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Biomedical subjects

A H Hassan

Publications and source records attributed to A H Hassan.

At least 19 recordsLinked to original sources
PubMed2001

Increased intimal apoptosis in coronary atherosclerotic vessel segments lacking compensatory enlargement.

OBJECTIVES: In a histopathologic study, we assessed the balance of cell proliferation and apoptosis by counting the number of apoptotic and proliferating cell nuclear antigen-positive cells in freshly harvested atherectomy specimens from 34 patients. BACKGROUND: Remodeling of human coronary arteries is an adaptive process that alters vascular lumen size. METHODS: Intravascular ultrasound was performed prior to atherectomy. Total vessel area (area within the external elastic lamina [EEL]), lumen area and plaque area were measured at the region of interest (ROI), and at a proximal and distal reference segment, utilizing the formula Delta(%)=100x(ROI-reference segment)/reference segment. Positive arterial remodeling (R+) resulting in luminal expansion was defined as DeltaEEL >10%. Absence of remodeling (0 < DeltaEEL <10%) and constrictive arterial remodeling (DeltaEEL <0) were considered as neutral remodeling (R0) and negative remodeling (R-), respectively. RESULTS: In R- lesions, apoptotic indices (APO) were significantly elevated (17.17 +/- 2.19%) compared with R+ lesions (4.89 +/- 1.7%; p = 0.0007). In a rabbit iliac percutaneous transluminal coronary angioplasty model intimal apoptosis was increased four weeks after balloon angioplasty injury (APO 8.8 +/- 0.03%) compared with contralateral untreated segments (APO 3.0 +/- 0.04%, n = 6). Lesions with an EEL/intimal area <3.0 showed significantly more intimal apoptosis than untreated lesions (p = 0.02). CONCLUSIONS: The data indicate that constrictive remodeling of atherosclerotic coronary lesions is associated with increased apoptosis of intimal cells. We speculate that increased apoptosis is due to extensive plaque healing after episodes of symptomatic or asymptomatic plaque rupture.

Adaptation, Physiological↗
PubMed2001

Promoter targeting of chromatin-modifying complexes.

The action of multi-subunit complexes that are able to overcome the repressive effects of chromatin is an important step in the regulation of eukaryotic gene expression. Identification of complexes that modify the structure of chromatin to help factors access the underlying DNA has enhanced our understanding of how some genes are controlled. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) represent one group of complexes that regulate the level of acetylation on the N-terminal tails of core histone proteins. The SWI/SNF complex is the prototype of a second group of complexes, which use the energy of ATP-hydrolysis to alter histone-DNA contacts, leading to changes in chromatin conformation. Genetic studies in yeast have revealed that some of these multi-subunit complexes interact in vivo to control transcription of a subset of genes. It has become apparent that some gene promoters require modifications by both types of complexes. An important question regarding these two types of complexes is how they are recruited to the promoters of genes that are dependent on their activity for their expression. This review will tie together many studies on promoter recruitment of both HATs and SWI/SNF. Emphasis will be placed on recent data that demonstrates functional interplay between these two types of chromatin-remodeling activities. In addition, this review summarizes recent data demonstrating the ability of repressors and corepressors to recruit histone deacetylase complexes. Interestingly, many subunits of chromatin-modifying complexes in humans have been implicated in the development of cancer. Thus, studying how these complexes work can help us better understand human diseases.

Acetyltransferases↗
PubMed2001

Histone acetyltransferase complexes stabilize swi/snf binding to promoter nucleosomes.

To investigate the function of SWI/SNF in site-specific chromatin remodeling at promoters, we have used a purified system to analyze its distribution, function, and retention following recruitment by a sequence-specific transcription activator. Activator recruitment of SWI/SNF bound the complex to promoter proximal nucleosomes and led to localized nucleosome disruption. However, retention of SWI/SNF on the promoter required either the continued binding of the transcription activator or acetylated histones. Histone acetylation by either the SAGA or NuA4 HAT complexes increased the retention of SWI/SNF on the promoter. These data illustrate a functional link between HAT complexes and the SWI/SNF chromatin remodeling complex and provide a mechanistic basis for the ordered recruitment of these complexes.

Acetyltransferases↗
PubMed2000

Longitudinal plaque redistribution during stent expansion.

The purpose of this study was to clarify the 3-dimensional behavior of plaque during coronary stent expansion. Serial intravascular ultrasound (IVUS) studies, preintervention, and poststenting were evaluated in 32 patients treated with a single-balloon expandable tubular stent. External elastic membrane (EEM), lumen, stent, and plaque + media cross-sectional area were measured at 1-mm intervals through the entire stent as well as proximal and distal reference segments 5 mm from the stent edge. Volumetric calculations were based on Simpson's rule. Overall, the plaque + media volume through the entire lesion did not change during stent expansion (218 +/- 51 vs 217 +/- 47 mm3, p = 0.69). However, EEM and lumen volume increased significantly (EEM volume, 391 +/- 84 vs 448 +/- 87 mm3 [p < 0.0001]; lumen volume, 173 +/- 52 vs 231 +/- 54 mm3 [p < 0.0001]). The change in lumen volume correlated strongly with the change in EEM volume (r = 0.85, p < 0.0001), but poorly with the change in plaque + media volume (r = 0.37, p = 0.03). Plaque + media volume decreased in the midstent zone (59 +/- 14 vs 53 +/- 11 mm3, p = 0.0005), and increased in the distal stent zone (40 +/- 11 vs 44 +/- 9 mm3, p = 0.003), but did not change in either the proximal stent zone or reference segments. The mechanism of stent expansion is a combination of vessel stretch and plaque redistribution, translating disease accumulation from the midstent zone to the distal stent zone.

Angioplasty, Balloon, Coronary↗
PubMed2000

Subtle shifts in the ratio between pro- and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate.

Glucocorticoid receptor (GR) activation induces apoptosis of granule cells in the hippocampus. In contrast, neuroprotection is seen after mineralocorticoid receptor (MR) activation. To date there is no in vivo evidence for direct interactions between corticosteroids and any of the key regulatory molecules of programmed cell death. In this report, we show that the opposing actions of MR and GR on neuronal survival result from their ability to differentially influence the expression of members of the bcl-2 gene family; specifically, in the rat hippocampus, activation of GR induces cell death by increasing the ratio of the proapoptotic molecule Bax relative to the antiapoptotic molecules Bcl-2 or Bcl-x(L); the opposite effect is observed after stimulation of MR. The same results were obtained in both young and aged animals; however, older subjects (which were more susceptible to GR-mediated apoptosis) tended to express the antiapoptotic genes more robustly. Using a loss-of-function mouse model, we corroborated the observations made in the rat, demonstrating Bax to be essential in the GR-mediated cell death-signaling cascade. In addition, we show that GR activation increases and MR activation decreases levels of the tumor suppressor protein p53 (a direct transcriptional regulator of bax and bcl-2 genes), thus providing new information on the early genetic events linking corticosteroid receptors with apoptosis in the nervous system.

Aging↗
PubMed2000

Recruitment of the SWI-SNF chromatin remodeling complex as a mechanism of gene activation by the glucocorticoid receptor tau1 activation domain.

The SWI-SNF complex has been shown to alter nucleosome conformation in an ATP-dependent manner, leading to increased accessibility of nucleosomal DNA to transcription factors. In this study, we show that the SWI-SNF complex can potentiate the activity of the glucocorticoid receptor (GR) through the N-terminal transactivation domain, tau1, in both yeast and mammalian cells. GR-tau1 can directly interact with purified SWI-SNF complex, and mutations in tau1 that affect the transactivation activity in vivo also directly affect tau1 interaction with SWI-SNF. Furthermore, the SWI-SNF complex can stimulate tau1-driven transcription from chromatin templates in vitro. Taken together, these results support a model in which the GR can directly recruit the SWI-SNF complex to target promoters during glucocorticoid-dependent gene activation. We also provide evidence that the SWI-SNF and SAGA complexes represent independent pathways of tau1-mediated activation but play overlapping roles that are able to compensate for one another under some conditions.

Amino Acid Sequence↗
PubMed1999

Activation domain-mediated targeting of the SWI/SNF complex to promoters stimulates transcription from nucleosome arrays.

The yeast SWI/SNF complex is required for the transcription of several yeast genes and has been shown to alter nucleosome structure in an ATP-dependent reaction. In this study, we show that the complex stimulated in vitro transcription from nucleosome templates in an activation domain-dependent manner. Transcription stimulation by SWI/SNF required an activation domain with which it directly interacts. The acidic activation domains of VP16, Gcn4, Swi5, and Hap4 interacted directly with the purified SWI/SNF complex and with the SWI/SNF complex in whole-cell extracts. The similarity of activation domain interactions and transcriptional stimulation between SWI/SNF and the SAGA histone acetyltransferase complex may account for their apparent overlapping functions in vivo.

CCAAT-Binding Factor↗
PubMed1999

Plasticity of hippocampal corticosteroid receptors during aging in the rat.

Aging is commonly associated with dysregulation of the hypothalamo-pituitary-adrenal axis and cognitive impairment. On the basis of suggestions that these disruptions ensue from changes in the hippocampal complement of corticosteroid (mineralocorticoid and glucocorticoid) receptors (MR and GR), we examined the availability of hippocampal MR and GR by measuring the in vivo uptake of 3H-aldosterone and 3H-dexamethasone (selective MR and GR agonists, respectively); MR and GR mRNA levels were also measured. We observed age-related declines in both the synthesis of MR and GR and the uptake of their respective ligands. Whereas MR mRNA levels and ligand uptake declined in parallel, GR binding declined more steeply than GR mRNA. This latter result, together with our finding that aged rats show impaired corticosteroid receptor mRNA and protein up-regulation after corticosteroid withdrawal, indicates decreased transcription of MR and GR genes and posttranslational modification of GR mRNA during aging. Given that corticosteroids can influence MR and GR synthesis and binding, and based on the finding that aged subjects show reduced basal secretion of corticosterone, we propose that this relative hypocorticalism may be responsible for the changes observed in MR and GR activity, which then leads to disturbances in neuroendocrine regulation and cognitive function in aged subjects.

Aging↗
PubMed1998

Inherent glucocorticoid response potential of isolated hypothalamic neuroendocrine neurons.

Within the broader framework of facilitating investigations into the inherent responses of restricted neuronal phenotypes devoid of their in vivo afferents, serum- and steroid-free cultures enriched in corticotropin-releasing hormone (CRH), arginine vasopressin (AVP), and beta-endorphin (beta-END) peptidergic neurons were prepared from the hypothalamic paraventricular (PVN: CRH and AVP) and/or arcuate (ARC: beta-END) nuclei of juvenile male rats. The functional viability of these ARC/PVN cultures was verified by their ability to synthesize and secrete CRH, AVP, and beta-END under basal and depolarizing (veratridine) conditions in vitro. Peptide secretion was shown to be Ca2+ and Na+ dependent in that it was blocked in the presence of verapamil and tetrodotoxin, respectively. Exposure of ARC/PVN cocultures to the glucocorticoid dexamethasone (DEX) resulted in a dose-dependent increase of CRH secretion and an inhibition of AVP and beta-END; the CRH responses deviated strikingly from predictions based on in vivo experiments. Steroid withdrawal or treatment with the glucocorticoid receptor antagonist RU38486 reversed these trends. Opposite effects of DEX on CRH secretion were observed in cultures consisting of PVN cells only. Supported by studies using an opioid receptor agonist (morphine) and antagonist (naloxone), these observations demonstrate that ARC-derived (beta-END) neurons modulate the responses of PVN neurons to DEX.

Animals↗
PubMed1996

Local upregulation of corticotropin-releasing hormone and interleukin-1 receptors in rats with painful hindlimb inflammation.

Opioid peptides derived from immune cells produce analgesia by activating opioid receptors on peripheral sensory nerves in inflammation. Corticotropin-releasing hormone (CRH) and interleukin-1 beta (IL-1 beta) can release these opioids. Here we show that both corticotropin-releasing hormone and interleukin-1 beta elicit receptor-specific antinociception in inflamed paws of rats by an opioid-mediated mechanism. Autoradiographic studies demonstrate 125I-CRH and 125I-IL-1 beta binding sites on immune cells in lymph nodes and inflamed paws. This binding is of high affinity and displaceable by the respective unlabeled agonist and antagonist ligands but not by opioid or adrenergic compounds. 125I-CRH and 125I-IL-1 beta binding sites are absent on nerves and in non-inflamed subcutaneous tissue but their number is greatly enhanced in inflamed paws and lymph nodes. This upregulation of binding sites for the opioid-releasing agents corticotropin-releasing hormone and interleukin-1 beta likely represents part of the body's local response to combat inflammatory pain.

Animals↗
PubMed1996

No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia.

Pain treatment with centrally acting opiates is limited by tolerance. Tolerance is a decreasing effect of a drug with prolonged administration of that drug or of a related (e.g., endogenous) compound acting at the same receptor. This is often associated with a downregulation of receptors. In peripheral inflamed tissue, both locally expressed opioid peptides and morphine can produce powerful analgesia mediated by similar populations of opioid receptors. We hypothesized that the chronic presence of endogenous opioids in inflamed joints might convey downregulation of peripheral opioid receptors and tolerance to the analgesic effects of intraarticular morphine. We assessed these effects after arthroscopic surgery in patients with and without histologically verified synovial cellular infiltration, and we examined synovial opioid peptides and opioid receptors by immunocytochemistry and autoradiography, respectively. We found that, despite an abundance of opioid-containing cells in pronounced synovitis, morphine is at least as effective as in patients without such cellular infiltrations, and there is no major downregulation of peripheral opioid receptors. Thus, opioids expressed in inflamed tissue do not produce tolerance to peripheral morphine analgesia. Tolerance may be less pronounced for peripherally than for centrally acting opioids, which provides a promising perspective for the treatment of chronic pain in arthritis and other inflammatory conditions.

Adolescent↗
PubMed1996

Exacerbation of apoptosis in the dentate gyrus of the aged rat by dexamethasone and the protective role of corticosterone.

Glucocorticoid-induced cell loss in the dentate gyrus of rats of various ages was studied using the TUNEL procedure to detect apoptotic cells. A highly significant increase in the incidence of apoptosis was observed within the dentate hilus and granule cell layer within 24 h of a single injection of dexamethasone (DEX) in rats aged between 1 and 36 months; DEX-induced apoptosis was more pronounced with increasing age. Corticosterone (CORT) did not cause an increase in the rate of apoptosis above that found in age-matched controls. However, CORT pretreatment (3 h) resulted in a significantly attenuated DEX-induced apoptosis in both areas of the dentate gyrus. Serum CORT levels in saline-treated rats peaked at 6 months of age and reached a nadir at 36 months of age. The results indicate that (i) aged subjects are more susceptible to DEX in terms of dentate gyrus cell loss by apoptosis, (ii) CORT, which binds to Type I corticosteroid receptors with a high affinity, might serve to protect against the damaging effects of DEX which is a ligand of the Type II glucocorticoid receptor, and (iii) declining endogenous levels of CORT may increase the vulnerability of the dentate gyrus of aged rats to insult by DEX.

Aging↗
PubMed1996

The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus.

The neurosteroid tetrahydroprogesterone (5 alpha-pregnan-3 alpha-ol-20-one, allopregnanolone, THP), has been previously shown to counteract the anxiogenic effects of corticotropin-releasing hormone (CRH) and to interfere with noradrenergic and corticosteroid-mediated regulation of CRH release and gene transcription. Those observations indicated that, besides its sedative and analgesic activity, THP may also affect the neuroendocrine response to stress in a mode resembling that of corticosteroids. To examine this possibility, we compared the ability of THP, its precursor progesterone (P4), and the glucocorticoids dexamethasone (DEX) and corticosterone (CORT) to influence the pituitary-adrenal response to acute emotional stress and the adrenalectomy-induced increase in the gene transcription of the stress-related peptide arginine vasopressin (AVP) and of corticosteroid receptors (MR and GR) in the brain. Pretreatment of rats with a single dose of THP or P4 (50 micrograms/kg) significantly attenuated the elevation of plasma adrenocorticotropin (ACTH) and serum corticosterone after emotional stress; both steroids were, however, less potent than a similar dose of DEX. Administration of 1 mg of THP, CORT, or P4 to adrenalectomized (ADX) rats attenuated the increase in AVP mRNA levels in the ventromedial subdivision of the hypothalamic paraventricular nucleus (PVN), as compared with vehicle-treated ADX rats. However, whereas CORT and P4 influenced the ADX-induced increase in the transcription of both types of corticosteroid receptors in the hippocampus, these were unaffected by THP. In contrast to the glucocorticoids, THP and P4 failed to decrease plasma ACTH levels in rats deprived of endogenous steroids. These results demonstrate that the neurosteroid THP and its precursor P4 resemble glucocorticoids in their suppression of the pituitary-adrenal response to emotional stress; however, THP influences the transcription of glucocorticoid-responsive genes in brain structures involved in the regulation of the hypothalamo-pituitary-adrenal system in a fashion that is quite distinct from that obtained with glucocorticoids.

Adrenocorticotropic Hormone↗
PubMed1995

Lactation as a model for naturally reversible hypercorticalism plasticity in the mechanisms governing hypothalamo-pituitary- adrenocortical activity in rats.

Steady state levels of hypothalamic expression of the genes encoding corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), arginine vasopressin (AVP), and oxytocin (OT) were studied in rats to investigate the mechanisms underlying the transitions between hypercorticalism during lactation and normocorticalism upon weaning. During lactation, CRH mRNA levels and blood titers of adrenocorticotropin (ACTH) were found to be significantly reduced, although POMC mRNA levels in the anterior pituitary were not significantly different from those found in cycling virgin (control) rats; during all phases of lactation, an inverse relationship was observed between the blood levels of ACTH and corticosterone (CORT). Plasma prolactin (PRL) concentrations were elevated approximately 30-fold during lactation. Whereas steady state levels of OT mRNA were markedly increased throughout lactation, those of AVP mRNA were only transiently (initially) elevated, and the blood levels of these hormones were not significantly altered in lactating as compared with cycling virgin and postlactating rats. CRH and POMC gene expression and blood levels of ACTH, CORT, and PRL were normalized within 1-3 d of removal of suckling pups. The temporal relationships between the biosynthetic profiles of the various peptide hormones and the patterns of ACTH and CORT secretion during the two physiological states suggest that lactation-associated hypercorticalism does not merely result from increased ACTH secretion; although still not well substantiated at this time, the evidence points to contributory roles of PRL, OT, and AVP in the hypercorticalismic state found during lactation.

Adrenal Cortex↗
PubMed1995

Peripheral opioid receptors.

Recent experimental and clinical research has demonstrated that opioids can produce potent and receptor-specific analgesic effects outside the central nervous system. Opioid receptors are localized on peripheral terminals of sensory nerves and their endogenous ligands, opioid peptides, have been discovered in immune cells within inflamed tissue. Many controlled clinical studies confirm the experimental data. These findings open up the exciting perspective of the development of an entirely novel generation of peripherally active opioid analgesics devoid of centrally mediated side effects.

Analgesia↗
PubMed1995

Costs, resource utilisation and financing of public and private hospitals in Uganda.

A descriptive cross-sectional, retrospective cost analysis was conducted in a public and private hospitals in Arua district, Uganda with the aim of assessing the resource use, costs, and financing of those hospitals. It employed the "full costing" approach to hospital costing. The results showed that most of the government recurrent expenditure on health facilities in the district went to the public hospital, while most of the revenues at the private hospital was from donations. The distribution of costs by category of inputs showed that materials and supplies costs were highest in both hospital, followed by employee costs. The administration, pharmacy and store had the highest cost at both hospitals. The cost of the kitchen was very high in the public hospital. The ratio of the unit costs of an out patient visit to an inpatient day and to the unit cost per case treated was 1:1:6 in the private and 1:7:46 in the public. This indicates the relative low cost of public hospital outpatient service and the relative high cost of the outpatient in the private hospital. The employee costs and the drug costs were the most important components of the unit costs in the OPD at both hospitals while in the inpatient wards, besides the above mentioned components, there were also the kitchen, blood bank (public) and theatre in both hospitals. It is concluded that hospitals should look for ways of increasing the level of recurrent funding available to them by increasing the efficiency of their operations and by mobilising additional resources from other sources other than government.

Costs and Cost Analysis↗