Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current evidence indicates that the neuroendocrine system is the highest regulator of immune/inflammatory reactions. Prolactin and growth hormone stimulate the production of leukocytes, including lymphocytes, and maintain immunocompetence. The hypothalamus-pituitary-adrenal axis constitutes the most powerful circuit regulating the immune system. The neuropeptides constituting this axis, namely corticotrophin releasing factor, adrenocorticotrophic hormone, alpha-melanocyte stimulating hormone, and beta-endorphin are powerful immunoregulators, which have a direct regulatory effect on lymphoid cells, regulating immune reactions by the stimulation of immunoregulatory hormones (glucocorticoids) and also by acting on the central nervous system which in turn generates immunoregulatory nerve impulses. Peptidergic nerves are major regulators of the inflammatory response. Substance P and calcitonin gene-related peptide are pro-inflammatory mediators and somatostatin is anti-inflammatory. The neuroendocrine regulation of the inflammatory response is of major significance from the point of view of immune homeostasis. Malfunction of this circuit leads to disease and often is life-threatening. The immune system emits signals towards the neuroendocrine system by cytokine mediators which reach significant blood levels (cytokine-hormones) during systemic immune/inflammatory reactions. Interleukin-1, -6, and TNF-alpha are the major cytokine hormones mediating the acute phase response. These cytokines induce profound neuroendocrine and metabolic changes by interacting with the central nervous system and with many other organs and tissues in the body. Corticotrophin releasing factor functions under these conditions as a major co-ordinator of the response and is responsible for activating the ACTH-adrenal axis for regulating fever and for other CNS effects leading to a sympathetic outflow. Increased ACTH secretion leads to glucocorticoid production. alpha-melanocyte stimulating hormone functions under these conditions as a cytokine antagonist and an anti-pyretic hormone. The sympathetic outflow, in conjunction with increased adrenal activity. leads to the elevation of catecholamines in the bloodstream and in tissues. Current evidence suggests that neuroimmune mechanisms are essential in normal physiology, such as tissue turnover, involution, atrophy, intestinal function, and reproduction. Host defence against infection, trauma and shock relies heavily on the neuroimmunoregulatory network. Moreover, abnormalities of neuroimmunoregulation contribute to the aetiology of autoimmune disease, chronic inflammatory disease, immunodeficiency, allergy, and asthma. Finally, neuroimmune mechanisms play an important role in regeneration and healing.
 ...
PMID:The immune effects of neuropeptides. 891 48

Infection with the human immunodeficiency virus (HIV) can lead to global alterations in metabolism as well as immunodeficiency. There is dysregulation of endocrine function in adults and children, the extent and magnitude correlating with disease progression. Some of the more prominent abnormalities occur in the thyroid, gonadal, and somatomedin axes. Clinical manifestations of these abnormalities are growth failure in children, which is one of the most sensitive indicators of disease progression, and a wasting syndrome in adults and children. Although there are case reports of growth hormone (GH) deficiency in HIV-infected children, most patients with growth failure have normal serum levels of GH and normal to low levels of insulin-like growth factor-I (IGF-I). Antiretrovial therapy can improve the growth rate in children for a period of time if there is a drop in viral titer, but as the viral load increases, the growth rate decreases again. Administration of GH or IGF-I to these patients can improve the growth rate and lean body mass, and in some patients improve immune function. Although studies on resting energy expenditure in HIV-infected patients have shown increases, these are not proportional to disease progression, but may be dependent upon cytokine activation and other abnormalities. Adult patients with wasting have been shown to have relatively normal total energy expenditure, but decreased intake. Appetite stimulants have been shown to have some benefit, but do not increase lean body mass. The most significant clinical benefit has come from administration of GH in short-term trials. GH and IGF-I are both able to inhibit apoptosis and reconstitute the immune system in rodents treated with ablative therapy. In addition, GH can modulate the marrow suppressive effects of zidovudine and may enhance its ability to inhibit viral reverse transcriptase. Current clinical trials are ongoing in both adults and children. GH and IGF-I may have a role in regimens intended for immune reconstruction, and could be useful as adjuvant therapy in selected patients with HIV infection.
 ...
PMID:Use of human recombinant growth hormone and human recombinant insulin-like growth factor-I in patients with human immunodeficiency virus infection. 895 Jun 24

Profound weight loss and progressive depletion of muscle mass is a common sequela of chronic diseases such as cancer, tuberculosis, and human immunodeficiency virus (HIV) infection. Studies of HIV-associated wasting have revealed several possible mechanisms. Alterations in anabolic hormones, energy intake, energy expenditure, and production of proinflammatory cytokines, which cause cachexia, may contribute to wasting in HIV-infected patients. These studies have revealed the complexity of the interactions between cytokines and the hormones that typically regulate catabolic-anabolic homeostasis. Despite this complexity, HIV-associated wasting should be manageable. Several strategies are currently under investigation, including anabolic steroid and human growth hormone therapy, appetite stimulants, nutritional supplementation, and cytokine antagonists. Some of these approaches have shown early promise. Further research in these areas should facilitate development of effective intervention strategies and lead to improvements in quality of life for patients suffering from wasting syndromes.
 ...
PMID:Human immunodeficiency virus-associated wasting and mechanisms of cachexia associated with inflammation. 948 43

Weight loss and wasting are significant contributors to morbidity in patients infected with the human immunodeficiency virus (HIV). The approach to the patient with HIV and weight loss needs to be proactive and comprehensive, as early intervention may be beneficial and the weight loss may be multifactorial. Evaluation for weight loss needs to be directed at any apparent contributing cause and can include dietary evaluation, treatment of intercurrent complicating infections or malignancies, and maximization of HIV therapy. Some patients will also benefit from an evaluation of the gastrointestinal tract to document malabsorption and/or opportunistic enteric infections. It is also prudent to evaluate testosterone levels in male patients. Interventions in the patient who is not able to take in sufficient calories should include dietary advice and/or nutritional supplements, as well as the use of appetite stimulants. Megace (Bristol-Myers Squibb, Princeton, NJ) has been shown to effectively increase appetite, oral intake, and body weight. For the patient with malabsorption and/or diarrhea, treatment of enteric infections should be attempted. These patients may benefit from the replacement of some dietary fat with medium-chain triglycerides, either in a nutritional product or to replace cooking oils. Other patients may benefit from the use of anabolic agents such as growth hormone, nandrolone, testosterone, or oxandrolone, which are all effective at increasing lean body mass. For select patients, agents such as thalidomide might be of benefit, although its mechanism of action is not clear. There are few data from prospective, controlled trials of combinations of these agents, but these studies are underway. It is likely that the optimal interventions for patients will be combinations of agents to improve oral intake and add lean body mass, which will permit a reduction in morbidity from weight loss and an improvement in quality of life for the HIV-infected patient.
 ...
PMID:Single-agent/combination therapy of human immunodeficiency virus-related wasting. 962 91

Recent studies of the growth hormone insulinlike growth factor I (IGFI) axis suggest that these hormones are involved in several physiologic processes, in addition to growth. Thus, several lines of evidence indicate an increasingly important role for recombinant human growth hormone as a part of the modern therapeutic armamentarium. In addition to the treatment of children with growth hormone deficiency, administration of growth hormone appears to be of considerable benefit to girls with Turner syndrome, children with chronic renal failure, and adults with growth hormone deficiency or human immunodeficiency virus (HIV) wasting syndrome. Moreover, its therapeutic use is being investigated in other conditions, such as children with idiopathic short stature, the healthy elderly, and the critically ill. However, long-term surveillance among growth hormone recipients is needed to fully evaluate its risk-benefit profile.
 ...
PMID:Recombinant human growth hormone: old and novel uses. 968 21

The Jak-STAT pathway was originally discovered through the study of interferon induced intracellular signal transduction. Meanwhile, a large number of cytokines, hormones and growth factors have been found to activate Jaks and STATs. Jaks (Janus Kinases) are a unique class of tyrosine kinases that associate with cytokine receptors. Upon ligand binding, they activate members of the Signal Transducers and Activators of Transcription (STAT) family through phosphorylation on a single tyrosine. Activated STATs form dimers, translocate to the nucleus, bind to specific response elements in promotors of target genes, and transcriptionally activate these genes. Both positive and negative regulations of the Jak-STAT pathway have been identified. In a positive feedback loop, interferons transcriptionally activate the genes for components of the interferon stimulated gene factor 3 (ISGF3). A number of cytokines that activate the Jak-STAT pathway, e.g. IL-6, IL-4, LIF, G-CSF, have been shown to upregulate the expression of SOCS-JABs-SSIs, a recently discovered class of STAT inhibitors. Targeted disruption of genes for a number of Jaks and STATs in mice have revealed specific biological functions for many of them. Although most of the STATs are activated in cell culture by many different ligands, STAT knockout mice mostly show defects in a single or a few cytokine dependent processes. STAT1 knockout mice have an impaired interferon signalling, STAT4 knockouts impaired IL-12 signalling, STAT5a knockouts impaired prolactin signalling, STAT5b knockouts impaired growth hormone signalling, and STAT6 knockout impaired IL-4 and IL-13 signalling. Defects in the Jak-STAT pathway have already been identified in a number of human diseases. Prominent amongst them are leukaemias, lymphomas and inherited immunodeficiency syndromes. It can be expected that additional Jak-STAT related diseases will be identified over the next years. To date, specific STAT inhibitory drugs are not known, but a number of specific protein-protein interactions in the Jak-STAT pathway are potential targets for pharmaceutical interventions.
 ...
PMID:The Jak-STAT pathway: cytokine signalling from the receptor to the nucleus. 1007 51

Lentiviral vectors have gained much attention in recent years mainly because they integrate into nondividing host-cell genomes. For clinical applications, a safe and efficient lentiviral vector system is required. Previously, we have established a human immunodeficiency virus type 1 (HIV-1)-derived three-plasmid lentiviral vector system for viral vector production which includes a packaging vector pHP, a transducing vector pTV, and an envelope-encoding plasmid pHEF-VSVG. Cotransfection of these three plasmids into TE671 human rhabdomyosarcoma cells routinely yields 10(5)-10(6) infectious units per milliliter in 24 h. Here we have extensively modified long terminal repeats (LTRs) of pTV to generate a safer lentiviral vector system. The 5' U3 was replaced with a truncated cytomegalovirus (CMV) immediate early (IE) enhancer/TATA promoter and the 3' U3 (except for the integration attachment site) was also deleted. These modifications resulted in a vector with 80% wild-type vector efficiency. Further deletion of 3' U5 impaired vector function; however, this problem was solved by replacing the 3' U5 with bovine growth hormone polyadenylation (bGHpA) sequence. The pTV vector containing all these modifications including the 5' promoter substitution, the 3' U3 deletion, and the substitution of 3' U5 with bGHpA exhibited a self-inactivating (SIN) phenotype after transduction, transduced both dividing and nondividing cells at similar efficiencies, and produced vector titers twice as high as that of the wild-type construct. Thus, both safety and efficacy of the HP/TV vector have been improved by these LTR modifications. Further deletion of 5' U5 impaired vector efficiency, suggesting that the 5' U5 has critical roles in vector function.
 ...
PMID:Self-inactivating lentiviral vectors with U3 and U5 modifications. 1044 60

Body wasting and loss of lean body mass (LBM) have been associated with increased mortality and disease progression, and reduced quality of life, in patients with human immunodeficiency virus (HIV) infection. The failure of nutritional therapies and, more recently, of effective viral suppression, to consistently restore LBM has prompted investigation of the pharmacologic use of a number of specific protein anabolic agents, including recombinant human growth hormone (rhGH), insulin-like growth factor I (rhIGF-I), and synthetic testosterone derivatives, such as nandrolone decanoate, oxandrolone, and oxymetholone. In a placebo-controlled trial, treatment with rhGH resulted in a significant and sustained increase in weight that was accompanied by an even greater increase in LBM and a decrease in fat, and improvement in treadmill work output. Preliminary data suggest that short-term rhGH treatment may be effective in mitigating weight loss in patients with secondary infections. Open-label studies of nandrolone decanoate suggest that this injectable agent also can increase weight and LBM. Two oral agents, oxandrolone and oxymetholone, can increase weight, but their effects on LBM in placebo-controlled trials have not been reported. Taken together, these studies demonstrate that HIV-infected individuals can regain weight and LBM under the proper therapeutic circumstances. The effects of reversal of wasting on survival and disease progression, long-term safety, and the potential value of these therapies in the treatment of fat redistribution remain to be determined.
 ...
PMID:Use of growth hormone and other anabolic agents in AIDS wasting. 1057 56

Patients with acquired immunodeficiency syndrome (AIDS) often suffer from weight loss manifested by a loss of body cell mass (BCM). The causes of human immunodeficiency virus (HIV)-associated wasting may include anorexia, malabsorption, and a variety of altered metabolic states. Malabsorption and diarrhea may result from gastrointestinal tract opportunistic infections or from direct effects of HIV on the gastrointestinal tract. Infection with HIV may produce metabolic derangements that alter nutrient utilization, resulting in loss of BCM. Nutritional assessment of the patient with AIDS should include an evaluation of BCM and physical and psychosocial functioning. Antiretroviral therapy and eradication of opportunistic infections do not always reverse wasting. Treatment should include nutritional counseling. Total parenteral nutrition is sometimes of benefit, particularly in patients with damaged gastrointestinal tracts. Dronabinol and megestrol acetate may promote weight gain; however, dronabinol may have adverse effects, and most of the gain with megestrol acetate is in fat rather than BCM. If gonadal dysfunction is present, testosterone replacement therapy should be included in the treatment plan. Some studies suggest that oral anabolic steroids may improve muscle strength and body composition. In randomized, placebo-controlled trials, mammalian-derived human growth hormone (rhGH[m]) has produced sustained weight and BCM gains in AIDS patients. If a patient continues to lose BCM after the above factors have been addressed and corrected, a 12-week course of rhGH[m] is indicated. Halting the progression of HIV-associated wasting may improve survival, enhance physical and social functioning, and enrich quality of life.
 ...
PMID:Treatment guidelines for HIV-associated wasting. 1076 94

Recombinant human growth hormone (rhGH) is an important treatment option for patients with human immunodeficiency virus (HIV) wasting syndrome. Side effects of rhGH are minimal when administered at physiologic and moderately high dosages, as seen in growth hormone deficiency and Turner's syndrome, respectively. The dosage of rhGH is significantly higher to treat wasting syndrome and still is being studied to determine its long-term efficacy and safety. Individuals with HIV infection are at increased risk for adverse effects due to polypharmacy, immune system alterations, and treatment with newer agents that lack long-term safety data. In addition, rhGH's potential for side effects becomes greater when given at high dosages for wasting syndrome. Clinically significant hyperglycemia developed in an HIV-positive man who started rhGH for wasting syndrome 38 days before the diagnosis of diabetes mellitus.
 ...
PMID:Diabetes mellitus associated with recombinant human growth hormone for HIV wasting syndrome. 1099 8


<< Previous 1 2 3 4 5 6 7 Next >>