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Biomedical subjects

M H Weiss

Publications and source records attributed to M H Weiss.

At least 37 records · Page 2Linked to original sources
PubMed1997

Attenuation of brain injury and reduction of neuron-specific enolase by nicardipine in systemic circulation following focal ischemia and reperfusion in a rat model.

A reversible middle cerebral artery occlusion was performed in rats to determine whether nicardipine, a dihydropyridine voltage-sensitive Ca++ channel (VSCC) antagonist, exerts neuroprotective effects when administered 10 minutes following an ischemic insult, and if it does, whether this is due to its vasodilatory action and effect on cerebral blood flow (CBF) or to direct blockade of Ca++ entry into ischemic brain cells. An increase in the intracellular calcium, [Ca++]i, plays a major role in neuronal injury during cerebral ischemia. Although a large amount of Ca++ enters neurons through the VSCC during ischemia, inconsistent neuroprotective effects have been reported with the antagonists of the VSCC. An intraperitoneal injection of nicardipine (1.2 mg/kg) was administered to rats 10 minutes after the onset of ischemia, and 8, 16, and 24 hours after occlusion. Cortical CBF was determined by laser-Doppler flowmetry. Neurological and neuropathological examinations were performed after 72 hours. Neuron-specific enolase, a specific marker for the incidence of neuronal injury, was measured in plasma. The CBF and other physiological parameters were not affected by nicardipine during occlusion or reperfusion. However, nicardipine treatment significantly improved motor neurological outcome by 29%, and the infarction and edema volume in the pallium as well as the edema volume in the striatum were significantly reduced by 27%, 37%, and 52%, respectively. Nicardipine also reduced the neuron-specific enolase plasma levels by 50%, 42%, and 59% at 24, 48, and 72 hours after the occlusion, respectively. It is concluded that nicardipine may attenuate focal ischemic brain injury by exerting direct neuroprotective and antiedematous effects that do not depend on CBF.

Animals↗
PubMed1996

Transport of circulating reduced glutathione at the basolateral side of the anterior lens epithelium: physiologic importance and manipulations.

Transport of circulating reduced glutathione (GSH) was studied at the basolateral side of the lens epithelium by using an in situ vascular eye perfusion technique in guinea-pigs with rapid sampling to ensure detecting initial uptakes. The unidirectional transport rates of [35S]-GSH (4 nM) from plasma and aqueous into the epithelial cytosol were 0.046 +/- 0.003 and 6.88 +/- 0.39 min-1, respectively. HPLC analysis indicated that over 94% of [35S]-GSH remained intact in the epithelium and cortex in the presence or absence of gamma-glutamyl transpeptidase inhibitor, serine borate. Simultaneous infusion of [35S-cysteine]-GSH and [3H-glycine]-GSH confirmed the non-involvement of gamma-glutamyl transpeptidase in GSH transport across the lenticular membranes by showing that 35S/3H ratio in the epithelium and cortex was the same as in the aqueous and plasma. GSH epithelial influx was reduced by 53% (P < 0.01) by 0.3 mM sulphobromophtalein-GSH, a GSH conjugate that does not inhibit the facilitative GSH transporter, RcGshT, recently found in the lens. At physiologic concentration of circulating GSH at 30 microM, GSH epithelial influx was 0.77 nmol min-1 g-1; a t1/2 of 85.4 hr was estimated if endogenous epithelial GSH had to be replaced exclusively by plasma-derived GSH. The level of GSH in the epithelium was increased by 38% (P < 0.05) by 1 hr arterial infusion of GSH at 20 mM. The aqueous concentration of GSH under these conditions was 1.2 mM so that accumulation in the epithelium occurred a greater than six-fold concentration gradient. It is concluded that: (a) transport of GSH at the basolateral side of the epithelium is mediated by a concentrative mechanism distinct from RcGshT: (b) circulating GSH may represent a major source for epithelial GSH under physiologic conditions; and (c) the level of GSH in the epithelium can be manipulated by exogenous GSH.

Animals↗
PubMed1996

Protein kinase C and growth regulation of pituitary adenomas.

The present study was undertaken to explore the role of the Protein Kinase C (PKC) signal transduction system in growth regulation of pituitary adenomas. Primary tumor cultures were plated from fresh surgical tumor specimens. The PKC inhibitors Staurosporine and Tamoxifen were added at varying dosages to the cell cultures. Measurements of cell proliferation were performed by [3H]-thymidine uptake and the [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide] (MTT) assay. After a 48 h treatment period, both [3H]-thymidine uptake and absorbance on the MTT assay decreased in a dose-related manner in both the staurosporine and tamoxifen-treated cultures (IC50 of 10 nM and 30 microM respectively). Direct measurement of PKC activity using an in vitro assay revealed very high activity (range of 1465-5708 pmol/min/mg protein; within the range previously published for malignant glioma specimens) in 12 frozen specimens of pituitary adenomas (9 nonfunctional adenomas, 1 prolactinoma, 1 gonadotrophin-secreting and 1 corticotroph-secreting adenoma). In contrast, PKC activity measured in normal adenohypophysis was comparatively very low. These data indicate that pituitary adenoma cells display high PKC activity and are sensitive to growth inhibition by PKC inhibitors. These data suggest a role for the PKC system in regulating pituitary tumor growth, which may have implications for future therapy of these tumors.

Adenoma↗
PubMed1996

Transport of dopamine at the blood-brain barrier of the guinea pig: inhibition by psychotropic drugs and nicotine.

PURPOSE: Transport of dopamine (DA) across the blood-brain barrier (BBB) was examined in guinea pigs. METHODS: In situ brain perfusion (1-10 min), capillary depletion, and high pressure liquid chromatography (HPLC) were used. RESULTS: There was a saturable DA influx into the brain with a KM of 389 +/- 55 nM, and a VMAX of 1.95 +/- 0.25 pmol/min/g of brain. The diffusion constant, KD, was not significantly different from zero. About 0.5% of DA remained tightly bound to cerebral microvessels isolated from the perfused brain. DA influx into the brain was not altered by the monoamine oxidase-B (MAO-B) inhibitor pargyline (50 microM). HPLC analysis of perfused brain confirmed transport of intact DA, and no detectable increases in DA metabolites were observed. At perfusate concentrations of 500 nM, several dopaminergic receptor antagonists inhibited [3H]-DA (21 nM) influx; the percent inhibitions for the mixed D1 and D2 antagonists haloperidol and chlorpromazine, the D1 antagonist SCH-23390, and the D2 antagonist spiperone were 90%, 68%, 77%, and 50%, respectively. Brain perfusion with nicotine (500 nM) inhibited DA uptake by 86%. This nicotine effect was not altered by mecamylamine, but was partially prevented by the nicotinic receptor antagonist hexamethonium. CONCLUSIONS: (a) A significant cerebrovascular permeability to intact DA is mediated by a MAO-B independent specific transport system at the BBB, (b) this system could be inhibited by D1 and D2 DA receptor antagonists, and (c) DA blood-to-brain transport was inhibited by nicotine.

Animals↗
PubMed1996

Cellular uptake and transport of methylprednisolone at the blood-brain barrier.

Methylprednisolone (MP) is one of the most widely used neuroprotective drugs in neurosurgery. Our knowledge of its pharmacokinetics in the brain and, in particular, whether it can penetrate the blood-brain barrier (BBB) and act in the brain parenchyma is still limited. In this study, we used a vascular brain perfusion technique in guinea pigs, combined with a capillary depletion method, to determine brain uptake and transport of MP at the BBB. 3H-Labeled MP was delivered to the brain by carotid arterial infusions lasting from 1 to 10 minutes; the effects of plasma protein binding, different concentrations of MP, and the glucocorticoid receptor inhibitor, RU486, were examined. The existence of a transport system was inferred from the observation that the volume of distribution of MP in the brain after perfusion exceeded by 2.6 to 6.3 times the plasma volume of the cerebrovascular space marker, sucrose. The rates of undirectional [3H]MP blood-to-brain transport of 0.5 to 0.7 microliters per minute per gram indicated significant but slow transfer. MP available for BBB transport was not restricted to its free plasma fraction but, instead, included the albumin- and globulin-bound fractions. A portion of steroid remained concentrated (sequestered) by the capillary endothelium, and from there, the label was distributed into brain parenchyma. Both MP binding and transport at the BBB exhibited saturable kinetics. RU486 produced an inhibition of MP BBB transport and binding with an affinity that seemed to be 30 to 60% higher than that of the steroid itself. We concluded that MP first binds to the brain capillaries and then crosses the BBB at a low rate, most likely by using a saturable mechanism that may involve a cytoplasmic endothelial glucocorticoid receptor.

Animals↗
PubMed1996

Petroclival meningiomas: surgical experience in 109 cases.

The surgical removal of petroclival meningiomas has historically been associated with a high incidence of morbidity and mortality. The 109 consecutive patients included in the present retrospective study represent a combined series of tumors operated on by the four authors during a period from 1980 to 1992. The series is composed of 40 men and 69 women ranging in age from 25 to 75 years (mean 51 years). Surgical approaches to tumors in this series included simple retromastoid (60 cases), combined supra- and infratentorial petrosal (22), transtemporal (primary transsigmoid retrolabyrinthine, translabyrinthine, or transcochlear (12), subtemporal (11), and frontotemporal transcavernous (eight). Gross-total removal was achieved in 75 patients (69%). Recurrence or progression of disease occurred in 14 patients (13%) over a 6.1-year mean follow-up period, and it was found within the cavernous sinus in 12 of these cases. Four recurrent cases demonstrated histological compatibility with malignant meningioma. Perioperative death occurred in four patients, and there were 56 significant complications in 35 other patients. Review of this series, with the attendant complications, has facilitated the authors' decision-making when considering the risk of gross-total removal in selected patients with asymptomatic cavernous sinus invasion or tumor adherent to the brainstem.

Adult↗
PubMed1996

Inhibition of cellular growth and induction of apoptosis in pituitary adenoma cell lines by the protein kinase C inhibitor hypericin: potential therapeutic application.

Protein kinase C (PKC) is an enzyme involved in the regulation of cellular growth, proliferation, and differentiation in a number of tissues including the anterior pituitary, in which it is also believed to play a role in hormone secretion. Protein kinase C activity and expression have been found to be greater in adenomatous pituitary cells than in normal human and rat pituitary cells and higher in invasive pituitary tumor cells than in noninvasive ones. Inhibition of PKC activity has been shown in a variety of tumor cells to inhibit growth in a dose-related fashion. The purpose of the current study was to determine whether hypericin, a potent inhibitor of PKC activity that may be administered clinically, alters the growth and proliferation in established pituitary adenoma lines and to determine if inhibition of PKC activity induces apoptosis, as reported in some other tumor cell types. Two established pituitary adenoma cell lines, AtT-20 and GH4C1, were treated with hypericin in tissue culture for defined periods following passage. Inhibition of growth was found to be dose dependent in all three cell lines in low micromolar concentrations of hypericin, as determined by viable cell counts, methylthiotetrazole assay, and [3H]thymidine uptake studies. Concentrations of hypericin as low as 100 nM also induced apoptosis in these established lines, whereas treatment of normal human fibroblasts with a concentration of 10 microM failed to induce apoptosis. The potential use of hypericin in the therapy of pituitary adenomas warrants additional in vitro investigations with the aim of later moving toward therapeutic trials in selected patients in whom surgical or medical therapy has failed.

Adenoma↗
PubMed1996

Septic cavernous sinus thrombosis following transsphenoidal craniotomy. Case report.

The authors present a case of late-onset cavernous sinus thrombosis in a 74-year-old man who had undergone transsphenoidal craniotomy for a pituitary macroadenoma 9 weeks previously. The patient developed headache, rapidly progressive ophthalmoplegia, and signs of orbital congestion. After 2 days of ineffective broad spectrum antibiotic therapy he underwent a second transsphenoidal craniotomy for abscess drainage. Intraoperative cultures grew 4+ non-hemolytic Streptococcus, 4+ Staphylococcus coagulase negative, and 4+ Haemophilus influenzae. The patient was maintained on intravenous antibiotic therapy for the following 6 weeks, resulting in a complete clinical recovery. To the authors' knowledge, this is the first report of a septic cavernous sinus thrombosis following a transsphenoidal craniotomy.

Aged↗
PubMed1996

Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen.

The present clinical trial was undertaken to assess the clinical safety and possible efficacy of administering tamoxifen to patients with recurrent malignant glial tumors at dosages calculated to achieve levels sufficient to inhibit protein kinase C within the tumor cells. Chronic p.o. tamoxifen was administered in very high dosages to 32 patients (20 males and 12 females; age range, 26-75 years; mean, 49 years) with histologically verified malignant glioma [anaplastic astrocytoma (12 patients) or glioblastoma multiforme (20 patients)] who had demonstrated clinical and radiographical progression or recurrence following external beam radiation therapy (and additional chemotherapy in 11; immunotherapy in 2). The dosage of tamoxifen administered was 200 mg/day to males and 160 mg/day to females given in a twice daily schedule. Clinical and radiographical (defined as a greater than 50% decrease in volume of the enhancing lesion volume on magnetic resonance imaging and a decrease in metabolic activity on serial positron emission tomographic scans) response was noted in 8 patients (25%; 4/12 with anaplastic astrocytoma and 4/20 glioblastoma multiforme), with an additional 6 patients (19%) exhibiting stabilization of disease with minimal side effects. Median survival from the time of diagnosis for the entire cohort was 24 months (104 weeks), for the anaplastic astrocytoma group 42.5 months (185 weeks), and for the glioblastoma group 17.4 months (75.5 weeks). From the initiation of tamoxifen, median survival for the entire cohort was 10.1 months (44 weeks), for the anaplastic astrocytoma group 16 months (69 weeks), and for the glioblastoma group 7.2 months (31 weeks). The mean length of follow-up of all patients after initiating tamoxifen was 16 months (69 weeks), while the mean length of follow-up of alive patients is 22.6 months (98 weeks) (range up to 51 months). These data suggest that a subgroup of patients with malignant gliomas respond or stabilize with chronic high-dose tamoxifen therapy. This therapy may represent an alternative or adjuvant to existing chemotherapies for these tumors; further clinical trials are warranted.

Administration, Oral↗
PubMed1996

Enhancement of radiosensitivity in human malignant glioma cells by hypericin in vitro.

Hypericin, an antidepressant and antiviral agent being evaluated in phase I and II trials for patients with HIV infection, is known to be a potent protein kinase C inhibitor. We have investigated its effects on cellular response to radiation via a tetrazolium-formazan cell growth rate assay using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and clonogenic assay in three human glioblastoma cell lines, U87-MG, A-172, and T98G, and a low-passage malignant glioma culture, 93-492. At a concentration of 5 microM, hypericin inhibited these cells slightly but caused significant radiosensitization (e.g., the cell survival rate after the radiation treatment was 50.2 and 26.0% in cells treated with 6 Gy and 6 Gy plus 5 microM hypericin in U87-MG cells, respectively; P = 0.0285). Hypericin also enhanced the radiosensitivity significantly in the low-passage glioma 93-492 cells. These findings suggest that hypericin represents a potential new agent in combination with radiation therapy of malignant gliomas.

Anthracenes↗
PubMed1995

Tracheoesophageal puncture in irradiated patients.

Tracheoesophageal puncture (TEP) with use of a voice prosthesis is widely accepted as an excellent method of postlaryngectomy vocal rehabilitation. Many patients with advanced cancer require postoperative radiotherapy (RT), while other cancer patients have been treated with RT as a primary treatment and come to laryngectomy for salvage. The influence of RT on outcome of the TEP procedure with respect to successful speech and potential complications has not been widely discussed. We retrospectively reviewed 77 consecutive cases of TEP in patients who had received RT and laryngectomy for laryngeal cancer. All cases had a minimum of 6 months of follow-up. All 77 patients were successful in obtaining speech with the TEP, and 75 (97%) continued to be TEP users thereafter. Eight patients (10%) developed complications in the course of treatment. There was no mortality. In selected patients, TEP after RT is a relatively safe and effective method of vocal rehabilitation.

Aged↗
PubMed1995

Tonsil lymphoma presenting as tonsillitis after bone marrow transplantation.

Bone marrow transplantation for the treatment of leukemia is increasingly successful in rendering patients disease free. However, it has become evident that the associated severe immunosuppression predisposes this population to an increased risk for other neoplastic disorders. We report on six patients in whom non-Hodgkin's lymphoma of the tonsillar region developed within 5 months after T-cell-depleted bone marrow transplantation for the treatment of leukemia at Memorial Sloan-Kettering Cancer Center from October 1990 to October 1992. These patients initially had what appeared to be infectious exudative pharyngitis/tonsillitis; however, they did not improve with medical therapy. Because of the persistence of pharyngitis/tonsillitis in association with cervical lymphadenopathy and odynophagia, the patients underwent definitive biopsy in the form of tonsillectomy, cervical lymph node biopsy, or both. Histopathologic review revealed non-Hodgkin's lymphoma. An association with Epstein-Barr virus has been noted in five of these patients. This article is aimed at alerting the clinician to consider the diagnosis of lymphoma in a patient with persistent pharyngitis/tonsillitis despite adequate medical therapy after bone marrow transplantation.

Adult↗
PubMed1995

Organ-function preservation in advanced oropharynx cancer: results with induction chemotherapy and radiation.

PURPOSE: To evaluate the feasibility and efficacy of a strategy using induction chemotherapy followed by radiation therapy (RT) as a means of organ-function preservation in patients with advanced oropharynx cancer. PATIENTS AND METHODS: From January 1983 to December 1990, 33 patients with advanced squamous cell oropharynx cancer whose appropriate surgical management would have required a tongue procedure and potential total laryngectomy were treated with one to three cycles of cisplatin (CDDP)-based induction chemotherapy. Patients with a complete response (CR) or partial response (PR) at the primary site then received definitive external-beam RT with or without interstitial implant with or without neck dissection with surgery to the primary tumor site reserved for disease persistence or relapse; patients with less than a PR after chemotherapy had appropriate surgery and postoperative RT recommended. RESULTS: With a median follow-up period of 6.2 years, actuarial overall and failure-free survival rates at 5 years are 41% and 42%, respectively. Chemotherapy toxicity contributed to the death of two patients and was possibly a factor in two others. Local control was achieved in 14 patients (42%) without any surgery to the larynx or tongue. Among 13 patients currently alive, all had a preserved larynx and only one required tongue surgery; 12 of 13 have speech subjectively described as always understandable; and nine of 13 have no significant restrictions in their diet. CONCLUSION: This treatment program is feasible and effective in patients with advanced oropharynx cancer and produces an excellent functional outcome in most long-term survivors. Modifications to optimize patient selection, minimize toxicity, and improve local control are indicated. The relative toxicity, efficacy, and functional outcome provided by this and other chemotherapy and RT programs versus either standard surgery and/or RT options can only be addressed in a randomized comparison of these therapies.

Adult↗
PubMed1995

Paradoxical elevation of Ki-67 labeling with protein kinase inhibition in malignant gliomas.

The monoclonal antibody Ki-67 recognizes a nuclear antigen expressed in the G1, S, G2, and M phase of the cell cycle and has been used extensively as an indicator of cellular proliferation in malignant gliomas, both in the laboratory and clinically. Recently, protein kinase C (PKC) inhibitors have been demonstrated to inhibit malignant glioma growth both in in vitro and in vivo. This study was undertaken to determine whether Ki-67 could function as an indicator of cellular proliferation rate after PKC inhibition in gliomas and to explore cell cycle specificity of such inhibition. Both established and low-passage malignant glioma cell lines have previously been shown to be sensitive to growth inhibition by the PKC inhibitors staurosporine and tamoxifen in vitro (IC50 in the nanomolar and micromolar ranges, respectively), as measured by cell numbers, [3H]thymidine uptake, and flow-cytometric DNA analysis. However, in the same cells that are inhibited by staurosporine and tamoxifen on these assays, and on the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) assay in the present study, the Ki-67 labeling index paradoxically increased in a dose-related manner with the same treatments, as measured by immunohistochemistry and confirmed by flow cytometry. For example, in established line U-87, a 20.5% decrease in thymidine uptake and a 28.5% decrease in absorbance on the MTT assay produced by tamoxifen at 1 microM was associated with an increase in Ki-67 labeling from 42% to 62%; staurosporine, which produces a 78.8% decrease in thymidine uptake in cell line A-172 at 10 nM, produced an increase in Ki-67 labeling from 19% to 32%. In this regard, Ki-67 labeling of glioblastoma tissue from a patient treated with high-dose tamoxifen yielded results within the range of 10% to 15% (consistent with values seen in untreated glioblastoma), despite tumor regression with treatment. The authors' interpretation of these results is that these PKC inhibitors are halting the cell cycle in the G1 phase or the G1-S transition (beyond G0 but before S-phase), resulting in a paradoxical increase in labeling while arresting growth. Two important implications from these observations are that Ki-67 is not a reliable indicator of cellular proliferation after treatment with PKC inhibitors and that these inhibitors used at the doses given above halt cell growth in a phase-specific manner.

Alkaloids↗
PubMed1995

The transfacet pedicle-sparing approach for thoracic disc removal: cadaveric morphometric analysis and preliminary clinical experience.

A number of operative techniques have been described for the treatment of herniated thoracic discs. The transfacet pedicle-sparing approach allows for complete disc removal with limited spinal column disruption and soft-tissue dissection. Fifteen cadaveric spinal columns were used for evaluation of exposure, development of thoracic microdiscectomy instrumentation, and establishment of morphometric measurements. This approach was used to remove eight thoracic discs in six patients. Levels of herniation ranged from T-7 through T-11. Preoperatively, all patients had moderate to severe axial pain, and three (50%) of the six had radicular pain. Myelopathy was present in four (67%) of the six patients. Through a 4-cm opening, the ipsilateral paraspinal muscles were reflected, and a partial facetectomy was performed. The disc was then removed using specially designed microscopic instrumentation. Postoperatively, the radiculopathy resolved in all patients. Axial pain and myelopathy were completely resolved or significantly improved in all patients. The minimal amount of bone resection and muscle dissection involved in the operation allows for: 1) decreased operative time and blood loss; 2) diminished perioperative pain; 3) shorter hospitalization time and faster return to premorbid activity; 4) avoidance of closed chest tube drainage; and 5) preservation of the integrity of the facet-pedicle complex, with potential for improvement in outcome related to axial pain. This technique appears best suited for the removal of all centrolateral discs, although it has been used successfully for treating a disc occupying nearly the entire ventral canal. The initial experience suggests that this approach may be used to safely remove appropriately selected thoracic disc herniations with good results.

Adult↗
PubMed1995

Secondary pharyngeal myotomy for tracheoesophageal speech.

Pharyngeal myotomy in the post-laryngectomy patient has been described to reduce pharyngoesophageal spasm and facilitate vocal rehabilitation and tracheoesophageal speech. This report describes the complications and speech outcomes in 22 consecutive patients who underwent a secondary pharyngeal myotomy. The patients were all drawn from a hospital clinic dedicated to voice rehabilitation after laryngectomies. Their ages ranged from 54 to 81-years-old with a mean of 64. Two patients suffered surgical complications--both had pharyngocutaneous fistulas which resolved with conservative management. One patient had an incomplete myotomy and was treated with injection of boulinum toxin in the pharyngeal plexus. This treatment resulted in good vocalization. Seventeen of 22 patients in the study were long-term TEP users, and all of these were judged to have good speech quality. Our experience with myotomy for TEP speech demonstrates that many patients with pharyngoesophageal spasm can benefit from the procedure and successfully phonate. There were several complications related to the procedure, but these were successfully managed conservatively and without long-term sequela. Pharyngeal myotomy as an adjunct to TEP is useful and effective in selected patients.

Aged↗