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Biomedical subjects

C J Allen

Publications and source records attributed to C J Allen.

At least 37 records · Page 2Linked to original sources
PubMed1994

Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major.

BACKGROUND: To determine whether deferoxamine prevents the complications of transfusional iron overload in thalassemia major, we evaluated 59 patients (30 were female and 29 male; age range, 7 to 31 years) periodically for 4 to 10 years or until death. METHODS: At each follow-up visit, we performed a detailed clinical and laboratory evaluation and measured hepatic iron stores with a noninvasive magnetic device. RESULTS: The body iron burden as assessed by magnetic measurement of hepatic iron stores was closely correlated (R = 0.89, P < 0.001) with the ratio of cumulative transfusional iron load to cumulative deferoxamine use (expressed in millimoles of iron per kilogram of body weight, in relation to grams of deferoxamine per kilogram, transformed into the natural logarithm). Each increase of one unit in the natural logarithm of the ratio (transfusional iron load to deferoxamine use) was associated with an increased risk of impaired glucose tolerance (relative risk, 19.3; 95 percent confidence interval, 4.8 to 77.4), diabetes mellitus (relative risk, 9.2; 95 percent confidence interval, 1.8 to 47.7), cardiac disease (relative risk, 9.9; 95 percent confidence interval, 1.9 to 51.2), and death (relative risk, 12.6; 95 percent confidence interval, 2.4 to 65.4). All nine deaths during the study occurred among the 23 patients who had begun chelation therapy later and used less deferoxamine in relation to their transfusional iron load (P < 0.001). CONCLUSIONS: The early use of deferoxamine in an amount proportional to the transfusional iron load reduces the body iron burden and helps protect against diabetes mellitus, cardiac disease, and early death in patients with thalassemia major.

Adolescent↗
PubMed1994

Cholecystokinin and neuropeptide Y receptors on single rabbit vagal afferent ganglion neurons: site of prejunctional modulation of visceral sensory neurons.

A [125I]cholecystokinin (CCK) analog and [125I]peptide YY (PYY) were used to localize and characterize CCK and neuropeptide Y (NPY) receptor binding sites in the rabbit vagal afferent (nodose) ganglion. High concentrations of CCK and NPY binding sites were observed in 10.6% and 9.2% of the nodose ganglion neurons, respectively. Pharmacological experiments using CCK or NPY analogs suggest that both subtypes of CCK (CCK-A and CCK-B) and NPY (Y1 and Y2) receptor binding sites are expressed by discrete populations of neurons in the nodose ganglion. These results suggest sites at which CCK or NPY, released in either the nucleus of the solitary tract or a peripheral tissue, may modulate the release of neurotransmitters from a select population of visceral primary afferent neurons. Possible functions mediated by these receptors include modulation of satiety, opiate analgesia, and the development of morphine tolerance.

Amino Acid Sequence↗
PubMed1994

Some sensory neurons express neuropeptide Y receptors: potential paracrine inhibition of primary afferent nociceptors following peripheral nerve injury.

Neuropeptide Y (NPY) has been suggested to exert antinociceptive actions by inhibiting the release of neurotransmitters from trigeminal and dorsal root ganglia (DRG) neurons, but the site of direct NPY action in vivo and the NPY receptor subtype mediating these effects are unknown. 125I-peptide YY (PYY) was used to localize and characterize NPY receptor binding sites in trigeminal ganglia, DRG, and spinal cord of the rat, rabbit, and monkey. In the rat, rabbit, and monkey, 5-20% of trigeminal ganglia and DRG neurons express NPY binding sites. Unilateral cuff-induced neuropathy or transection of the rat sciatic nerve did not significantly alter the density or number of DRG neurons expressing NPY receptors. A unimodal size distribution for L4 and L5 DRG neurons expressing NPY binding sites in the rat was determined, with a mean cross-sectional area of 947 microns 2. In the spinal cord the highest concentration of NPY receptors is found in laminae I, II, V, X, and Onuf's nucleus. Pharmacological experiments using selective Y1 and Y2 receptor antagonists suggest that Y2 is the prominent NPY receptor subtype expressed in trigeminal ganglia neurons, DRG neurons, and spinal cord. Previous studies have demonstrated that a population of large-diameter, presumably myelinated primary afferents express NPY after peripheral nerve injury. NPY released from these injured large-diameter DRG neurons may act in a paracrine fashion to block the transmission of nociceptive information from the small- and medium-diameter DRG neurons that constitutively express NPY receptors. NPY receptors are therefore uniquely positioned to inhibit primary afferent nociceptors directly, especially after peripheral nerve injury.

Animals↗
PubMed1993

Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major.

To examine the relationship between hepatic iron stores and plasma ferritin concentration in individuals treated with red cell transfusion and iron chelation therapy, 37 patients with sickle cell anemia and 74 patients with thalassemia major were studied. In each patient, hepatic iron stores were measured by an independently validated noninvasive magnetic method, and plasma ferritin was determined by immunoassay. The correlation between hepatic iron and plasma ferritin was significant both in patients with sickle cell anemia (R = 0.75, P < 0.0001) and in those with thalassemia major (R = 0.76, P < 0.0001). Regression analysis showed no significant difference between the two groups in the linear relationships between hepatic iron stores and plasma ferritin. Considering all 111 transfused patients as a group, the coefficient of correlation between hepatic iron stores and plasma ferritin was highly significant (R = 0.76, P < 0.0001). Regression analysis found that variation in body iron stores, as assessed by magnetic determinations of hepatic iron, accounted for only approximately 57% of the variation in plasma ferritin, suggesting that the remainder was the result of other factors, such as hemolysis, ineffective erythropoiesis, ascorbate deficiency, inflammation, and liver disease. The 95% prediction intervals for hepatic iron concentration, given the plasma ferritin, were so broad as to make a single determination of plasma ferritin an unreliable predictor of body iron stores. Variability resulting from factors other than iron status limits the clinical usefulness of the plasma ferritin concentration as a predictor of body iron stores.

Adolescent↗
PubMed1993

Neuropeptide Y/peptide YY receptor binding sites in the heart: localization and pharmacological characterization.

[125I]Peptide YY was used to localize and characterize peptide YY and neuropeptide Y receptor binding sites in the heart. In the rat and rabbit heart, nearly every artery and arteriole that could be histologically identified also expressed saturable binding sites for [125I]peptide YY. In the arteries, these [125I]peptide YY binding sites were primarily associated with the smooth muscle layer. Pharmacological experiments demonstrated that peptide YY and neuropeptide Y were equipotent in competing for [125I]peptide YY binding in the heart. In another competition series, [Leu31,Pro34]-neuropeptide Y (a Y1 receptor-specific agonist when used with [125I]peptide YY) was significantly more potent than neuropeptide Y (a Y2 receptor-specific agonist when used with [125I]peptide YY) in competing for [125I]peptide YY binding from coronary arteries, suggesting that the receptor binding sites on cardiac arteries and arterioles are of the Y1 subtype. These results demonstrate that smooth muscle cells of the atrial and ventricular arteries and arterioles in rat and rabbit heart express Y1 receptors and suggest a possible direct effect of neuropeptide Y on coronary blood vessels to induce vasoconstriction.

Animals↗
PubMed1993

Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide.

A major pathological feature of Alzheimer's disease (AD) is the presence of a high density of amyloid plaques in the brain tissue of patients. The plaques are predominantly composed of human beta-amyloid peptide beta A4, a 40-mer whose neurotoxicity is related to its aggregation. Certain metals have been proposed as risk factors for AD, but the mechanism by which the metals may exert their effects is unclear. Radioiodinated human beta A4 has been used to assess the effects of various metals on the aggregation of the peptide in dilute solution (10(-10) M). In physiological buffers, 10(-3) M calcium, cobalt, copper, manganese, magnesium, sodium, or potassium had no effect on the rate of beta A4 aggregation. In sharp contrast, aluminum, iron, and zinc under the same conditions strongly promoted aggregation (rate enhancement of 100-1,000-fold). The aggregation of beta A4 induced by aluminum and iron is distinguishable from that induced by zinc in terms of rate, extent, pH and temperature dependence. These results suggest that high concentrations of certain metals may play a role in the pathogenesis of AD by promoting aggregation of beta A4.

Aluminum↗
PubMed1993

Intraepithelial mast cells in allergic and nonallergic asthma. Assessment using bronchial brushings.

Mast cell mediators are known to contribute to the pathogenesis of asthma. There is some disagreement concerning the numbers of mast cells in asthmatic mucosa. In this study a standardized bronchial brush technique was developed and used to assess intraepithelial mast cells and other inflammatory cells in allergic and nonallergic asthmatic and nonasthmatic subjects. A total of 10 nonasthmatic (5 allergic) and 13 asthmatic (8 allergic) subjects with stable controlled asthma treated with beta-agonist only were assessed by history, spirometry, allergy prick tests, and methacholine airway responsiveness. During fiberoptic bronchoscopy, bronchoalveolar lavage (BAL) was performed from the middle lobe and standardized bronchial brushings were taken from the lingula and left lower lobe bronchi. Quantitative cell counts were performed blind to the clinical characteristics of the subjects. The average total cell recovery from the brushings was 1.04 (SEM 0.09) x 10(6) ml, with a cell viability of 64% (5.3%). Reproducible total cell and mast cell counts were obtained from brushings taken from two lobar bronchi (ICC 0.86). Mast cells were significantly elevated in asthmatic compared with nonasthmatic subjects (1.5 +/- 0.34 versus 0.15 +/- 0.06%). Allergic asthmatic subjects had the greatest numbers of mast cells (1.86 +/- 0.48%); however, the numbers present in brushings from nonallergic asthmatic subjects were also increased (1.03 +/- 0.45%). The mast cells had the staining characteristics of mucosal mast cells, with formalin-blockable metachromatic staining and positive staining for tryptase. Both asthmatic groups also had elevated BAL eosinophils, and neutrophils were elevated in nonallergic asthmatic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Reversible in vitro growth of Alzheimer disease beta-amyloid plaques by deposition of labeled amyloid peptide.

The salient pathological feature of Alzheimer disease (AD) is the presence of a high density of amyloid plaques in the brain tissue of victims. The plaques are predominantly composed of human beta-amyloid peptide (beta A4), a 40-mer whose neurotoxicity is related to its aggregation. Radioiodinated human beta A4 is rapidly deposited in vitro from a dilute (less than 10 pM) solution onto neuritic and diffuse plaques and cerebrovascular amyloid in AD brain tissue, whereas no deposition is detectable in tissue without performed plaques. This growth of plaques by deposition of radiolabeled beta A4 to plaques is reversible, with a dissociation half-time of approximately 1 h. The fraction of grey matter occupied by plaques that bind radiolabeled beta A4 in vitro is dramatically larger in AD cortex (23 +/- 11%) than in age-matched normal controls (less than 2%). In contrast to the human peptide, rat/mouse beta A4 (differing at three positions from human beta A4) does not affect the deposition of radiolabeled human beta A4. beta A4 has no detectable interaction with tachykinin receptors in rat or human brain. The use of radioiodinated beta A4 provides an in vitro system for the quantitative evaluation of agents or conditions that may inhibit or enhance the growth or dissolution of AD plaques. This reagent also provides an extremely sensitive method for visualizing various types of amyloid deposits and a means for characterizing and locating sites of amyloid peptide binding to cells and tissues.

Aged↗
PubMed1992

Membrane cofactor protein (CD46) protects cells from complement-mediated attack by an intrinsic mechanism.

The cleavage of C3 is a critical step for complement (C) activation in the classical and alternative pathways. This reaction is controlled by the regulators of C activation protein family. Membrane cofactor protein (MCP) is a cofactor for the factor I-mediated inactivation of C3b and C4b. As a widely distributed membrane protein, MCP may protect host cells from inadvertent C activation. Human MCP has recently been shown to protect transfected rodent cells from human C-mediated lysis. In this report the relationship of MCP expression to C3b deposition and cytoprotection was examined using NIH/3T3 cells transfected with human MCP and exposed to human serum as a source of C and naturally occurring anti-mouse antibody. MCP inhibited C3b deposition in a dose-dependent fashion and inhibited lysis of the mouse cells expressing it. MCP did not inhibit lysis on bystander cells. These results demonstrate the protective role of MCP, at the cellular level, by an intrinsic mechanism.

3T3 Cells↗
PubMed1992

Receptor binding sites for cholecystokinin, galanin, somatostatin, substance P and vasoactive intestinal polypeptide in sympathetic ganglia.

Sympathetic ganglia are innervated by neuropeptide-containing fibers originating from pre- and postganglionic sympathetic neurons, dorsal root ganglion neurons, and in some cases, myenteric neurons. In the present report receptor autoradiography was used to determine whether sympathetic ganglia express receptor binding sites for several of these neuropeptides including bombesin, calcitonin gene-related peptide-alpha, cholecystokinin, galanin, neurokinin A, somatostatin, substance P, and vasoactive intestinal polypeptide. The sympathetic ganglia examined included the rat and rabbit superior cervical ganglia and the rabbit superior mesenteric ganglion. High levels of receptor binding sites for cholecystokinin, galanin, somatostatin, substance P, and vasoactive intestinal polypeptide were observed in all sympathetic ganglia examined, although only discrete neuronal populations within each ganglion appeared to express receptor binding sites for any particular neuropeptide. These data suggest that discrete populations of postganglionic sympathetic neurons may be regulated by neuropeptides released from pre- and postganglionic sympathetic neurons, dorsal root ganglion neurons, and myenteric neurons.

Animals↗
PubMed1992

Trigeminal and dorsal root ganglion neurons express CCK receptor binding sites in the rat, rabbit, and monkey: possible site of opiate-CCK analgesic interactions.

125I-Bolton-Hunter sulfated cholecystokinin-8 was used to localize and characterize cholecystokinin (CCK) receptor binding sites in trigeminal and dorsal root ganglia, and in the spinal cord of the rat, rabbit, and monkey. In the rabbit and monkey, a substantial number, 90 +/- 21% and 24 +/- 8%, respectively, of trigeminal and dorsal root ganglion neurons express CCK binding sites. In the spinal cord, the highest concentration of CCK receptors is found in laminae I and II, which is the major termination site of dorsal root ganglia neurons expressing CCK receptor binding sites. Neonatal capsaicin treatment of the rat results in a 70% decline in CCK receptor binding sites in laminae I and II of the spinal cord, indicating that dorsal root ganglia neurons are a major source of CCK receptors in the spinal cord. Pharmacological experiments using selective CCK-A and CCK-B receptor antagonists demonstrate that CCK-B is the prominent CCK receptor subtype in trigeminal and dorsal root ganglia neurons in the rat, rabbit, and monkey. In the rat and rabbit spinal cord, CCK-B binding sites are the prominent subtype, whereas in the monkey cord, CCK-A is the prominent receptor subtype. These results demonstrate that CCK-B receptors are expressed by a substantial percentage of dorsal root ganglion neurons at all spinal levels, and that CCK may antagonize opiate analgesia at the level of the primary afferent neuron itself.

Analgesics↗
PubMed1989

Chronic cough and gastroesophageal reflux.

We reviewed the charts of 20 patients with chronic cough of unknown cause who had been referred to a tertiary care respiratory centre from 1980 to 1984 to determine whether gastroesophageal reflux (GER) was a contributing factor. Fifteen of the patients complained of symptoms suggestive of GER: radiologic investigation of the upper gastrointestinal tract revealed hiatus hernia and GER in four, hiatus hernia alone in three, GER alone in two, decreased esophageal peristalsis in one and normal findings in four. Fibreoptic bronchoscopy in the four former smokers and one nonsmoker showed diffuse mucosal erythema. A chest x-ray film in one patient showed an infiltrate at the base of the right lung; transbronchial biopsy revealed vegetable material, which confirmed pulmonary aspiration. A 3-month course of medical antireflux treatment (dietary and lifestyle changes, elevation of the head of the bed and administration of cimetidine, antacid and metoclopramide) relieved the chronic cough in 14 of the 20 patients. Of the remaining patients one was lost to follow-up and five had GER confirmed by means of esophagoscopy, esophageal motility testing and long-term intraesophageal pH monitoring; four of the five patients underwent fundoplication and were asymptomatic 3 months after surgery. Antireflux therapy should be considered in patients with chronic cough when other causes have been ruled out, even if there are no GER symptoms. If the treatment fails, full investigation for GER is recommended; if GER is confirmed, surgery should be considered.

Adult↗
PubMed1986

Gastroesophageal reflux: clinical presentations, diagnosis and management.

Symptomatic gastroesophageal reflux occurs daily in an estimated 7% of adults and weekly or monthly in 29%. Untreated it can lead to esophageal erosions, ulceration and stricture formation. The pathogenesis is often multifactorial: defects in the function of the lower esophageal sphincter, esophageal clearance mechanisms and gastric emptying combine to produce frequent lengthy periods during which the lower esophagus is bathed in regurgitated acid. In most patients reflux disease is easily recognized as recurrent heartburn, regurgitation or dysphagia, or a combination. When acute chest pain or respiratory illness is the primary presenting complaint the patient needs particularly careful investigation to determine whether the symptoms are due to a primary cardiac or respiratory condition, are secondary to gastroesophageal reflux alone or represent a combination of disorders. Endoscopy with biopsy and long-term pH monitoring are the most reliable ways of determining whether reflux disease is present. Additional investigations, such as exercise testing, cardiac catheterization or inhalation challenge, may be needed in patients with cardiac or respiratory symptoms. Treatment should follow a stepped-care approach and in most patients should begin with changes in lifestyle, including dietary manipulation, reducing alcohol and cigarette consumption, and raising the head of the bed, together with appropriate use of antacids or alginate-antacid combinations. H2-receptor antagonists and agents to improve both gastric emptying and the tone of the lower esophageal sphincter may be added in sequence. Most patients will respond well to this regimen. Surgery should be considered only for those with intractable symptoms or with complications (e.g., stricture formation, bleeding, development of dysplastic epithelium in those with Barrett's esophagus, or secondary pulmonary disease that does not respond to medical management). It is successful in 85% of well-selected patients and has few complications.

Antacids↗
PubMed1984

Rate of change of alveolar carbon dioxide and the control of ventilation during exercise.

The relationship between rate of change of alveolar PCO2 (delta PA, CO2/delta te), CO2 output (VCO2) and ventilation (VE) has been determined following a rapid increase in exercise intensity, to test the hypothesis that VE is related to VCO2 by a feed-forward control system responding to delta PA, CO2/delta te. There was a close relationship between delta PA, CO2/delta te and VCO2 (delta PA, CO2/delta te = 3.2 VCO2 + 0.85), but delta PA, CO2/delta te increased more rapidly than VCO2. Increases in mean inspiratory flow, an index of inspiratory drive, were more closely related to changes in delta PA, CO2/delta te than to changes in VCO2. Increases in VE during transient and steady-state conditions may be described by the equation: VE = 6.76 delta PA, CO2/delta te -3.50, a relationship which is consistent with a feed-forward control system.

Carbon Dioxide↗
PubMed1984

Alveolar gas exchange during exercise: a single-breath analysis.

Changes in expired alveolar O2 and CO2 were measured breath-by-breath in six healthy male subjects (mean age 30 yr, mean weight 80 kg) at rest, 600 kpm/min, and 1,200 kpm/min. Changes were expressed in relation to expired volume (liters) and time (s) and separated into an initial dead-space component using the Fowler method applied to expired CO2 and O2, and alveolar slope. The alveolar slopes with respect to time (dPACO2, dPAO2, Torr/s) increased in relation to CO2 output (VCO2, 1/min, STPD) and O2 intake (VO2, 1/min, STPD) but were reduced by increasing tidal volume (VT, liters, BTPS): dPACO2 = 2.7 + 4.6(VCO2) - 1.9(VT) (r = 0.97); and dPAO2 = 2.3 + 5.5(VO2) - 1.9(VT) (r = 0.96). From the alveolar slopes, tidal volume, and airway dead-space volume, mean expired alveolar PO2 and PCO2 (PAO2, PACO2) were calculated. There was no change in arterialized capillary PCO2 (PaCO2) between rest (38.9 +/- 0.66 Torr) and heavy exercise (38.2 +/- 2.18 Torr), but mean PACO2 rose from 36.7 +/- 0.55 to 40.8 +/- 1.67 Torr during heavy exercise. There was no change in arterialized capillary (mean = 84.3 +/- 0.7 Torr) or alveolar (mean = 107.2 +/- 1.03 Torr) PO2. Exercise increases the fluctuations in alveolar gas composition leading to discrepancies between the PCO2 in mean alveolar gas and arterial blood to an extent that is dependent on VCO2 and VT.

Adult↗
PubMed1984

Gastroesophageal reflux and chronic respiratory disease.

Recent advances in technology have made it possible to detect gastroesophageal reflux (GER) through monitoring of esophageal pH, lower esophageal sphincter pressure, and esophageal motility for prolonged periods, including sleep. When these methods are applied to patients with chronic respiratory disease, as many as 65% have GER; improvement in respiratory status has often been reported after treatment of the GER. This article reviews the evidence for the association between GER and chronic respiratory disease, the possible physiologic mechanisms underlying this association, and the implications for therapy.

Asthma↗