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Biomedical subjects

J M Hanifin

Publications and source records attributed to J M Hanifin.

At least 91 records · Page 5Linked to original sources
PubMed1988

Altered leukocyte protein kinase activity in atopic dermatitis.

Previous studies have demonstrated elevated cyclic-AMP-specific phosphodiesterase (PDE) activity in mononuclear leukocytes (MNL) from patients with atopic dermatitis (AD). We questioned whether increased kinase activation could account for this observation. In these studies, we measured abnormally lower basal calcium/phospholipid-dependent protein kinase (PK-C) phosphorylation in MNL from patients with AD. Basal cAMP-dependent protein kinase (PK-A) phosphorylation was concomitantly higher in MNL from patients with AD. These results are in agreement with earlier reports that PK-A activity may have a negative influence on PK-C activity in certain cell systems. Stimulation with the H1-histamine agonist, thiazolylethylamine (TEA), of MNL from normal donors but not patients with AD, resulted in statistically significant increases in PK-C phosphorylation. This implies receptor down regulation or functional desensitization in AD cells. Altered basal protein kinase phosphorylation and abnormal response to selective histamine agonists seen in MNL from patients with AD could explain elevated PDE activity.

Dermatitis, Atopic↗
PubMed1988

Atopic dermatitis.

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3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Histamine induced elevation of cyclic AMP phosphodiesterase activity in human monocytes.

We have previously reported histamine desensitization of human blood mononuclear leukocytes resulting in reduced cAMP responses to beta-adrenergic agonists, histamine and prostaglandin E1. This heterologous desensitization occurred at low, micromolar histamine concentrations and was accompanied by elevation of cAMP-phosphodiesterase (PDE) activity in these cells. We have now investigated the activity of PDE in the lymphocyte and monocyte fractions of mononuclear leukocytes to determine the site of histamine effect. PDE activity per cell was higher in monocytes (0.075 +/- 0.070 units) than lymphocytes (0.026 +/- 0.08) units). Monocytes responded to 10(-6) M histamine stimulation with a much greater increase in PDE activity (0.354 +/- 0.1 units) than did lymphocytes (0.047 +/- 0.015 units). Histamine receptor studies, using thiazolylethylamine and chlorpheniramine as H1-agonist and antagonist respectively and dimaprit and cimetidine as H2-agonists and antagonists respectively, indicated that the histamine stimulation of PDE activity is mediated predominantly through H1 histamine receptor in the monocytes and the H1 receptor in the lymphocytes. Previously histamine had been thought to increase cyclic AMP by acting on H2 receptors to activate adenylate cyclase. Our studies show that stimulation of H1 or H2 receptors by low histamine concentration can cause the opposite effect i.e. increased catabolism and a net reduction in cAMP levels. The localization of this effect predominantly to monocytes indicates a potentially important mechanism for histamine action on immune regulation.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Elevated mononuclear leukocyte phosphodiesterase in allergic dogs with and without airway hyperresponsiveness.

To investigate if mononuclear leukocyte beta-adrenergic hyporesponsiveness of Basenji greyhound (BG) dogs is associated with atopy or nonspecific airway hyperresponsiveness, we examined the relationship between mononuclear leukocyte cAMP phosphodiesterase levels, airway responsiveness to methacholine, and intradermal allergen responses in 17 BG dogs, five unrelated purebred Basenjis, and five greyhounds. BG dogs were hyperresponsive to aerosols of methacholine compared to Basenjis and greyhounds. Both BG dogs and Basenjis were allergic and had increased leukocyte cAMP phosphodiesterase activity compared to greyhounds. We concluded that the leukocyte abnormality is not associated with airway hyperresponsiveness. The leukocyte abnormality is either associated with the allergic state, with some hereditary trait that BG dogs acquired from the Basenji ancestry, or the leukocyte abnormality is necessary but not sufficient for the development of airway hyperresponsiveness.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Clinical effects of diaper types on the skin of normal infants and infants with atopic dermatitis.

Cloth diapers, cellulose core diapers (conventional disposable diapers), and cellulose core diapers containing absorbent gelling material were examined for their effects on diaper rash and skin microbiology of normal infants and infants with atopic dermatitis in a 26-week double-blind clinical trial. Infants with atopic dermatitis wearing the diapers containing absorbent gelling material had significantly lower diaper rash grades than infants with atopic dermatitis wearing cloth diapers at five of eight grading visits. Infants with atopic dermatitis wearing conventional cellulose core diapers had statistically less rash at one of eight visits. There was no statistically significant difference between diaper types at three of the eight visits. At no time did the cloth group have less diaper rash than the conventional cellulose or absorbent gelling material disposable diaper group. A statistical correlation between the severity of general atopic dermatitis outside the diaper area and the diaper rash condition under the diaper occurred only in the atopic dermatitis group wearing cloth diapers. Isolation of microorganisms from the intact, uninvolved skin surface both inside and outside the diaper showed no biologically significant changes in the presence or numbers of selected skin organisms. Repeated isolation, at multiple grading visits of Staphylococcus aureus from uncompromised skin inside the diaper area was infrequent but correlated with the diagnosis of atopic dermatitis when observed.

Acrylic Resins↗
PubMed1987

Substance P-induced histamine release in human cutaneous mast cells.

Substance P is an undecapeptide found in multiple sites throughout the central and peripheral nervous systems including small unmyelinated (type C) cutaneous nerve fibers. Previous studies demonstrated that antidromic stimulation results in substance P (SP) release from nerve endings, SP stimulates histamine release (HR) from rat mast cells in vitro, and intradermal SP in humans produces wheals identical to those induced by histamine. These studies suggest a possible role for SP as a link between neurologic events and cutaneous mast cell-mediated reactions. We therefore investigated SP-induced HR in an in vitro preparation of human skin mast cells. Human foreskin sections were incubated with varying concentrations of SP. Histamine was assayed using automated fluorimetry and release was calculated as a percentage of total tissue histamine. Substance P caused dose-dependent HR over a range from 10(-5) M (1.3%) to 5 X 10(-4) M (25.1%). Histamine release was optimal at 3 mM calcium and was blocked by pretreatment with calcium chelation. Naloxone failed to block HR. These studies suggest that HR from skin mast cells by SP may play a role in neural modulation of poorly understood inflammatory skin conditions.

Calcium↗
PubMed1987

Cyclic nucleotide function in trachealis muscle of dogs with and without airway hyperresponsiveness.

We examined basal adenosine 3',5'-cyclic monophosphate (cAMP) levels, isoproterenol (ISO)-stimulated cAMP responses, basal cAMP, and guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase (PDE) activities and protein-kinase (PK) activities in trachealis muscle from five Basenji-greyhound (BG) and four greyhound dogs to determine whether the inverse relationship between in vivo and in vitro airway responsiveness could be due to altered cyclic nucleotide metabolism. Basal cAMP levels were not significantly different (PNS) in muscle from BG (11.6 +/- 0.53 pmol/mg protein) and greyhound dogs (10.30 +/- 1.60 pmol/mg protein). The cAMP responses to stimulation with ISO were enhanced in BG compared with greyhound dogs. The low Michaelis constant (1) for Km-cAMP PDE activity (Km = 0.63 microM) was significantly less (P less than 0.005) in BG dogs (1.54 +/- 0.28 pmol.min-1.mg protein-1) than greyhounds (11.76 +/- 2.48). Endogenously active PK activity was significantly greater (P less than 0.005) in BG (54.74 +/- 5.39 pmol.min-1.mg protein-1) than in greyhound dogs (15.50 +/0 2.20). Increases in PK activity with 5 microM cAMP added were not significantly different between BG (14.79 +/- 6.00) and greyhound dogs (7.04 +/- 2.14). Approximately 90% of both endogenous PK activity and cAMP-activated PK activity in BG and greyhound dogs was inhibited by a cAMP-dependent PK inhibitor (PKI'). These data suggest that decreased cyclic nucleotide degradation due to decreased cyclic nucleotide PDE activity with increased PK could account for the in vitro hyporesponsiveness of airway smooth muscle in BG dogs as a protective adaptive mechanism.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

[Changed phosphodiesterase activity of leukocytes in atopic eczema].

Leukocytes of patients with atopic eczema exhibit a variety of biochemical abnormalities, particularly an alteration in cyclic nucleotide metabolism. The basic defect is an elevation of phosphodiesterase activity in these cells, which leads to a diminished modulation of cellular immune function by cAMP. This, in turn, leads to an elevation of IgE synthesis and enhanced release of inflammatory mediators from mast cells and basophils. The phosphodiesterase defect offers new approaches to the treatment of atopic eczema.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1987

Clinical and microbial effects of cloth, cellulose core, and cellulose core/absorbent gel diapers in atopic dermatitis.

Atopic dermatitis (AD) is an inherited cutaneous inflammatory condition which may affect 10% of infants. Persons with this diathesis are more susceptible to irritants and to superficial infections. Little is known about diaper rash and diapering materials in AD. In this study we set firm criteria to identify a large group of infants with AD for comparison with a nonatopic, normal control group in terms of severity of diaper dermatitis; relationship of diaper dermatitis to diaper materials; and influence of modifying factors (bacterial and candidal colonization/infection, diarrhea, antibiotics, other illnesses, food allergy or intolerance). Babies with eczema were recruited and, from a group of 2,443 respondents, 87 satisfied carefully defined criteria for atopic dermatitis. A similarly sized (90) control group matched for age, sex, and weight was selected for absence of features of atopy or familial atopic history. Infants were assigned into balanced subgroups wearing cloth diapers, conventional cellulose diapers, or diapers containing cellulose and absorbent gelling material (AGM). Assessment of grading for atopic parameters showed statistically significant differences between the AD and normal groups at every visit. Mean diaper rash grades, as assessed by the same physicians at each visit, were significantly higher in the AD group wearing cloth diapers compared with those in AGM subgroups at five of eight visits. There was significant correlation between AD severity and diaper rash scores overall and in the AD cloth group, but not in other subgroups. Quantitative total bacterial plate counts were significantly lower in AGM than cloth diaper areas on three of eight sampling periods in the AD group.(ABSTRACT TRUNCATED AT 250 WORDS)

Cellulose↗
PubMed1986

Abnormal retinal function associated with isotretinoin therapy for acne.

Three of 50 patients treated with isotretinoin (1 mg/kg/day) for cystic acne complained of poor night vision and/or excessive glare sensitivity. While still receiving the drug or shortly thereafter, two patients were found to have abnormal dark-adaptation curves, with elevations of either cone or rod thresholds, or both. Two patients had abnormal electroretinograms (ERGs). One had a mildly abnormal electro-oculogram. The dark-adaptation curves were normal for one patient several months after isotretinoin therapy was discontinued. Two patients had elevated cone thresholds at least one year later. Six months following cessation of therapy, the ERG was still abnormal for one patient, but continued improvement was evident at 25 months; for the second patient, the ERG was normal at one year. Analysis of Naka-Rushton parameters for the ERG scotopic b-wave stimulus-response curves indicated response compression for two patients, as evidenced by a reduction in the maximum response. For one patient, the half-saturation constant was elevated 0.7 log units, suggesting reduction of retinal sensitivity, perhaps from decrease in retinal photopigment concentration. We suspect that isotretinoin may complete for normal retinol binding sites on cell surfaces or transport molecules. A prospective study is currently underway to determine if a clinically measurable adverse effect on retinal function is seen with greater frequency.

Acne Vulgaris↗
PubMed1986

Functional differences between human cutaneous mast cells and basophils: a comparison of morphine-induced histamine release.

Intravenous administration of morphine sulfate often produces urticarial and hypotensive reactions associated with elevations in plasma histamine. The source of this histamine and mechanisms controlling its release are poorly understood. Previous studies of morphine-induced histamine release compared human leukocytes to rat peritoneal mast cells. The effects of morphine on human cutaneous mast cells has not been examined. We studied in vitro histamine release from human basophils and human skin preparations containing cutaneous mast cells to evaluate their relative contribution to the pharmacologic effects of morphine. Human skin mast cell preparations showed dose-dependent histamine release over a morphine concentration range of 1.5 X 10(-5) to 4.5 X 10(-3) M, with peak release occurring at 5 X 10(-4) M, with peak release occurring at 5 X 10(-4) M. Clinically, morphine sulfate is usually injected as a 1.5 X 10(-2) M solution. Histamine release was calcium dependent and equivalent to that obtained with 3 and 10 mM strontium. Morphologic examination revealed degranulation and exocytosis occurring in morphine-stimulated tissue but not in specimens exposed to buffer alone. Lactate dehydrogenase levels did not increase following morphine incubation, thus supporting a noncytolytic mechanism of histamine release. Basophils, in contrast, showed no significant histamine release from exposure to morphine up to 10(-2) M. Concanavalin A, as a positive control in these same preparations, produced a mean histamine release of 21.0%.(ABSTRACT TRUNCATED AT 250 WORDS)

Basophils↗
PubMed1986

Pharmacophysiology of atopic dermatitis.

Atopic dermatitis is clearly characterized by altered cutaneous physiologic responses. There is a tendency to acral vasoconstriction. Rubbing causes skin pallor and white dermographism. Vascular instability is demonstrated by responses to cholinergic agents, histamine, and nicotinates. Psychophysiologic studies demonstrate exaggerated vasodilator responses to emotional stress with consequent pruritus and scratching. The itch threshold is low, duration is prolonged, and nighttime scratching movements may be frequent or almost continuous. Regardless of the inciting trigger factors, the scratching causes the damage and the severe dermatitis. Thermal as well as emotional stimuli to sweating cause severe itching in AD, yet the concept of a miliaria-type, poral occlusion mechanism remains unproven. Some studies suggest actually increased sweating along with erythema and pruritus during acute flares of AD. The concept of sweat-borne allergens causing skin reactions during sweating is interesting but has never been proven. Studies of sweat responses to pharmacologic agents have produced conflicting data, and attempts to link these responses to Szentivanyi's beta-adrenergic blockade theory are not convincing. The numerous variables of climate, season, sex, age, and habitus affect sweating greatly. Future studies must carefully control for each of these factors before pharmacologically induced sweat responses can be interpreted clearly. A number of lines of evidence suggest involvement of histamine and other mediators in the evolution of erythema, pruritus, and scratching in AD. Flares of the condition have been reproducibly evoked by only two incitants: experimental emotional stress interviews and specific food challenge in selected sensitive individuals. In the latter, increased plasma histamine has been demonstrated, presumably generated by antigen/IgE stimulated degranulation of mast cells in the gut and/or skin. The demonstrated increased histamine releasability of basophils from atopic individuals may be the result of defective cellular regulatory mechanisms. Recent studies have demonstrated increased cyclic AMP-phosphodiesterase activity in leukocytes from atopic individuals. The resultant decreased intracellular cyclic AMP removes an inhibitory factor, which in turn causes net cellular hyperresponsiveness. This effect has been shown to account, at least in part, for increased histamine release from leukocytes of patients with AD. These and other studies focused upon cell functional regulation are providing better understanding of basic biochemical abnormalities and may lead to improved diagnostic and therapeutic approaches in managing atopic disease.

Biofeedback, Psychology↗
PubMed1986

Anaphylactic reaction during anaesthesia associated with positive intradermal skin test to fentanyl.

A 29 year-old female patient suffered vascular collapse which became apparent immediately after general anaesthesia. Resuscitation was prolonged and difficult, and complicated by the need for reoperation. Based on the time history, fentanyl was suspected as the causative agent. Fentanyl allergy was confirmed by skin testing one month later. The case is discussed, and the possible reasons for the delay in appearance of symptoms and signs are considered.

Adult↗
PubMed1986

Monocyte localization of elevated cAMP phosphodiesterase activity in atopic dermatitis.

Patients with atopic dermatitis (AD) manifest a number of immune abnormalities which correlate with in vitro defects including lymphocyte transformation, chemotaxis, and cytotoxicity. Past studies have shown reduced leukocyte cyclic 3',5'-adenosine monophosphate (cAMP) levels after exposure to adenylate cyclase-active agonists, and we have demonstrated that this results from increased catabolism due to elevated cAMP-phosphodiesterase activity. These results were obtained in preparations containing mixtures of lymphocytes and monocytes. In order to determine more precisely the cellular site of the defect we have separated the leukocytes into lymphocyte- and monocyte-enriched preparations using either Percoll-gradient centrifugation or adherence isolation. Both techniques yielded over 93% pure lymphocytes, whereas the former yielded 64% monocytes compared with the latter method which generated 94% pure monocytes. Atopic monocytes, obtained by either technique, consistently showed elevated phosphodiesterase activity compared with those of the nonatopic monocytes. Such differences were not evident in lymphocyte preparations from normal and atopic subjects. In spite of the increased rate of cAMP degradation in atopic leukocytes, the resting cAMP levels do not differ from those of normal subjects. We questioned whether this is caused by increased cAMP synthesis and evaluated cellular adenylate cyclase activity. We found no evidence in AD cells for an increased rate of adenylate cyclase catalysis, either basal activity or after stimulation by forskolin. Therefore, the resting cAMP levels must have been compensated by other mechanisms. Impaired cyclic nucleotide metabolism in atopic monocytes may affect a number of immunologic and inflammatory reactions and could account for many of the clinical abnormalities in atopic diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1986

Increased metachromatic cells and lymphocytes in bronchoalveolar lavage fluid of dogs with airway hyperreactivity.

Bronchoalveolar lavage (BAL) was performed in 11 basenji greyhound (BG) dogs, which showed persistent airway hyperreactivity to methacholine and citric acid aerosols, and in 15 non-BG dogs, which were significantly less reactive to these challenges. Five of the BG dogs had never received any aerosols prior to BAL, and 3 of the non-BG dogs were allergic to Ascaris suum. No dog received aerosols for 2 wk prior to BAL. Fluid recovered was centrifuged, and aliquots were taken for histamine content and cell identification. Total cell numbers were similar in BG and non-BG dogs. The BG dogs had increased percentages of lymphocytes and metachromatic cells in BAL fluid compared with those in non-BG dogs. Lymphocytes averaged 35.5 +/- 2.3% (mean +/- SEM) and 17.2 +/- 1.2% (p less than 0.005) in BG and non-BG dogs, respectively. The BG dogs that had received previous aerosol challenge and the BG dogs never challenged had 6.2 +/- 0.4% (mean +/- SEM) and 4.6 +/- 0.6% metachromatic cells in BAL. Nonallergic non-BG dogs had 0.91 +/- 0.2% and allergic non-BG dogs had 2.6 +/- 0.5% metachromatic cells in BAL (p less than 0.05 from BG). Total histamine closely correlated with numbers of metachromatic cells in BAL (r = 0.86). Forty-nine percent fewer mast cells were detected in cell preparations fixed in formalin than in cell preparations fixed in basic lead acetate. Electron micrographs revealed 2 mast cell types on the basis of structural characteristics of the granules.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗