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Biomedical subjects

A Ahmad

Publications and source records attributed to A Ahmad.

At least 73 records · Page 4Linked to original sources
PubMed2000

Functional plasticity in extrastriate visual cortex following neonatal visual cortex damage and monocular enucleation.

Neonatal lesions of primary visual cortex (areas 17, 18 and 19; VC) in cats lead to significant changes in the organization of visual pathways, including severe retrograde degeneration of retinal ganglion cells of the X/beta class. Cells in posteromedial lateral suprasylvian (PMLS) cortex display plasticity in that they develop normal receptive-field properties despite these changes, but they do not acquire the response properties of striate neurons that were damaged (e.g., high spatial-frequency tuning, low contrast threshold). One possibility is that the loss of X-pathway information, which is thought to underlie striate cortical properties in normal animals, precludes the acquisition of these responses by cells in remaining brain areas following neonatal VC damage. Previously, we have shown that monocular enucleation at the time of VC lesion prevents the X-/beta-cell loss in the remaining eye. The purpose of the present study was to determine whether this sparing of retinal X-cells leads to the development of striate-like response properties in PMLS cortex. We recorded the responses of PMLS neurons to visual stimuli to assess spatial-frequency tuning, spatial resolution, and contrast threshold. Results indicated that some PMLS cells in animals with a neonatal VC lesion and monocular enucleation displayed a preference for higher spatial frequencies, had higher spatial resolution, and had lower contrast thresholds than PMLS cells in cats with VC lesion alone. Taken together, these results suggest that preserving X-pathway input during this critical period leads to the addition of some X-like properties to PMLS visual responses.

Animals↗
PubMed2000

Mdx mice inducibly expressing dystrophin provide insights into the potential of gene therapy for duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by the lack of expression of the dystrophin protein in muscle tissues. We genetically engineered a mouse model (mdx) of DMD that allowed for the high level and inducible transcription of a dystrophin mini-gene. This was achieved via the tetracycline-responsive transactivator (tTA) system. Multiple analyses confirmed that dystrophin expression in the mice was: (i) tTA dependent; (ii) correctly localized to the sarcolemmal membranes; (iii) capable of preventing the onset of dystrophy; and (iv) effectively blocked by the oral administration of tetracyclines. The model allowed us to somatically extinguish or induce dystrophin gene transcription. Somatic induction of dystrophin transcription prevented the onset of muscular dystrophy in some muscle groups. The levels of phenotypic rescue were influenced, however, by the age of the animals at the time of dystrophin induction. We also found that despite somatic termination of dystrophin gene transcription, the dystrophin protein was found to be associated with the sarcolemmal membrane for at least 26 weeks. Persistent detection of dystrophin was also accompanied by a prolonged protection of the muscle cells from the onset of dystrophy. The findings demonstrated that somatic transfer of the dystrophin gene not only may allow for the prevention of muscular dystrophy in multiple muscle groups, but also may be accompanied by persistent efficacy, secondary to the long-term functional stability of the dystrophin protein in vivo. This model should be useful in future studies concerning the potential of genetic therapy for DMD, as well as other muscle disorders.

Animals↗
PubMed2000

Thrombin induces apoptosis in human tumor cells.

Thrombin is a serine protease that is produced during the coagulation process and plays an essential role for hemostasis, thrombosis and wound healing. It is a potent activator of platelets, induces proliferation of a wide variety of normal and malignant human cells, and enhances their invasiveness and metastatic potential. We studied the effect of thrombin on the proliferation of a wide variety of human tumor cells and report here that, at low concentrations, thrombin induces proliferation of these cells. However, at higher concentrations, thrombin inhibited their proliferation. We show that this inhibition of cell proliferation was due to apoptosis of the tumor cells. The thrombin-mediated apoptosis was inhibited significantly by its specific inhibitor, hirudin. Furthermore, no consistent pattern of induction and/or modulation of p53, p21 and bcl-2 was observed in the thrombin-mediated apoptosis. To our knowledge, this is the first report to describe the pro-apoptotic effects of thrombin on human tumor cells and may have implications for chemotherapy in cancer patients and for the pathogenesis of AIDS as well.

Antineoplastic Agents↗
PubMed2000

Trichloroacetic acid and trifluoroacetic acid-induced unfolding of cytochrome c: stabilization of a native-like folded intermediate(1).

A systematic investigation of trichloroacetic acid (TCA) and trifluoroacetic acid (TFA)-induced equilibrium unfolding of native horse cytochrome c has been carried out using a combination of optical spectroscopy and electrospray ionization mass spectroscopy (ESI MS). In the presence of an increasing concentration of TCA the native cytochrome c does not undergo significant unfolding but stabilization of a partially folded intermediate is observed. This TCA-induced partially folding intermediate of cytochrome c had an enhanced secondary structure and slightly disrupted tertiary structure compared to native protein and undergoes extensive unfolding in the presence of TFA. However, in the presence of an increasing concentration of TFA, cytochrome c was found to undergo extensive unfolding characterized by a significant breakdown of the secondary and tertiary structure of protein. The TFA-unfolded cytochrome c was found to undergo folding in the presence of TCA and low guanidine hydrochloride (GdmCl) resulting in the stabilization of the partially folded intermediate. The effectiveness of TCA as compared to TFA in the stabilization of intermediates was further supported by the observation that low concentrations of TCA were found to induce refolding of HCl-denatured cytochrome c whereas, under similar concentrations of acid, no significant effect on the unfolded structure of protein was observed in the presence of TFA. ESI MS studies indicated that the trichloroacetate anion has a greater affinity for cytochrome c compared to trifluoroacetate anion, which might be the reason for the stabilization of the native-like folded intermediate during TCA-induced denaturation of cytochrome c as compared to extensive unfolding observed in the presence of TFA.

Animals↗
PubMed2000

DNA breakage by resveratrol and Cu(II): reaction mechanism and bacteriophage inactivation.

Resveratrol (3,4',5-trihydroxy stilbene) is a phytoalexin and a polyphenolic compound present in human dietary material such as peanuts, mulberries, grapes and red wine. It is widely considered to possess cardiovascular protective properties and has also been shown to be chemopreventive against various stages of chemically induced carcinogenesis. It has recently been shown that resveratrol induces strand breakage in DNA in the presence of copper ions. In this paper, we have shown that resveratrol catalyzes the reduction of Cu(II) to Cu(I), which is accompanied by the formation of 'oxidized product(s)' of resveratrol, which in turn also appear to catalyze the reduction of Cu(II). Strand scission by the resveratrol-Cu(II) system was found to be biologically active as assayed by bacteriophage inactivation. The results are discussed in relation to the putative chemopreventive mechanism of resveratrol.

Animals↗
PubMed2000

Binding of the Epstein-Barr virus major envelope glycoprotein gp350 results in the upregulation of the TNF-alpha gene expression in monocytic cells via NF-kappaB involving PKC, PI3-K and tyrosine kinases.

Epstein-Barr virus (EBV) is a human herpesvirus that interacts with various immunocompetent cells that carry the EBV receptor (CD21/CR2). EBV binds to CR2 through its major envelope glycoprotein 350 (gp350). Previously we had demonstrated that EBV and other human herpesviruses are capable of modulating cytokine synthesis through the deregulated expression of cytokine genes interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-2 (IL-2). Here we show that, in contrast to infectious EBV, purified recombinant gp350 upregulates TNF-alpha gene expression in human monocyte/macrophages (M/M) as well as in a monocytoid cell line, U937. Our results also demonstrate that this increased expression is due to both enhanced transcription and stability of TNF-alpha mRNA in gp350-treated cells. The specificity of this effect is evidenced by the fact that pre-incubation of cells with anti-CR2 monoclonal antibody OKB7, which blocks binding of gp350 to CR2, inhibits the above mentioned effects of gp350. Furthermore, we demonstrate that activation of TNF-alpha by gp350 is mediated by NF-kappaB through signal transduction pathways involving PKC, PI3-K and tyrosine kinases. To our knowledge this is the first report describing the modulation of TNF-alpha gene expression by the EBV-gp350 molecule following its interaction with the viral receptor CR2 on cells of the monocytic lineage.

Antibodies, Monoclonal↗
PubMed2000

Anti-oxidant, pro-oxidant properties of tannic acid and its binding to DNA.

Tannic acid has numerous food and pharmacological applications. It is an additive in medicinal products, and is used as a flavouring agent and as an anti-oxidant in various foods and beverages. We have previously shown that tannic acid in the presence of Cu(II) causes DNA degradation through generation of reactive oxygen species. On the other hand, it exhibits antimutagenic and anticarcinogenic activities, and induces apoptosis in animal cells. It is known that most plant-derived polyphenolic anti-oxidants also act as pro-oxidants under certain conditions. In this paper, we compare the anti-oxidant and pro-oxidant properties of tannic acid and its structural component gallic acid. It is shown that tannic acid is the most efficient generator of the hydroxyl radical in the presence of Cu(II), as compared with gallic acid and its analogues syringic acid and pyrogallol. The anti-oxidant activity of tannic acid was studied by its effect on hydroxyl radical and singlet oxygen mediated cleavage of plasmid DNA. Again, tannic acid provided the maximum protection against cleavage, while gallic acid and its structural analogues were found to be non-inhibitory or partially inhibitory. The results suggest that the structural features of tannic acid that are important for its anti-oxidant action are also those that contribute to the generation of hydroxyl radicals in the presence of Cu(II). Restriction analysis of treated phage DNA and thermal melting profiles of calf thymus DNA indicated that tannic acid strongly binds to DNA. Indirect evidence indicates that modification of DNA bases may also occur.

Animals↗
PubMed2000

Analysis and significance of anti-latent membrane protein-1 antibodies in the sera of patients with EBV-associated diseases.

Anti-latent membrane protein-1 (LMP-1) is an EBV-encoded type III integral membrane protein with oncogenic potential that is expressed most consistently in various EBV-associated malignancies. Unlike many other EBV proteins, LMP-1 Abs have rarely been demonstrated in EBV-associated disease conditions. We established a high level LMP-1-expressing cell clone and used it for the detection, quantitation, and characterization of these Abs in various human sera in immunoblots and ELISA. Our results demonstrate that, in contrast to the commonly held notion, LMP-1 induces significant humoral immune responses in EBV-associated malignant conditions especially in nasopharyngeal carcinoma (NPC) patients in whom >70% sera are positive for these Abs, and their titers correlate with the clinical condition of the tumors. Interestingly, anti-LMP-1 Abs of IgA isotype were found only in NPC patients. These Abs were absent from the sera of infectious mononucleosis and chronic EBV infection patients, whereas a small fraction ( approximately 5%) of the healthy, EBV-seropositive individuals were positive for them; however, their OD values were much lower than those of NPC patients. These studies demonstrate, for the first time, the potential significance of LMP-1-specific Abs for the diagnosis and prognosis of EBV-associated malignancies, especially of NPC.

Antibodies, Viral↗
PubMed2000

Posttraumatic stress disorder in children after the military operation "Anfal" in Iraqi Kurdistan.

Five years after the military operation "Anfal" in Iraqi Kurdistan, 45 families were randomly selected among the survivors in two displacement camps. The Posttraumatic Stress Symptoms for Children (PTSS-C) and the Harvard Trauma Questionnaire (HTQ) were administered to the oldest child and the caregiver in each family, respectively. Posttraumatic stress disorder (PTSD) was reported in 87% of children and 60% of their caregivers. While childhood PTSD was only significantly predicted by child trauma score and the duration of captivity, it was neither predicted by maternal PTSD nor did it disappear after the reunion with the PTSD-free father. However, the small sample size makes the results hypotheses rather than conclusive.

Adolescent↗
PubMed2000

Reliability and validity of a child-specific cross-cultural instrument for assessing posttraumatic stress disorder.

The Posttraumatic Stress Symptoms in Children (PTSS-C) was developed as a cross-cultural semi-structured interview to diagnose posttraumatic stress disorder (PTSD) and to identify PTSD-non-related posttraumatic stress symptoms in children after various traumatic experiences. The psychometric properties were studied in two different child populations in Iraqi Kurdistan (the survivors of the military operation "Anfal", and the orphans), in a sample of Kurdistanian refugee children in Sweden, and in a comparison sample of Swedish children. The instrument yielded satisfactory internal consistency, high interrater agreement, and excellent validity on cross-validation with the Child Posttraumatic Stress Disorder Reaction Index (CPTSD-RI) and the Diagnostic Interview for Children and Adolescents (DICA) according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).

Adolescent↗
PubMed2000

Inhibition of L-DOPA-Cu(II)-mediated DNA cleavage by bilirubin.

It has been proposed that considerable DNA damage may be caused by endogenous metabolites produced during the body's normal metabolic processes. We have previously shown that L-DOPA, in the presence of Cu(II), leads to oxidative DNA breakage in vitro. Bilirubin is a degradation product of heme and is considered to possess antioxidant properties. In this paper we report that bilirubin inhibits L-DOPA-Cu(II)-mediated DNA cleavage to an appreciable extent of 50% at a concentration of 50 microM. Bilirubin was also shown to directly quench the generation of hydroxyl radicals by L-DOPA-Cu(II) to an extent of 30% at a concentration of 20 microM. The results support the putative antioxidant role of bilirubin in higher primates.

Animals↗
PubMed2000

Novel sulfonylurea and non-sulfonylurea drugs to promote the secretion of insulin.

The onset of type 2 diabetes is characterized by two determining factors: the insufficient ability to secrete insulin and/or the resistance to its biological action. Although in a very small proportion of individuals, one of those two metabolic abnormalities is the leading cause of diabetes, in most subjects, the coexistence of both appears to be necessary for the clinical manifestation of diabetes. Current biomedical research continues to clarify the relative contributions of these defects to the pathogenesis of type 2 diabetes, and novel pharmacological agents are specifically designed to correct either the impaired insulin secretory activity or the resistance to the action of insulin. The aim of this article is to provide a critical review of new sulfonylurea and non-sulfonylurea drugs that have been recently introduced for the treatment of diabetes, as well as drugs that are still under investigation and are likely to be made available in the near future.

Humans↗
PubMed2000

Reduced hepatic content of dehydroepiandrosterone sulphotransferase in chronic liver diseases.

AIMS/BACKGROUND: Dehydroepiandrosterone sulphotransferase (DHEA ST) is the enzyme responsible for sulphation of lithocholic acid and other potentially hepatotoxic steroids. We have previously shown that DHEA ST activity is reduced in cytosol of liver from miscellaneous patients with chronic liver disease. The aim of this study was to investigate the cause of diminished sulphotransferase activity in order to further our understanding of whether a reduction in the ability to sulphate potentially hepatotoxic bile acids might play a role in the aetiology of primary cholestatic liver disease. METHODS: We quantified DHEA ST in human liver cytosol from groups of patients with chronic liver diseases and normal subjects using a semiquantitative sodium dodecyl sulphate/polyacrylamide gel electrophoresis (SDS-PAGE)/ immunoblotting method, and an enzyme-linked immunosorbent assay (ELISA). We determined DHEA ST enzyme activity and correlated it with its immunoreactive concentration in 87 samples of human liver tissue. RESULTS: DHEA ST activity and concentration were significantly reduced in primary biliary cirrhosis, primary sclerosing cholangitis, chronic active hepatitis and alcoholic cirrhosis but not in cryptogenic cirrhosis when compared to normal liver. There were no significant differences among disease groups. In all groups enzyme activity and cellular concentration correlated, suggesting that no aberrant non-functional enzyme was produced. CONCLUSION: These results confirm that DHEA ST activity is diminished in liver disease and that the reduction is due to diminished enzyme presence. Further studies are required to show whether the reduction has any pathogenetic significance or is merely a consequence of disease.

Adult↗
PubMed2000

Effects of potassium channel opener KRN4884 on human conduit arteries used as coronary bypass grafts.

AIMS: The effects of a new potassium channel opener KRN4884 on human arteries have not been studied. This study was designed to investigate the effects of KRN4884 on the human internal mammary artery (IMA) in order to provide information on possible clinical applications of KRN4884 for preventing and relieving vasospasm of arterial grafts in coronary artery bypass grafting. METHODS: IMA segments (n = 140) taken from patients undergoing coronary surgery were studied in the organ chamber. Concentration-relaxation curves for KRN4884 were established in the IMA precontracted with noradrenaline (NA), 5-hydroxytryptamine (5-HT), angiotensin II (ANG II), and endothelin-1 (ET-1). The effect of glibenclamide (GBC) on the KRN4884-induced relaxation was also examined in NA or 5-HT-precontracted IMA. Concentration-contraction curves for the four vasoconstrictors were constructed without/with pretreatment of KNR4884 (1 or 30 microM) for 15 min. RESULTS: KRN4884 induced less relaxation (P < 0.05) in the precontraction induced by ET-1 (72.9 +/- 5.5%) than by ANG II (94.2 +/- 3.2%) or NA (93.7 +/- 4.1%) with lower EC50 (P < 0.05) for ANG II (-8.54 +/- 0.54 log M) than that for NA (-6.14 +/- 0.15 log M) or ET-1 (-6.69 +/- 0.34 log M). The relaxation in the IMA pretreated with GBC was less than that in control (P < 0.05). KRN4884-pretreatment significantly reduced the contraction (P < 0.05) induced by NA (151.3 +/- 18.4% vs 82.7 +/- 8. 7%), 5-HT (82.7 +/- 12.2% vs 30.1 +/- 7.3%), and ANG II (24.3 +/- 6. 3% vs 5.4 +/- 1.6%), but did not significantly reduce the contraction induced by ET-1 (P > 0.05). CONCLUSION: KRN4884 has marked vasorelaxant effects on the human IMA contracted by a variety of vasoconstrictors and the effect is vasoconstrictor-selective.

Aged↗
PubMed2000

Putative mechanism for anticancer and apoptosis-inducing properties of plant-derived polyphenolic compounds.

Several plant-derived polyphenolic compounds are considered to possess anticancer and apoptosis-inducing properties in cancer cells. Such compounds are recognized as naturally occurring antioxidants but also exhibit prooxidant properties under appropriate conditions. Evidence in the literature suggests that the antioxidant properties of polyphenolics such as gallotannins, curcumin, and resveratrol may not fully account for their chemopreventive effects. We propose a mechanism for the cytotoxic action of these compounds against cancer cells that involves mobilization of endogenous copper and the consequent prooxidant action.

Animals↗
PubMed2000

Innate immune response of the human host to exposure with herpes simplex virus type 1: in vitro control of the virus infection by enhanced natural killer activity via interleukin-15 induction.

Infections with herpes simplex virus type 1 (HSV-1) in humans and in animal models are accompanied by enhanced natural killer (NK) activity. In vitro, HSV-1 also enhances the NK activity of human peripheral blood mononuclear cells (PBMC). The molecular basis of this enhanced NK activity, however, is not well characterized. We investigated the role of human interleukin-15 (IL-15) in this phenomenon and report here that HSV-1-mediated enhanced NK activity was abrogated by neutralizing antibodies for IL-15 but not for other cytokines (i.e., IL-2, IL-12, gamma interferon [IFN-gamma], tumor necrosis factor alpha, or IFN-alpha). Anti-CD122 antibodies which block signaling through IL-2 receptor beta chain, and therefore neutralize the effects of IL-15 (and IL-2), also abrogated this enhancement. Furthermore, HSV-1 increased the levels of IL-15 mRNA and the production of IL-15 in HSV-1-infected PBMC cultures. The neutralization of IL-15 in cocultures of PBMC with HSV-1-infected cells significantly increased HSV-1 production. These results strongly suggest a role for IL-15 in the HSV-1-mediated in vitro enhancement of NK activity and in the PBMC-mediated suppression of HSV-1 replication.

Antibodies, Monoclonal↗
PubMed2000

Elevated serum transforming growth factor beta1 levels in Epstein-Barr virus-associated diseases and their correlation with virus-specific immunoglobulin A (IgA) and IgM.

Transforming growth factor beta (TGF-beta) is an immunosuppressive cytokine which can induce immunoglobulin A (IgA) switch and Epstein-Barr virus (EBV) replication in latently infected cells. Here we report elevated serum levels of TGF-beta in various EBV-associated diseases correlating positively with EBV-specific IgA titers and negatively with IgM titers, suggesting a role for this cytokine in the pathogenesis of these diseases.

Antibodies, Viral↗