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Biomedical subjects

M H Weiss

Publications and source records attributed to M H Weiss.

At least 55 records · Page 3Linked to original sources
PubMed1994

Evidence for transcapillary transport of reduced glutathione in vascular perfused guinea-pig brain.

Using a vascular brain perfusion model in the guinea-pig, the net uptake of [35S]-GSH by the brain was found to be linear and similar in various regions during 10 min perfusion. Dual labeled [35S and 3H] GSH taken up by the brain had the same isotope ratio as the injected stock whether or not gamma- glutamyl transferase was inhibited. Greater than 96% of brain uptake of [35S]-cysteine-labeled GSH and [3H]-glycine-labeled GSH were in intact form. Transcytosis of [35S]-GSH from lumen into brain parenchyma was demonstrated using a capillary depletion technique. Both GSH and GSH-monoethyl ester inhibited [35S]-GSH transport. Thus, we have demonstrated blood-brain barrier extraction of circulating GSH in a brain perfusion model, and the transcytosis of intact GSH into the brain parenchyma without breakdown.

Animals↗
PubMed1994

Protein kinase C inhibitors induce apoptosis in human malignant glioma cell lines.

Previous work has demonstrated the importance of the protein kinase C (PKC) system in regulating glioma growth, and has led to clinical trials utilizing PKC inhibitors as adjuncts in the therapy of patients harboring malignant gliomas. This study was performed to explore the possibility that inhibition of PKC in gliomas was triggering an apoptosis signal. Glioma cell lines were treated with PKC inhibitors staurosporine (10 nM), and tamoxifen (10 microM). DNA from cells treated with each of these drugs exhibited a 'ladder' pattern of oligonucleosome-sized fragments characteristic of apoptosis, thus suggesting that in glioma cells, these drugs may be cytocidal in action.

Alkaloids↗
PubMed1994

Nicotine downregulates alpha 2 isoform of Na,K-ATPase at the blood-brain barrier and brain in rats.

Effects of chronic nicotine treatment on the relative levels of expression of Na,K-ATPase alpha and beta subunit isoforms were determined in rat cerebral microvessels and capillary-depleted brain homogenates by Western blot analysis. Nicotine, 4.5 mg/kg/day, was administered s.c. by osmotic mini-pumps for 14 days. Expression of alpha 2 isoform in microvessels and brains of nicotine-treated rats was reduced to 0.26 and 0.58 of control levels, respectively. Expression of alpha 1, alpha 3, beta 1 or beta 2 was unchanged. Nicotine decreased cerebromicrovascular and brain Na,ATPase enzymatic activities by 22% and 17%, respectively. It is suggested that chronic exposure to nicotine reduces expression of functional Na,K-ATPase at the blood-brain barrier and brain by downregulating the alpha 2 isoform.

Animals↗
PubMed1994

Use of decision analysis in planning a management strategy for the stage N0 neck.

OBJECTIVE: There are three major strategies in the treatment of patients with a stage N0 neck with squamous cell cancer of the head and neck: elective neck dissection, elective neck irradiation, and observation. Each has appropriate salvage strategies in the event of local recurrence. We used decision analysis to determine the optimal strategy for neck treatment as a function of the probability of occult cervical metastasis. DATA SOURCES: We used the bibliographies of current articles and books to access clinical studies of patients with stage N0 neck cancer. STUDY SELECTION: Studies that included large numbers of patients and contained a minimum 2-year follow-up, with results analyzed in terms of outcome as a function of stage of neck disease, were included. DATA EXTRACTION: Specific data points were extracted from the studies independently by multiple observers, and mean values were used in the decision analysis. DATA SYNTHESIS: A decision tree was constructed with use of a computer model to compare the three management strategies. Probabilities of each of the possible events depicted in the trees were inserted into the tree structure. These probabilities were gleaned from the literature as described above. A sensitivity analysis was performed to determine the optimal threshold for treatment of the neck. CONCLUSION: A patient with primary squamous cell carcinoma of the head and neck and stage N0 neck status should be observed if the probability of occult cervical metastasis is less than 20%. If the probability is greater than 20%, treatment of the neck is warranted. The treatment plan should ideally involve a single modality of therapy; both neck dissection and radiation therapy are quite efficacious in the clinical context, and the decision of which one to employ should be driven by the treatment of the primary lesion. Decision analysis is useful in complex clinical situations.

Carcinoma, Squamous Cell↗
PubMed1994

Blood-to-lens transport of reduced glutathione in an in situ perfused guinea-pig eye.

Transport mechanisms of reduced glutathione (GSH) in intact eye are poorly understood. In this study, an in situ vascular eye perfusion (VEP) model was used to characterize the transport kinetics of circulating GSH into the aqueous humor and lens in guinea pigs. Radiolabeled [35S]GSH or [3H]GSH and [14C]sucrose (an extracellular space marker) were exposed to the blood-aqueous barrier up to 10 min, and uptake of tracers by the aqueous humor and lens was determined in the presence of different concentrations of unlabeled peptide as GSH, a gamma-glutamyl compound as a derivative of GSH (GSH monoethyl ester), and an inhibitor of gamma-glutamyl transpeptidase (GGT) activity. Plasma-aqueous and aqueous-lens compartmental unidirectional transport constant, K(in), and the initial rapid volume of distribution, Vi, were estimated by multiple-time-point graphic analysis. Our results indicated that both labeled GSH and sucrose entered the aqueous humor slowly at comparable rates with respective blood-aqueous K(in) values of 1.34 +/- 0.12 and 1.25 +/- 0.08 min-1 x 10(3). In contrast to blood-aqueous transport, GSH uptake by the lens was rapid, and the respective aqueous-lens K(in) values for labeled GSH and sucrose were 79.3 +/- 4.1 and 3.5 +/- 0.7 min-1 x 10(3). Over 94% of plasma-derived GSH remained in its original molecular form of GSH in the lens, during the 10 min perfusion both with and without the GGT inhibitor, serine borate. The amount of [35S]GSH in lens anterior epithelium (dpm mg-1) was more than three times that of aqueous humor (dpm microliter-1) within only 10 min of VEP. There was also significant accumulation of [35S]GSH in the interior cortex, as indicated by 10-min cortex/aqueous ratio of 0.65. A specific GGT independent GSH transport system was demonstrated in the lens in situ, with a Km of 26 +/- 3 microM, and Vmax of 34 +/- 3 pmol min-1 g-1 of whole lens tissue water. The lenticular influx of GSH was inhibited by GSH monoethyl ester with an affinity that was half that for GSH. It is concluded that: (a) uptake of plasma-derived GSH into the aqueous humor is by simple diffusion, and (b) cellular uptake of GSH by the lens is carrier-mediated via mechanism that is separate from the transpeptidation metabolic pathway.

Animals↗
PubMed1994

Interleukin-6 and interleukin-6 receptor gene expression in pituitary tumors.

Interleukin-6 (IL-6) is a multifunctional cytokine which plays a role in the stimulation, inhibition, differentiation, and regulation of cell growth. IL-6 has been shown to act as an autocrine growth factor in several tumors, and is expressed by a variety of tumors. IL-6 also exhibits a regulatory role in the hypothalamo-pituitary axis. It is produced by both the hypothalamus and the pituitary, and it induces the secretion of anterior pituitary hormones. Because of the regulatory role of IL-6 in tumor growth and its involvement in the pituitary, we decided to evaluate IL-6 and IL-6 receptor expression in pituitary tumors. For this purpose we utilized complimentary cDNA probes specific for the IL-6 and IL-6 receptor mRNA, as well as monoclonal anti-IL-6 antibodies for immunohistochemical analysis. Our results show that the IL-6 gene is expressed in the normal pituitary tissue. However, the non-functioning and functioning pituitary tumors such as the prolactin and growth hormone secreting tumors express increased levels of the IL-6 gene. The IL-6 receptor gene was only expressed in the prolactin secreting and non-functioning pituitary tumors. These results show that the IL-6 and IL-6 receptor gene expression is enhanced in pituitary tumors, thus suggesting a possible role of IL-6 in the pathogenesis of these tumors.

Adenoma↗
PubMed1994

Larynx preservation with combined chemotherapy and radiation therapy in advanced hypopharynx cancer.

Twenty-five untreated patients with advanced, resectable squamous cell carcinoma of the hypopharynx, for whom standard treatment would have required total laryngectomy, were treated with one to three cycles of cisplatin-based chemotherapy with larynx preservation as the goal. Patients with a major (complete or partial) response to chemotherapy at the primary site were treated with definitive radiation therapy, with total laryngectomy reserved for salvage; patients with less than a partial response to chemotherapy had total laryngectomy and postoperative radiation therapy recommended. Four patients had a poor response to chemotherapy and thus were not candidates for laryngectomy. Total laryngectomy was required for initial induction chemotherapy failure in five patients and for local recurrence in five others. Three additional patients had unresectable recurrence. Successful larynx preservation was achieved in 32% (8 of 25). With a median follow-up period of 41 months, the actuarial overall and failure-free 2-year survival rates were 44% and 32%, respectively. These preliminary data suggest larynx preservation is feasible in patients with advanced lesions of the hypopharynx. Improved local and regional control must be incorporated into the larynx preservation approach for hypopharyngeal lesions. A prospective, randomized study is necessary for a more valid comparison with conventional therapy, including comparative assessments of survival, morbidity, cost and functional results.

Adult↗
PubMed1994

Hypericin: a potential antiglioma therapy.

Hypericin, a polycyclic aromatic dione isolated from plants, is presently being clinically evaluated as an antiviral agent in the treatment of human immunodeficiency virus (HIV) infection. In addition, it is known to be a potent protein kinase C inhibitor. To evaluate its potential as an inhibitor of glioma growth, an established (U87) and low-passage glioma line (93-492) were treated with hypericin in tissue culture for a period of 48 hours after passage. Hypericin inhibited the glioma growth in a dose-related manner, with a marked inhibition of growth in the low-micromolar concentration range (e.g., in line U87 and low-passage line 93-492, a concentration of hypericin of 10 mumol/L produced 62 and 76% decreases in [3H]thymidine uptake, respectively). Because the reported inhibitory effects of protein kinase C are enhanced by visible light, [3H]thymidine uptake was measured in both the presence and the absence of visible light. In glioma line A172, the presence of light slightly increased the inhibitory effect of hypericin. Moreover, an apoptosis (i.e., programmed cell death) assay was performed to determine whether the treatment of glioma cells with hypericin was cytostatic or cytocidal. Cells were harvested, and purified deoxyribonucleic acid (DNA) was analyzed by agarose gel electrophoresis. DNA from cells treated with hypericin for 48 hours exhibited a classical "ladder" pattern of oligonucleosome-sized fragments characteristic of apoptosis. These data suggest that the proven safe drug hypericin may have potential as an antiglioma agent; we suggest clinical trials.

Anthracenes↗
PubMed1994

Otitis media with effusion in head and neck cancer patients.

Fifty-two patients who had otitis media with effusion associated with head and neck malignancies were identified and studied retrospectively. Forty-three of the patients underwent myringotomy and tube for treatment of the effusion. Ten (23%) of the 43 patients had either multiple infections or continuous otorrhea necessitating tube removal. The patients identified as having the highest rate of serious complications following myringotomy and tube were those individuals who had nasopharyngeal carcinoma, with 6 (55%) of 11 patients in this group having suffered major infections during the study. Myringotomy and tube is a satisfactory treatment for most patients who have effusions as a result of non-malignant etiologies; however, infections were more common and more severe in the study group than those anticipated in noncancer patients. Expectant management and the use of amplification in selected cases may prove to be a viable alternative in patients with unilateral effusion and/or relatively mild symptoms.

Follow-Up Studies↗
PubMed1994

Cranioplasty with the Medpor porous polyethylene flexblock implant. Technical note.

The authors describe the use of a porous polyethylene Flexblock implant for cosmetic cranioplasty. The implant may be used to cover any small- or medium-sized (< 8 cm) cranial defect, offering similar cosmetic results to standard alloplast cranioplasty while decreasing operation time. The porous implant design permits ingrowth of soft tissue and bone to increase implant strength and decrease the risk of infection. The Flexblock alloplast has been utilized in 25 cases with excellent cosmetic results and no implant-related complications.

Biocompatible Materials↗
PubMed1994

Galactose-induced cataract formation in guinea pigs: morphologic changes and accumulation of galactitol.

PURPOSE: To develop and characterize a new model of galactose-induced cataract formation in young, 3- to 4-week-old Hartley guinea pigs. METHODS: Experimental animals were fed 50% galactose in powdered guinea pig chow containing 0.5 g ascorbate/kg diet. Control animals were fed normal powdered guinea pig chow (0.5 g ascorbate/kg diet). Lenses from all animals were subjected to photo-slit-lamp examination, light microscopic analysis, and high-pressure liquid chromatography (HPLC) analysis of polyol content. RESULTS: Photo-slit-lamp examination indicated initial opacities in equatorial subcapsular region between 3 and 5 days in all galactose-fed animals (20/20); opacities progressed toward the anterior pole when diet was extended to 14 days. Histologic analysis of the equatorial changes confirmed progressive cataract formation consisting of small intra-fibrillar vacuoles in the pre-equatorial region (3 days), an increased number of enlarged and coalesced vacuoles (6 days), and progressive tissue swellings with cellular disruption and signs of epithelial multilayering (14 days). The anterior epithelium showed increased cell height and swelling after 3 days of the galactose diet. HPLC analysis of lens tissue indicated progressive accumulation of galactitol, 18 mM after 3 days, which plateaued to about 30 mM between 6 and 14 days. The level of myo-inositol dropped from a control value of 2.8 +/- 0.7 mM to 1.5 +/- 0.7 mM after 3 days, and was nearly undetectable after 14 days of the galactose diet. CONCLUSIONS: The current study suggests that the guinea pig model may serve as a valuable new tool to study sugar-induced cataract formation and to characterize the early morphologic and biochemical events in cataractogenesis.

Animals↗
PubMed1993

Blood-brain barrier transport of circulating Alzheimer's amyloid beta.

The origin of amyloid beta (A beta) deposited in brain and cerebral blood vessels of patients with Alzheimer's Disease (AD) is not known. In this study, we tested whether soluble A beta (sA beta) can cross the blood-brain barrier (BBB). An in vivo vascular brain perfusion model and capillary depletion technique in guinea-pigs were used to determine cerebral capillary sequestration and blood-brain transport of a synthetic peptide identical with residues 1-40 (SP-40) of A beta. A saturable, specific binding of SP-40 has been demonstrated at the luminal side of the BBB, with the Kd of 25 +/- 2 nM, and Bmax of 188 +/- 11 fmol/min/g of isolated microvessels. A specific transcellular BBB transport of SP-40 into brain parenchyma exhibited the Km of 49 +/- 10 nM, and Vmax of 111 +/- 19 fmol/min/g of capillary depleted brain. We concluded that the BBB has the capability to control the cerebrovascular sequestration and blood-to-brain transport of circulating sA beta. Hence, sA beta can contribute to both cerebrovascular and parenchymal amyloid formation.

Amyloid beta-Peptides↗
PubMed1993

Clinical and radiographic response in a minority of patients with recurrent malignant gliomas treated with high-dose tamoxifen.

Previous work has demonstrated the importance of the Protein Kinase C (PKC) signal transduction system in regulating the growth rate of malignant gliomas in vitro. Tamoxifen inhibits PKC in a minority of malignant gliomas within the micromolar concentration range in vitro, a property distinct from its estrogen receptor blockade effect. Tamoxifen was administered orally in very high dosages to 11 patients (9 males:2 females, age range 26-73, mean 45 years) with malignant gliomas (anaplastic astrocytoma or glioblastoma multiforme) who had failed treatment with external beam radiation therapy (and additional chemotherapy in 2). The dosage administered was estimated to be that necessary to achieve tissue concentrations within the low micromolar range, shown necessary to inhibit PKC in these tumors in vitro, and is approximately 5 times that used for standard antiestrogen therapy. Tumor reduction on radiographic images (MRI and PET [18FdG uptake]) with clinical improvement occurred in 3 patients; halting of tumor progression clinically and radiographically occurred in an additional patient. Of the remaining seven patients, three patients had marked and rapid progression of their disease despite treatment (dead after 3, 4, and 6 months respectively). Complications of treatment included a deep venous thrombosis requiring anticoagulation in one patient, nausea in one patient, and "hot-flashes" in a third patient. Tumor biopsy and measurement of tamoxifen and its active metabolite within the tumor of one patient (non-responder) showed levels within the middle of the in vitro therapeutic range. Follow-up of alive patients ranges from 4-18 months (mean 10 months). These encouraging preliminary results in a minority of these patients suggests some potential for this type of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗