchioles and alveoli whereas Griffonia simplicifolia I (GS-I) binds to the endothelium of alveolar capillaries. The differential binding affinity of these lectins was examined on semithin (approximately 0.5 microns) and thin (less than 0.1 (microns) frozen sections of rat lung lavaged to remove alveolar macrophages. On semithin frozen sections, LEA bound to epithelial cells lining bronchioles and the alveoli (type I, but not type II epithelial cells). On thin frozen sections, biotinylated Lycopersicon esculentum (bLEA)-streptavidin-gold conjugates were confined primarily to the luminal plasmalemma of type I cells. bGS-I-streptavidin-Texas Red was detected on the endothelial cells of alveolar capillaries and postcapillary venules but not on those of larger venules, veins or arterioles. By electron microscopy, GS-I-streptavidin-gold complexes were localized primarily to the luminal plasmalemma of thick and thin regions of the capillary endothelium. Neither lectin labeled type II alveolar cells, but both lectins labeled macrophages in the interstitia and in incompletely lavaged alveoli.
Acute renal failure after contrast media injection has been recognized for at least 35 years but the exact mechanism responsible for the renal injury remains an enigma. The clinical characteristics of contrast-induced nephropathy (CAN) are well-known although more recently the nonoliguric presentation has occurred at an increased frequency--in 70 to 90% of cases. For nonoliguric presentation of CAN, one can expect an asymptomatic increase in serum creatinine, the mean peak occurring at 4.2 days. If oliguric, the fractional excretion of sodium will be less than 1% and resistant to either fluid challenge or loop diuretics. Preexisting renal insufficiency, with or without diabetes mellitus, increases the risk of CAN 6- to 10-fold but recovery is expected, with less than 10% of all patients requiring dialytic support. Despite the growing body of published reports, the lack of a suitable animal model to evaluate various proposed mechanisms of renal injury has compromised our ability to devise a technique for preventing CAN. A popular scheme has been proposed to describe the possible sequence by which ischemia or nephrotoxins, or both, induce acute renal failure. In particular, a vascular mechanism (i.e., ischemia), is an appealing explanation for CAN since acute changes in renal hemodynamics after contrast media injection have been confirmed by several animal experiments. Unlike other vascular beds in which contrast media induce acute vasoconstriction followed by vasodilatation, the initial effect on the renal circulation is acute vasodilatation, followed by progressive vasoconstriction, increasing renal vascular resistance and a concomitant decrease in both renal blood flow and glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)