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Biomedical subjects

D J Hirsch

Publications and source records attributed to D J Hirsch.

At least 19 recordsLinked to original sources
PubMed2000

Calcified subcutaneous arterioles with infarcts of the subcutis and skin ("calciphylaxis") in chronic renal failure.

Patients with chronic renal failure (CRF) are at increased risk for pathological calcifications because of increased serum calcium-phosphorus products. A minority, including those undergoing dialysis, develop a syndrome of deep skin ulcerations in association with calcification of subcutaneous arterioles. The body distribution of the skin lesions may be proximal (central), distal (peripheral), or both. Since 1968, this syndrome has been called "calciphylaxis" in the belief that it is the human analogue of Selye's experimental models of tissue calcification. Our review emphasizes that this syndrome comprises two separate processes not found in calciphylaxis: calcification of subcutaneous arterioles and infarctions of subcutaneous adipose tissue (panniculus adiposus) and skin. The infarctions are acute and clinically dramatic, whereas the calcific arteriolopathy is preexistent, having developed slowly, sometimes over years, and silently. Separating these two processes facilitates analyses of pathogenetic factors, such as those that target subcutaneous arterioles for calcification and those that interfere with blood flow through the calcified arterioles, sufficient in some patients to cause the infarctions, and of why obesity in CRF is a syndrome risk factor. This approach further helps to provide a much needed standardized definition of the syndrome, thereby facilitating comparisons of the results of such treatments as parathyroidectomy, anticoagulants, and phosphate binders. Finally, the separation shows why the application of such terms as calciphylaxis and calcifying panniculitis to this syndrome is inappropriate.

Animals↗
PubMed1999

Identification of the major intestinal fatty acid transport protein.

While intestinal transport systems for metabolites such as carbohydrates have been well characterized, the molecular mechanisms of fatty acid (FA) transport across the apical plasmalemma of enterocytes have remained largely unclear. Here, we show that FATP4, a member of a large family of FA transport proteins (FATPs), is expressed at high levels on the apical side of mature enterocytes in the small intestine. Further, overexpression of FATP4 in 293 cells facilitates uptake of long chain FAs with the same specificity as enterocytes, while reduction of FATP4 expression in primary enterocytes by antisense oligonucleotides inhibits FA uptake by 50%. This suggests that FATP4 is the principal fatty acid transporter in enterocytes and may constitute a novel target for antiobesity therapy.

Binding, Competitive↗
PubMed1999

Peritoneal dialysis reduces the use of non native fistula access in dialysis programs.

Access problems remain the major difficulty associated with chronic hemodialysis. Despite recent recommendations by the Dialysis Outcomes Quality Initiative (DOQI) that native arteriovenous (AV) fistulae are the optimal form of vascular access, grafts and central catheters are used by many patients. We analyzed our large Canadian regional dialysis program, which has a high prevalence of peritoneal dialysis, to examine the effect of dialysis modality choice on vascular access utilization. Point prevalence data were collected from our program in October 1997, and technique and patient survival data for the period 1990-1996 were analyzed and compared to data for the remainder of Canada from the Canadian Organ Replacement Register. Mortality rate ratios were estimated using a Poisson regression model to correct for comorbidity, age, and end-stage renal disease etiology. Of 141 in-center hemodialysis patients, 91 had an AV fistula, 1 had a polytetrafluoroethylene (PTFE) graft, and 49 were catheter-dependent. The program also included 20 home hemodialysis patients with AV fistulae, and 156 patients on peritoneal dialysis. No mortality risk differences between hemodialysis and peritoneal dialysis are seen in our center, nor are they seen for each modality in comparison with the remainder of Canada. Technique survival for peritoneal dialysis at our center was about 80% at 2 years, significantly greater than for Canada. For the program as a whole, 49% of patients used peritoneal dialysis 35% a native AV fistula, and 15% a central catheter. For Canada and the U.S.A. respectively, the comparable data were: peritoneal dialysis, 32% and 17%; native fistula, 33% and 15%; PTFE, 19% and 41%; and central catheter 16% and 27%. These data suggest that the use of peritoneal dialysis may allow reduced use of non native AV fistula access without mortality penalty.

Aged↗
PubMed1998

Photodynamic tumor therapy: mitochondrial benzodiazepine receptors as a therapeutic target.

BACKGROUND: Photodynamic therapy employs photosensitive agents such as porphyrins to treat a variety of tumors accessible to light-emitting probes. This approach capitalizes on the selective retention of porphyrins by cancer cells. Cancer cells also have elevated levels of mitochondrial benzodiazepine receptors which bind porphyrins with high affinity. METHODS: Cultured cancer cell lines were exposed to porphyrin and porphyrin-like compounds and then irradiated with light. Cytotoxicity of this treatment was measured via clonogenic assays. Mitochondrial benzodiazepine receptor pharmacology was studied using [3H] PK11195 binding to cancer cell homogenates and isolated kidney mitochondrial membranes. RESULTS: We show that therapeutic potencies of porphyrins correlate closely with affinities for mitochondrial benzodiazepine receptors. Sensitivities of tumor cell lines to photodynamic therapy parallel their densities of these receptors. CONCLUSION: We propose that porphyrin photodynamic therapy is mediated by mitochondrial benzodiazepine receptors.

Mitochondria↗
PubMed1997

Polyurethane catheters for long-term hemodialysis access.

Chronic hemodialysis patients with failed native fistulas and/or synthetic arteriovenous grafts are usually dialyzed via surgically placed silicone jugular catheters such as the PermCath (Quinton, Seattle, WA, U.S.A.). We report a successful experience with the use of double lumen polyurethane central venous catheters placed percutaneously. Catheters with poor flows were replaced over a guidewire at the bedside. Eleven long-term hemodialysis patients failed arteriovenous access, 9 of them having had multiple attempts at fistulas and/or grafts. Seven of these patients had also failed peritoneal dialysis. They were dialyzed with polyurethane catheters for a mean of 681 +/- 280 days (range 282-1150 days), requiring a mean of 3.4 +/- 0.4 new venous punctures and 8.2 +/- 1.5 catheter changes over a guidewire over that period of time. Actuarial patient survival was 50% at 2 years, and mean urea reduction during dialysis was 64.2 +/- 1.7%. The septicemia rate was only 1.2 episodes per 1,000 catheter-days, but about 20% of patients experienced central venous occlusion, attributable to the use of subclavian catheter placement in 82% of the sites. The success of this technique and its elimination of the need for urokinase, radiologic interventions, and surgical placement warrant its consideration as an acceptable form of long-term vascular access, provided jugular placement allows reduced central venous occlusion rates.

Aged↗
PubMed1997

Contrast media induced changes in tubular electrophysiology and glomerular filtration rate in the mouse kidney.

The isolated perfused mouse proximal tubule was used to examine electrophysiologic effects of diatrizoate and ioversol. Luminal or basolateral application of diatrizoate resulted in a dose-dependent, reversible hyperpolarization of the proximal tubule cell basolateral membrane potential (VB), which could be abolished by the addition of 10 microM probenecid. While there was a modest reduction in intracellular ATP following a 60-min exposure to diatrizoate, there was no deterioration of VB after 90 min of diatrizoate exposure, even following a 20-min hypoxic insult. Ioversol did not elicit an electrical response. Neither diatrizoate nor ioversol significantly affected transepithelial potential (VT) in the isolated perfused medullary thick ascending limb. In vivo studies showed that only the ionic contrast agent diatrizoate significantly reduced glomerular filtration rate, by 70%. The observed acute contrast media induced reduction in glomerular filtration rate does not appear to depend on direct renal tubular cytotoxicity.

Adenosine Triphosphate↗
PubMed1996

Breast infarction in a patient with chronic renal failure: a case report.

A 41-year-old woman who had chronic renal failure required a simple mastectomy for infarction of one breast. On initial presentation her condition was managed as a skin ulcer. Arterial calcification is common in chronic renal failure and its pathogenetic connection with this uncommon event is relevant to the management of "skin ulcers" in general in this population.

Adult↗
PubMed1994

Experience with not offering dialysis to patients with a poor prognosis.

Despite ongoing discussion of dialysis rationing in the nephrology community, there are little available data describing current practice in treatment selection for very ill renal patients with a poor prognosis. We report a prospective survey of end-stage renal patients referred to our Canadian regional dialysis center who were not accepted to the dialysis program on the grounds of poor prognosis and low quality of life. One quarter of patients referred during 1992 were not accepted to the program, with a mean age of 74 +/- 11 years. Patients were predominantly female and most suffered from a combination of renovascular and cardiovascular disease, with very poor functional capacity as determined by the Karnofsky scale. Nonacceptance to the dialysis program did not create legal difficulties or requests for second opinions. Based on our experience, we propose guidelines for nonacceptance of patients to dialysis programs.

Adult↗
PubMed1994

Excellent technique survival on home peritoneal dialysis: results of a regional program.

OBJECTIVE: To examine peritoneal dialysis technique survival in our regional, continuous ambulatory peritoneal dialysis (CAPD) program. DESIGN: Retrospective analysis. SETTING: Tertiary care dialysis program at an academic medical center. PATIENTS: 155 patients representing all those in the peritoneal dialysis program between October 1, 1987 and October 1, 1990. OUTCOME MEASURES: The study analyzed patient and technique survival as well as the reasons for discontinuation of dialysis. In addition, the incidence and type of peritonitis and exit-site infection were also analyzed. RESULTS: Three-year actuarial patient survival was 66% and three-year technique survival was 86%, with data censored for death and transplant patients. Fifty-seven percent of transfers to hemodialysis were due to peritonitis, usually fungal or multiorganism bacterial. Only 1 patient failed due to exit-site and tunnel infection, and 1 due to inadequate dialysis. The catheter removal rate was 0.04 per patient-year. CONCLUSIONS: Excellent CAPD technique survival can be achieved if exit-site and tunnel infection rates are low.

Female↗
PubMed1993

Carbon monoxide: a putative neural messenger.

Carbon monoxide, an activator of guanylyl cyclase, is formed by the action of the enzyme heme oxygenase. By in situ hybridization in brain slices, discrete neuronal localization of messenger RNA for the constitutive form of heme oxygenase throughout the brain has been demonstrated. This localization is essentially the same as that for soluble guanylyl cyclase messenger RNA. In primary cultures of olfactory neurons, zinc protoporphyrin-9, a potent selective inhibitor of heme oxygenase, depletes endogenous guanosine 3',5'-monophosphate (cGMP). Thus, carbon monoxide, like nitric oxide, may be a physiologic regulator of cGMP. These findings, together with the neuronal localizations of heme oxygenase, suggest that carbon monoxide may function as a neurotransmitter.

5-Aminolevulinate Synthetase↗
PubMed1993

Functional integrity of proximal tubule cells: effects of temperature and preservation solutions.

Electrophysiologic and morphologic changes during cooling and perfusion with preservation solutions in isolated perfused proximal straight tubules from Swiss white mice were investigated. In standard Ringer-substrate solution, cooling from 37 degrees C to 22 and 4 degrees C depolarized both transepithelial potential and basolateral cell membrane potential. Basolateral k+ transference number and cell membrane conductances were also significantly reduced. An increase in intracellular Na+ activity was observed only during cooling from 37 to 4 degrees C. No cell swelling was detected when tubules were perfused with Ringer-substrate solution at all three temperatures up to 1 h. Perfusion with Euro-Collins' (EC) solution at 37 degrees C resulted in rapid cell swelling, associated with rapid deterioration of transepithelial potential. Substitution of glucose with mannitol abolished the damaging effect of EC solution at 37 degrees C. EC perfusion at 22 degrees C also led to cell swelling and deterioration of transepithelial potential, but after a 10-min delay. In comparison, perfusion with University of Wisconsin (UW) solution at 22 or 37 degrees C had no effect on cell volume. Less damage to transepithelial potential was observed after the UW perfusion. It was concluded that EC solution is more damaging than UW solution to kidney tubules at 22 and 37 degrees C. The presence of EC solution in the renal interstitium during the rewarming phase may contribute significantly to reperfusion injuries in kidney transplantation.

Adenosine↗
PubMed1993

Response of mouse proximal straight tubule and medullary thick ascending limb to beta-agonist.

Scatchard analysis of (3H)CGP-12177 and (125I)cyanopindolol (CYP) radioligand binding data revealed the presence of specific beta-adrenergic receptor-binding sites on microdissected mouse proximal straight and medullary thick ascending limb (mTAL) tubules. beta-Receptor (10(-6) M isoproterenol) stimulation of isolated perfused mTAL tubules produced a consistent hyperpolarization of the transepithelial potential that was blocked by propranolol (10(-6) M), a beta-receptor antagonist, and furosemide (10(-4) M), an inhibitor of the Na+/K+/2 Cl- triporter. In contrast, there was no electrogenic response to isoproterenol stimulation in isolated perfused proximal straight tubules. In summary, radioligand binding data show that both proximal straight and mTAL tubules possess beta-receptor-binding sites. Electrogenic transport in the mTAL can be modulated by beta-agonists, but there was no detectable electrogenic response to beta-receptor stimulation in proximal straight tubules.

Adrenergic beta-Antagonists↗