Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-Arginine is the only endogenous nitrogen-containing substrate of NO synthase (NOS), and it thus governs the production of NO during nervous system development as well as in disease states such as stroke, multiple sclerosis, Parkinson's disease, and HIV dementia. The "arginine paradox" refers to the dependence of cellular NO production on exogenous L-arginine concentration despite the theoretical saturation of NOS enzymes with intracellular L-arginine. Herein, we report that decreased availability of L-arginine blocked induction of NO production in cytokine-stimulated astrocytes, owing to inhibition of inducible NOS (iNOS) protein expression. However, activity of the promoter of the iNOS gene, induction of iNOS mRNA, and stability of iNOS protein were not inhibited under these conditions. Our results indicate that inhibition of iNOS activity by arginine depletion in stimulated astrocyte cultures occurs via inhibition of translation of iNOS mRNA. After stimulation by cytokines, uptake of L-arginine negatively regulates the phosphorylation status of the eukaryotic initiation factor (eIF2 alpha), which, in turn, regulates translation of iNOS mRNA. eIF2 alpha phosphorylation correlates with phosphorylation of the mammalian homolog of yeast GCN2 eIF2 alpha kinase. As the kinase activity of GCN2 is activated by phosphorylation, these findings suggest that GCN2 activity represents a proximal step in the iNOS translational regulation by availability of l-arginine. These results provide an explanation for the arginine paradox for iNOS and define a distinct mechanism by which a substrate can regulate the activity of its associated enzyme.
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PMID:Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. 1265 43

Understanding the reaction mechanism of co-catalytic metallopeptidases provides a starting point for the design and synthesis of new molecules that can be screened as potential pharmaceuticals. Many of the enzymes that contain co-catalytic metallo-active sites play important roles in cellular processes such as tissue repair, protein maturation, hormone level regulation, cell-cycle control and protein degradation. Therefore, these enzymes play central roles in several disease states including cancer, HIV, stroke, diabetes, bacterial infections, neurological processes, schizophrenia, seizure disorders, and amyotrophic lateral sclerosis. The mechanism of AAP, an aminopeptidase from Aeromonas proteolytica, is one of the best-characterized examples of a metallopeptidase containing a co-catalytic metallo-active site, although this enzyme is not a specific pharmaceutical target at this time. As a large majority of co-catalytic metallopeptidases contain active sites that are nearly identical to the one observed in AAP, the major steps of their catalytic mechanisms are likely to be very similar. With this in mind, it is possible to propose a general catalytic mechanism for the hydrolysis of amino acid substrates.
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PMID:Co-catalytic metallopeptidases as pharmaceutical targets. 1271 52

Studies describing posttraumatic stress disorder (PTSD) as a result of physical illness and its treatment were reviewed. PTSD was described in studies investigating myocardial infarction (MI), cardiac surgery, haemorrhage and stroke, childbirth, miscarriage, abortion and gynaecological procedures, intensive care treatment, human immunodeficiency virus (HIV) infection, awareness under anaesthesia, and in a group of miscellaneous conditions. Cancer medicine was not included as it had been the subject of a recent review in this journal. Studies were reviewed in terms of the prevalence rates for PTSD, intrusive and avoidance symptoms, predictive and associated factors and the consequences of PTSD on healthcare utilization and outcome. There was considerable variability both in the study methodology and design and in the results. The highest prevalence rates were identified in patients treated in intensive care units (ICUs) and those with HIV infection. Irrespective of the physical illness, posttraumatic symptomatology is more common than PTSD caseness. Existing characteristics of the patient may well predispose individuals to the development of PTSD as do other factors such as poor social support and negative interactions with healthcare staff. Generally, the severity of the illness itself is not predictive of PTSD. Issues relating to sampling, attrition, diagnosis, the course of symptoms, aetiological pathways, and the consequences of the disorder are discussed. The presence of PTSD most probably influences the patient's use of healthcare resources and may affect their clinical outcome.
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PMID:Posttraumatic stress disorder following medical illness and treatment. 1272 79

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anticarbonic anhydrase, diuretic, hypoglycemic, and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial protease inhibitory properties. Of particular interest are some metalloprotease inhibitors belonging to this class, which by inhibiting several matrix metalloproteases (MMPs) show interesting antitumor properties. Some of these compounds are currently being evaluated in clinical trials. The large number of sulfonamide MMP inhibitors ultimately reported also lead to the design of effective tumor necrosis factor-alpha converting enzyme (TACE) inhibitors, potentially useful in the treatment of inflammatory states of various types. Since both MMPs and TACE contribute synergistically to the pathophysiology of many diseases, such as arthritis, bacterial meningitis, tumor invasion; the dual inhibition of these enzymes emerged as an interesting target for the drug design of anticancer/antiinflammatory drugs, and many such sulfonamide derivatives were recently reported. Human neutrophyl elastase (HNE) inhibitors of the sulfonamide type may also be useful in the treatment of inflammatory conditions, such as emphysema, cystic fibrosis, chronic bronchitis, ischemia reperfusion injury, and acute respiratory distress syndrome. Inhibition of some cysteine proteases, such as several caspase and cathepsin isozymes, may lead to the development of pharmacological agents effective for the management of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, brain damage, and stroke. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Some clinically used HIV protease inhibitors (such as amprenavir) possess sulfonamide moieties in their molecules, which are critical for the potency of these drugs, as shown by means of X-ray crystallography, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with lower toxicity or augmented activity against viruses resistant to the such first generation drugs. Other viral proteases, such as those isolated from several types of herpes viruses may be inhibited by sulfonamide derivatives, leading thus to more effective classes of antiviral drugs.
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PMID:Protease inhibitors of the sulfonamide type: anticancer, antiinflammatory, and antiviral agents. 1278 86

A 42-year-old man with chronic myelogenous leukemia presented to the hospital with hip pain. After undergoing surgical repair for a hip fracture, he developed aphasia, facial droop and fever. He was initially diagnosed with a stroke. A lumbar puncture excluded common infections, and an ELISA test for HIV was negative. Serial MRI scans revealed a progressive demyelinating pattern. Polymerase chain reaction performed on cerebrospinal fluid was positive for the JC virus (JC are the initials of the first person diagnosed with this virus). The patient was treated with cidofovir but died before a full course could be administered. JC virus is present in most adult hosts but is only harmful in immuno-compromised hosts. The active form of the disease is known as progressive multifocal leukoencephalopathy. This is the first reported case of a patient developing progressive multifocal leukoencephalopathy. with chronic myelogenous leukemia as the only underlying condition.
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PMID:Progressive multifocal leukoencephalopathy in a patient with chronic myelogenous leukemia. 1280 40

Within the clinical and public health communities, it is often unnoticed that the developing world is experiencing an aging population with its attendant increase in the burden of chronic, noncommunicable diseases. From July 1999 to July 2000, 77% of the world's net gain in elderly persons occurred in developing countries. In Sub-Saharan Africa alone, the number of persons aged 65 years and older is expected to increase by 50% in 2015, from 19.3 million to 28.9 million. This demographic change has profound implications for developing countries that already shoulder a huge burden of communicable diseases, especially the HIV/AIDS epidemic, and continue to be challenged by basic infrastructure needs and economic development. In the 30-year period from 2000 to 2030, the population of elderly persons is projected to double in many Sub-Saharan African countries including the Democratic Republic of Congo, Mozambique, Cameroon, and Ghana. The scale and magnitude of these demographic changes are unprecedented. Since advancing age is the most powerful independent predictor of cardiovascular morbidity and mortality, the impact of these demographic changes on heart disease and stroke will be substantial. Aggressive efforts in promoting healthy aging and the prevention of cardiovascular risk factors will be crucial in preventing an impending cardiovascular epidemic in these countries.
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PMID:Population aging and implications for epidemic cardiovascular disease in Sub-Saharan Africa. 1367 18

The life-stage approach, which views the behaviours and exposures of an individual from the preconceptual situation of the parent through pregnancy, infancy, childhood and adolescence, and into the advancing years through adulthood, is the basis of analysis of strategies to improve long-term health. Among the behaviours of note is the dietary selection pattern, conditioning our exposure to nutrients and dietary constituents that influences growth, nutriture, cognitive and physical performance, and disease resistance and susceptibility. The African Diaspora created a population displaced from Africa to the Western Hemisphere as part of the African slave trade from the 16th to 18th centuries. It continues to manifest distinct dietary and lifestyle practices in the context of a health experience that is different both from the population in their African countries of origin and from the other ethnicities in their countries of displacement and current residence. Afro-Americans are more susceptible to a series of diseases and conditions including low birth weight, violence, and HIV/AIDS, as well as the non-communicable diseases: obesity, diabetes mellitus, cardiovascular disease, hypertension, stroke, renal failure, breast cancer, prostate cancer and lead poisoning. The differential nature of dietary practices are conditioned at times by the poverty and marginalisation of the populace, resulting in either disadvantageous or beneficial outcomes relative to others' eating habits. Serious consideration must be given to the possibility that ethnic difference give rise to different requirements and tolerances for essential nutrients and distinct protective or adverse responses to foods and dietary substances. The major challenges to health improvement for the African Diaspora is coming to grips with the policy and programmatic nuances of differential treatment and the effecting the behavioural changes that would be needed in a population skeptical of the motives of media and of the power elites of their societies.
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PMID:Diet and long-term health: an African Diaspora perspective. 1450 96

Highly active antiretroviral therapy (HAART) has prolonged many patients' lives, but many cardiac sequelae of HIV are not affected by HAART and continue to develop even with treatment. In addition, HAART itself causes in a high proportion of patients a metabolic syndrome, characterized by lipodystrophy/lipoatrophy, dyslipidemia and insulin resistance that may be associated with an increase in coronary artery disease and stroke. Careful cardiovascular evaluation in the course of HIV disease can identify cardiac complications early enough to treat. All HIV-infected patients are candidates for antiretroviral therapy and patients already under treatment should undergo an assessment that includes the evaluation of the cardiovascular risk according to the available guidelines.
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PMID:Highly active antiretroviral therapy and the cardiovascular system: the heart of the matter. 1462 56

Measurement of total homocysteine (tHcy) in healthy and diseased children has documented the utility of this marker in pediatric research and diagnostics. This article focuses on novel data obtained in infants, children and adolescents, with emphasis on cobalamin status in infants. In children, determinants of plasma tHcy are similar to those established in adults, and include age, gender, nutrition, B-vitamin status, and some drugs interfering with B-vitamin function. In infants (age < 1 year), tHcy is moderately elevated and related to serum cobalamin, whereas in older children and throughout childhood, plasma tHcy is low (about 60% of adult levels), and folate status becomes a strong tHcy determinant. As in adults, hyperhomocysteinemia in childhood is a risk factor for stroke, and folate-responsive hyperhomocysteinemia has been detected in children with renal failure. tHcy seems to be a sensitive indicator of folate deficiency in children on a poor diet, in HIV-infected children, and in children treated with anti-folate drugs. In children at increased risk of cobalamin deficiency, which includes children born to vegetarian mothers or children in developing countries on a poor diet, tHcy and methylmalonic acid are responsive indicators of a deficiency state. In newborns and infants born to mothers with an adequate nutrition, there are consistent observations of low cobalamin, elevated tHcy and methylmalonic acid, and reduction of both metabolites by cobalamin supplementation. These data have raised the question whether cobalamin deficiency may be widespread and undetected in babies born to non-vegetarian women on a Westernized diet.
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PMID:Hyperhomocysteinemia and B-vitamin deficiencies in infants and children. 1465 20

The oxygen-dependent, renal cytokine eythropoietin (Epo) is well known to increase red cell production. Binding of Epo to the Epo receptor (EpoR) represses apoptosis of erythroid progenitor cells, thereby allowing their final maturation. We and others showed that Epo and its receptor are expressed in many other tissues, including brain, spinal cord, retina and testis. The presence of a blood barrier suggests that Epo plays a local role in these organs. Indeed, therapeutically applied or hypoxically induced Epo has been shown to reduce the infarct volume in various stroke animal models, to prevent retinal degeneration, and to ameliorate spinal cord injury. In a study conducted by Ehrenreich and colleagues, stroke patients treated with Epo showed reduced infarct volume, fast neurological recovery and improved clinical outcome. In analogy to its function on erythroid progenitor cells, this neuroprotective effect of Epo might be explained by repression of programmed cell death. Apart from neuroprotection, there is an assumption that Epo present in breast milk has the potential to protect against mother-to-infant transmission of HIV. When using Epo at high doses for longer time periods; however, care has to be taken to control the resulting chronic polycythemia that most probably caused enlarged cerebral infarct volumes in a transgenic mouse model that due to Epo-overexpression reached hematocrit levels of about 0.8. Overall, these data strongly support the notion that Epo will soon find new applications in the clinic.
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PMID:Non-erythroid functions of erythropoietin. 1471 31


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