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R J Mark

Publications and source records attributed to R J Mark.

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

4-hydroxynonenal, a lipid peroxidation product, rapidly accumulates following traumatic spinal cord injury and inhibits glutamate uptake.

Traumatic injury to the spinal cord initiates a host of pathophysiological events that are secondary to the initial insult. One such event is the accumulation of free radicals that damage lipids, proteins, and nucleic acids. A major reactive product formed following lipid peroxidation is the aldehyde, 4-hydroxynonenal (HNE), which cross-links to side chain amino acids and inhibits the function of several key metabolic enzymes. In the present study, we used immunocytochemical and immunoblotting techniques to examine the accumulation of protein-bound HNE, and synaptosomal preparations to study the effects of spinal cord injury and HNE formation on glutamate uptake. Protein-bound HNE increased in content in the damaged spinal cord at early times following injury (1-24 h) and was found to accumulate in myelinated fibers distant to the site of injury. Immunoblots revealed that protein-bound HNE levels increased dramatically over the same postinjury interval. Glutamate uptake in synaptosomal preparations from injured spinal cords was decreased by 65% at 24 h following injury. Treatment of control spinal cord synaptosomes with HNE was found to decrease significantly, in a dose-dependent fashion, glutamate uptake, an effect that was mimicked by inducers of lipid peroxidation. Taken together, these findings demonstrate that the lipid peroxidation product HNE rapidly accumulates in the spinal cord following injury and that a major consequence of HNE accumulation is a decrease in glutamate uptake, which may potentiate neuronal cell dysfunction and death through excitotoxic mechanisms.

ATP-Binding Cassette Transporters↗
PubMed1997

4-Hydroxynonenal, an aldehydic product of lipid peroxidation, impairs signal transduction associated with muscarinic acetylcholine and metabotropic glutamate receptors: possible action on G alpha(q/11).

Considerable data indicate that oxidative stress and membrane lipid peroxidation contribute to neuronal degeneration in an array of age-related neurodegenerative disorders. In contrast, the impact of subtoxic levels of membrane lipid peroxidation on neuronal function is largely unknown. We now report that 4-hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, disrupts coupling of muscarinic cholinergic receptors and metabotropic glutamate receptors to phospholipase C-linked GTP-binding proteins in cultured rat cerebrocortical neurons. At subtoxic concentrations, HNE markedly inhibited GTPase activity, inositol phosphate release, and elevation of intracellular calcium levels induced by carbachol (muscarinic agonist) and (RS)-3,5-dihydroxyphenyl glycine (metabotropic glutamate receptor agonist). Maximal impairment of agonist-induced responses occurred within 30 min of exposure to HNE. Other aldehydes, including malondialdehyde, had little effect on agonist-induced responses. Antioxidants that suppress lipid peroxidation did not prevent impairment of agonist-induced responses by HNE, whereas glutathione, which is known to bind and detoxify HNE, did prevent impairment of agonist-induced responses. HNE itself did not induce oxidative stress. Immunoprecipitation-western blot analysis using an antibody to HNE-protein conjugates showed that HNE can bind to G alpha(q/11). HNE also significantly suppressed inositol phosphate release induced by aluminum fluoride. Collectively, our data suggest that HNE plays a role in altering receptor-G protein coupling in neurons under conditions of oxidative stress that may occur both normally, and before cell degeneration and death in pathological settings.

Aldehydes↗
PubMed1996

Amyloid beta-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons.

Cholinergic pathways serve important functions in learning and memory processes, and deficits in cholinergic transmission occur in Alzheimer disease (AD). A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C, resulting in the liberation of inositol trisphosphate and Ca2+ release from intracellular stores. We now report that amyloid beta-peptide (Abeta), which forms plaques in the brain in AD, impairs muscarinic receptor activation of G proteins in cultured rat cortical neurons. Exposure of rodent fetal cortical neurons to Abeta25-35 and Abeta1-40 resulted in a concentration and time-dependent attenuation of carbachol-induced GTPase activity without affecting muscarinic receptor ligand binding parameters. Downstream events in the signal transduction cascade were similarly attenuated by Abeta. Carbachol-induced accumulation of inositol phosphates (IP, IP2, IP3, and IP4) was decreased and calcium imaging studies revealed that carbachol-induced release of calcium was severely impaired in neurons pretreated with Abeta. Muscarinic cholinergic signal transduction was disrupted with subtoxic levels of exposure to AP. The effects of Abeta on carbachol-induced GTPase activity and calcium release were attenuated by antioxidants, implicating free radicals in the mechanism whereby Abeta induced uncoupling of muscarinic receptors. These data demonstrate that Abeta disrupts muscarinic receptor coupling to G proteins that mediate induction of phosphoinositide accumulation and calcium release, findings that implicate Abeta in the impairment of cholinergic transmission that occurs in AD.

Amyloid beta-Peptides↗
PubMed1996

Angiosarcoma. A report of 67 patients and a review of the literature.

BACKGROUND: Angiosarcomas (AS) are rare, aggressive tumors. Optimal treatment has not been well defined. The authors undertook a retrospective review of patients seen at their institution with the intent of identifying prognostic factors and optimal treatment strategies. METHODS: Between 1955 and 1990, 67 patients with AS were seen at the University of California, at Los Angeles Medical Center. Follow-up ranged from 1 to 173 months with a median of 30 months. RESULTS: The overall prognosis was poor. The actuarial 2- and 5-year disease free survivals (DFS) were 44% and 24%, respectively. Of 52 recurrences after primary treatment, 81% (42 of 52) had a component of local failure. Twenty-eight patients had developed distant metastases at last follow-up. Of patients who received surgery (S) and radiation therapy (RT), with or without chemotherapy (CT), 5-year actuarial DFS was 43%, compared with 17% for patients who underwent S +/- CT as initial treatment (P = 0.03). Only 9% of patients (1 of 11) treated with RT +/- CT were rendered free of disease. CONCLUSIONS: Patients with AS usually present with high grade histology, and with multifocal disease. There is a propensity for both local recurrence and distant metastases. Our results and a review of the literature, suggest that S plus RT offers the best chance for long term control of this aggressive tumor. The role of CT remains undefined.

Actuarial Analysis↗
PubMed1996

Amyloid beta-peptide and oxidative cellular injury in Alzheimer's disease.

Alzheimer's disease is a progressive neurodegenerative disorder that affects primarily learning and memory functions. There is significant neuronal loss and impairment of metabolic functioning in the temporal lobe, an area believed to be crucial for learning and memory tasks. Aggregated deposits of amyloid beta-peptide may have a causative role in the development and progression of AD. We review the cellular actions of A beta and how they can contribute to the cytotoxicity observed in AD. A beta causes plasma membrane lipid peroxidation, impairment of ion-motive ATPases, glutamate uptake, uncoupling of a G-protein linked receptor, and generation of reactive oxygen species. These effects contribute to the loss of intracellular calcium homeostasis reported in cultured neurons. Many cell types other than neurons show alterations in the Alzheimer's brain. The effects of A beta on these cell types is also reviewed.

Alzheimer Disease↗
PubMed1996

Postirradiation sarcoma of the gynecologic tract. A report of 13 cases and a discussion of the risk of radiation-induced gynecologic malignancies.

With improvement in survival after cancer treatment, it is becoming increasingly important to examine treatment-related morbidity and mortality. Sarcomas can develop within the irradiated field after radiation therapy (RT) for gynecologic malignancies. We undertook a study to assess the outcome after treatment of postirradiation sarcoma (PIS) of the gynecologic tract. In reviewing our data and the literature, we compare the absolute risk of PIS and other radiation-associated second malignant neoplasms (SMNs) with the mortality risk of surgery and general anesthesia. Between 1955 and 1987, 114 patients with uterine sarcomas were seen at the University of California, Los Angeles (UCLA), Medical Center. Thirteen had a prior history of RT. Conditions for which these patients received RT included choriocarcinoma (one), menorraghia (four), cervical cancer (six), and ovarian cancer (two). RT doses were known in six cases and ranged from 4,000 to 8,000 cGy. Latency time from RT to the development of PIS ranged from 3 to 30 years, with a median of 17 years. Twelve patients were treated with surgery or additional RT. Two patients remain alive 5 months and 57 months, respectively, following salvage therapy. Five-year disease-specific survival for all patients is 17%. From our data and a review of the literature, we estimate that the absolute risk of PIS with long-term follow-up ranges from 0.03 to 0.8%. Postirradiation sarcoma of the gynecologic tract is a relatively rate event associated with a poor prognosis. Mortality risks of radiation-associated SMN are similar to mortality risks of surgery and general anesthesia. Given the large number of patients with gynecologic malignancies who can be cured or palliated with RT, concern regarding radiation sarcomagenesis should not be a major factor influencing treatment decisions.

Adult↗
PubMed1996

Capsular contracture after lumpectomy and radiation therapy in patients who have undergone uncomplicated bilateral augmentation mammoplasty.

PURPOSE: To assess complications and cosmesis in patients with breast cancer who underwent lumpectomy and radiation therapy and who previously underwent uncomplicated bilateral augmentation mammoplasty. MATERIALS AND METHODS: Twenty-one patients (aged 36-70 years; median age, 50 years) with breast cancer who had previously undergone bilateral breast augmentation without complications underwent ipsilateral lumpectomy and radiation therapy. Radiation therapy was delivered to the augmented breast in opposed tangential fields with a 4- or 6-MV linear accelerator. The tangential fields received an average radiation dose of 5,021 cGy (range, 4,500-5,600 cGy), with an average fraction of 187 cGy (range, 180- 200 cGy). Sixteen patients received an additional 1,000-2,000-cGy boost to the surgical bed with a 9-18-MeV electron beam. Follow-up was 4-48 months (median, 22 months). RESULTS: At the last follow-up examination, 18 (86%) of the 21 patients were free of disease. Twelve patients had capsular contracture (57%). Seven patients underwent attempted surgical repair of capsular contracture. Twelve patients (57%) reported fair to poor cosmesis. The radiation dose, the location of the implant, the type of implant, and systemic therapy were not correlated with poor cosmesis. CONCLUSION: Lumpectomy and radiation therapy in patients with breast cancer who have previously undergone augmentation mammoplasty result in a high prevalence of capsular contracture and suboptimal cosmesis.

Adult↗
PubMed1995

Pediatric rhabdomyosarcoma of the head and neck.

The optimal treatment for most patients with pediatric rhabdomyosarcoma (RMS) of the head and neck has been shown to be a combination of surgery, chemotherapy and radiation therapy. A retrospective review of patients seen at our institution is presented to analyze the impact of multimodality treatment on survival in 32 pediatric RMS patients. Sixty-five percent (21/32) of the patients were disease free at the most recent follow-up. The 5 year disease free survival was 57% (17/30). Combined modality treatment in 25 patients consisting of chemotherapy, radiation therapy and surgical resection (in 5 patients) rendered 18 (72%) patients free of disease. Only 1 of 7 (14%) patients who underwent surgery alone as primary management was cured. Two of these 7 patients were salvaged, both with combined modality treatment. The Intergroup Rhabdomyosarcoma Study (IRS) protocols have resulted in increased survival in pediatric patients with RMS of the head and neck. Our results reflect the significant improvement since the IRS study was completed.

Adolescent↗
PubMed1995

Craniopharyngioma: treatment in the CT and MR imaging era.

PURPOSE: To determine optimal treatment in patients with craniopharyngiomas. MATERIALS AND METHODS: In 1977-1990, 49 patients (age range, 3-67 years; median age, 35 years; 25 female, 24 male) with craniopharyngiomas were examined. Follow-up was 5-17 years (median, 8 years). Fifteen patients were aged younger than 18 years. RESULTS: All patients underwent surgical resection. Complete resection was achieved in 19. Seven patients underwent additional surgery for recurrent disease. Rate of mortality due to surgical complications was 10% (n = 5). Eight patients had marked perioperative or long-term morbidity. Twenty-five patients judged to have undergone subtotal resection underwent postoperative radiation therapy (RT). RT doses were 4,600-6,287 cGy administered in fractions of 180-200-cGy/d. Actuarial 5-year progression-free survival in patients who underwent complete resection was 63% (12 of 19 patients) versus 96% (24 of 25 patients) in patients who underwent subtotal resection followed by RT (P = .04). No RT dose response was observed. Patient functional status has not been substantially affected by adjuvant RT. CONCLUSION: RT achieves excellent tumor control after subtotal resection of craniopharyngiomas.

Adolescent↗
PubMed1995

Amyloid beta-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death.

The amyloid beta-peptide (A beta) that accumulates as insoluble plaques in the brain in Alzheimer's disease can be directly neurotoxic and can increase neuronal vulnerability to excitotoxic insults. The mechanism of A beta toxicity is unclear but is believed to involve generation of reactive oxygen species (ROS) and loss of calcium homeostasis. We now report that exposure of cultured rat hippocampal neurons to A beta 1-40 or A beta 25-35 causes a selective reduction in Na+/K(+)-ATPase activity which precedes loss of calcium homeostasis and cell degeneration. Na+/K(+)-ATPase activity was reduced within 30 min of exposure to A beta 25-35 and declined to less than 40% of basal level by 3 hr. A beta did not impair other Mg(2+)-dependent ATPase activities or Na+/Ca2+ exchange. Experiments with ouabain, a specific inhibitor of the Na+/K(+)-ATPase, demonstrated that impairment of this enzyme was sufficient to induce an elevation of [Ca2+]i and neuronal injury. Impairment of Na+/K(+)-ATPase activity appeared to be causally involved in the elevation of [Ca2+]i and neurotoxicity since suppression of Na+ influx significantly reduced A beta- and ouabain-induced [Ca2+]i elevation and neuronal death. Neuronal degeneration induced by ouabain appeared to be of an apoptotic form as indicated by nuclear condensation and DNA fragmentation. The antioxidant free radical scavengers vitamin E and propylgallate significantly attenuated A beta-induced impairment of Na+/K(+)-ATPase activity, elevation of [Ca2+]i and neurotoxicity, suggesting a role for ROS. Finally, exposure of synaptosomes from postmortem human hippocampus to A beta resulted in a significant and specific reduction in Na+/K(+)-ATPase and Ca(2+)-ATPase activities, without affecting other Mg(2+)-dependent ATPase activities or Na+/Ca2+ exchange. These data suggest that impairment of ion-motive ATPases may play a role in the pathogenesis of neuronal injury in Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed1994

Postirradiation sarcomas. A single-institution study and review of the literature.

BACKGROUND: With improvement in survival after cancer treatment, it is becoming increasingly important to examine treatment-related morbidity and mortality. Sarcomas can develop in the irradiated field after radiation therapy (RT). The authors undertook a study to estimate the risk, and compared the risk of postirradiation sarcoma (PIS) with other treatment modalities used against cancer. METHODS: Since 1987 the authors have reviewed the records of 1089 patients with head and neck, gynecologic, gastrointestinal, and extremity sarcomas. Of these 1089 patients, 37 had a prior history of RT. RESULTS: Conditions for which these patients received RT included: Hodgkin's disease (2 patients), retinoblastoma (3), non-Hodgkin's lymphoma (2), acne (1), astrocytoma (1), multiple recurrent mixed parotid tumor (1), laryngeal cancer (1), papillary adenocarcinoma of the thyroid (1), bony fibrous dysplasia (1), lymphangioma (1), squamous cell carcinoma of the nasopharynx (1), Ewing's sarcoma (1), choriocarcinoma (1), menorrhagia (4), cervical cancer (6), ovarian cancer (2), breast cancer (7), and hypoplasia (1). RT doses ranged from 3000 to 12,440 cGy. Latency time from RT to the development of PIS averaged 12 years. More than 15,000 patients have received RT for various conditions at our institution since 1955. CONCLUSIONS: From our data and a review of the literature, we estimate the risk of PIS with long-term follow-up to be 0.03-0.8%. From a review of the literature that compared mortality risks of chemotherapy, general surgery, and anesthesia, the risk of PIS appears no worse. Thus, given the large number of patients who can be cured or receive palliative treatment with RT, concern regarding PIS should not be a major factor influencing treatment decisions in patients with cancer.

Adolescent↗
PubMed1994

Sarcomas of the nasal cavity and paranasal sinuses.

Sarcomas of the nose and paranasal sinuses are rare malignancies. Key issues remain unresolved in the management of these tumors, particularly with regard to the role of radiotherapy. To help clarify these issues, 48 consecutive cases of nasal and paranasal sinus sarcomas treated at the University of California, Los Angeles, between 1958 and 1988 were retrospectively reviewed. Six of 16 patients managed initially with surgery alone were cured. All had negative surgical margins and 5 of the 6 had low-grade tumors. Of 5 patients with high-grade lesions treated with surgery only, 1 was rendered free of disease. Twelve patients with positive surgical margins were treated with adjuvant radiotherapy; 5 were cured with this approach. Grade and surgical margin status were found to be significantly related to outcome for sinonasal sarcoma. There were 14 patients with rhabdomyosarcoma; 3 were cured with modern combined-modality therapy. Patients with positive surgical margins should be treated with adjuvant radiotherapy. Surgical therapy is effective for low-grade lesions that are completely excised.

Actuarial Analysis↗
PubMed1993

Postirradiation sarcoma of the head and neck.

BACKGROUND: With improvement in survival after cancer treatment, it is becoming increasingly important to study treatment-related morbidity and mortality. Sarcoma can develop in the irradiated field after radiation therapy. The authors performed a study to estimate the risk, and compared the risk of sarcoma after radiation therapy with that of other treatment modalities used against cancer. METHODS: Between 1955 and 1988, 229 patients with sarcoma of the head and neck were seen at the University of California, Los Angeles (UCLA), Medical Center. Of these, 13 (6%) had a previous history of radiation therapy to the head and neck. RESULTS: Radiation doses were known in 10 of 13 patients and ranged from 30 to 124.4 Gy. The latency time from radiation therapy to the development of postirradiation sarcoma (PIS) ranged from 3 months to 50 years, with a median of 12 years. More than 2000 patients have received radiation therapy to the head and neck for various conditions at the UCLA Medical Center since 1955. CONCLUSIONS: The authors conclude that most head and neck sarcomas are not radiation related and that the risk of PIS after head and neck irradiation for other diseases is low. From a review of the literature comparing mortality risks of chemotherapy, general surgery, and anesthesia, the risk of PIS appears no worse. Given the large number of patients who can be cured or receive palliation with radiation therapy, concern about PIS should not be a major factor influencing treatment decisions in patients with cancer.

Adolescent↗
PubMed1993

Dermatofibrosarcoma protuberans of the head and neck. A report of 16 cases.

Dermatofibrosarcoma protuberans of the head and neck is a rare neoplasm. Overall, sarcomas account for less than 1% of all head and neck malignancies. Of 229 patients with sarcomas of the head and neck seen at our institution between 1955 and 1988, 14 (7%) were assigned the diagnosis of dermatofibrosarcoma protuberans after pathologic review. Two additional cases have been seen since 1988, bringing the total to 16. All cases were low-grade lesions. Follow-up ranged from 36 to 198 months, with a median of 114 months. Fifteen patients were managed with surgery alone, and nine (60%) developed local recurrence. Eight were salvaged with further surgery. There were no regional lymph node recurrences or distant metastases. One patient was judged to be a poor surgical candidate and received primary radiation therapy. He died disease free 3 years after treatment. At last follow-up, 15 (94%) of 16 patients were ultimately disease free after salvage treatment. The overall 5-year survival rate was 93% (13/14). We conclude from this series, and from a review of the literature, that wide surgical resection achieving good margins offers excellent probability of cure, and that radiation therapy is a reasonable alternative in patients who have unresectable lesions or who are medically inoperable.

Adolescent↗
PubMed1993

Angiosarcoma of the head and neck. The UCLA experience 1955 through 1990.

Between 1955 and 1990, 28 patients with angiosarcoma of the head and neck were seen at UCLA Medical Center, Los Angeles, Calif. Half the lesions arose on the scalp; the remainder occurred in the soft tissues of the face and neck. Nine patients presented with multifocal disease. Follow-up ranged from 3 to 159 months, with a median of 32 months. The overall prognosis was poor, with a 5-year disease-free survival of 26% (7/27 patients). Of 21 patients having recurrences after primary treatment, 90% (19/21 patients) had a component of local failure. Distant metastasis had developed in nine patients at last follow-up. Of patients treated initially with surgery alone, 8% (1/12 patients) remain disease free vs 67% (4/6 patients) who received postoperative radiation therapy, with or without chemotherapy. Only one (14%) of seven patients treated primarily with radiation therapy with or without chemotherapy was rendered disease free. Angiosarcoma usually presents with high-grade histologic features and frequently with multifocal disease. There is propensity for both local recurrence and distant metastasis. Our results and a review of the literature suggest that combined modality therapy offers the best chance for long-term control in patients with angiosarcoma of the head and neck.

Adolescent↗