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At least 1,099 records · Page 61Linked to original sources
PubMed1993

Human immunodeficiency virus infection in pregnancy.

Human immunodeficiency virus (HIV) infection in women is an increasing problem. World wide, at least 25% of all infections occur in adolescent or adult women, most of whom are of child-bearing age. The commonest modes of acquisition of HIV infection are sexual contact with an HIV-infected male and sharing needles during injecting drug use. Vertical transmission is the major route of HIV infection in infants and children and can occur in utero, intrapartum, through exposure to infected blood or secretions, or post partum, via breast milk. HIV infection has not been demonstrated to affect fertility, or to influence the outcome of pregnancy unless there is evidence of significant immune dysfunction, with CD4 counts below 400/mm3. Though data are limited, pregnancy does not appear to affect the course of HIV infection. Low CD4 counts predispose women to the opportunistic infectious complications of HIV. Pathogens include Candida sp., Mycobacterium tuberculosis, Pneumocystis carinii, Toxoplasma gondii, Cryptococcus neoformans and Cryptosporidium. These pathogens require early recognition and diagnosis if optimal treatment and outcome are to be attained. Treatment with zidovudine and prophylaxis against Pneumocystis carinii are appropriate when CD4 counts are less than 200/mm3, though the safety of zidovudine in early pregnancy is not known. Similarly it is not known whether zidovudine treatment of the mother prevents transmission of HIV infection to her baby. Caesarean section does not prevent peripartum transmission of HIV and should be undertaken only for other appropriate indications. The utility of antenatal screening for HIV depends upon the seroprevalence in the population. Such programmes must be supported by comprehensive clinical care as well as sensitive and non-judgemental counselling.

Female↗
PubMed1999

Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient.

The major mechanism for the repair of DNA double-strand breaks (DSBs) in mammalian cells is non-homologous end-joining (NHEJ), a process that involves the DNA-dependent protein kinase [1] [2], XRCC4 and DNA ligase IV [3] [4] [5] [6]. Rodent cells and mice defective in these components are radiation-sensitive and defective in V(D)J-recombination, showing that NHEJ also functions to rejoin DSBs introduced during lymphocyte development [7] [8]. 180BR is a radiosensitive cell line defective in DSB repair, which was derived from a leukaemia patient who was highly sensitive to radiotherapy [9] [10] [11]. We have identified a mutation within a highly conserved motif encompassing the active site in DNA ligase IV from 180BR cells. The mutated protein is severely compromised in its ability to form a stable enzyme-adenylate complex, although residual activity can be detected at high ATP concentrations. Our results characterize the first patient with a defect in an NHEJ component and suggest that a significant defect in NHEJ that leads to pronounced radiosensitivity is compatible with normal human viability and does not cause any major immune dysfunction. The defect, however, may confer a predisposition to leukaemia.

Animals↗
PubMed1995

HIV retrotransposon activity and the immunopathogenesis of AIDS.

This article presents the new hypothesis that HIV retrotransposon insertional mutagenesis induces genomic effects that bring about immune dysfunction through disruption, deletion or rearrangement of the genome of the host. This activity may be augmented by the action of most, if not all, the cofactors of HIV-induced disease.

Acquired Immunodeficiency Syndrome↗
PubMed2001

The AIDS disease of CD4C/HIV transgenic mice shows impaired germinal centers and autoantibodies and develops in the absence of IFN-gamma and IL-6.

The mechanisms responsible for degeneration of germinal centers (GC) and follicular dendritic cell (FDC) networks during progression to AIDS remain elusive. Here, we show that CD4(+) T cells from CD4C/HIV-1 Tg mice, which develop a severe AIDS-like disease, express low levels of CD40 ligand. Accordingly, GC formation, FDC networks, and immunoglobulin isotype switching are impaired in these animals. However, Tg B cells respond to in vitro CD40 stimulation. Total serum IgG levels are reduced in Tg mice, whereas total IgM levels are increased with a significant amount showing DNA specificity. IFN-gamma- and IL-6-deficient CD4C/HIV Tg mice also develop the AIDS-like disease and produce auto-Ab. Thus, CD4C/HIV Tg mice have immune dysfunction accompanied by autoimmune responses.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Novel human herpesviruses (human herpesviruses 6, 7 and 8).

The number of members in the family Herpesviridae has increased in the last 10 years due to the description of three novel human herpesviruses: human herpesvirus 6 (HHV-6) in 1986, human herpesvirus 7 (HHV-7) in 1990, and human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), in 1994. HHV-6 and HHV-7 were first isolated from blood lymphocyte cultures, while HHV-8 was identified following a specific molecular biology approach in the search for the etiologic agent of Kaposi's sarcoma. The three viruses are lymphotropic, T-cells being the targets of HHV-6 and HHV-7, and B-cells being probably those of HHV-8. The ability to be propagated in cell cultures in vitro differs according to the virus concerned: this can be done readily with HHV-6, with more difficulties in the case of HHV-7, and has not yet been achieved in the case of HHV-8. Human infection with HHV-6 and HHV-7 is ubiquitous, widespread and acquired early in life. HHV-8 epidemiology is still unclear, and there are two hypotheses: a restricted dissemination in the general population like herpes simplex virus type 2, or a widespread infection like all other human herpesviruses. The polymerase chain reaction is the common method for the detection of infection using specific primers and probes for HHV-6, HHV-7 and HHV-8 respectively. Serologic assays are only available for HHV-6 and HHV-7, with limitations being due, in particular, to possible cross-reactions with cytomegalovirus. HHV-6 is the causative agent of exanthem subitum (sixth disease). Its role as an opportunistic agent and immune dysfunction inducer is debated and currently under investigation. The pathogenic role of HHV-7 seems to be modest, with one case of exanthem subitum reported so far. HHV-8 is strongly associated with three diseases: Kaposi's sarcoma, Castleman's disease and body-cavity-based lymphomas. The therapy against these novel viruses has to be considered in the future.

Journal Article↗
PubMed2000

Epstein-Barr virus (EBV) and human disease: facts, opinions and problems.

The human herpesvirus, Epstein-Barr virus (EBV), has classically been associated with two pathologies with frequencies approaching 100%. One of these, Burkitt's lymphoma (BL), is of B-cell origin and the other, nasopharyngeal carcinoma (NPC), is a tumour of poorly differentiated epithelial cells. More recently, EBV had been identified with frequencies from a few percent to 100% (in one case) with a variety of other malignancies. These include Hodgkin's disease (HD; where in the west, the frequency of association is about 50%), sino-nasal T-cell lymphomas, lymphoepitheliomas, some sarcomas and breast cancers, other cancers from the head and neck, and lymphomas arising in patients with immune dysfunctions. Since EBV is ubiquitous, with the vast majority of the world's population having met and seroconverted to the virus, the diversity of tumours with which it has now been associated represents a substantial health burden. In a recent IARC monograph, EBV was classified as a group 1 carcinogen. Here, the data on BL and NPC, as they relate to geographical restrictions, viral strain variation, co-factors in disease, and genetic components are reexamined. We raise the question whether in their origins, these tumours genuinely reflect distinct and independent events, as deemed at present, or may represent a response by different cell types to common extracellular factors. For example, a situation in Kenya apparently existed in the past, where both BL and NPC were observed in ethnic Africans with roughly equal frequencies; more recently, in Kenya, EBV has been identified in nearly 100% of the tumours in children with HD. We also consider tumours where the viral association is reportedly of low frequency, and offer explanations for these data, including the possibility of loss of the viral genome once malignancy has been initiated. If this phenomenon occurs as a frequent secondary event, EBV could be an even greater health risk than presently believed.

Burkitt Lymphoma↗
PubMed1999

Measles virus infection causes transient depletion of activated T cells from peripheral circulation.

BACKGROUND: Natural measles virus infection as well as vaccination with attenuated measles virus induce temporary immunosuppression, which is responsible for part of the morbidity and mortality associated with measles. The underlying molecular mechanisms are not known. Recently, in vitro studies have revealed a marked increase of LFA-1 expression of lymphocytes in the presence of infectious measles virus. OBJECTIVES: In order to further investigate immune dysfunction in measles we analyzed the expression of leukocyte function-associated antigen 1 (LFA-1) on ex vivo derived circulating human T cells. STUDY DESIGN: Expression of LFA-1 was measured by flow cytometry using monoclonal antibodies directed against CD11a and CD18. LFA-1 expression was followed in the course of infection in four adult seronegative vaccinees and in four patients with natural measles. RESULTS: There was a remarkable loss of LFA-1-bright cells during natural measles and after measles vaccination. The number of LFA-1-bright cells reached a minimum on day 7-14 after vaccination, and at the onset of rash during natural measles infection, and approached normal levels within 3-5 weeks. CONCLUSION: It is suggested that measles virus infection interferes with lymphocyte trafficking and reallocation. Disruption of recirculation and random homing of lymphocytes might contribute to the immunosuppression, which is characteristic for measles virus infection.

Adult↗
PubMed2003

Infections and biological therapy in rheumatoid arthritis.

Infections are common in patients with rheumatic disorders. Reasons for such vulnerability include alterations of immunoregulation, disease severity, debility, co-morbid illnesses and the use of immunosuppressive medications. The advent of new biological agents has precipitated a further examination of the links between infection, the underlying disease and its treatment, resulting in several interesting observations. Interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF-alpha), the major pro-inflammatory cytokines, play important roles in host defence against infection. Inhibition of their activity could therefore be anticipated to augment the risk of infection in patients with pre-existing abnormalities of immune regulation. Slight increases in the rates of infection were noted in the clinical trials of IL-1 receptor antagonist (IL-1Ra). In addition, a small number of opportunistic infections have been observed with the TNF inhibitor, etanercept. However, a marked increase in opportunistic infection, particularly tuberculosis, has occurred with the use of infliximab, an agent that also blocks TNF activity. The precise mechanisms by which these agents predispose to infection are currently being explored. The answers are likely to add significantly to our knowledge of how immune dysfunction contributes both to the pathophysiology of disease and the complications of therapy.

Adalimumab↗
PubMed2003

Treatment of experimental asthma by long-term gene therapy directed against IL-4 and IL-13.

The clinical manifestations of allergic asthma are believed to result from a dysregulated, T helper 2 lymphocyte (Th2)-biased response to antigen. Although asthma symptoms can be controlled acutely, there is a need for a therapy that will address the underlying immune dysfunction and provide continuous control of chronic airway inflammation. The Th2-type cytokines, IL-13 and IL-4, have been demonstrated to play a crucial role in asthma pathogenesis and their selective neutralization results in the alleviation of asthmatic symptoms in mouse models. The activity of both of these cytokines can be inhibited by a mutant IL-4 protein, IL-4 receptor antagonist (IL-4RA), and thus, continual IL-4RA therapy might be beneficial in treatment of chronic asthma. To explore the potential utility of long-term gene therapy for the treatment of asthma we used a recombinant adeno-associated virus (AAV) vector to deliver and provide sustained expression of IL-4RA in vivo. We show that AAV-mediated delivery of IL-4RA to the airways of mice reduces airway hyperresponsiveness (AHR) and airway eosinophilia triggered by either IL-13 or IL-4. Furthermore, AAV-delivered IL-4RA, expressed either systemically or in the airways of mice following allergen sensitization, significantly inhibited development of airway eosinophilia and mucus production and reduced the levels of asthma-associated Th2 cytokines and AHR in the experimental mouse model of allergic asthma. Thus, gene therapy can be a potential therapeutic option to treat and control chronic airway inflammation and asthmatic symptoms.

Animals↗
PubMed2004

Cortisol does not mediate the suppressive effects of psychiatric morbidity on natural killer cell activity: a cross-sectional study of patients with early breast cancer.

BACKGROUND: There is evidence that depression impairs natural killer cell activity (NKA); this could have implications for anti-tumour immunity. Our aim was to examine the role of the hypothalamic-pituitary-adrenal (HPA) axis in suppressing NKA in a population of patients with early breast cancer, screened for depression. Secondary aims were to study the relationship between psychological, endocrine and immune variables and baseline tumour characteristics. METHOD: A cross-sectional population of female patients (n=55) with early breast cancer was sampled prior to primary surgery. Structured interview and psychometric instruments measured psychological distress. Flow cytometry was used to enumerate NK cells and lymphocytes were cryopreserved for use in a 51Cr-release assay, to estimate NKA. Midnight and three early morning saliva samples were collected to measure free cortisol levels. Tumour characteristics were obtained from hospital laboratory data. RESULTS: A high rate of psychological morbidity (40%) was observed in the population. NKA was reduced in those with past or current psychiatric illness compared to those without (344 v. 553 LU20 and 455 v. 569 LU20 respectively, p < 0.05 for both). Cortisol was not related to psychological status but was modestly positively correlated to NKA. A positive correlation was observed between the Fighting Spirit subscale of the Mental Adjustment to Cancer Scale and tumour size (r=0.383, p=0.012). CONCLUSIONS: Our data support the evidence that psychological morbidity is associated with immune dysfunction; however, the most obvious candidate mediator of this effect, the HPA axis, does not appear responsible for this effect. Possible reasons for this are discussed.

Adult↗
PubMed1999

Psychological influences on the perception of immune function.

BACKGROUND: Perception of deficiencies in immunity are common in a number of patient complaints. However, little is known about the way in which individuals form perceptions about the competence of their immune system. In two studies we examined the relationship between subjects' perceptions of their immune functioning, physical symptoms, mood and measures of immunity. METHODS: In Study 1, 20 healthy volunteers completed global ratings of their immune system functioning, as well as mood and symptom reports, twice a week for 5 weeks. At the same time, blood samples were taken to assess serum IgA, IgG, and IgM antibodies. In Study 2, another sample of 58 subjects completed the same measures weekly for 5 weeks and their blood was tested for concentrations of CD3, CD4, CD8, and CD16 lymphocytes. RESULTS: We found perceptions of immune functioning to be unrelated to the concentrations of serum antibodies or blood lymphocytes. Immune perceptions were strongly related to mood and in particular, feelings of fatigue and vigour. The experience of recent physical symptoms, while not as strong as mood variables, was also important in perceptions of immune functioning. CONCLUSIONS: Mood seems to be an important determinant in the perception of immune function, and complaints about immune dysfunction in clinical situation should be investigated with this possibility in mind.

Adult↗
PubMed2003

Eating habits and appetite control in the elderly: the anorexia of aging.

Although a high prevalence of overweight is present in elderly people, the main concern in the elderly is the reported decline in food intake and the loss of the motivation to eat. This suggests the presence of problems associated with the regulation of energy balance and the control of food intake. A reduced energy intake causing body weight loss may be caused by social or physiological factors, or a combination of both. Poverty, loneliness, and social isolation are the predominant social factors that contribute to decreased food intake in the elderly. Depression, often associated with loss or deterioration of social networks, is a common psychological problem in the elderly and a significant cause of loss of appetite. The reduction in food intake may be due to the reduced drive to eat (hunger) resulting from a lower need state, or it arises because of more rapidly acting or more potent inhibitory (satiety) signals. The early satiation appears to be predominantly due to a decrease in adaptive relaxation of the stomach fundus resulting in early antral filling, while increased levels and effectiveness of cholecystokinin play a role in the anorexia of aging. The central feeding drive (both the opioid and the neuropeptide Y effects) appears to decline with age. Physical factors such as poor dentition and ill-fitting dentures or age-associated changes in taste and smell may influence food choice and limit the type and quantity of food eaten in older people. Common medical conditions in the elderly such as gastrointestinal disease, malabsorption syndromes, acute and chronic infections, and hypermetabolism often cause anorexia, micronutrient deficiencies, and increased energy and protein requirements. Furthermore, the elderly are major users of prescription medications, a number of which can cause malabsorption of nutrients, gastrointestinal symptoms, and loss of appetite. There is now good evidence that, although age-related reduction in energy intake is largely a physiologic effect of healthy aging, it may predispose to the harmful anorectic effects of psychological, social, and physical problems that become increasingly frequent with aging. Poor nutritional status has been implicated in the development and progression of chronic diseases commonly affecting the elderly. Protein-energy malnutrition is associated with impaired muscle function, decreased bone mass, immune dysfunction, anemia, reduced cognitive function, poor wound healing, delayed recovery from surgery, and ultimately increased morbidity and mortality. An increasing understanding of the factors that contribute to poor nutrition in the elderly should enable the development of appropriate preventive and treatment strategies and improve the health of older people.

Aged↗
PubMed2005

The effects of celecoxib augmentation on cytokine levels in schizophrenia.

Celecoxib augmentation therapy has been reported to enhance the rate of clinical response for patients with schizophrenia. This may be due in part to an effect of celecoxib in the immune dysfunction associated with schizophrenia. Given concerns about the safety of COX-2 inhibitors, studies investigating cytokine levels in medicated patients with schizophrenia are of public health importance. Twenty-eight schizophrenia subjects stabilized on olanzapine or risperidone were randomized to receive 8 wk of celecoxib (400 mg/d) or placebo. Serum soluble IL-2 receptor (sIL-2r) and in-vitro PHA-stimulated whole-blood cytokine production levels were measured at baseline, 1 wk, and 8 wk. Celecoxib augmentation did not alter any of the cytokine parameters measured for the overall study group. However, 1 wk of celecoxib augmentation increased TNF-alpha and IL-2 production levels in olanzapine-treated subjects. These elevations did not persist by week 8. Overall, celecoxib does not significantly modify cytokine levels in medicated schizophrenia subjects.

Adult↗
PubMed2005

Selective small molecules blocking HIV-1 Tat and coactivator PCAF association.

Development of drug resistance from mutations in the targeted viral proteins leads to continuation of viral production by chronically infected cells, contributing to HIV-mediated immune dysfunction. Targeting a host cell protein essential for viral reproduction, rather than a viral protein, may minimize the viral drug resistance problem as observed with HIV protease inhibitors. We report here the development of a novel class of N1-aryl-propane-1,3-diamine compounds using a structure-based approach that selectively inhibit the activity of the bromodomain of the human transcriptional co-activator PCAF, of which association with the HIV trans-activator Tat is essential for transcription and replication of the integrated HIV provirus.

Acetyltransferases↗
PubMed2000

Anticonvulsant-induced suppression of IFN-gamma production by lymphocytes obtained from cervical lymph nodes in glioma-bearing mice.

It is well known that phenytoin can cause impairment of cellular immunity. The authors investigated the potential role of other anticonvulsant drugs in the development of antitumor immunity in murine malignant glioma models. The survival rate was determined in murine glioma models using syngeneic 203 glioma cells following treatment with four anticonvulsants, which are most commonly administered to glioma patients, i.e., phenytoin, phenobarbital, valproate and zonisamide. In a second set of experiments, we further examined the effect of these drugs on interferon-gamma (IFN-gamma) secretion by lymphocytes prepared from cervical lymph nodes (CLN) in the same models. The IFN-gamma production of CLN lymphocytes as measured by ELISA method was markedly impaired in the early stage of tumor-bearing mice treated with phenytoin or zonisamide, and the median survival time (MST) of controls and of mice treated with either phenytoin or zonisamide was 13, 10 and 11 days, respectively, which was not a statistically significant difference. Phenobarbital and valproate did not affect either IFN-gamma production or their survival rate. In addition, immunohistochemistry showed a reduction in tumor-infiltrating lymphocytes containing CD4 and CD8 antigens in the mice treated with phenytoin and zonisamide. Two anticonvulsants, phenytoin and zonisamide, showed a significant inhibitory effect on IFN-gamma production by CLN lymphocytes in murine glioma models, although there was no statistically significant difference in MST between controls and the anticonvulsant-treated mice. These drugs might have some detrimental influence on the prognosis of brain tumor patients when combined with the latent immune dysfunction accompanying the tumor-bearing state.

Animals↗
PubMed2004

Elevated vasoactive intestinal peptide concentrations in patients with irritable bowel syndrome.

The aim was to assess the roles of gut hormones and immune dysfunction in irritable bowel. In Study I, rectal mucosal samples examined blindly showed no histological evidence of inflammation in 16 irritable bowel patients compared to 17 healthy controls. The proinflammatory mediators interleukin-1beta and prostaglandin E2 also failed to show evidence of inflammation. Vasoactive intestinal peptide was elevated in irritable bowel (P = 0.01), but substance P, calcitonin gene-related peptide, and somatostatin levels were similar to control values. In Study II, 30 irritable bowel patients had elevated (P = 0.002) plasma concentrations of vasoactive intestinal peptide compared to 30 controls, and peptide levels were unrelated to whether the patient's predominant bowel habit was constipation, diarrhea, or both in alternation. In conclusion, no evidence of inflammation was detected in irritable bowel patients, but elevated vasoactive intestinal peptide concentrations were observed in both studies and might represent a potential diagnostic tool for irritable bowel syndrome.

Adult↗
PubMed2001

Immune function in Swedish élite orienteers.

During 1979-1992 an increased frequency of sudden unexpected cardiac death (SUD) occurred among young male Swedish élite orienteers. Subacute-to-chronic myocarditis was found in 12/16 (75%) at autopsy and Chlamydia pneumoniae, or a cross-reacting agent, was suspected on the basis of diagnostic tests performed. Because myocarditis is an infrequent cause of SUD and clusters of SUD are rare, whereas Chlamydia pneumoniae infections are ubiquitous and seldom cause severe myocarditis, 119 top ranked élite orienteers (67 males and 52 females) and 36 highly trained male middle-distance runners and cross-country skiers, serving as controls, underwent immunologic screening in an effort to reveal possible immune dysfunction. Except for two orienteers and one runner/skier who showed genetic C3-deficiency or IgA-deficiency, the results showed no significant differences between the orienteers and controls with respect to immunoglobulin levels, complement activation, lymphocyte subsets, including activated T lymphocytes, and sIL-2r-alpha. IL-1 beta, IL-6, TNF-alpha, and sCD8, tested in the orienteers only, were normal. However, IFN-gamma was significantly higher in controls than in orienteers, who showed normal levels, whereas the orienteers had increased sELAM-1 and sICAM-1 levels. Finally, sIL-2 receptor-alpha was similarly elevated in orienteers and controls. We conclude that, with the tests employed, no immunologic disturbance could be revealed in the orienteers that may potentially have increased their susceptibility to myocarditis and SUD.

Adolescent↗
PubMed1997

Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation.

Ataxia telangiectasia (AT) is a rare human autosomal recessive disorder with pleiotropic phenotypes, including neuronal degeneration, immune dysfunction, premature ageing and increased cancer risk. The gene mutated in AT, ATM, encodes a putative lipid or protein kinase. Most of the human AT patient phenotypes are recapitulated in Atm-deficient mice. Cells derived from Atm-/- mice, like those from AT patients, exhibit abnormal response to ionizing radiation. One of the known responses to ionizing radiation is the activation of a nuclear tyrosine kinase encoded by the c-abl proto-oncogene. Ionizing radiation does not activate c-Abl in cells from AT patients or in thymocytes or fibroblasts from the Atm-deficient mice. Ectopic expression of a functional ATM kinase domain corrects this defect, as it phosphorylates the c-Abl tyrosine kinase in vitro at Ser 465, leading to the activation of c-Abl. A mutant c-Abl with Ser 465 changed to Ala 465 is not activated by ionizing radiation or ATM kinase in vivo. These findings identify the c-Abl tyrosine kinase as a downstream target of phosphorylation and activation by the ATM kinase in the cellular response to ionizing radiation.

3T3 Cells↗