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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
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↗
PubMed1992

Cloned, expressed rat cerebellar nitric oxide synthase contains stoichiometric amounts of heme, which binds carbon monoxide.

The endogenous formation of nitric oxide (NO) has become an area of intense interest as evidence for its biological functions has been obtained in three distinct tissues: circulating macrophages, in which it exerts cytotoxic effects; blood vessels, in which it has been identified as endothelium-derived relaxing factor; and neuronal cells, in which it functions as a neurotransmitter. The formation of NO in brain extracts has been shown to be catalyzed by an enzyme, termed NO synthase, which generates the NO responsible for stimulation of cGMP formation, the highest levels of which occur in the cerebellum. NO synthase catalyzes the formation of citrulline from arginine with the coincident production of NO and has been shown to be a flavoprotein, containing 1 mol each of FAD and FMN, tetrahydrobiopterin, and iron. It is also reported to contain an alpha-helical, calmodulin-binding consensus sequence consistent with its stimulation by calmodulin in the presence of Ca2+. The formation of NO requires incorporation of one of the atoms of molecular oxygen into one of the guanidinium nitrogen atoms of arginine with the coincident formation of citrulline. This communication reports that rat cerebellar NO synthase, cloned and stably expressed in human kidney 293 cells, contains heme in amounts stoichiometric with the flavins FAD and FMN as evidenced by the appearance of a pyridine hemochrome and a reduced CO difference spectrum with an absorbance maximum at approximately 445 nm. The finding of a CO-binding heme moiety explains the presence of iron in the enzyme and suggests a role for prosthetic heme as an oxygenase reaction center. This report also presents evidence for incorporation of delta-[14C]aminolevulinate specifically into immunoprecipitable NO synthase in stably transfected human kidney 293 cells but not in nontransfected cells. Simultaneously, K. A. White and M. A. Marletta [(1992) Biochemistry 31, 6627-6631] have demonstrated a CO-binding heme prosthetic group in purified murine macrophage NO synthase and have suggested the identity of these reaction centers in both the constitutive (cerebellar) and inducible (macrophage) forms of NO synthase.

Amino Acid Oxidoreductases↗