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Biomedical subjects

M R Clarke

Publications and source records attributed to M R Clarke.

At least 37 records · Page 2Linked to original sources
PubMed1995

Cancer immunotherapy of established tumors with IL-12. Effective delivery by genetically engineered fibroblasts.

IL-12 is a heterodimeric cytokine produced by macrophages, mitogen stimulated- or EBV infected-B lymphocytes, keratinocytes, and probably dendritic cells, with important immunoregulatory functions in vitro and in vivo. It directly stimulates activated NK and T cells to produce high levels of IFN-gamma, enhances their cytolytic activity, and promotes maturation of Th1 cells as well as IL-2-activated B cells. We have tested paracrine delivery of IL-12 using autologous or allogeneic fibroblasts engineered to secrete high levels of IL-12 to treat established tumors. Injection of IL-12-engineered fibroblasts at the site of an established (day 8) MCA207 sarcoma could efficiently eliminate or suppress tumor growth in a dose-dependent manner, requiring delivery of > 150 ng/kg/dose of bioactive IL-12. Weekly inoculations for 3 wk could also be used to effectively treat a day 4 sarcoma located intradermally in the opposite flank (80% protection using autologous fibroblasts), resulting in long-term protective antitumor immunity. In less immunogenic tumors (MCA102, MC38), 7-day established lung metastases could be significantly reduced (p = 0.001) following IL-12 delivery by fibroblasts and systemic administration of low doses of IL-2. Histologic findings included a mixed infiltrate of CD4+ and CD8+ T effectors and macrophages in the regressing sarcoma on day 21. In a day 41 MCA207 sarcoma locally injected in situ, similar findings were observed. No lymphoid hyperplasia or tissue necrosis were noted in liver, spleen, or lungs in mice receiving repeated inocula of IL-12-engineered fibroblasts. Tests of liver and renal function monitored during the repetitive weekly treatments were within the normal range. IL-12-engineered fibroblasts thus seem to serve as a safe and efficient means to deliver IL-12 in these three tumor models.

Animals↗
PubMed1995

Irritable bladder syndrome in an animal model: a continuous monitoring study.

Irritable bladder syndrome (IBS) was induced in four female African green monkeys (Cercopithecus aethiops) by the use of intravesical instillation of acetone. The animals were housed in a modified metabolic cage for continuous micturition monitoring, and two uroflowmeters connected to a remote PC monitored the frequency, voided volumes, and peak flows. Before and after, urea absorption studies and urodynamics were obtained for each animal. Urea absorption increased significantly after acetone instillation and returned to baseline after 4 weeks (26 to 66 to 32%). Intravesical acetone instillation produced marked effects on bladder physiology in the first week. Bladder compliance dropped from a baseline of 10.47 to 0.58 ml/cm H2O. The voiding pattern changed from a normal pattern with a mean voided volume of 17.58 ml into marked increase in frequency and dribbling pattern with few voids (mean = 5.03 ml). Systematic behavioral observations were carried out for 4 hours per day utilizing an observation program on a laptop computer. Activity patterns, attention, sterotypic behaviors, and self-directed activities were recorded for each monkey. The animals demonstrated decreased frequency of activity and increased frequency in self-directed activities (groom, scratch), behaviors consistent with an animal experiencing pain or discomfort. The findings suggested that IBS induction in monkeys is feasible and produces a clinical picture similar to interstitial cystitis in humans. It offers a suitable animal model to enhance the understanding of voiding dysfunction with its neural pathways and to test the different therapeutic modalities to control IBS.

Acetone↗
PubMed1995

Pyruvate inhibits clofibrate-induced hepatic peroxisomal proliferation and free radical production in rats.

In an effort to identify the effects of the 3-carbon compound pyruvate on free radical production, we measured hepatic total peroxisomal beta-oxidation and catalase activity and the production of lipofuscin-like products in male Sprague-Dawley rats consuming an adequate diet supplemented with pyruvate, vitamin E, or the peroxisome proliferator and free radical enhancer clofibrate for 22 days (n = 5 in each group). Clofibrate feeding induced hepatomegaly, a fivefold increase in total peroxisomal beta-oxidation activity, and a threefold increase in hepatic lipofuscin-like products (P < .05). Pyruvate but not vitamin E inhibited the increase in liver size by 70% (P < .05). Both pyruvate and vitamin E completely inhibited clofibrate-induced increases in lipofuscin-like products (P < .05). Pyruvate but not clofibrate or vitamin E increased plasma concentrations of the nitric oxide metabolites nitrite and nitrate (P < .05). We conclude that with clofibrate-induced peroxisomal proliferation and free radical production, pyruvate will inhibit peroxisomal proliferation and free radical production, inhibit free radical-induced lipid peroxidation, and enhance metabolism of nitric oxide.

Animals↗
PubMed1995

Prognostic significance of CD44 expression in adenocarcinoma of the lung.

Aims-To determine whether expression of CD44 in neoplasia is associated with tumour grade, stage and prognosis.Methods-The immunohistochemical expression of CD44 was evaluated using the mouse antihuman monoclonal antibody 3G12 which recognises regions shared by all CD44 isoforms to determine whether expression in formalin fixed, paraffin wax embedded tissue correlates with tumour grade, stage or survival in adenocarcinoma of the lung. Thirty one adenocarcinomas of the lung, 16 T2N0 and 15 T2N1, and their nodal metastases were studied.Results-Of the 31 tumours, 25 were positive for the CD44 antigen. CD44 expression correlated with tumour grade, in that intense staining was seen only in moderately and/or poorly differentiated tumours. CD44 did not correlate with nodal status, tumour size, pleural invasion, angiolymphatic invasion, or host inflammatory response, but did correlate with survival. A median survival of 46 months was observed in patients with moderate to strong CD44 expression compared with 24 months for those with no or weak expression. Nine patients were alive without evidence of disease at a median follow up of 61 months. Six (66%) of these nine patients had strong CD44 expression. This contrasts with strong expression in only three (17%) of the 17 patients dying with a median survival of 28 months.Conclusion-In primary adenocarcinoma of the lung loss of CD44 expression is associated with less favorable outcome and may indicate a more aggressive neoplasm. CD44 may be a useful prognostic marker in lung carcinoma.

Journal Article↗
PubMed1995

Developmental expression and anatomical localization of endothelin-1 messenger ribonucleic acid and immunoreactivity in the rat placenta: a northern analysis and immunohistochemistry study.

Endothelin-1 (ET-1) immunoreactivity and messenger ribonucleic acid (mRNA) have previously been identified in the mammalian placenta. In the present study we examined the developmental expression of ET-1 mRNA and the localization of ET-1 mRNA and immunoreactivity within the rat placenta. Placental tissues were removed from primiparous Sprague-Dawley rats on gestational days 14, 18, and 21 and processed for blot hybridization of ET-1 mRNA and immunohistochemistry of ET-1 immunoreactive peptide. Placental tissue contained a 2.3 kb size ET-1 mRNA transcript. Placental ET-1 mRNA abundance increased approximately five-fold from day 14 to 21 of gestation (p = 0.02). To localize ET-1 mRNA within the rat placenta, day 18 placentas were dissected into the basal and labyrinth layers and processed separately for blot hybridization of ET-1 mRNA. ET-1 mRNA localized to the labyrinth zone. This was confirmed by immunohistochemical staining of day 18, 20, and 21 placental tissues with an antiserum specific to ET-1. The presence of ET-1 immunoreactivity and the stage-specific increase in ET-1 mRNA in the rat placenta suggest that ET-1 may exert paracrine effects on the placenta or uterus of the pregnant rat.

Animals↗
PubMed1994

Pyruvate inhibits growth of mammary adenocarcinoma 13762 in rats.

The growth of implanted mammary adenocarcinoma 13762 was measured in rats consuming a liquid diet (35% fat, 18% protein, 47% carbohydrate) supplemented with pyruvate (37.3 g/liter; n = 13) or maltose-dextrin (placebo; n = 13) for 21 days. Mean tumor diameter, measured on day 11, 14, 18, and 21 subsequent to tumor implantation, was 41, 32, 21, and 19% smaller in the pyruvate group (P < 0.05). When euthanized, tumor weight was also smaller in the pyruvate group: pyruvate = 15.0 +/- 2.3 (SEM) g; placebo = 24.9 +/- 3.2 g, P < 0.05. Visual inspection of organs suggested decreased lung metastases with pyruvate feeding (P < 0.05). Upon microscopic evaluation of organs, hepatic tumor was found only in the placebo group. We conclude that pyruvate inhibits implanted tumor growth in rats.

Adenocarcinoma↗
PubMed1994

Intraoperative imprint cytology for evaluation of mediastinal lymphadenopathy.

Frozen-section (FS) analysis of mediastinal lymph nodes is commonly used in the staging of lung cancer and the evaluation of diagnostic tissue at mediastinoscopy. This approach facilitates definitive surgical intervention in a single operation and reduces costs. However, FS analysis can be labor intensive for the pathology department and time-consuming while the patient is anesthetized. Imprint cytology is more rapid than the FS procedure (average, 2 minutes versus 11 minutes per node) and allows more extensive sampling of the specimen. In this prospective study, we compared the diagnostic accuracy of imprint cytology and permanent sections on 121 mediastinal lymph nodes from 38 patients. There were no false-positive results and one false-negative result, although that patient was correctly classified based on positive cytology from another node. The sensitivity was 96.6%, the specificity was 100%, and the predictive value of a positive result was 100%, as no false-positives results were observed. The predictive value of a negative result was 98.9%, and the overall efficiency was 99.2%. These results compare favorably with those in other studies comparing the diagnostic accuracy of imprint cytology with that of FS analysis and with reported accuracy rates of FS technique. Our findings confirm the usefulness of this technique as an adjunct or substitute for FS analysis in the intraoperative pathologic evaluation of mediastinal lymphadenopathy.

Adult↗
PubMed1993

The diet of sperm whales (Physeter macrocephalus Linnaeus 1758) off the Azores.

Stomach contents from 17 sperm whales, 15 males and two females, caught during commercial activities in 1981-1984 in the Azores region were identified and measured. A total of 28,738 cephalopods and 16 fish were represented in the collections. In addition, there were tunicates in two whales and man-made products in three whales. None of the stomachs were empty. Flesh was present in 94.1% and indigestible fragments alone, including mandibles (beaks) of cephalopods, were present in 5.9% of the stomachs. Twelve species of cephalopod were represented by flesh and 40 species were represented by lower beaks. The cephalopod families contributing food to the whales in this region are, in order of their contribution by estimated mass, the Octopoteuthidae (39.8%), the Histioteuthidae (32.7%), the Architeuthidae (12.1%), the Lepidoteuthidae (4.5%), the Ommastrephidae (3.4%), the Pholidoteuthidae (2.1%), the Cycloteuthidae (1.9%), the Cranchiidae (1.7%) and eight other families each contributing less than 1% by mass. Presence of Gonatus beaks in the stomachs show which whales have migrated southwards to the Azores just prior to capture and the presence of a large Megalocranchia species possibly shows which whales have migrated from higher latitudes off Iceland. However, the presence of Teuthowenia maculata shows which whales came north from the West coast of Africa, just prior to capture. The modal mass of cephalopods consumed is 400-450 g which represents 0.00001 of the whales' body mass. 77.5% of the species eaten have luminous organs and 82% of the species are neutrally buoyant. It seems likely that the sperm whale is obtaining 77% of its food by swimming through luminous shoals of slow-swimming, neutrally bouyant squids and only about 23% by chasing faster swimming, larger cephalopods. Cephalopods not previously recorded from the North Atlantic are Onychoteuthis boreali-japonicus, and Histioteuthis bonnellii corpuscula. Histioteuthis ?miranda may have been collected by the whales much further south than the Azores. Species not recorded previously in the diet of sperm whales in the North Atlantic are Ommastrephes bartrami, Gonatus steenstrupi, Histioteuthis ?miranda, H. bonnellii corpuscula, H. meleagroteuthis, Discoteuthis laciniosa, Mastigoteuthis species, Chiroteuthis species, ?Helicocranchia, Liocranchia reinhardti, and ?Liguriella.

Animal Nutritional Physiological Phenomena↗
PubMed1993

Uterine malignant mixed müllerian tumor in a patient on long-term tamoxifen therapy for breast cancer.

A case of malignant mixed müllerian tumor of the uterus, heterologous type, in an 83-year-old woman on tamoxifen (TAM) therapy for 9 years for breast cancer is presented. Benign endometrial polyps were diagnosed on endometrial curettings for postmenopausal bleeding after the patient had been on TAM for 5 years. Recurrent postmenopausal bleeding developed 4 years later. Endometrial curettings and hysterectomy revealed a 10-cm polypoid malignant mixed müllerian tumor (MMMT) and endometrial polyps. There was no invasion of the myometrium or endocervix and no evidence of metastatic tumor in 13 pelvic lymph nodes, peritoneal washings, or omentum. TAM has been associated with the development of endometrial polyps, hyperplasia, and adenocarcinoma possibly mediated through its agonistic estrogenic properties. Only one other case of MMMT arising in patients on TAM therapy has been previously reported, but may also be a consequence of the estrogenic effects of TAM therapy.

Aged↗
PubMed1993

Endothelin-1 gene expression in human pheochromocytoma.

We examined expression of human endothelin-1 (ET-1) in adrenal tissues removed from five patients with pheochromocytomas and two patients with aldosterone-producing adenomas. The pheochromocytomas contained a 2.3 kilobase ET-1 transcript, which was not found int he aldosteronomas. Constitutive expression of ET-1 varied in magnitude among the pheochromocytomas but was generally at a low level. Immunohistochemical staining of the pheochromocytomas with an antiserum to human ET-1 showed the presence of immunoreactive ET-1 as well. The presence of ET-1 messenger ribonucleic acid and ET-1 immunoreactivity in human pheochromocytomas suggests a possible paracrine role for this peptide in human chromaffin cells.

Adenoma↗
PubMed1990

Behavioral development and socialization of infants in a free-ranging group of howling monkeys (Alouatta palliata).

A 22-month field study was carried out on free-ranging mantled howlers in Costa Rica. Six female and 5 male infants were observed systematically from birth until they died, left the group, or the study ended. Interaction patterns, activity patterns, and proximity data were analyzed from 703 h of focal observations and 753 h of ad lib observations. Developmental trends in weaning and nonmother care were associated with mothers' feeding patterns, suggesting an increase in maternal feeding efficiency. As howler immigration patterns resulted in groups of adults of low relatedness, analyses based on social bonding or kin selection were inappropriate, and socialization patterns instead appeared to prepare howler infants to respond predictably in an adult world. Females, which were more sociable as adults, were also more sociable as infants, initiating interactions and reacting positively. They also exhibited less weaning stress than males. Males, which were forced out of the group sooner, remained solitary longer, and primarily interacted with adult females as adults, were forced to be independent sooner, reacted negatively to interactions, and ceased interacting with adult males by 3 months of age. Ecological constraints on development could not be determined from this study, although there was no evidence for developmental trends being influenced by predator stress.

Age Factors↗
PubMed1990

A coprological survey of parasites of wild mantled howling monkeys, Alouatta palliata palliata.

Fecal samples from 155 mantled howling monkeys (Alouatta palliata palliata) examined at Centro Ecologico La Pacifica, Guanacaste Province, Costa Rica, revealed 75 (48%) had parasitic infections. A sampling of nine howling monkeys from Santa Rosa National Park. Costa Rica indicated only one infected animal (11%). Only three of 19 (16%) spider monkeys (Ateles geoffroyi) also from Santa Rosa were infected. Controrchis biliophilus, Trypanoxyuris minutus, unidentified strongylid eggs and Isospora sp. oocysts were found. Three monkeys from La Pacifica died and were examined for adult helminths. They were infected with Ascaris lumbricoides, C. biliophilus and T. minutus.

Alouatta↗
PubMed1990

Vitamin C deficiency in captive nonhuman primates fed commercial primate diet.

Scurvy was diagnosed in 19 rhesus monkeys (Macaca mulatta) and four squirrel monkeys (Saimiri sciureus) from a colony of nonhuman primates maintained on a commercial diet. Signs of weakness, reluctance to move, gingival hemorrhage, bruising, proximal and distal metaphyseal fractures, weight loss and anemia appeared in juvenile and young adult rhesus monkeys over a 2 week period. Clinical signs subsided after 5 days of vitamin C therapy. At the same time, cephalohematomas and weakness developed in squirrel monkeys, which failed to respond to treatment. These cases were associated with manufacturer's admitted error in preparation of the commercially prepared monkey diet.

Anemia↗
PubMed1987

Relative size of the anterior thalamic nuclei differentiates anthropoids by social system.

Anthropoid primates differ in the sizes of their limbic nuclei. Morphometric analysis of the anterior principal thalamic nucleus and the medial mamillary nuclei reveal that both regions increase in size as a function of brain weight. However, after controlling for the size of the brain, anthropoids classified as having single-male societies have more anterior principal thalamic neurons than do primates that are classified as multi-male. The relative sizes of the mamillary nuclei do not show this clustering. The differences in the size of the anterior nucleus are hypothesized to be specific for this nucleus and not the result of a general limbic or of heterochronic changes.

Animals↗