Mechanism of rhinovirus-induced changes in airway smooth muscle responsiveness

An important interplay exists between specific viral respiratory infections and altered airway responsiveness in the development and exacerbations of asthma. However, the mechanistic basis of this interplay remains to be identified. This study addressed the hypothesis that rhinovirus (RV), the most common viral respiratory pathogen associated with acute asthma attacks, directly affects airway smooth muscle (ASM) to produce proasthmatic changes in receptor-coupled ASM responsiveness. Isolated rabbit and human ASM tissue and cultured ASM cells were inoculated with human RV (serotype 16) or adenovirus, each for 6 or 24 h. In contrast to adenovirus, which had no effect, inoculation of ASM tissue with RV induced heightened ASM tissue constrictor responsiveness to acetylcholine and attenuated the dose-dependent relaxation of ASM to beta-adrenoceptor stimulation with isoproterenol. These RV-induced changes in ASM responsiveness were largely prevented by pretreating the tissues with pertussis toxin or with a monoclonal blocking antibody to intercellular adhesion molecule-1 (ICAM-1), the principal endogenous receptor for most RVs. In extended studies, we found that the RV-induced changes in ASM responsiveness were associated with diminished cAMP accumulation in response to dose-dependent administration of isoproterenol, and this effect was accompanied by autologously upregulated expression of the Gi protein subtype, Gialpha3, in the ASM. Finally, in separate experiments, we found that the RV-induced effects on ASM responsiveness were also accompanied by autologously induced upregulated mRNA and cell surface protein expression of ICAM-1. Taken together, these findings provide new evidence that RV directly induces proasthmatic phenotypic changes in ASM responsiveness, that this effect is triggered by binding of RV to its ICAM-1 receptor in ASM, and that this binding is associated with the induced endogenously upregulated expression of ICAM-1 and enhanced expression and activation of Gi protein in the RV-infected ASM.     

Cytokine responsiveness of primitive progenitors in acute myelogenous leukemia

Long-term cultures (LTC) and immunodeficient (NOD/SCID) mice have been used to quantitate and characterize primitive malignant progenitors from patients with acute myelogenous leukemia (AML). In 5-week-old LTC of cells from newly diagnosed patients with AML cytogenetically abnormal as well as normal progenitors could be easily detected and their numbers increased by cytokine supplements to the cultures. Sixty percent of AML samples will engraft in NOD/SCID mouse marrow. The frequency and level of engraftment of human cells detected appears to vary among the different subtypes of AML but is not generally affected by treatment of the mice with human cytokines. Both the LTC and NOD/SCID mouse assay show promise as tools to allow characterization of differences between leukemic stem cells which maintain malignant hematopoiesis in individual patients and, more importantly, between these cells and their normal stem cell counterparts.     

Seasonal changes in growth and energy status in the Third World

Two-color immunofluorescence histochemistry and immunohistochemistry in combination with retrograde tract-tracing techniques were used to examine the relationship of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)-selective glutamate receptor subunits (GluR1, GluR2/3/4c and GluR4) to identified populations of striatal projection neurons and interneurons. The majority of striatonigral and striatopallidal neurons were double-labeled for GluR2/3/4c. These findings were confirmed using calbindin to label matrix projection neurons. In contrast, immunostaining of the GluR1 subunit was not observed to co-localize with any striatal projection neurons. Striatal interneurons immunostained for parvalbumin were also labeled by antibodies directed against the GluR1 subunit. Approximately 50% of parvalbumin neurons also contained GluR2/3/4c. Somatostatin immunoreactivity did not co-localize with either the GluR1 or GluR2/3/4c subunits. GluR4-immunoreactive neurons were not observed in striatum. This study demonstrates that AMPA-selective glutamate receptors are differentially localized on subpopulations of striatal neurons and interneurons. These findings suggest that discrete striatal neuron populations may express different AMPA receptor subunit combinations which may account for their functional specificity.     

CD95 predicts responsiveness to tretinoin in acute promyelocytic leukemia

We describe a predictive marker (CD95) for the responsiveness to tretinoin (RA) in acute promyelocytic leukemia (APL). Functional CD95 expression during RA treatment have been observed only in those patients who responded to RA. Expression of CD95 (Fas antigen), which plays a major role in apoptosis, was determined by fluorescence activated cell sorter (FACS) analysis. APL cases in which no enhancement of CD95 expression was observed showed no response to RA and did not obtain complete remission. We propose that CD95 can predict the clinical response to RA probably due to differentiation.     

Age-related changes in responsiveness of various rat tissue lymphocytes to mitogens

The effect of age on the mitogen responses of rat lymphoid tissues was investigated. Evaluation was based on using the in vitro proliferative response of lymphocytes from various tissues of Fischer-344 rats (2, 7, 13, 19 and 25 months) using concanavalin A (Con A), phytohemagglutinin-P (PHA-P), pokeweed mitogen (PWM) and Mycoplasma neurolyticum. The stimulation index (S.I.) for cervical, mesenteric, thymic and splenic lymphocytes treated with Con A and PHA-P was greatest for 2-month-old rats and lowest for 19-month-old rats; however, no age-related change was observed with either PWM or M. neurolyticum. The levels of mitogenic responses for lymph nodes in the two different anatomical sites paralleled one another, with the cervical lymphocytes showing a greater response. The splenic lymphocytes responded less than either lymph node lymphocyte population. When PHA-P treatment of splenic lymphocytes followed the removal of the plastic adherent population, the S. I. of the resulting non-adherent population was comparable to the S. I. of other tissue lymphocytes; however, an age-related decrease was still observed. The PHA-P proliferative response of either the 7- or 19-month non-adherent population was suppressed by the 7-month adherent population and not by the 19-month adherent population i.e., adherent population interaction with non-adherent population decreases with age.     

Angiographic changes following acute spinal cord compression: an experimental study in monkeys

Acute paraplegia was produced in monkeys by abruptly inflating a balloon catheter within the epidural space. The arteriographic and epidural venous changes following such trauma were serially evaluated. Spinal-cord arteriograms following cord injury remained normal during an acute (four-hour) follow-up. Serial epidural venograms demonstrated obstruction of epidural veins within four hours at the site of contusion in less than half of the animals studied. Neither spinal arteries nor epidural showed consistent diagnostic changes following trauma due to acute epidural compression.     

Establishment of an adrenocortical carcinoma xenograft with normotensive hyperaldosteronism in vivo

We established a xenograft line of human adrenocortical carcinoma (ADR-1), and analyzed the hyperaldosteronism induced by the xenograft in vivo. Adrenocortical carcinoma specimens from a 25-year-old woman were subcutaneously inoculated into nude mice (BALB/c-nu/nu) followed by serial passages in vivo. ADR-1 retained the histopathological features (trabecular and sinusoid nests) seen in the primary carcinoma. The patient showed hyperaldosteronism (serum aldosterone >4000 pg/ml) and hypokalemia (serum K 2.1 mEq/l), but did not show hypertension. The nude rat (F344-rnu/rnu) bearing ADR-1 showed hyperaldosteronism (serum aldosterone 3320+/-1420 pg/ml; control 191+/-130 pg/ml) and hypokalemia (serum K 3.4+/-0.4 mEq/l; control 5.2+/-1.0 mEq/l) in vivo, and hypertension was not obvious. ADR-1 was shown immunohistochemically to retain production of human-specific corticosteroid synthetase. The xenograft ADR-1 will be useful to elucidate the regulatory mechanism of normotensive hyperaldosteronism.     

Seasonal changes in heat balance of dogs acclimatized to outdoor climate

Heat production (M), dry heat loss (R+C), evaporative heat loss (E) and rectal temperature (Tre) were measured in a direct calorimeter in female mongrel dogs acclimatized to outdoor climate at Kanazawa (latitude; 36 degrees 35" N), Japan. M and total dry and evaporative heat losses (HL) were minimum at calorimeter wall temperatures (TW) of 26-29 degrees C in summer and 22-26 degrees C in winter (thermoneutral temperature; TNT). The seasonal shift of the lower critical temperature was confirmed. At TW below TNT, the values of M and HL were significantly higher in summer. At TW above TNT, these values increased. A TNT and above, M and HL were significantly higher in winter. (R+C) decreased linearly with increasing TW in both seasons. AT TW below 26 degrees C, (R+C) were significantly higher in summer. At TW above 26 degrees C, E increased greatly. The values of E were significantly higher in winter at TW 29-32 degrees C. Tre remained nearly constant at TNT and below, and increased at TW above TNT in both seasons. Mean body surface temperature (Tsf) decreased with decreasing TW. Body thermal conductance (K) was minimum at TW below 26 degrees C in summer and at TW below 22 degrees C in winter. At TW above these temperatures, K increased significantly. Whole body insulation (I) was significantly higher in winter, particularly at TW 18 degrees C. These results suggest that the dogs reared outdoors in winter acclimatized to cold in two ways; by increasing the insulating effect of the fur coat and by elevating resting heat production.     

The expression of steroidogenic acute regulatory protein (StAR) in bovine adrenocortical cells

StAR protein may facilitate rapid transfer of cholesterol from the outer to the inner mitochondrial membrane, the site at which cholesterol is converted to pregnenolone by the cholesterol side chain cleavage complex. We have studied the effect of ACTH treatment on StAR mRNA and protein levels in bovine adrenocortical cells in primary culture. Cells were initially cultured for 3 days after isolation, and then treated with ACTH (10(-8) M) for various times up to 24 hours. Northern analysis of total BAC mRNA, using a [alpha32P]-labelled cDNA probe encoding a 5' region of bovine StAR mRNA, revealed two principal hybridising species of 1.6 and 3.0 kb. Western immunoblot analysis revealed a principal band at 30 kDa. Levels of both StAR mRNA and protein showed an increase at 1 hour, reached a maximum at around 6 hours and declined to basal levels at 24 hours. Cortisol secretion (measured by RIA) showed a similar change over the same period. From these results it appears that StAR mRNA and protein levels in BAC are acutely regulated in concert with ACTH-stimulated cortisol secretion.     

Electrocardiographic changes in acute n-butylisocyanate poisoning

The effect of phenobarbital and phenylbutazone treatment on the renal damage induced by the toxic mushroom Cortinarius speciosissimus was studied in female rats. Phenobarbital sodium was given in drinking water (0.05% solution) for 11 days prior to the administration of mushroom. Phenylbutazone was given s.c. in doses of 50 and 100 mg/kg 1 h before the mushroom administration. Homogenized mushroom was given orally by stomach tube at a dose of 250 mg dried mushroom/kg body weight. It was found that the phenobarbital treatment strongly increased the damage induced by C. speciosissimus in the tubules of the kidney cortex but had no effect on the inflammation in the renal outer medullary zone induced by this toxic mushroom. Phenylbutazone treatment had no effect on the renal damage induced by C. speciosissimus.     

Effect of acute corticotropin releasing factor on pituitary-adrenocortical responsiveness in elderly women and men

Aging is related to critical changes of the hypothalamo-pituitary-adrenal function. A decline in serum DHEA levels has been demonstrated in healthy elderly subjects, while ACTH and cortisol concentrations remain at normal values. The purpose of the present study was to investigate the effect of aging on pituitary-adrenal responsiveness to hCRF in subjects of both sexes. A group of 12 physically and mentally healthy elderly subjects and a group of 12 young controls of both sexes have been selected. Blood samples were collected before and after i.v. bolus injection of hCRF; ACTH, cortisol and DHEA levels were then determined by RIA. Basal ACTH and cortisol levels did not result statistically different between controls and elderly subjects, while DHEA showed a clear and significant age-related decrease (p < 0.01). Following the hCRF injection, the responses of ACTH, cortisol and DHEA in aged subjects were higher than in young controls; ACTH (p < 0.03) and cortisol (p < 0.01) were higher in aged women than in men. The present study demonstrated that aging is associated with an increased responsiveness of ACTH, cortisol and DHEA to exogenous hCRF supply. A hyperactivation of the pituitary-adrenal secretory activity may explain the age-related of the same axis. Gender probably has a significant influence on basal and stimulated hormonal secretion. In conclusion, hCRF test may become a useful clinical tool in establishing a neuroendocrine correlation with central disturbances associated to aging.     

Prepartum changes in maternal responsiveness and nest defense in Rattus norvegicus..

Examined 297 female rats for changes in maternal responsiveness during late pregnancy by exposing Ss to foster pups in tests lasting 15–30 min under conditions favoring the rapid initiation of maternal behavior. Ss were divided into 17 groups according to state of pregnancy (nonpregnant, Day 17, Day 20, Day 21, or Day 22); type of nest; and parity. Nulliparous Ss were compared with primiparous and with experienced breeders. Nest defense was observed by introducing unfamiliar males (2-min tests) on Day 22. Results are presented for 3 periods: Days 17–20, when maternal responsiveness was lower than in the nonpregnant condition; Day 21, when maternal responsiveness returned to or rose above nonpregnant levels; and on Day 22 (the 3.5 hrs prior to delivery), during which 90% of Ss almost immediately retrieved, gathered, and tended foster pups and during which 92% attacked the unfamiliar intruders. (Attacks were rare earlier.) Maternally experienced Ss were more responsive to pups than nulliparous Ss when nonpregnant and throughout late pregnancy, but both groups were equally likely to show prepartum aggression. (22 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Seasonal changes in plasma 25-hydroxyvitamin D concentrations of young American black and white women

Seasonal changes in 25-hydroxyvitamin D concentrations were studied in 51 black and 39 white women aged 20-40 y from Boston. Individual measurements were made in February or March (February-March), June or July (June-July), October or November (October-November), and the following February or March (February-March). Samples from the four visits were analyzed in batches at the end of the study. Plasma 25-hydroxyvitamin D was substantially lower in black than in white women at all the time points, including February-March when values were lowest (30.2 +/- 19.7 nmol/L in black and 60.0 +/- 21.4 nmol/L in white women) and June-July when they were highest (41.0 +/- 16.4 nmol/L in black and 85.4 +/- 33.0 nmol/L in white women). Although both groups showed seasonal variation in 25-hydroxyvitamin D concentrations, the mean increase between February-March and June-July was smaller in black women (10.8 +/- 14.0 nmol/L compared with 25.4 +/- 29.8 nmol/L in white women, P = 0.006) and their overall amplitude of seasonal change was lower (P = 0.001). Concentrations of serum parathyroid hormone in February-March were significantly higher (P < 0.005) in black women (5.29 +/- 2.32 pmol/L) than in white women (4.08 +/- 1.41 pmol/L) and were significantly inversely correlated with 25-hydroxyvitamin D in blacks (r = -0.42, P = 0.002) but not in whites (r = -0.19, P = 0.246). Although it is well established that blacks have denser bones and lower fracture rates than whites, elevated parathyroid hormone concentrations resulting from low 25-hydroxyvitamin D concentrations may have negative skeletal consequences within black populations.     

A test of heightened external responsiveness in an alcoholic population.

In an effort to extend S. Schachter's stimulus-bound hypothesis from obesity to alcoholism, comparisons among 45 alcoholic, obese, and nonalcoholic normal-weight outpatients at a VA hospital were made on 4 measures of externality. It was predicted that alcoholics and obese persons would be significantly more responsive to external stimuli than control Ss, and alcoholics and obese persons would not differ significantly from each other. The predictions were confirmed on 2 measures, 1 of which (a reaction time task) was a replication from Schachter and J. Rodin (1974). The methodological adequacy of the other 2 tests is questioned, especially with respect to their validity in measuring externality. Results lend some support to the hypothesis that alcoholics, like the obese, exhibit a differential reliance on external and internal cues. The implications of heightened external responsiveness for understanding craving and loss of control, 2 defining symptoms of alcoholism, and recent treatment strategies are discussed. (36 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hematological and biochemical changes in acute leukemic patients after chemotherapy

AIM: To study hematological and biochemical profiles in acute leukemic patients before and after chemotherapy. METHODS: Sera from 20 normal persons were compared with those from 40 patients of whom 20 patients were followed up after 6-8 months of treatment with cyclophosphamide, vincristine, and prednisolone. RESULTS: Hemoglobin, hematocrit and platelet count were decreased while reticulocyte count, blood sedimentation, total leukocyte count, bleeding time, bilirubin, blood coagulation time, alanine aminotransferase, lactate dehydrogenase, creatinine, and urea were increased in acute myelocytic patients compared to normal. A similar pattern was observed in acute lymphocytic patients except there was no significant increase in serum urea. CONCLUSION: In acute leukemic patients blood chemistry and hematology are useful during diagnosis and treatment. After 6-8 months of treatment 50% remission occurred.     

Expression of adrenomedullin mRNA in adrenocortical tumors and secretion of adrenomedullin by cultured adrenocortical carcinoma cells

Immunoreactive-adrenomedullin concentrations and the expression of adrenomedullin mRNA were studied in the tumor tissues of adrenocortical tumors. Northern blot analysis showed the expression of adrenomedullin mRNA in tumor tissues of adrenocortical tumors, including aldosterone-producing adenomas, cortisol-producing adenomas, a non-functioning adenoma and adrenocortical carcinomas, as well as normal parts of adrenal glands and pheochromocytomas. On the other hand, immunoreactive-adrenomedullin was not detected in about 90% cases of adrenocortical tumors (<0.12 pmol/g wet weight (ww)). Immunoreactive-adrenomedullin concentrations ranged from 0.44 to 198.2 pmol/g ww in tumor tissues of pheochromocytomas and were 9.2 +/- 1.2 pmol/g ww (mean +/- SD, n = 4) in normal parts of adrenal glands. Adrenomedullin mRNA was expressed in an adrenocortical adenocarcinoma cell line, SW-13 and immunoreactive-adrenomedullin was detected in the culture medium of SW-13 (48.9 +/- 1.8 fmol/10(5) cells/24h, mean +/- SEM, n = 4). On the other hand, immunoreactive-adrenomedullin was not detectable in the extract of SW-13 cells (<0.09 fmol/10(5) cells), suggesting that adrenomedullin was actively secreted from SW-13 cells without long-term storage. These findings indicate that adrenomedullin is produced and secreted, not only by pheochromocytomas, but also by adrenocortical tumors. Undetectable or low levels of immunoreactive-adrenomedullin in the tumor tissues of adrenocortical tumors may be due to very rapid secretion of this peptide soon after the translation from these tumors.