Decrease of regulatory T cells in patients with systemic lupus erythematosus.
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Adult↗
Biomedical subjects
J A Vargas
Publications and source records attributed to J A Vargas.
[Young woman with long-course back pain].
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Back Pain↗
Pneumococcal cellulitis in a patient with systemic lupus erythematosus: a case report and review.
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Adult↗
A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells.
The progressive rise of mature CD5+ B lymphocytes, despite the low proportion of proliferating cells, has led to the notion that B cell chronic lymphocytic leukemia (B-CLL) is primarily related to defective apoptosis. The microenvironment likely plays a prominent role because the malignant cells progressively accumulate in vivo, whereas they rapidly undergo spontaneous apoptosis when cultured in vitro. To assess microenvironment-mediated survival signals, B-CLL cells were cultured with a murine fibroblast cell line, Ltk-, with and without an agonistic antibody to CD40. Spontaneous apoptosis was associated with the loss of Akt and NF-kappaB activities. Interactions with fibroblasts sustained a basal level of Akt and NF-kappaB activities, which was dependent on phosphatidylinositol-3 kinase (PI3K). Constitutive activity of the PI3K pathway in B-CLL cells when cultured with fibroblasts prevented the downregulation of the prosurvival Bcl-2 family protein Bcl-xL and the caspase inhibitor proteins FLIPL and XIAP, and consequently caspase-3 activation and apoptosis. CD40 crosslinking in B-CLL cells did not further prevent murine fibroblasts-mediated apoptosis but induced cell proliferation, which was associated with an increase of Akt and NF-kappaB activation compared with cells cultured with fibroblasts alone. The PI3K pathway seems to play a pivotal role in B-CLL cell survival and growth.
Adult↗
The dinucleotide repeat polymorphism in the 3'UTR of the CD154 gene has a functional role on protein expression and is associated with systemic lupus erythematosus.
OBJECTIVE: To investigate the association of the (CA)n dinucleotide repeat in the 3' untranslated region (3'UTR) of the CD154 gene with systemic lupus erythematosus (SLE), and its functional role in protein expression. METHODS: The allelic and genotypic distributions of the polymorphism were compared in 80 patients with SLE and 80 controls. A complete clinical and analytical database was recorded in each patient in order to correlate the clinical manifestations in SLE with different alleles. To investigate the functional role of the polymorphism, the CD154 protein expression on activated lymphocytes from healthy homozygous controls was evaluated by flow cytometry. RESULTS: The 24 CA allele was the most represented in controls (p = 0.029), whereas the alleles containing >24 CA repeats were found in patients (p = 0.0043). Furthermore, when only homozygous women were considered, most controls carried two 24 CA alleles (p = 0.041), whereas most patients carried two alleles containing >24 CA repeats (p = 0.032). Also, patients carrying at least one 24 CA allele had less neurological involvement (p = 0.034), and carriers of at least one allele with fewer than 24 CA repeats presented more livedo reticularis (p = 0.006) and anti-Sm (p = 0.01) and anti-RNP (p = 0.038) autoantibodies. CD154 maximum expression in activated lymphocytes from all controls was reached after 54 hours, but it was more prolonged in controls carrying two alleles with >24 CA repeats (p = 0.0068). CONCLUSION: The CD154 3'UTR microsatellite is associated with SLE, and the most represented alleles in patients were accompanied by a more prolonged protein expression in activated lymphocytes from controls.
3' Untranslated Regions↗
Fenticonazole nitrate for treatment of vulvovaginitis: efficacy, safety, and tolerability of 1-gram ovules, administered as ultra-short 2-day regimen.
Because of its potential as a low cost first-line monotherapy for the most common vulvovaginal infections, we evaluated fenticonazole nitrate in a prospective, open-label, multicenter pilot study with 101 sexually active women (per-protocol; 16 to 61 years of age) with vulvovaginitis involving single or mixed infections with Candida albicans, Trichomonas vaginalis, and/or Gardnerella vaginalis. Fenticonazole nitrate (1 g) was administered as vaginal ovules, once daily on days 1 and 3. Eradication (direct phase-contrast microscopy of vaginal swabs and/or microbiological culture) on day 8 was 90% (C. albicans, 26/29, p < 0.001), 70% (T. vaginalis, 7/10, p = 0.161), 67% (G. vaginalis, 22/33, p < 0.009), and 45% (mixed infection, 13/29, p = 0.001). After 28 days, relapse was 0% for candidiasis and trichomoniasis, 27% (6/22) for G. vaginalis, and 23% (3/13) for mixed infection. Overall, eradication of all offending pathogens was achieved in 67% of the total per-protocol population, with a relapse rate of only 16%. Score sums for symptoms improved from 7.0 (baseline) to 1.7 (day 8), and 0.71 (day 28), (p < 0.001). Treatment was safe and well tolerated. The results of our pilot study suggest that application of fenticonazole nitrate 1 g intravaginal ovules on 2 alternate days is a suitable first-line treatment of vulvovaginitis with acceptable broad-spectrum efficacy against the most commonly involved pathogens and with a low rate of early relapse, reserving antibiotics for patients with treatment failure or relapse of infection. Our results should encourage further examination of this approach in larger and well controlled clinical trials.
Administration, Intravaginal↗
Host gender in parasitic infections of mammals: an evaluation of the female host supremacy paradigm.
A review of current literature on mammalian hosts' sexual dimorphism (SD) in parasitic infections revealed that (1) it is a scarcely and superficially studied biological phenomenon of considerable significance for individual health, behavior, and lifestyles and for the evolution of species; (2) there are many notable exceptions to the rule of a favorable female bias in susceptibility to infection; (3) a complex network of molecular and cellular reactions connecting the host's immuno-neuroendocrine systems with those of the parasite is responsible for the host-parasite relationship rather than just an adaptive immune response and sex hormones; (4) a lack of gender-specific immune profiles in response to different infections; (5) the direct effects of the host hormones on parasite physiology may significantly contribute to SD in parasitism; and (6) the need to enrich the reductionist approach to complex biological issues, like SD, with more penetrating approaches to the study of cause-effect relationships, i.e., network theory. The review concludes by advising against generalization regarding SD and parasitism and by pointing to some of the most promising lines of research.
Animals↗
Nuclear androdioecy and gynodioecy.
We formulate two single-locus Mendelian models, one for androdioecy and the other one for gynodioecy, each with 3 parameters: t the male (female) fertility rate of males (females) to hermaphrodites, s the fraction of the progeny derived from selfing; and g the fitness of inbreeders. Each model is expressed as a transformation of a 3 dimensional zygotic algebra, which we interpret as a rational map of the projective plane. We then study the dynamics for the evolution of each reproductive system; and compare our results with similar published models. In this process, we introduce a general concept of fitness and list some of its properties, obtaining a relative measure of population growth, computable as an eigenvalue of a mixed mating transformation for a population in equilibrium. Our results concur with previous models of the evolution of androdioecy and gynodioecy regarding the threshold values above which the sexual polymophism is stable, although the previous models assume constant the fraction of ovules from hermaphrodites that are self pollinated, while we assume constant the fraction of the progeny derived from selfing. A stable androdioecy requires more stringent conditions than a stable gynodioecy if the amount of pollen used for selfing is negligible in comparison with the total amount of pollen produced by hermaphrodites. Otherwise, both models are identical. We show explicitly that the genotype fitnesses depend linearly on their frequencies. Simulations show that any population not at equilibrium always converges to the equilibrium point of higher fitness. However, at intermediate steps, the fitness function occasionally decreases.
Algorithms↗
Production of intracellular IL-2, TNF-alpha, and IFN-gamma by T cells in B-CLL.
BACKGROUND: Recent evidence indicates that the slowly expanding population of CD5(+) B cells that characterizes B-cell chronic lymphocytic leukemia (B-CLL) could be related to defects in the response to cytokine produced by T cells that regulate apoptosis. We studied the intracellular expressions of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in T-helper 1 cells (Th1 response) of B-CLL. METHODS: Peripheral blood mononuclear cells from 21 healthy individuals and purified T cells from 21 early-stage and 15 late-stage B-CLL patients were activated with phorbol myristate acetate and ionomycin. The Th1 cytoplasmic cytokines were evaluated in CD4(+) and CD8(+) T cells by flow cytometry. RESULTS: The percentages of CD4(+) and CD8(+) T cells positive for IL-2 were significantly lower in B-CLL patients than in healthy individuals (P = 0.030 and 0.049, respectively). No significant differences in TNF-alpha or IFN-gamma intracellular expressions were found between patients and healthy individuals. TNF-alpha- and IFN-gamma-expressing CD8 T cells were disease stage dependent, being significantly higher in late-stage patients (P < 0.001 for both cytokines). CONCLUSIONS: Our present observations suggested that Th1 cytokines may be of major importance in the pathogenesis of B-CLL.
Adult↗
Flow-cytometric assessment of lymphocyte cytokine production in tuberculosis.
We assessed by flow-cytometry the Th1/Th2 profiles in peripheral blood lymphocytes (PBL) from patients with active tuberculosis (TB), before and after antituberculous therapy, and from healthy tuberculin-positive and -negative reactors. PBL from patients showed a reduced potential for Th1-cytokine (notably IFN- gamma) production after culture with a policlonal stimulus. When these PBL from patients were cultured with a M. tuberculosis (MTB)-specific antigen such as PPD (10 microg/ml), there was no detectable production of Th1 cytokines. Only the Th2 cytokine IL10 was detected in PBL from patients but not from controls. However, at the site of the tuberculosis disease, T lymphocytes from bronchoalveolar lavage, after culture with PPD, produced IFN- gamma. After completion of tuberculosis therapy, PBL did not produce IL10. These data indicate that the immunosuppression observed in PBL during active tuberculosis infection may be related to IL10 production, and to the compartmentalization of the antigen-Th1 response to sites of active MTB infection.
Adult↗
Does the serological testing really play a role in the diagnosis immune-mediated inner ear disease?
In order to analyse the clinical presentation and laboratory tests used for the diagnosis of immune-mediated sensorineural hearing loss (IMSNHL) a prospective study was conducted involving 125 patients affected by diverse clinical forms of the disease. The following methods were used: analysis of clinical evolution, pure-tone audiometry, determination of the immunophenotype of peripheral blood lymphocytes, immunoglobulins, complement factors C3 and C4, erythrocyte sedimentation rate, antinuclear autoantibodies (ANA) and heat shock protein 70 and the response to therapy. Levels CD4 (p = 0.03) and CD4CD45RA (p = 0.002) T cells were significantly reduced in patients with sudden sensorineural hearing loss. ANA were found in 34.4% of patients and the incidence of antibodies to HSP-70 was similar in both patients and control subjects. Diagnosis of IMSNHL is still based on clinical impressions as laboratory testing is not sufficiently diagnostic. However, the long-term evolution of IMSNHL presented by the patients included in this study may explain the negative results obtained in the tests. The existence of a typical profile patient, including the clinical course, immunological changes (presence of ANA and detection of abnormalities in T-cell subpopulations) and the response to steroid therapy can facilitate diagnosis. Further investigation to help identify a specific marker characteristic of IMSNHL is required.
Adult↗
[Study of pulmonary lesions with (99m)Tc-Tetrafosmin and chest spect. Determination of uptake related factors, diagnostic value and prognosis].
One hundred fifteen patients with 119 pulmonary lesions in which malignancy was suspected underwent a SPECT study with 99mTc-Tetrofosmin (TTF) to assess the possible factors involved in the uptake of the radiopharmaceutical. The TTF uptake rate in the lung tumor with respect to that of healthy tissue (TTF index) was evaluated in terms of: benignity and malignancy, histological type, stage, cell differentiation, size, necrosis, survival and the influence of P-glycoprotein (Pgp), detected by immunohistochemistry, on the TTF uptake. The mean TTF index in the 18 benign lesions studied was 1.01 0.05, while that of the 101 malignant lesions was 1.59 0.45 (p < 0.001), with a positive predictive value of 97.7% and a negative predictive value of 50%. The comparison of the histological types, degree of cell differentiation, necrosis and stage revealed no statistically significant differences. With respect to size, those tumors measuring > 3 cm showed greater uptake than smaller lesions. In patients with non-small cell lung cancer, a positive relationship was observed between the TTF index and survival, a circumstance that did not occur in patients with small cell lung cancer. In the cases in which the presence of Pgp was assessed, there was an inverse relationship between the TTF ratio and Pgp expression. In conclusion, thoracic SPECT with 99mTc-TTF has a high positive predictive value for the presence of lung cancer, although a negative study does not rule out the existence of the disease. The reason for this is the inverse relationship between 99mTc-TTF uptake and the density of Pgp expression.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Genetic associations under mixed mating systems: the Bennett-Binet effect.
Using elementary algebraic geometry and computational commutative algebra, supported by the program Macaulay2, we studied and developed operators that define the zygotic and gametic evolution under a mixed-mating system with parameters s selfing rate, r recombination rate, and g relative fitness of inbreeders, for any possible combination of initial zygotic or gametic frequencies with two alleles at each of two loci. We found that (i) the allelic frequencies are preserved in every generation; (ii) the gametic frequencies converge to values that depend exclusively on the allelic frequencies; (iii) every zygotic population converges to a population in equilibrium with double heterozygotes equally frequent; (iv) the rate of convergence decreases to arbitrary small values with sufficiently small values of r or with sufficiently large values of s and (v) as g decreases, the maximal 'association between the two loci' occurs with higher values of selfing. We also found generalizations for the case of several alleles at each locus.
Alleles↗
Aminoguanidine reduces apoptosis of circulating V Beta 8.2 T lymphocytes in Lewis rats with actively induced experimental autoimmune encephalomyelitis. Association with persistent inflammation of the central nervous system and lack of recovery.
Aminoguanidine therapy delayed the onset of actively induced EAE in Lewis rats, but recovery was impaired in most animals. In the central nervous system this was correlated with persistent inflammation and production of proinflammatory cytokines. In the periphery of aminoguanidine-treated animals, T lymphocytes showed increased proliferation against myelin basic protein, and the percentage of Vbeta 8.2(+) T lymphocytes undergoing early apoptosis was markedly decreased, although it was unchanged in Vbeta 8.2(+) T cells isolated from the spinal cord. These results suggest that the prolonged survival of circulating encephalitogenic cells achieved by aminoguanidine would favor a longer lasting entry of these cells into the nervous system resulting in persistent inflammation and lack of recovery.
Animals↗
Candida infection of cerebrospinal fluid shunt devices: report of two cases and review of the literature.
Use of CSF shunt devices is a common practice in neurosurgery, and infection of the shunt is the most frequent complication. In spite of the fact that bacteria are the most widely implicated pathogens, reports of fungal infections, especially due to Candida sp., have increased in recent years. Their reported frequency ranges between 6% and 17%. Many factors have been implicated in the pathogenesis of Candida meningitis, such as broad spectrum antibiotics used in the treatment of a bacterial meningitis, steroids and indwelling bladder and intravenous catheters. The treatment of Candida meningitis still consists of systemic antifungal agents and removal of the shunt.
Adolescent↗
Role of viral and Mycoplasma pneumoniae infection in idiopathic sudden sensorineural hearing loss.
Sudden deafness constitutes a challenge in terms of the etiopathogenic diagnosis. The causative origin of sudden deafness usually remains unknown. However, available evidence suggests that viral and Mycoplasma pneumoniae infection could be one factor involved. In order to analyze the incidence of these infectious agents, a microbiology study was carried out during the acute phase of the disease, and during convalescence, in 24 patients (17 men and 7 women; mean age 39.7 years; range 17-63 years) with idiopathic sudden hearing loss (SHL) according to previously published criteria. In the acute phase most of the patients presented IgG antibodies to Epstein-Barr virus (n = 23), herpes simplex virus (n = 24), parainfluenza virus (n = 24), varicella-zoster virus (n = 24) and cytomegalovirus (n = 20). Results obtained from 3 patients suggested the existence of a recent infectious process caused by Mycoplasma pneumoniae (IgM+) in 1 patient, Mycoplasma (IgM+) and influenza A virus (complement fixation titer > 1/64) in another and parainfluenza virus seroconversion (a fourfold higher titer between the acute phase and convalescence) in the third. In conclusion, the low incidence of documented positive serological tests in our series (12.5%) may be due to the presence of pathological situations other than acute infection and does not justify routine serological studies in patients with SHL.
Acute Disease↗
Modulation of apoptosis by cytokines in B-cell chronic lymphocytic leukemia.
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the slow and progressive accumulation of monoclonal apparently mature, CD5(+) B lymphocytes. The majority of circulating cells appear to be nondividing, and it has been suggested that a prolonged life span is mainly responsible for the accumulation of the leukemic cells. However, spontaneous programmed cell death by apoptosis occurs when B chronic lymphocytic leukemia cells are cultured in vitro. This may be because of the lack of an unidentified essential cytokine present in vivo. Thus, we investigate interleukin-2 (IL-2), IL-4, IL-6 and IL-10 in vitro effects on apoptosis of B cells from 32 previously untreated patients with B-CLL in initial clinical stages. B cells were isolated from peripheral blood, and apoptosis was measured in these cells immediately after isolation and following incubation in vitro, without and with the different cytokines, for 24 and 48 h. Distribution of cellular DNA content and quantitative analysis of apoptosis were determined by standard propidium iodide staining and flow cytometry. Spontaneous apoptosis occurred in B-CLL cells incubated in vitro in the absence of cytokines. Our results indicate that both IL-2 and IL-4, but not IL-6, inhibit in vitro apoptosis in a large percentage of B-CLL patients. IL-10 increases in vitro apoptotic cell number in stage 0 patients, but not in stage I and II. These data support the hypothesis that IL-2 or IL-4, may be cell survival factors in vivo and that IL-10 might be a candidate for immune therapy of early B-CLL.
Adult↗
Characterization of adrenal medullary chromaffin cells by flow cytometry.
BACKGROUND: Adrenomedullary chromaffin cells are neural crest derivatives widely used as a model system to study neurosecretory mechanisms. Morphological, immunohistochemical, and functional data indicate that chromaffin cells are heterogeneous and support the distinction between adrenaline (A)- and noradrenaline (NA)-producing and secreting cells. The aim of this study was to characterize by flow cytometry the two main chromaffin cell subtypes in suspensions of cultured bovine chromaffin cells. METHODS: An indirect immunofluorescence method was used for the specific labeling of two intracellular enzymes, dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT), involved in the synthesis of NA and A, respectively. Flow cytometry analysis of fluorescence labeling was performed in two chromaffin cell fractions differentially enriched in A-containing cells by centrifugation through density gradients. PNMT and DBH-related fluorescence was also correlated with the A and NA content of the cells assayed by HPLC measurements. RESULTS: No significant differences were found in forward-side scatter plots between the two cell fractions (A-enriched cells and mixed cells); however, the degree of labeling of the enzymes and the corresponding PNMT/DBH-related fluorescence ratio was significantly greater in the A-enriched cell fraction. The existence of changes in DBH and PNMT content of chromaffin cells over time (1 week) in culture was also examined. No significant variation in enzyme related fluorescence values was detected in any of the two cell fractions, and this result correlated well with HPLC determinations of the catecholamine content (A and NA) of the cells. CONCLUSIONS: Flow cytometry appears to be a useful technique to characterize chromaffin cell subtypes and to follow their phenotypic changes in response to growth factors.
Adrenal Medulla↗