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Biomedical subjects

D J O'Shaughnessy

Publications and source records attributed to D J O'Shaughnessy.

16 recordsLinked to original sources
PubMed1993

Calcitonin gene-related peptide in treatment of severe peripheral vascular insufficiency in Raynaud's phenomenon.

Calcitonin gene-related peptide (CGRP) is a potent vasodilator that may be involved in the regulation of the peripheral circulation and in its response to cold. There is evidence that CGRP in digital cutaneous perivascular nerves is deficient in Raynaud's phenomenon. Our pilot study of intravenous CGRP suggested that this substance is beneficial in patients with Raynaud's phenomenon; here we have extended our studies. Ten patients with severe Raynaud's phenomenon secondary to connective tissue disease were randomly assigned to groups receiving intravenous CGRP (0.6 micrograms/min for 3 h per day on 5 days) or saline. Hand and digital blood flow and skin temperature were measured by thermocouple and laser doppler flowmetry. Blood flow was significantly (p < 0.05) increased by CGRP in both hands (median blood flow after infusion as percentage of baseline reading 179 [range 100-355]%) and fingers (149 [100-161]%); saline had no effect (hands 102 [84-123]%, fingers 96 [81-113]%). Hand temperature was increased more by CGRP than by saline (2.8 [1.5-4.0] vs 1.0 [-1.0 to 2.5] degrees C, p < 0.05). Digital temperature increased after CGRP but the difference between the treatment groups in temperature rise was not significant, perhaps because saline caused increases in some patients. All ulcers healed in four of five CGRP-treated patients but in no saline-treated patients. Thus intravenous CGRP effectively dilates the compromised digital cutaneous vasculature in severe Raynaud's phenomenon.

Adult↗
PubMed1989

A comparison of the effects of human alpha calcitonin gene-related peptide and glyceryl trinitrate on regional blood velocity in man.

1. Human alpha calcitonin gene-related peptide (h alpha CGRP) is a potent vasodilator which in doses up to 1.5 micrograms min-1 i.v. produces little or no fall in blood pressure in normal volunteers, but does cause a substantial tachycardia. 2. We have explored the underlying mechanism of this effect by comparing h alpha CGRP infused so as to maintain heart rate 25-30% above baseline with glyceryl trinitrate (GTN) in a dose sufficient to maintain a throbbing headache. 3. Ten normal volunteers were studied. In addition to blood pressure and heart rate, blood velocity and pulsatility index (PI) were determined from Doppler signals recorded from the internal and external carotid, renal and femoral arteries. 4. Following h alpha CGRP blood pressure (mean +/- s.d., mm Hg) did not significantly change: 120 +/- 10/70 +/- 7 before compared with 121 +/- 12/67 +/- 7 during h alpha CGRP infusion. Heart rate (mean +/- s.d., beats min-1) increased from 62 +/- 8 to 86 +/- 10 (P less than 0.0001). In contrast the blood pressure fell following GTN: 124 +/- 12/74 +/- 8 before compared with 111 +/- 13/62 +/- 6 following treatment (P less than 0.02). Heart rate did not change following GTN: 64 +/- 9 compared with 69 +/- 10. 5. GTN significantly increased PI (mean +/- s.d.) in the common carotid artery from 2.8 +/- 0.5 to 3.4 +/- 0.5 (P less than 0.003) while h alpha CGRP increased PI in the internal carotid from 1.3 +/- 0.2 to 2.1 +/- 0.4 (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Quantitative immunocytochemistry by digital image analysis: application to toxicologic pathology.

Recent advances in immunocytochemical techniques allow the localization of specific antigens in tissue sections. The work reported here attempts to evaluate the application of antibody-labeled, disease-related protein, followed by microscopy and computerized image analysis. Using an experimental anti-tumor, polyclonal antibody (anti-oncomodulin) as a model, various tissues were prepared for light microscope immunocytochemistry. Sections were incubated with primary antibody, then biotinylated secondary antibody. This was followed by incubation with avidin-biotin-peroxidase (ABC method). Marker was visualized by the presence of precipitated diaminobenzidine. Samples were evaluated using a Zeiss/Kontron IBAS I & II semi-automatic digital image analysis system. Statistical analyses were performed on output data. Results demonstrated the localization and determined optical density of immunolabel. Statistical comparisons showed significant differences between control and experimental sections. The practical application of these combined techniques provides the toxicologic pathologist with a powerful tool for accurate and objective determination of the location and relative amount of selected proteins in normal and abnormal tissues.

Calcium-Binding Proteins↗
PubMed1986

Peripheral and central nervous system lesions caused by triethyl- and trimethyltin salts in rats.

Both trimethyltin and triethyltin salts are known to produce toxic lesions in the central nervous system. Triethyltin intoxication has been associated with central intramyelin edema, while trimethyltin has been shown to produce neuronal necrosis in selected limbic and sensory regions of the brain. Only scant attention has been paid to peripheral nerves of animals treated with alkyltins. In this study, we have treated rats with 6 or 8 mg/kg trimethyltin, and 1, 2, 4, 6, or 8 mg/kg triethyltin (single or multiple exposure), and evaluated in detail at the light microscope level both central and peripheral nervous system lesions. In addition to the central neuron necrosis or myelin edema described previously, both compounds produced peripheral axon degeneration and chromatolysis of large spinal cord and brain stem neurons. Chromatolysis was seen in reticular neurons of the brain stem and ventral horn or spinal cord in rats receiving high doses (6 or 8 mg/kg) of triethyltin, and in these same areas plus mesencephalic trigeminal nucleus in animals treated with trimethyltin. Wallerian-like degeneration of peripheral axons was seen in sciatic and tibial nerve and ventral roots of animals receiving 3 injections of 4 mg/kg or single or multiple injections of 6 or 8 mg/kg triethyltin. Axon degeneration was also seen in sciatic and tibial nerves 21 days after a single exposure to 8 mg/kg trimethyltin. Since myelin edema is believed to be reversible, the axonal changes described here may be of greater clinical significance in relation to human exposure.

Animals↗
PubMed1986

Comparison of central and peripheral nervous system lesions caused by high-dose short-term and low-dose subchronic acrylamide treatment in rats.

The effects of high-dose subacute acrylamide treatment of up to 50 mg/kg/day for 4 or 10 d were compared to those of subchronic exposure, up to 12 mg/kg/day for 90 d. In the subacute study, Purkinje cells, long ascending tracts of the spinal cord, optic tract terminal or preterminal regions in superior colliculus, sensory ganglion cells, and distal large-caliber peripheral axons were severely affected. Purkinje cells and fasciculus gracilis changes were the earliest lesions. In the subchronic study, the dominant lesion was confined to the distal peripheral axon, with only minor changes occurring in spinal cord and medulla. Paranodal swellings with the characteristic appearance of neurofilament aggregations were not seen. This morphological study suggests a significant difference between high- and low-dose acrylamide-induced lesions. If there is a reduced tendency for long-term low-dose acrylamide exposure to produce CNS lesions, the risk of irreversible nervous system damage would be less than that predicted from subacute studies.

Acrylamide↗
PubMed1985

Influence of somatostatin and bombesin on plasma enteroglucagon and cell proliferation after intestinal resection in the rat.

The possible relationship between enteroglucagon and cellular proliferation in a rat model of intestinal adaptation after suppression and stimulation of enteroglucagon by somatostatin and bombesin has been investigated. Forty eight rats were divided into three groups of 16 animals, each group being further sub-divided into eight animals having intestinal resection and eight having intestinal transection. Group 1 was given somatostatin to suppress enteroglucagon, group 2 was given bombesin to stimulate enteroglucagon and group 3 (control group) had neither peptide. All animals were killed 12 days after operation. Circulating enteroglucagon and crypt cell production rate (CCPR) in the terminal ileum were measured. After administration of somatostatin (group 1) both CCPR and plasma enteroglucagon were lower after resection than controls (group 3) (p less than 0.001). Transected rats receiving somatostatin showed a reduction in both plasma enteroglucagon and CCPR, but only the fall in enteroglucagon was statistically significant (p less than 0.001). Transected rats receiving bombesin (group 2) had raised plasma enteroglucagon and CCPR compared with the control group (group 3) (P less than 0.005) but there was no significant further rise in these already raised parameters in resected animals. This study indicates that cell proliferation in the rat small bowel after surgery can be influenced by regulatory peptides. The changes in enteroglucagon corresponded closely with changes in CCPR, and this peptide remains a favoured candidate for the humorally mediated trophic influence on the small bowel.

Adaptation, Physiological↗
PubMed1985

Somatostatin-14 modulates postprandial glucose levels and release of gastrointestinal and pancreatic hormones.

Ingestion of a 4,500-kcal mixed meal by healthy volunteers resulted in a significant rise of plasma somatostatin-14-like immunoreactivity (9 +/- 1 pmol l-1. Whether this peptide has a role as a humoral agent or not is still controversial and, until recently, most studies investigating its effects by exogenous administration have produced vastly supraphysiological circulating plasma levels. In order to reproduce the rise obtained following the large meal, synthetic somatostatin-14 was infused at a dose of 0.8 pmol kg-1 min-1 before and during a 530-kcal test breakfast. This resulted in a rise of 8 + 2 pmol l-1 in the peripheral circulation. This infusion produced a significant reduction in the postprandial release of insulin, gastric inhibitory polypeptide, pancreatic polypeptide and in the preprandial motilin levels. In contrast, blood glucose levels following the breakfast were elevated when compared to the control saline infusion. This suggests that somatostatin possesses true endocrine functions and is capable of profoundly altering the postprandial glucose and hormone response.

Adult↗
PubMed1984

Regional distribution of bombesin and seven other regulatory peptides in the human brain.

In order to compare within the same brains the quantitative distributions of a range of neuropeptides, bombesin, N- and C-terminal glucagon, cholecystokinin, neurotensin, somatostatin, substance P and vasoactive intestinal polypeptide immunoreactivities were determined by radioimmunoassay in 24 regions of 5 normal adult human brains. Each peptide showed a different distribution pattern. Of the peptides not previously mapped in detail in the human brain, bombesin-like immunoreactivity was present in all regions with the highest concentrations in particular areas of the hypothalamus, septal nuclei, nucleus accumbens, globus pallidus, amygdala, periaqueductal grey and substantia nigra. C- and N-terminal glucagon immunoreactivities were detected only in the ventromedial hypothalamus. The concentrations of the remaining 5 peptide immunoreactivities, and their molecular forms, were in good general agreement with those reported individually by others in both human brains and those of experimental animals. The quantitative mapping of the regulatory peptides in the human brain provides an essential base for further comparative study in diseased postmortem brains.

Adult↗
PubMed1983

Distribution of bombesin, somatostatin, substance-P and vasoactive intestinal polypeptide in feline and porcine skin.

The content and distribution of several regulatory peptides in the skin of cats and pigs, freshly obtained at surgery, have been investigated. Immunoreactive bombesin was evenly distributed at low concentrations in both species, being below the detection limit in the body and nose of the cat, and showing a peak value of 1.6 +/- 0.7 pmol/g in the tip of the pig's ear. Similar concentrations of somatostatin-immunoreactivity (-IR) were found but greater regional variation occurred in the pig with a low in the mid back of 0.4 +/- 0.1 and the highest value in the snout of 3.1 +/- 0.8. Substance-P-IR in the pig showed a marked variation in concentration, apparently parallelling skin sensitivity, with a low in the back of 0.4 +/- 0.7 and higher values around the anus (8.1 +/- 1.6), legs (6.8 +/- 1.8) and snout (13.5 +/- 3.6) whilst in the cat values ranged from 0.3 +/- 0.06 in the body to 5.0 +/- 0.9 in the front footpads. In contrast, vasoactive intestinal polypeptide (VIP)-IR showed greater variability in the cat, being below the assay's detection in the body and highest in the front and rear footpads (17 +/- 7 and 29 +/- 6 respectively), but in the pig most regions exhibited low concentrations with the exception of the snout which peaked at 12.0 +/- 5.0. Immunocytochemical localisation showed the peptides to be present in nerve fibres. Substance-P-IR was particularly localised in the snout of the pig just below the epithelium while VIP-IR was more concentrated in deeper layers, often associated with sweat glands and blood vessels.

Animals↗
PubMed1983

Peptidergic innervation of the human male genital tract.

Four peptides--vasoactive intestinal polypeptide, substance P, somatostatin and a peptide-like avian pancreatic polypeptide--have been found in nerves of the human male genitalia using highly sensitive and specific methods of immunocytochemistry and radioimmunoassay. Five other peptides (met-enkephalin, leu-enkephalin, neurotensin, bombesin and cholecystokinin-8) were absent. Vasoactive intestinal polypeptide was the most abundant peptide, its highest concentration being in the proximal corpus cavernosum. Immunoelectron microscopy localized this peptide to large (97 +/- 20 nm), round, electron-dense granules of p-type nerve terminals. Vasoactive intestinal polypeptide-immunoreactive neuronal cell bodies were found in the prostate gland and the root of the corpus cavernosum. Substance P immunoreactive material was present in smaller concentration and was mainly localized in nerves around the corpuscular receptors of the glans penis. Somatostatin immunoreactive nerves were associated mainly with the smooth muscle of the seminal vesicle and the vas deferens. When antiserum to avian pancreatic polypeptide was applied, certain nerves were stained, particularly in the vas deferens, the prostate gland and the seminal vesicle. However, chromatography detected no pure avian pancreatic polypeptide suggesting the presence of a structurally related substance, possibly neuropeptide Y, which cross-reacts with the avian pancreatic polypeptide antiserum. Similar distributions between vasoactive intestinal polypeptide-immunoreactive and acetylcholinesterase-positive nerves and between avian pancreatic polypeptide-immunoreactive and adrenergic nerves were observed. A general neuronal marker, neuron-specific enolase, was used to investigate the general pattern of the organ's innervation. The abundance and distribution patterns of these peptide-immunoreactive nerves indicate that they may play important roles in the male sexual physiology.

Adult↗
PubMed1983

Tissue localization and relative distribution of regulatory peptides in separated layers from the human bowel.

The localization and distribution of regulatory peptides was studied in separated epithelium, lamina propria, submucosa, and external muscular layer from 16 specimens of human bowel. Immunoreactive enteroglucagon, gastric inhibitory polypeptide, and neurotensin were almost confined to the epithelial fraction (97.5 +/- 2.2%, 97.5 +/- 4.2%, and 99.3 +/- 1.1% of their respective total content, mean +/- SEM) and were only localized in endocrine cells. Vasoactive intestinal polypeptide-, substance P-, and bombesinlike peptides were virtually restricted to the nonepithelial layers (99.6 +/- 0.2%, 99.6 +/- 0.2%, and 100%) and were demonstrated exclusively in nerves. A particularly rich vasoactive intestinal polypeptide- and substance P-immunoreactive nerve supply was seen in the nonepithelial mucosa, which contained the highest concentrations of these peptides, while bombesin was mainly recovered from the external muscle (87.7 +/- 2.7%). Somatostatin, measured with an antiserum highly specific for somatostatin-14, was found throughout the wall, mainly in the epithelium (39.9 +/- 5.2%) and lamina propria (29.5 +/- 5.9%), but could be immunostained only in endocrine cells.

Aged↗
PubMed1982

Developmental changes in bombesin, substance P, somatostatin and vasoactive intestinal polypeptide in the rat brain.

The regional distribution of the 4 neuropeptides, bombesin, substance P, somatostatin and vasoactive intestinal polypeptide (VIP) were investigated in the developing rat brain. Specific radioimmunoassay and immunocytochemistry were employed. VIP and bombesin were undetectable in the foetal brain whereas substance P and somatostatin were shown to be present in all regions as early as 14 days postcoitus. There was a dramatic postnatal increase in all 4 peptides in most regions. These results are discussed and compared with results of previous investigations of the ontogeny of the classic neurotransmitters.

Aging↗
PubMed1982

Effects of intravenous somatostatin and motilin on the blood glucose and hormonal response to oral glucose.

Exogenous intravenous infusions of control saline, somatostatin, motilin and somatostatin and motilin together were compared in normal volunteers for their effects on the rise of blood glucose following 50 g oral glucose and for their effects on gastric emptying and plasma hormone concentrations. All regulatory peptide infusions increased the rate of gastric emptying by between 182% and 198% at 60 min post-ingestion. The glucose response during the oral glucose tolerance test was suppressed when somatostatin with or without motilin was infused but was increased during motilin. The somatostatin infusion reduced concentrations of motilin, insulin, gastric inhibitory polypeptide, gastrin and neurotensin whilst the motilin infusion was associated with an increased initial rise in insulin and gastric inhibitory polypeptide. The metabolic effects of the motilin infusion were overriden by the effects of somatostatin when both peptides were infused together; this suggests that somatostatin inhibits both the effects and secretion of motilin.

Adult↗
PubMed1981

The effect of somatostatin analogs on secretion of growth, pancreatic, and gastrointestinal hormones in man.

The potency and specificity of somatostatin (SS) and four of its analogs were compared in seven patients with pancreatic endocrine tumors. The analogs tested were [D-Trp8]-SS, [D-Trp8, D-Cys14]-SS, Des-Asn5-[D-Trp8, D-Ser13]-SS, and Des (AA)1,2,4,5,12,13, [D-Trp8]-SS, and they did not show selective effects on the suppression of basal concentrations of GH, insulin, glucagon, pancreatic polypeptide, gastrin, gastric inhibitory peptide, motilin, enteroglucagon, or neurotensin. The observation that the potency of these analogs is similar to that of the parent molecule throws considerable light on the structure/activity relationship of the somatostatin molecule. Des-AA1,2,4,5,12,13, [D-Trp8]-Ss has been reported to have a prolonged action when administered sc. When administered iv, however, this octapeptide analog ws not long acting, suggesting that the prolonged action seen in the previous study was a result of delayed uptake from the injection site. An increment in plasma SS concentrations of 19 +/- 3 pmol/liter suppressed basal concentrations of GH, insulin, glucagon, and several gastrointestinal hormones by more than 50%, suggesting that even small changes in plasma SS levels may be physiologically important.

Adult↗
PubMed1980

Neural and hormonal peptides in rectal biopsy specimens from patients with Chagas' disease and chronic autonomic failure.

The neural and hormonal peptide content of rectal biopsy specimens from 10 patients with chronic autonomic failure, 10 patients with chronic gastrointestinal Chagas' disease, and 13 controls was studied with radioimmunoassay and immunocytochemistry. In the patients with Chagas' disease the mean concentrations of rectal vasoactive intestinal polypeptide, enteroglucagon, substance P, and somatostatin were all less than half of those in controls and in patients with chronic autonomic failure. Immunocytochemistry revealed a considerable reduction in the number and immunostaining of the peptide-containing cells and nerves. Concentrations of regulatory peptides in the rectum are thus reduced in association with intrinsic but not extrinsic autonomic neuropathy.

Autonomic Nervous System↗