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Biomedical subjects

G R Harsh

Publications and source records attributed to G R Harsh.

49 records · Page 3Linked to original sources
PubMed1988

Transcriptional regulation of the A and B chain genes of platelet-derived growth factor in microvascular endothelial cells.

Platelet-derived growth factor is expressed as dimers of two homologous polypeptide chains, termed A and B, encoded by different genes. A and B chain mRNA levels in microvascular endothelial cells are increased by phorbol ester, thrombin, and transforming growth factor-beta (TGF-beta) and are reduced by agents that elevate cyclic AMP. In this report, we investigated the effects of these regulatory agents on A and B chain transcription rates. By nuclear run-on analysis, TGF-beta stimulated transcription of both A and B chain genes. Thrombin and phorbol ester stimulated B chain transcription and had little or no detectable effect on A chain transcription. Pretreatment of cultures with 50 microM forskolin, a potent activator of adenylyl cyclase, completely blocked B chain transcription by thrombin and TGF-beta, but did not inhibit A chain transcription induced by TGF-beta. These results show that expression of platelet-derived growth factor mRNA involves both positive and negative transcriptional regulation and that there are differences in the transcriptional control of the A and B chain genes.

Endothelium, Vascular↗
PubMed1987

Regulated expression of the platelet-derived growth factor A chain gene in microvascular endothelial cells.

Platelet-derived growth factor (PDGF) is composed of homologous polypeptide chains, termed A and B, that are expressed as mitogenically active A-A, B-B, or A-B dimers. Previous work in our laboratory has demonstrated that PDGF B chain mRNA expression is stimulated in microvascular endothelial cells by phorbol esters (PMA), thrombin, and transforming growth factor-beta (TGF-beta) and blocked by agents that elevate cyclic AMP (cAMP). Here we report the first evidence that the expression of A chain mRNA is also regulated in these cells. PDGF A chain mRNA levels were increased 5-25-fold by phorbol esters, thrombin, and TGF-beta. Transcripts of four different sizes were induced. The increase in A chain mRNA stimulated by TGF-beta was more prolonged (peak 4 h, duration 48 h) than the increase stimulated by PMA and thrombin (peak 4 h, duration 8 h). Among the agents known to increase B chain mRNA levels, PMA was most efficacious, followed in decreasing order by thrombin and TGF-beta. However, for A chain mRNA induction by these same agents, the order was reversed; TGF-beta was most efficacious, followed in decreasing order by thrombin and PMA. Agents that elevate cyclic AMP, known to block induction of B chain mRNA, blocked A chain induction by thrombin but had less effect on A chain mRNA induced by TGF-beta. Thus PDGF A chain mRNA levels are regulated by the same agents that regulate B chain mRNA levels in microvascular endothelial cells. While the changes in A chain mRNA are qualitatively similar to the changes in B chain mRNA in microvascular endothelial cells, there are differences in the relative efficacies of these agents in the regulation of PDGF A and B chain genes. These differences suggest that the forms of PDGF produced by endothelial cells depend on the nature of the inducing stimulus.

Cells, Cultured↗
PubMed1987

Reoperation for recurrent glioblastoma and anaplastic astrocytoma.

The advisability of a second operation for recurrent glioblastoma multiforme or anaplastic astrocytoma depends on the expected duration and quality of subsequent survival. We reviewed the results in 70 consecutive patients who underwent reoperation for supratentorial glioblastoma multiforme (n = 39) or anaplastic astrocytoma (n = 31) between 1975 and 1984. The operative morbidity rate was 5.7% (4 of 70 patients); the 6-week postoperative mortality rate was 4.3% (3 of 70 patients). The median duration of survival after reoperation was 36 weeks in patients with glioblastoma multiforme and 88 weeks in those with anaplastic astrocytoma. The median duration of high quality survival (defined as the period during which the patient had a Karnofsky performance score of at least 70) after reoperation was 10 weeks for patients with glioblastoma multiforme and 83 weeks for patients with anaplastic astrocytoma. Age and preoperative Karnofsky score in patients with glioblastoma multiforme and age in patients with anaplastic astrocytoma had statistically significant effects on the duration of high quality survival after reoperation, but not on postoperative survival independent of quality. Although age and functional status do not significantly affect the duration of survival after reoperation, they do have a significant effect on the quality of life after reoperation. Frequently, a patient can expect to spend a greater portion of his life at a higher level of function than he would have without reoperation. As adjunctive forms of therapy improve, reoperation will play an increasingly prominent role in the management of recurrent malignant astrocytic tumors.

Adult↗
PubMed1987

Cervical spine stenosis secondary to ossification of the posterior longitudinal ligament.

Ossification of the posterior longitudinal ligament (OPLL) is a well-documented cause of cervical spine stenosis and myelopathy among Japanese patients. Reports of OPLL in North Americans are rare. Choices of diagnostic method and treatment for this entity remain controversial. The authors report the results of management of 20 patients in the United States with symptomatic OPLL of the cervical spine. These represented 10% to 20% of patients operated on over the last 3 years for myelopathy secondary to structural spinal compression. Most of these OPLL patients were Caucasian (60%), male (male:female 4:1), and middle-aged (median age 47.5 years). Six had previously undergone laminectomy or discectomy. Cervical roentgenograms and standard myelography occasionally suggested the diagnosis. Axial computerized tomography (CT) metrizamide myelography with small interslice intervals proved invaluable for diagnosis and operative planning. Magnetic resonance imaging was not necessary for diagnosis. Retrovertebral calcification extended over one to five bodies (mean 2.75). The mass ranged in size from 5 to 16 mm in anteroposterior diameter and reduced the residual canal diameter to a mean (+/- standard deviation) caliber of 9.42 +/- 2.41 mm (mean narrowing ratio 0.44 +/- 0.12). Anterior cervical decompression by medial corpectomy and discectomy with fusion uniformly reduced preoperative myelopathy. Complications were limited to transient neurological deterioration in two patients, recurrent laryngeal nerve palsy in one, and halo device pin site infections in two. At a mean postoperative interval of 15 months, improvement was seen in each category of deficit: extremity weakness, hypesthesia, hypertonia, and urinary dysfunction. All fusions produced solid unions. It is concluded that OPLL of the cervical spine is an unexpectedly prevalent cause of myelopathy among patients treated in the United States. Thin-section axial CT metrizamide myelography with small interslice intervals is essential for the investigation of patients who may have OPLL. Anterior decompression and stabilization by medial corpectomy, discectomy, removal of the calcified mass, and fusion is a safe and effective method of treatment.

Adult↗
PubMed1986

L-fucose labeling of brain tumors in rats.

These studies used L-[14C]fucose to identify 9L brain tumors in rats. Ten days after intracranial implantation of 9L tumor cells, labeled L-fucose was injected intravenously. Autoradiography demonstrated high levels of radioactive L-fucose in the resultant 9L tumors but very little L-fucose in normal brain tissue. In vitro studies comparing uptake of labeled fucose into 9L cells, normal rat fibroblasts and transformed rat fibroblasts, rat astrocytes, and human brain tissue suggest that fucose is not preferentially transported into the 9L cells. These data imply that a permissive blood-brain barrier rather than differences in fucose metabolism underlie 9L tumor labeling.

Animals↗
PubMed1986

A rabbit model of focal herpes simplex encephalitis.

Results from studies designed to create a model of focal encephalitis caused by herpes simplex virus (HSV) are reported. Anesthetized rabbits underwent exposure and inoculation of the olfactory bulb with three different doses of a wild-type HSV. Lethal infection resulted in 69% of the animals, without evidence for a dose-response relationship. Necropsy specimens obtained on or before day 10 after inoculation routinely yielded HSV in culture. In 76% of the animals with positive cultures for virus, these cultures originated exclusively or primarily from the pyriform (or temporal) cortex and frontal lobes. Virus could not be cultured from animals killed more than two weeks after inoculation. Histological examination of brains obtained three or more days after inoculation demonstrated evidence of viral infection, with more severe involvement of temporal cortex than of the surrounding brain in 80%. Immunohistochemical demonstration of viral antigens persisted for up to three weeks after inoculation.

Animals↗
PubMed1986

Aneurysmal compression of the anterior visual pathways.

Ten patients with aneurysmal compression of the anterior visual pathways had visual loss, unilateral in 4 and bilateral in 6. There was no typical clinical presentation. Visual loss was acute or gradual, acuity sometimes fluctuated, and visual field testing was highly variable. The aneurysms were supraclinoid (four patients), carotid-ophthalmic (two), anterior communicating-anterior cerebral (three), and intracavernous carotid (one). Nine patients had successful clipping of their aneurysm, and in one, ipsilateral common carotid ligation was performed. Postoperatively, visual acuity was improved in six cases, unchanged in three, and worse in one.

Adult↗
PubMed1986

Intracranial arachnoid cysts in children.

The clinical and radiographic findings, surgical treatment, and outcome in 16 pediatric patients with intracranial arachnoid cysts are reviewed. The clinical presentation reflected the anatomical location of the lesions. Computerized tomography or magnetic resonance imaging scans were diagnostic in all cases. Of the nine cysts treated primarily or secondarily by craniotomy for fenestration and drainage into the basilar cisterns, five recurred. Cyst-peritoneal shunting led to diminished cyst size and clinical improvement in all seven cases in which it was used as the initial treatment and in all four cases in which fenestration had been unsuccessful. The results in this series show that cyst-peritoneal shunting is the treatment of choice for most intracranial arachnoid cysts in children.

Adolescent↗
PubMed1985

Epidermal growth factor receptors in the human glioblastoma cell line SF268 differ from those in epidermoid carcinoma cell line A431.

Two established human tumor cell lines, epidermoid carcinoma line A431 and glioblastoma line SF268, were studied to compare the interaction of each with epidermal growth factor (EGF). SF268 cells bound [125I] EGF with 35-40 fold higher affinity than did the A431 cells. The EGF binding sites of both lines were photoaffinity labeled using 2,4-NAPS-[125I] EGF, a photoreactive derivative of EGF. Extracts of photolysed cells analyzed by SDS-PAGE showed a difference between the two cell lines in the high molecular weight component corresponding to the EGF receptor. EGF in a dose range from 0.3-200 nM had no effect on thymidine incorporation by SF268 cells, whereas thymidine incorporation by A431 cells was markedly inhibited by EGF.

Affinity Labels↗
PubMed1984

Lymphomatous optic neuropathy.

Optic neuropathy as the first sign of a lymphoreticular neoplasm is rare. A 65-year-old man complained of initially transient and then progressive visual loss in the right eye for two weeks. Computed tomography demonstrated a mass in the region of the intracranial portion of the right optic nerve. Frontal craniotomy was performed and histopathologic examination of the tumor disclosed a granulomatous process. Regrowth of the mass and visual deterioration, despite systemic steroid therapy, prompted surgical reexploration. Histopathologic examination confirmed large cell lymphoma. After local radiotherapy (2,500 rad), the patient is well and free of local or systemic lymphoma one year later. Other reported cases of lymphomatous optic neuropathy are reviewed and the diagnostic difficulties encountered are discussed.

Aged↗
PubMed1984

Central nervous system mesenchymal chondrosarcoma. Case report.

Local recurrence developed 6 years after the initial resection of an intraspinal meningeal tumor that originally was thought to be an angioblastic meningioma. Histological review of the pathology led to a change of that diagnosis to one of mesenchymal chondrosarcoma. The recurrent vascular tumor was embolized, then totally excised. Because this tumor had malignant features, the patient received irradiation and chemotherapy. No evidence of regrowth has been observed during a period of more than 4 years. Mesenchymal chondrosarcomas of the central nervous system and their treatment are reviewed.

Adult↗
PubMedDate not supplied

Retrovirus-mediated gene therapy of experimental brain neoplasms using the herpes simplex virus-thymidine kinase/ganciclovir paradigm.

Recent results in experimental brain tumors indicate that transfer of sensitizing genes to tumor cells in vivo with subsequent drug treatment can reduce tumor masses and prolong the survival of rodents. In the present study, the 9L rat gliosarcoma model was used to evaluate the therapeutic effectiveness of the herpes simplex virus-thymidine kinase (HSV-tk) gene, delivered by a retrovirus vector, against tumor cells in the rat brain after systemic application of the nucleoside analogue ganciclovir (GCV). The HSV-tk gene was inserted into a retroviral vector (pMFG), which was produced using the amphotropic packaging cell line CRIP-MFG-S-HSV-TK. Packaging cells were implanted into established 9L tumors in the brains of syngeneic rats to effect gene delivery to tumor cells, followed by intraperitoneal GCV injections. Treated animals survived significantly longer (more than twice as long) than did the control groups. Brains from GCV-treated and nontreated animals were examined immunohistochemically at different time intervals after grafting of CRIP-MFG-S-HSV-TK cells and GCV treatment. Tumors in GCV-treated animals were significantly smaller as compared with nontreated animals at all time points. Sections stained immunohistochemically for HSV-TK confirmed gene transfer to tumor cells, which could be distinguished from packaging cells by different morphology and immunohistochemical staining for the retroviral envelope protein gp70. Approximately 45% of the cells in tumors implanted with CRIP-MFG-S-HSV-TK cells, but not treated with GCV, showed immunocytochemical staining for HSV-TK, demonstrating a high-efficiency of retrovirus-mediated gene transfer. Tumors in rats treated with packaging cells and GCV showed only 9% HSV-TK-positive cells after treatment, indicating that most cells expressing the HSV-tk gene were killed. The success of this therapeutic modality in experimental animals depends in large parts on the high efficiency of gene delivery and on the immune response against tumor cells.

Animals↗