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A Berson

Publications and source records attributed to A Berson.

At least 19 recordsLinked to original sources
PubMed2000

Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice.

Extracellular ATP is implicated in numerous sensory processes ranging from the response to pain to the regulation of motility in visceral organs. The ATP receptor P2X3 is selectively expressed on small diameter sensory neurons, supporting this hypothesis. Here we show that mice deficient in P2X3 lose the rapidly desensitizing ATP-induced currents in dorsal root ganglion neurons. P2X3 deficiency also causes a reduction in the sustained ATP-induced currents in nodose ganglion neurons. P2X3-null mice have reduced pain-related behaviour in response to injection of ATP and formalin. Significantly, P2X3-null mice exhibit a marked urinary bladder hyporeflexia, characterized by decreased voiding frequency and increased bladder capacity, but normal bladder pressures. Immunohistochemical studies localize P2X3 to nerve fibres innervating the urinary bladder of wild-type mice, and show that loss of P2X3 does not alter sensory neuron innervation density. Thus, P2X3 is critical for peripheral pain responses and afferent pathways controlling urinary bladder volume reflexes. Antagonists to P2X3 may therefore have therapeutic potential in the treatment of disorders of urine storage and voiding such as overactive bladder.

Adenosine Triphosphate↗
PubMed2000

Opening of the mitochondrial permeability transition pore causes matrix expansion and outer membrane rupture in Fas-mediated hepatic apoptosis in mice.

Although Fas stimulation has been reported to cause outer mitochondrial membrane rupture in Jurkat cells, the mechanism of this effect is debated, and it is not known if outer membrane rupture also occurs in hepatocyte mitochondria. We studied the in vivo effects of Fas stimulation on ultrastructural lesions and mitochondrial function in mice. Four hours after administration of an agonistic anti-Fas antibody (8 microg/animal), caspase activity increased 5.4-fold. Nuclear DNA showed internucleosomal fragmentation, whereas supercoiled mitochondrial DNA was replaced by circular and linear forms. Mitochondrial cytochrome c was partly released into the cytosol. Ultrastructurally, mitochondrial lesions were observed in both apoptotic hepatocytes (with nuclear chromatin condensation/fragmentation) and nonapoptotic hepatocytes (without nuclear changes). In nonapoptotic cells, outer mitochondrial membrane rupture allowed herniation of the inner membrane and matrix through the outer membrane gap. In apoptotic hepatocytes, the matrix became electron-lucent and no longer protruded through the outer membrane gap. Mitochondria clustered around the nucleus, whereas rough endoplasmic reticulum cisternae became peripheral. In liver mitochondria isolated after Fas stimulation, the membrane potential decreased, whereas basal respiration increased. Pretreatment with either z-VAD-fmk (an inhibitor of caspases) or cyclosporin A (a permeability transition inhibitor) totally or mostly prevented mitochondrial outer membrane rupture, membrane potential decrease, cytochrome c release, and apoptosis. In conclusion, in vivo Fas stimulation causes caspase activation, mitochondrial permeability transition (decreasing the membrane potential and increasing basal respiration), mitochondrial matrix expansion (as shown by matrix herniation), outer mitochondrial membrane rupture, and cytochrome c release.

Animals↗
PubMed2000

Vesicular transport of newly synthesized cytochromes P4501A to the outside of rat hepatocyte plasma membranes.

Anti-cytochrome P450 (CYP)1A2 autoantibodies are found in dihydralazine-induced hepatitis, and CYPs2B and 2C have been shown to follow vesicular flow to the plasma membrane (PM). However, it is unknown whether other CYPs follow this route, whether NADPH-CYP reductase is present on the hepatocyte surface, and whether autoimmune hepatitis-inducing drugs increase PM CYPs. In this study, we determined the transmembrane topology and transport of CYPs1A in rat hepatocytes. In cultured hepatocytes, colchicine and other vesicular transport inhibitors decreased PM CYPs1A assessed by flow cytometry. Colchicine administration also decreased PM CYPs1A in vivo. Pulse chase experiments with [(35)S]methionine showed that only the newly synthesized CYP molecules are transferred to the PM, whereas microsomal CYP1A2 was stably radiolabeled for several hours. In contrast, radiolabeled CYP1A2 reached the PM and disappeared from the PM with half-lives of less than 30 min. Confocal microscopy, biotinylation, and coimmunoprecipitation experiments showed that PM CYPs1A and CYP reductase are present on the cell surface, and that the reductase is closely associated with PM CYPs. Exposure of whole cells to an anti-CYP1A1/2 antibody at 4 degrees C, before five washes and PM preparation, abolished PM CYPs1A-supported monooxygenase activity, indicating that PM CYPs are mostly located on the external surface. Dihydralazine and other CYPs1A inducers increased PM CYPs1A. In conclusion, newly synthesized CYPs1A follow vesicular flow to the outside of the PM, and NADPH-CYP reductase also is located on the hepatocyte surface. Dihydralazine administration increases PM CYP1A2, its autoimmune target.

Animals↗
PubMed1999

Diode-light transillumination for ophthalmic plaque localization around juxtapapillary choroidal melanomas.

PURPOSE: An evaluation of plaque-mounted diode-light transillumination (DLT) for localization of episcleral plaques beneath juxtapapillary tumors. METHODS AND MATERIALS: Two patients scheduled for radiotherapy for juxtapapillary melanomas were offered DLT as an additional method of ophthalmic plaque localization. Plaques were constructed by affixing 4 non-heat producing, light-emitting diodes with their apertures flush with the episcleral outer surface of the plaque's rim. Bio-implantable epoxy was used to encapsulate the electronic components. Then the plaques were loaded with 103Pd seeds. After the eye-plaques were sewn to the episclera covering the base of the intraocular tumors; the diode-lights were illuminated, viewed and recorded. Photodocumentation of the relative position of the 4 lights around tumor's base was obtained in both cases. RESULTS: Digital images of plaque-mounted diode retro-transillumination were obtained. No evidence of diode-light toxicity was noted. Both tumors were found to be covered by the ophthalmic plaques. CONCLUSION: Juxtapapillary tumors are often difficult or impossible to visualize with standard transillumination techniques and have been associated with poor local control rates. We have developed plaque-mounted DLT in an effort to improve ophthalmic plaque localization. Retrobulbar transillumination was viewed by indirect ophthalmoscopy and recorded with video-imaging. This technique provides unique photographic documentation of episcleral plaque localization beneath juxtapapillary tumors.

Choroid Neoplasms↗
PubMed1999

Decrease in hepatic cytochrome P450 after interleukin-2 immunotherapy.

Interleukin-2 (IL-2) has been shown to decrease cytochrome P450 (CYP) mRNAs and proteins in cultured rat hepatocytes, and IL-2 administration decreases CYPs in rats. Although high doses of IL-2 are administered to cancer patients, the effect on human CYPs has not yet been determined. Patients with hepatic metastases from colon or rectum carcinomas were randomly allocated to various daily doses of human recombinant IL-2 (from 0 to 12.10(6) units/m(2)). IL-2 was infused from day 7 to day 3 before hepatectomy and the conservation of a non-tumorous liver fragment in liquid nitrogen. Hepatic CYPs and monooxygenase activities were not significantly decreased in 5 patients receiving daily doses of 3 or 6 10(6) IL-2 units/m2, compared to 7 patients who did not receive IL-2. In contrast, in 6 patients receiving daily doses of 9 or 12 x 10(6) IL-2 units/m2, the mean values for immunoreactive CYP1A2, CYP2C, CYP2E1, and CYP3A4 were 37, 45, 60 and 39%, respectively, of those in controls; total CYP was significantly decreased by 34%, methoxyresorufin O-demethylation by 62%, and erythromycin N-demethylation by 50%. These observations suggest that high doses of IL-2 may decrease total CYP and monooxygenase activities in man.

Adenocarcinoma↗
PubMed1999

Ophthalmic plaque radiotherapy for age-related macular degeneration associated with subretinal neovascularization.

PURPOSE: To evaluate ophthalmic plaque radiotherapy for the treatment of subretinal neovascularization associated with age-related macular degeneration. METHODS: In a prospective phase I clinical trial, we treated 23 patients (23 eyes) with ophthalmic plaque radiotherapy for subfoveal exudative macular degeneration. Palladium 103 ophthalmic plaque brachytherapy was delivered to a retinal apex dose of 1,250 to 2,362 cGy (rad). Early Treatment Diabetic Retinopathy Study type visual acuity determinations, ophthalmic examinations, and angiography were performed before and after treatment. Clinical evaluations were performed in a nonrandomized and unmasked fashion. RESULTS: Patients were followed up for a mean (+/-SD) of 19 +/- 10.7 months (range, 3 to 37 months). Six months after radiation therapy, three (16%) of 19 eyes had lost 3 or more lines of best-corrected visual acuity; 12 months after radiation therapy, four eyes (31% of 13 eyes), and 24 months after radiation therapy, only two (22% of nine eyes) lost 3 or more lines of visual acuity. No eye suffered sudden irreversible loss of central vision. No radiation retinopathy, optic neuropathy, or cataract could be attributed to radiotherapy within this follow-up period. CONCLUSION: Ophthalmic plaque radiotherapy can be used to treat neovascular age-related macular degeneration. In contrast to external beam radiotherapy, ophthalmic plaque radiotherapy is a unilateral treatment, which allows a larger dose to be delivered to the macula with less irradiation of normal ocular structures. We have found no sight-limiting complications at the doses, dose rates, and follow-up evaluated in this study.

Aged↗
PubMed1999

An alcoholic binge causes massive degradation of hepatic mitochondrial DNA in mice.

BACKGROUND & AIMS: Ethanol causes oxidative stress in the hepatic mitochondria of experimental animals and mitochondrial DNA deletions in alcoholics. We postulated that ethanol intoxication may cause mitochondrial DNA strand breaks. METHODS: Effects of an intragastric dose of ethanol (5 g/kg) on hepatic mitochondrial DNA levels, structure, and synthesis were determined by slot blot hybridization, Southern blot hybridization, and in vivo [3H]thymidine incorporation, respectively. RESULTS: Two hours after ethanol administration, ethane exhalation (an index of lipid peroxidation) increased by 133%, although hepatic lipids were unchanged. Mitochondrial DNA was depleted by 51%. Its supercoiled form disappeared, whereas linearized forms increased. Long polymerase chain reaction evidenced lesions blocking polymerase progress on the mitochondrial genome. Mitochondrial transcripts decreased. Subsequently, [3H]thymidine incorporation into mitochondrial DNA increased, and mitochondrial DNA levels were restored. In contrast, nuclear DNA was not fragmented and its [3H]thymidine incorporation was unchanged. Liver ultrastructure only showed inconstant mitochondrial lesions. Ethanol-induced mitochondrial DNA depletion was prevented by 4-methylpyrazole, an inhibitor of ethanol metabolism, and attenuated by melatonin, an antioxidant. CONCLUSIONS: After an alcoholic binge, ethanol metabolism causes oxidative stress and hepatic mitochondrial DNA degradation in mice. DNA strand breaks may be involved in the development of mitochondrial DNA deletions in alcoholics.

Alcohol Drinking↗
PubMed1999

Palladium-103 plaque radiotherapy for choroidal melanoma: results of a 7-year study.

OBJECTIVE: To describe the first clinical experience with palladium-103 (103Pd) ophthalmic plaque radiotherapy for choroidal melanoma. DESIGN: Phase-I (nonrandomized) clinical trial. PARTICIPANTS: Eighty patients with uveal melanomas were diagnosed by clinical examination, found to be negative for metastatic disease, and offered 103Pd radioactive plaque treatment. Nine patients were concurrently treated with microwave hyperthermia. INTERVENTION: Palladium-103 ophthalmic plaque radiotherapy was employed for each patient. Eye plaques were sewn to the episclera to cover the base of the intraocular tumor, radiation was continuously delivered over 5 to 7 days, and then the plaques were removed. A mean apical dose of 81 Gy was delivered. MAIN OUTCOME MEASURES: The authors evaluated the ease of use of 103Pd seeds within standard gold eye plaques. Patient-related outcomes were control of tumor growth, change in visual acuity, the development of radiation damage (retinopathy, optic neuropathy, and cataract), and metastatic disease. RESULTS: From September 1990 to December 1997, 80 patients were treated with 103Pd and followed for an average of 38 months. Two patients were lost to follow-up. During this time, the authors found that 103Pd seeds were equivalent to iodine-125 (125I) with respect to plaque manufacture and ease of dosimetric calculations. Two patients in this series were treated for tumor recurrence after 125I plaque radiotherapy. They both failed secondary 103Pd treatment and were enucleated. When 103Pd was used as a primary treatment, it controlled the growth of 75 of 78 tumors (96%). Overall, there have been six enucleations: three failures of primary treatment, two failures of retreatment, and one for neovascular glaucoma. Visual acuity evaluations at the 36-month follow-up visit (including the enucleated patients) revealed that 38% of eyes had decreased 3 or more lines of vision, and 77% were 20/200 or better. CONCLUSION: Palladium-103 plaque radiotherapy can be used to treat uveal melanomas. Compared with 125I, computerized dosimetry suggests a more favorable dose distribution with 103Pd. Treatment of most patients resulted in tumor shrinkage and preservation of functional vision. The authors have noted no complications that might preclude the use of 103Pd ophthalmic plaque radiotherapy for choroidal melanoma.

Brachytherapy↗
PubMed1999

Mesalazine (5-aminosalicylic acid) induced chronic hepatitis.

BACKGROUND: Treatment of ulcerative colitis or Crohn's disease with sulphasalazine causes several adverse effects, including hepatitis. Sulphasalazine is cleaved by colonic bacteria into 5-aminosalicylic acid and sulphapyridine. Received wisdom was that 5-aminosalicylic acid was topically active, whereas sulphapyridine was absorbed and caused immunoallergic side effects. Mesalazine, a slow release formulation of 5-aminosalicylic acid, was expected to be a safe alternative. However, several cases of acute hepatitis have been reported. CASE REPORT: A 65 year old man had increased liver enzymes, anti-nuclear and anti-smooth muscle autoantibodies and IgG levels, and lesions of chronic hepatitis after 21 months of mesalazine treatment. Although liver dysfunction had been identified eight months earlier, simvastatin rather than mesalazine had been withdrawn, without any improvement. In contrast, liver enzyme and IgG levels became normal and autoantibodies disappeared after discontinuation of mesalazine administration. CONCLUSION: Contrary to initial expectations, mesalazine can cause most of the sulphasalazine induced adverse effects, and hepatic side effects may be almost as frequent. When liver dysfunction occurs, mesalazine administration should be discontinued to avoid the development of chronic hepatitis and liver fibrosis.

Aged↗
PubMed1999

Interleukin-2 overexpresses c-myc and down-regulates cytochrome P-450 in rat hepatocytes.

The interaction of interleukin-2 (IL-2) with its receptor (IL-2R) decreases cytochrome P-450 (CYP) expression in rat hepatocytes. Because IL-2 increases c-Myc in lymphocytes and because c-myc overexpression represses several genes, we postulated that the IL-2/IL-2R interaction may increase c-Myc and thereby down-regulate CYP in hepatocytes. Cultured rat hepatocytes were exposed for 24 h to IL-2 (350 U/ml) and other agents. IL-2 increased c-myc mRNA and protein but decreased total CYP and the mRNAs and proteins of CYP2C11 and CYP3A. The IL-2-mediated c-myc overexpression and CYP down-regulation were prevented by 1) genistein (a tyrosine kinase inhibitor that blocks the initial transduction of the IL-2R signal), 2) retinoic acid, butyric acid, or dimethyl sulfoxide (three agents that block c-myc transcription), or 3) an antisense c-myc oligonucleotide (which may cause rapid degradation of the c-myc transcript). It is concluded that IL-2 causes the overexpression of c-myc and the down-regulation of CYPs in rat hepatocytes. Block of c-myc overexpression, at three different levels with five different agents, prevents CYP down-regulation, suggesting that c-myc overexpression may directly or indirectly repress CYP in hepatocytes.

Animals↗
PubMed1998

Three-dimensional ultrasonography of choroidal melanoma: localization of radioactive eye plaques.

OBJECTIVE: To evaluate the use of 3-dimensional (3D) ultrasonography for the localization of episcleral eye plaques during the treatment of choroidal melanomas. METHODS: A series of 13 patients with choroidal melanoma were treated with radioactive palladium 103 seeds affixed into gold eye plaques. During surgery, 3D ultrasonography was performed with a commercially available system to evaluate the relative position of radioactive plaques secured beneath their intraocular tumors. This system consists of an automated, rotating, handheld, B-scan ultrasonographic probe operating at 10 MHz, a personal computer, and 3D imaging software. RESULTS: We measured the margins of the plaque extending beyond the tumor and the distance between the radioactive seeds and the tumor apex. We also evaluated the relationship between the plaque edge, the episclera, and the tumor's edges. While the plaques were well centered over the tumor in all cases, the plaque margins around the tumor were found to be variably sized. When comparing measurements taken at the time of plaque insertion with those taken at the time of plaque removal, we noted changes in the apical tumor height and in plaque centration. In the 1 patient with a juxtapapillary tumor, the posterior margin of the plaque was found to be displaced away from the sclera, or "tilted." CONCLUSIONS: Three-dimensional ultrasonography offers a new method for ophthalmic plaque localization. Unique perspectives can be visualized through the use of computer-aided 3D reconstructions that permit the assessment of the relative position of the plaque to the optic nerve and the measurement of the distance between the in vivo radioactive seed and the tumor apex. Our experience suggests that when compared with 2-dimensional ultrasonography, 3D ultrasonography offers new capabilities that can be used to improve plaque placement and radiation dose calculations.

Brachytherapy↗
PubMed1998

Long-term mechanical circulatory support system reliability recommendation: American Society for Artificial Internal Organs and The Society of Thoracic Surgeons: long-term mechanical circulatory support system reliability recommendation.

Jointly developed by members of the American Society for Artificial Internal Organs and the Society of Thoracic Surgeons along with staff from the Food and Drug Administration, the National Heart, Lung and Blood Institute and other experts, this recommendation describes the reliability considerations and goals for Investigational Device Exemption and Premarket Approval submissions for long-term, mechanical circulatory support systems. The recommendation includes a definition of system failure, a discussion of an appropriate reliability model, a suggested in vitro reliability test plan, reliability considerations for animal implantation tests, in vitro and animal in vivo performance goals, the qualification of design changes during the Investigational Device Exemption clinical trial, the development of a Failure Modes Effects and Criticality Analysis, and the reliability information for surgeons and patient candidates. The document will be periodically reviewed to assess its timeliness and appropriateness within five years.

Animals↗
PubMed1998

Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes.

BACKGROUND & AIMS: 4,4'-Diethylaminoethoxyhexestrol (DEAEH), amiodarone, and perhexiline cause steatohepatitis in humans. The mechanisms of these effects are unknown for DEAEH and have not been completely elucidated for amiodarone and perhexiline. The aim of this study was to determine these mechanisms. METHODS: Rat liver mitochondria, cultured rat hepatocytes, or rats were treated with these drugs, and the effects on mitochondrial respiration, beta-oxidation, reactive oxygen species formation, and lipid peroxidation were determined. RESULTS: DEAEH accumulated in mitochondria and inhibited carnitine palmitoyl transferase I and acyl-coenzyme A dehydrogenases; it decreased beta-oxidation and caused lipid deposits in hepatocytes. DEAEH also inhibited mitochondrial respiration and decreased adenosine triphosphate (ATP) levels in hepatocytes. DEAEH, amiodarone, and perhexiline augmented the mitochondrial formation of reactive oxygen species and caused lipid peroxidation in rats. CONCLUSIONS: Like amiodarone and perhexiline, DEAEH accumulates in mitochondria, where it inhibits both beta-oxidation (causing steatosis) and respiration. Inhibition of respiration decreases ATP and also increases the mitochondrial formation of reactive oxygen species. The latter oxidize fat deposits, causing lipid peroxidation. We suggest that ATP depletion and lipid peroxidation may cause cell death and that lipid peroxidation products may account, in part, for other steatohepatitis lesions.

Animals↗