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Biomedical subjects

G A Higgins

Publications and source records attributed to G A Higgins.

At least 109 records · Page 6Linked to original sources
PubMed1988

Differential regulation of amyloid-beta-protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer disease.

We have mapped the neuroanatomical distribution of amyloid-beta-protein mRNA within neuronal subpopulations of the hippocampal formation in the cynomolgus monkey (Macaca fascicularis), normal aged human, and patients with Alzheimer disease. Amyloid-beta-protein mRNA appears to be expressed in all hippocampal neurons, but at different levels of abundance. In the central nervous system of monkey and normal aged human, image analysis shows that neurons of the dentate gyrus and cornu Ammonis fields contain a 2.5-times-greater hybridization signal than is present in neurons of the subiculum and entorhinal cortex. In contrast, in the Alzheimer disease hippocampal formation, the levels of amyloid-beta-protein mRNA in the cornu Ammonis field 3 and parasubiculum are equivalent. These findings suggest that within certain neuronal subpopulations cell type-specific regulation of amyloid-beta-protein gene expression may be altered in Alzheimer disease.

Aged↗
PubMed1988

Distribution of precursor amyloid-beta-protein messenger RNA in human cerebral cortex: relationship to neurofibrillary tangles and neuritic plaques.

Neurofibrillary tangles (NFT) and neuritic plaques (NP), two neuropathological markers of Alzheimer disease, may both contain peptide fragments derived from the human amyloid beta protein. However, the nature of the relationship between NFT and NP and the source of the amyloid beta proteins found in each have remained unclear. We used in situ hybridization techniques to map the anatomical distribution of precursor amyloid-beta-protein mRNA in the neocortex of brains from three subjects with no known neurologic disease and from five patients with Alzheimer disease. In brains from control subjects, positively hybridizing neurons were present in cortical regions and layers that contain a high density of neuropathological markers in Alzheimer disease, as well as in those loci that contain NP but few NFT. Quantitative analyses of in situ hybridization patterns within layers III and V of the superior frontal cortex revealed that the presence of high numbers of NFT in Alzheimer-diseased brains was associated with a decrease in the number of positively hybridizing neurons compared to controls and Alzheimer-diseased brains with few NFT. In contrast, no correlation was found between the densities of NP and neurons containing precursor amyloid-beta-protein mRNA transcripts. These findings suggest that the expression of precursor amyloid-beta-protein mRNA may be a necessary but is clearly not a sufficient prerequisite for NFT formation. In addition, these results may indicate that the amyloid beta protein, present in NP in a given region or layer of cortex, is not derived from the resident neuronal cell bodies that express the mRNA for the precursor protein.

Aged↗
PubMed1987

Localization of amyloid beta protein messenger RNA in brains from patients with Alzheimer's disease.

The distribution of cells containing messenger RNA that encodes amyloid beta protein was determined in hippocampi and in various cortical regions from cynomolgus monkeys, normal humans, and patients with Alzheimer's disease by in situ hybridization. Both 35S-labeled RNA antisense and sense probes to amyloid beta protein messenger RNA were used to ensure specific hybridization. Messenger RNA for amyloid beta protein was expressed in a subset of neurons in the prefrontal cortex from monkeys, normal humans, and patients with Alzheimer's disease. This messenger RNA was also present in the neurons of all the hippocampal fields from monkeys, normal humans and, although to a lesser extent in cornu ammonis 1, patients with Alzheimer's disease. The distribution of amyloid beta protein messenger RNA was similar to that of the neurofibrillary tangles of Alzheimer's disease in some regions, but the messenger RNA was also expressed in other neurons that are not usually involved in the pathology of Alzheimer's disease.

Alzheimer Disease↗
PubMed1987

Developmentally regulated rat brain mRNAs: molecular and anatomical characterization.

In order to identify markers for developing neural cell populations and gain molecular insights into the processes of neural development and differentiation, we have selected cDNA clones of rat brain mRNAs that are expressed in brain at embryonic day 16 (E16) with at least 10-fold greater abundance than they are in adult brain. Eleven such clones were obtained from a cDNA library of E16 brain poly(A)+ RNA using a combination of differential and subtractive hybridization screens. The temporal and spatial patterns of expression of the mRNAs corresponding to these clones were characterized by Northern (RNA) blotting and by in situ hybridization. Although all the mRNAs were enriched in embryonic brain, different mRNAs demonstrated maximum abundance at different times in late embryogenesis. The mRNAs can be grouped into 3 classes on the basis of their patterns of spatial expression in the embryo: one cDNA clone from each class and its corresponding mRNAs have been characterized in more detail. Class C represents mRNAs that are highly enriched in the nervous system and may be expressed in newly differentiating neurons; the example chosen was shown by nucleotide sequence analysis to encode the brain alpha 1 isotype of tubulin. Class B mRNAs have a broader distribution in the developing embryo but are expressed predominantly in the ventricular germinal zones of the developing nervous system and may represent molecules involved with neurogenesis. A third class (Class A) includes mRNAs with a more homogeneous distribution within the embryo and developing nervous system, which may encode "housekeeping" molecules. These clones and their encoded products will provide markers for cell populations at particular stages of neural development.

Animals↗
PubMed1986

Preoperative radiation and surgery for cancer of the rectum. Veterans Administration Surgical Oncology Group Trial II.

In a prospective randomized trial, 361 male patients with histologically proven adenocarcinoma of the rectum, judged preoperatively to require abdominoperineal resection (APR), were treated by surgery alone or were given 3,150 rads of preoperative radiotherapy. Surgical resection was done on 320 patients, 262 having "curative" APR. Only moderate symptoms from radiotherapy were noted and postoperative complications and 30-day mortality were similar in both groups. Five-year survival for curative APR was the same in both groups (50% for both treated and control patients). The incidence of positive lymph nodes in the resected specimens was 35% in treated and 41% in controls. In the first preoperative radiotherapy trial conducted by the group, 5-year survival in patients undergoing "curative" APR was 47% in treated versus 34% in control groups. Additionally, the difference in positive lymph nodes in the resected specimens was substantially greater in the first trial (26% in treated versus 44% in controls).

Adenocarcinoma↗
PubMed1985

In situ hybridization of putative somatostatin mRNA within hypothalamus of the rat using synthetic oligonucleotide probes.

The distribution of mRNA with high sequence homology to somatostatin mRNA within the periventricular hypothalamus of rat was assessed using in situ hybridization techniques with synthetic oligodeoxyribonucleotide probes, complementary to the 3' coding region of rat somatostatin mRNA. The probes (22- and 24-mers) were 5'-end labeled using T4 polynucleotide kinase and gamma-32P-ATP. They were used either individually or after ligation with T4 DNA ligase to form a 46-mer. Serial tissue sections (less than 10 microns) were taken from the level of the preoptic/anterior hypothalamus through the paraventricular hypothalamus. In situ hybridizations were conducted at room temperature in hybridization buffer. Neurons immunoreactive with antiserum raised against somatostatin were identified in alternate sections using standard immunocytochemical procedures. The anatomical location of the hybridization signal was determined by autoradiography. Our results show that the peri- and paraventricular hypothalamus is rich in transcripts putatively coding for somatostatin and that these transcripts are co-distributed with neurons immunoreactive with antisomatostatin immunoglobulin.

Animals↗
PubMed1984

Efficacy of MER immunotherapy when added to a regimen of 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. A Veterans Administration Surgical Oncology Group report.

Two hundred four patients with a microscopically incomplete resection for carcinoma of the colon or rectum were accepted for study. All patients were treated with 5-fluorouracil and methyl-CCNU beginning about the second postoperative week. Concurrent immunotherapy with the methanol extraction residue of bacillus Calmette-Guérin (MER) was randomly assigned to 103 patients. Treatment was continued as long as acceptable to the patient, and until clinical recurrence. Toxic reactions to the drug were not increased by the addition of MER, and seldom were severe enough to require the discrimination of therapy. No evidence of improved survival was seen in treated patients. On the contrary, survival in patients who experienced severe reactions to treatment may have been impaired by MER, with the period of impairment continuing after all adjuvant therapy was stopped. Similar proportions of treated and control deaths were attributable to residual or recurrent disease.

Adult↗
PubMed1984

Distribution of neurotensin-immunoreactivity within baroreceptive portions of the nucleus of the tractus solitarius and the dorsal vagal nucleus of the rat.

We have examined the distribution of neurotensin immunoreactivity within subnuclear regions of the nucleus of the tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DVN) in the rat. In order to determine which regions of the NTS were involved in the regulation of baroreceptor reflexes, we mapped the central distribution of the aortic branch of the vagus nerve using transganglionic transport of horseradish peroxidase. Comparison of the pattern of aortic nerve innervation with that of the distribution of neurotensin-immunoreactive cells and fibers shows the dorsomedial nucleus of the NTS both to be the primary site of aortic baroreceptor termination and to contain the highest concentration of neurotensin-immunoreactive elements within the NTS. Neurotensin-immunoreactive fibers are also present in medial regions of the NTS adjacent to the area postrema where they may be involved in the modulation of vagal gastric afferents. Double-label experiments, in which, on the same tissue sections, neurotensin immunohistochemistry was combined with retrograde horseradish peroxidase labeling of DVN neurons, reveal a topographic innervation of vagal preganglionic motoneurons by neurotensin-immunoreactive fibers. The heaviest innervation is of lateral portions of the DVN and adjacent ventral portions of the NTS at the level of the obex, an area which may contain cardiac motoneurons. In this region neurotensin-immunoreactive fibers can be observed in close proximity to retrogradely labeled cells. The concentration of neurotensin elements in a region of the NTS which is involved in the control of baroreceptor reflexes provides a morphological basis for the cardiovascular effects produced by central administration of the peptide. Additional control may be exerted at the level of the motoneuron, as evidenced by apparent neurotensin fiber innervation of presumptive cardiac preganglionic neurons. Similarly, the distribution of neurotensin fibers suggests that the peptide may be acting in gastric regulatory areas of the NTS or on vagal secretomotor neurons to regulate gastric acid secretion.

Afferent Pathways↗
PubMed1984

Efficacy of prolonged intermittent therapy with combined 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. A Veterans Administration Surgical Oncology Group report.

This prospective evaluation of 5-FU and methyl-CCNU administered in combination to patients with curative surgery for histologically proved colorectal adenocarcinoma is based upon 645 patients randomized between August 1973 and July 1979. Beyond the requirement that the resection be clinically and microscopically complete, patients were not stratified prior to random treatment assignment to surgery alone or surgery followed by adjuvant chemotherapy. Drug therapy consisted of discrete 5-day courses administered at 7-week intervals, start to start. Toxic reactions were reported in association with 40% of courses. In 10% of patients with hematologic toxicity, the reactions were sufficiently severe to require the suspension or discontinuation of treatment. Treated patients experienced a slightly more favorable survival than did controls. However, the advantage was seen only in the 216 patients (34% of total) with one to four positive lymph nodes in the resected specimen. Similar proportions of treated and control deaths were attributed to residual or recurrent disease.

Adenocarcinoma↗
PubMed1984

Adjuvant therapy for carcinoma of the colon and rectum.

Because all types of cancer therapy are most effective when the tumor burden is small, adding adjuvant cancer treatment to surgical excision has great merit both in theory and experimentally. Even though large numbers of patients with large bowel cancer have been entered into various types of experimental trials over the past 25 years, the potential of multimodal cancer therapy has only been examined in a superficial manner at best. If this therapeutic approach had any substantial effectiveness, it would have long since become apparent. Surgical therapy is effective, with a five-year survival of 50%, and the various adjuvant therapies have shown only modest effectiveness when tested on patients with measurable disease. 5-Fluorouracil, with a response rate in measurable disease of approximately 20%, is the only consistently effective cancericidal drug, and its combination with other agents has thus far shown no increase in this response rate. Currently, available data would indicate a modest survival benefit from the use of postoperative 5-fluorouracil, particularly in patients with positive lymph nodes. There are a number of trials in progress studying the effectiveness of multiple drug combinations as well as combining chemotherapy with radiotherapy and/or immunotherapy in the adjuvant setting. Preliminary studies would suggest a benefit from infusing chemotherapy into the liver in the immediate postoperative period, although there has been no evidence substantiating improved survival from this approach. The multiple approaches for generating an effective immunologic response continue to be experimental and have little use in other than a highly controlled experimental environment. The use of radiotherapy as an adjuvant to surgery has been confined largely to patients with low-lying rectal cancer. There is substantial evidence that high-dosage radiotherapy for large bulky and fixed rectal cancer will result in shrinkage of the lesion, permitting more satisfactory surgical resection and decreasing the incidence of perineal recurrence. Evidence would also suggest that moderate-dosage preoperative radiotherapy may sufficiently alter cancer cells so that cells disseminated at the time of operation are no longer capable of growth. It has also been demonstrated that preoperative radiotherapy decreases the incidence of positive lymph nodes. Modest increase in survival following preoperative radiotherapy has also been demonstrated in numerous trials. Postoperative radiotherapy has not been tested for a sufficient period of time to either demonstrate its effectiveness or safety.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Agents↗
PubMed1983

Efficacy of prolonged intermittent therapy with combined 5-FU and methyl-CCNU following resection for gastric carcinoma. A Veterans Administration Surgical Oncology, Group report.

This prospective evaluation of 5-fluorouracil (5-FU) and methyl-CCNU administered in combination to patients with surgery for histologically proved gastric adenocarcinoma is based upon 312 patients randomized between August 1974 and May 1980. Patients were stratified into three categories of resectability, (1) complete, (2) proven incomplete, and (3) nonresectable, prior to random treatment assignment to surgery alone or surgery followed by adjuvant chemotherapy. Drug therapy consisted of discrete 5-day courses administered at 7-week intervals. Toxic reactions were reported in association with 42% of the courses. Treatment was suspended or discontinued in 6% of the courses because of hematologic toxicity. Treated patients with curative resections experienced a more favorable survival than did controls, but the early advantage was lost by the end of the second follow-up year. However, no statistically significant improvements in survival or reductions in risks of recurrence were observed. Similar proportions of treated and control deaths were attributable to residual or recurrent disease.

Adenocarcinoma↗
PubMed1983

Mediation of nicotine-induced convulsions by central nicotinic receptors of the 'C6' type.

The nature of the central receptors mediating the convulsant actions of nicotine has been investigated. Clonic tonic convulsions were seen in mice following intracerebroventricular (i.c.v.) injection of nicotinic agonists. (-)Nicotine was the most potent agonist tested, with a CD50 of 7.9 X 10(-9) mol. (+)Nicotine, cytisine, DMPP and lobeline were 10-100 times less potent than (-)nicotine. Nicotine induced convulsions were antagonized by ganglion blocking drugs administered intraventricularly. Pentolinium was the most potent antagonist, with an ED50 of 4 X 10(-11) mol. The ganglion-blockers also produced convulsions in their own right at doses 80-1000 times the anti-nicotine ED50 dose. 'C10' blockers, such as d-tubocurarine, did not antagonize nicotine-convulsions, but produced convulsions in their own right. alpha-Bungarotoxin had neither convulsant nor anticonvulsant activity at the doses tested. It is concluded that the central receptors mediating this nicotinic effect resemble ganglionic ('C6') receptors, rather than neuromuscular ('C10') receptors.

Animals↗
PubMed1982

Prolonged intermittent adjuvant chemotherapy with CCNU and hydroxyurea after resection of carcinoma of the lung.

Eight hundred sixty-five patients with a microscopically curative resection for carcinoma of the lung were accepted for study, none of whom were excluded from analysis. Adjuvant therapy was randomly assigned about the tenth to 14th postoperative day; 432 patients (treated) were to receive CCNU and hydroxyurea for one year, while 433 patients (controls) were to receive no adjuvant therapy. Toxic reactions to therapy were reported, but only 1% were severe enough to require stopping therapy. No evidence of improved survival or delayed recurrence of disease was seen in treated patients as a whole or when examined by cell type and by postsurgical TNM category. On the contrary, survival beyond the second year of follow-up may have been impaired by the drugs when administered to patients without evidence of tumor spread to the lymph nodes.

Carcinoma↗
PubMed1982

Large bowel cancer: an overview.

Cancer of the large bowel is a problem of international scope but with wide national incidence variations possibly related to climatic factors. Neither etiologic studies nor improved methods of early detection have thus far had an impact on national death rates. Surgical treatment, while comparatively effective, does not promise a significant increase in survival data, and thus far, adjuvant therapies have failed to fulfill early enthusiastic expectations. Nevertheless, continued research pursuit of the nature of the neoplastic process, development and application of improved diagnostic and screening methods, and synthesis of better combined modality therapy, will result in substantial improvements in therapeutic results.

Antineoplastic Agents↗