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We evaluated G-proteins that are components of adenylyl cyclase (AC) signal transduction in erythrocyte and lymphocyte membranes from 26 family history positive (FHP) non-alcoholic and 26 family history negative (FHN) nonalcoholic subjects. Subjects were classified as FHP if their father met criteria for alcohol dependence; as FHN, if there was no history of alcoholism in any first or second degree relatives. Immunoblot analysis indicated that levels of erythrocyte membrane Gs alpha from FHP subjects were greater than levels in FHN subjects (171 +/- 11 vs 100 +/- 6, P < 0.001). To confirm the results of the immunoblot analysis, Gs alpha was quantitated by cholera toxin-dependent [32P]ADP-ribosylation. Levels of erythrocyte [32P]ADP-ribose-Gs alpha from FHP subjects were greater than levels in FHN subjects (236 +/- 28 vs 100 +/- 14, P < 0.001). Gs alpha levels did not correlate with age or alcohol consumption. By contrast to differences in Gs alpha, immunoblot analysis showed similar levels of Gi(2)alpha and Gi(3)alpha in erythrocyte membranes of FHP and FHN subjects. Pertussis toxin-catalyzed [32P]ADP-ribosylation of Gi-like G-proteins confirmed the immunoblot observations. Lastly, compared to FHN subjects, FHP subjects had enhanced Gs alpha expression in lymphocyte membranes as well (138 +/- 11 vs 100 +/- 5.5; P < 0.02). In summary, compared to FHN nonalcoholic men, FHP nonalcoholic men had greater levels of the stimulatory G-protein, Gs alpha, in erythrocyte and lymphocyte membranes. Enhanced expression of Gs alpha may be a marker of increased risk for the future development of alcoholism.

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Alcoholism is a familial disorder with both genetic and environmental determinants. The sons of alcoholic fathers have been documented to have alterations in several neuroendocrine measures. We investigated the ACTH/cortisol response to ovine corticotropin-releasing hormone (oCRH) and ethanol in men with and without a family history of alcoholism. Men were defined as family history positive (FHP) (n = 7) if their father was alcoholic; as family history negative (FHN) (n = 16), if their father was nonalcoholic. Ethanol (0.75 g/kg) or placebo was ingested over 15 min, 1 microgram/kg oCRH was administered, and plasma ACTH/cortisol levels were determined at -20, 0, 15, 30, 60, and 90 min after oCRH. Following placebo, FHP men had lower peak ACTH response to oCRH than did FHN men (12 +/- 2 vs 20 +/- 2 pmol/liter, P = 0.04). In FHN men, plasma ACTH response to oCRH was blunted during the ethanol session compared to the placebo session (13 +/- 1 vs 20 +/- 2 pmol/liter; P = 0.006). In contrast, FHP men had similar ACTH responses to oCRH during ethanol and placebo sessions. Cortisol responses to oCRH were similar in both groups during both sessions. In summary, FHP and FHN nonalcoholic men had different plasma ACTH responses following the administration of oCRH.

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Historically, ethanol exposure has been thought to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. However, recent studies have demonstrated decreased responsiveness to metyrapone and insulin-induced hypoglycemia in alcoholic subjects. The present study investigated in more detail the effect of acute ethanol ingestion (0.75 g/kg) on the HPA axis in healthy nonalcoholic men (n = 14). In study 1, plasma ACTH/cortisol levels were determined basally and every 30 min over a 180-min period after the ingestion of placebo or ethanol (n = 8). When the subjects were analyzed as a group, ethanol did not alter ACTH or cortisol levels. However, in two of eight subjects, ethanol ingestion was accompanied by a rise in plasma ACTH. In study 2, ethanol or placebo was ingested over 15 min, and 1 microgram/kg ovine (o) CRH was administered (n = 9). Hormone levels were determined at 20 min before and 0, 15, 30, 60, and 90 min after iv oCRH. Compared to responses to placebo, plasma ACTH responses to oCRH were blunted during the ethanol session [peak ACTH, 14.2 +/- 1.4 vs. 20.3 +/- 3.1 pmol/L (P = 0.036); peak value minus baseline (delta), 7.3 +/- 1.4 vs. 13.4 +/- 2.6 pmol/L (P = 0.017); delta divided by baseline x 100, 131 +/- 28 vs. 197 +/- 29% (P = 0.041); area under the ACTH curve, 1082 +/- 116 vs. 1529 +/- 232 pmol/min.L (P = 0.024)]. Ethanol ingestion also significantly blunted plasma cortisol levels after oCRH compared to placebo treatment. In study 3, ethanol or placebo was ingested over 15 min, and 0.25 microgram ACTH-(1-24) was administered (n = 5). Cortisol levels, determined 20 min before and 0, 30, 60, and 90 min after ACTH treatment, were not altered by ethanol administration. In summary, mildly intoxicating doses of ethanol did not stimulate the HPA axis in six of eight subjects. However, mild intoxication significantly impaired oCRH-stimulated ACTH/cortisol secretion. We speculate that mild intoxication with ethanol may impair the ability of the HPA axis to respond to physiological stressors.

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Ethanol exposure alters signal transduction through the adenylyl cyclase (AC) system. To elucidate the basis for this effect, we investigated the AC system in peripheral lymphocytes from abstinent alcoholic men (n = 22), actively drinking alcoholic men (n = 41), and nonalcoholic control men (n = 16). Immunoblot analysis of lymphocyte membranes from abstinent alcoholics demonstrated a 3.0-fold increase in the level of Gi2 alpha protein (p < 0.05) compared with controls. However, levels of Gs alpha protein were similar in both groups. Abstinent alcoholics had a 2.9-fold increase in Gi2 alpha mRNA (p < 0.001) and a 2.7-fold increase in Gs alpha mRNA (p < 0.03) compared with lymphocytes from control subjects. Actively drinking alcoholics, in contrast, had unaltered Gs alpha protein, Gi2 alpha protein, and Gi2 alpha mRNA levels compared with control subjects, but did have a 1.8-fold increase (p < 0.01) in Gs alpha mRNA. Consistent with enhanced Gi2 alpha expression, lymphocyte membranes from abstinent alcoholics had decreased basal, prostaglandin E1-, guanosine 5'-0-(3-thiotriphosphate)-gamma S-, and forskolin-stimulated AC activity compared with both controls and actively drinking alcoholics (p < 0.05). We conclude that lymphocyte AC is reduced during abstinence from alcohol and enhanced expression of the inhibitory G-protein, Gi2 alpha, may account for this change.

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We investigated the effects of age on pituitary-adrenocortical function in healthy young (21-38 yr, n = 11) vs. old (66-78 yr, n = 11) men by drawing frequent serial basal blood samples from 2000-0800 h for measurement of ACTH and cortisol, followed by an iv ovine CRH (oCRH) stimulation test. Subjects were readmitted at intervals and given increasing doses of oral dexamethasone (0.15, 0.3, 0.6, 1 mg) at midnight, followed by repeat blood sampling from 0400-0800 h and oCRH testing. We compared mean hormone levels for the entire 12-h and three component 4-h periods of the basal visit, and for each 4-h dexamethasone visit using the Mann-Whitney U test and repeated measures analysis of variance. Pulsatile secretion was characterized using the Pulsar computer program. Basal mean 12-h and 4-h ACTH and cortisol values did not differ with age (P greater than 0.1). Pulse analysis revealed no age change in the corresponding values for peak frequency, amplitude, or duration for either hormone examined. Increasing doses of dexamethasone produced progressive inhibition of mean ACTH and cortisol levels (P less than 0.001) as well as decreased (P less than 0.01) pulse frequency, amplitude, and duration with no age differences (P greater than 0.1). ACTH and cortisol responses to oCRH were progressively suppressed by increasing doses of dexamethasone (P less than 0.02) and did not differ between age groups (P greater than 0.3) except for a slightly higher peak cortisol response (P = 0.05) in the older men at the 0.3 mg dexamethasone dose. We conclude that basal and oCRH-stimulated ACTH and cortisol secretion, as well as sensitivity of the ACTH-cortisol axis to glucocorticoid feedback suppression, are essentially unaltered with age in healthy men.

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Eleven adult Basenji dogs with immunoproliferative small intestinal disease (IPSID) were studied. Two items of history related to the digestive tract were characteristic: (i) chronic intractable diarrhea in most dogs, and (ii) progressive emaciation. Anorexia was intermittent in only a few dogs. In addition, skin lesions of various degrees of severity were observed, including alopecia of pinnae and ventrum, hyperpigmentation and hyperkeratosis of pinnae, and necrosis and ulcerations of margins of pinnae. The cause of the skin lesions was not determined; however, hypothyroidism did not appear to contribute to the skin changes. Standard hematologic and serum chemical values were not consistently abnormal. However, a poorly regenerative anemia, mild neutrophilia, and increased aspartate aminotransferase and alanine aminotransferase activities were generally observed in severely affected dogs. The Pelger-Huet anomaly was identified in dog 3. Maldigestion and malabsorption as determined by the N-benzoyl-L-tyrosyl-p-aminobenzoic acid and d-xylose test was documented to varying degrees in dogs with IPSID. Maldigestion was correlated with functional pancreatic exocrine insufficiency. Severe malabsorption was documented in only 3 dogs. Serum gastrin values were evaluated in these dogs because of a prior observation of parietal cell hyperplasia and gastric ulceration. Hypergastrinemia was documented in 3 dogs. Additional studies will be necessary to determine whether an acid hypersecretory state contributes to the pathogenesis of IPSID in Basenjis.

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Three Basenji dogs with renal tubular dysfunction were studied. Hyposthenuria and diminished urine concentrating ability, indicative of nephrogenic diabetes insipidus, were documented. Metabolic acidosis, hyperchloremia, and reduction in glomerular filtration rate also were detected in all dogs. In addition, an exaggerated response to the adrenocorticotropin test and hyperaldosteronism, believed to be secondary to decreased effective circulating blood volume, were detected in all 3 dogs. Thyroxine values were decreased in all dogs and could be correlated with histopathologic changes of the thyroid gland in 2 dogs. Gastropathy and hypergastrinemia were identified in 2 dogs. Diffuse lymphocytic-plasmacytic enteritis was evident in 2 dogs. It was concluded that a urine concentrating defect that may be secondary to hypercortisolism exists in Basenji dogs with renal tubular dysfunction.

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A serologic survey was conducted to characterize the electrophoretic patterns of serum proteins in healthy Basenji dogs (n = 137) and Basenjis with chronic diarrhea (n = 32). Serum protein electrophoresis values for Basenjis were similar to previously reported values from dogs of other breeds. Dogs with histologically confirmed lymphocytic-plasmacytic enteritis had a statistically significant (P less than 0.05) decrease in total protein, albumin, and albumin/globulin ratio. alpha 2-Globulin and gamma-globulin values were significantly increased in old dogs (9 years of age or older) with lymphocytic-plasmacytic enteritis. Although not statistically significant, gamma-globulin values were generally increased in Basenjis with lymphocytic-plasmacytic enteritis when compared with the values in age-matched clinically healthy Basenjis.

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Three dogs with demodectic mange uncomplicated by a bacterial infection and 9 dogs with demodectic mange and pyoderma were tested for their lymphocyte response to phytomitogens in vitro and for the presence of the serum's lymphocyte immunoregulatory factors (SLIF) suppressing blastogenesis. None of the 3 dogs with uncomplicated demodectic mange showed any detectable dysfunction of their lymphocytes or presence of the blastogenesis suppressing SLIF. Their lymphocytes generally responded to the mitogens with more blastogenesis than lymphocytes from healthy controls. On the other hand, in the group of 9 dogs with demodicosis complicated by a bacterial infection, high levels of the blastogenesis suppressing SLIF for concanavalin A-sensitive cells were detected in 4 dogs, for phytohemagglutinin-sensitive cells in 2 dogs, and for pokeweed mitogen-sensitive cells in 1 (of only 3 tested) dog. Dysfunction of lymphocytes per se (detected by a decreased blastogenesis in nonsuppressive normal canine and bovine sera) was detected in 3 dogs with demodicosis with pyoderma. The success of the treatment of demodectic mange or the bacterial skin infection did not correlate with the previous presence or absence of the blastogenesis suppressing SLIF. The treatment of pyoderma was less successful in dogs with an increase in blastogenesis of unstimulated cells in fresh normal canine serum over that in autologous serum. All 3 dogs with a detected dysfunction of their lymphocytes either died or were euthanatized as untreatable cases. It is concluded that the development of demodectic mange per se did not cause the appearance of the blastogenesis suppressing SLIF, which was primarily related to the appearance and extent of the secondary bacterial skin infection.

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The immunoregulatory effect of serum on phytomitogen-induced lymphocyte blastogenesis was studied in 4 sera from diseased dogs and 1 serum from a clinically healthy dog. The results indicated that: (1) Each of the diseased animals responded to the given infection with a specific pattern of blastogenesis inhibition. (2) The blastogenesis suppression in vitro was proportional to the content of the suppressive serum in the medium. (3) A simultaneous presence of the mitogen and the suppressing "serum's lymphocyte immunoregulatory factors" (SLIF) was necessary for inducing blastogenesis suppression. (4) The suppressive sera most probably acted directly on the cells. (5) The final effect of the sera on lymphocyte blastogenesis was a result of an orchestrated action of blastogenesis-supporting, augmenting, and suppressing SLIF cooperating with the mitogen. (6) The suppressive pattern varied with the individual peripheral blood lymphocytes populations used in the test. (7) The blastogenesis-suppressing SLIF was heat-stable, noncytotoxic, and was not or only partially removable by absorption with peripheral blood lymphocytes. (8) The testing of SLIF activities required the use of various animal lymphocytes and a relatively complex setup of mitogens and control serum combinations for correct interpretations.

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