The presence of IFL3/4 rs12979860 C allele influences the in vitro IP-10 production by mononuclear cells from patients with systemic lupus erythematosus.

OBJECTIVE: To explore whether the IFNL3/4 rs12979860 genotype may influence serum levels or production of interferon-inducible protein-10 (IP-10) by peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE). METHODS: Sixty-six patients with SLE and 22 healthy blood donors (controls) were included. The IFNL3/4 rs12979860 polymorphism was genotyped by real-time polymerase chain reaction. IP-10 levels in sera supernatants of IFNα stimulated peripheral blood mononuclear cells were measured by enzime-linked immunosorbent assay. RESULTS: Allelic frequencies were CC (29%), CT (52%) and TT (20%) in SLE, and CC (32%), CT (41%) and TT (27%) in healthy controls. Median serum IP-10 levels were higher in SLE patients than in controls (190.8 versus 118.1 pg/ml; p < 0.001), particularly in those with high disease activity (278.5 versus 177.2 pg/ml; p = 0.037). However, serum IP-10 levels were not influenced by IFNL3/4 genotypes. Higher IP-10 production by peripheral blood mononuclear cells was found in both SLE patients (median 519.3 versus 207.6 pg/ml; p = 0.012) and controls (median 454.0 versus 201.7 pg/ml; p = 0.034) carrying the IFNL3/4 C allele compared with carriers of the T allele. CONCLUSIONS: Although IFNL3/4 rs12979860 allele C does not appear to influence serum IP-10 levels in SLE, it plays an important role in the production of IP-10 by peripheral blood mononuclear cells after IFNα stimulation.

Relationship Between Specialized Pro-resolving Mediators and Inflammatory Markers in Chronic Cardiac Disorders.

The term cardiovascular diseases (CVD) refers to disorders of heart and blood vessels, and include coronary heart disease, cerebrovascular disease, peripheral vascular disease, and heart failure, among others. Atherosclerosis is a common background of these diseases. It is not infrequent that some acute diseases, such as coronary syndromes, appear superimposed on a chronic arterial disease. Acute coronary syndromes (ACS), found worldwide among the leading causes of death, can be the origin of disabling chronic CVD such as heart failure [46]. Clinical and experimental evidence associates this group of alterations with an inflammatory process that takes part in its pathophysiology. In fact, inflammation is one of the most important factors for its initiation, progression, and consolidation [6].

Enhanced survival from CLP-induced sepsis following late administration of low doses of anti-IFNγ F(ab')2 antibody fragments.

OBJECTIVE: To assess the impact of different doses of anti-interferon gamma (anti-IFNγ) F(ab')2 fragments, administered prophylactically, on survival and on serum concentration of cytokines in a murine model of sepsis induced by cecal ligation and puncture (CLP). We further explore the impact of therapeutic administration of the most protective dose on survival. SUBJECTS AND TREATMENT: Balb/c mice were prophylactically treated by the intraperitoneal route with anti-IFNγ initiated 2 h before CLP and every 24 h for a total of five times in each of the following doses: 0.01, 0.1, or 1 mg/kg. Sham and control groups received sterile saline solution in a similar scheme. METHODS: Serum tumor necrosis factor (TNF), interleukin (IL)-1ß, IL-6, IL-10 and IFNγ were measured at 3, 24 and 48 h after CLP by ELISA. Survival curves were compared using a Mantel-Haenzel method. RESULTS: Significant prophylactic protection was found only with 0.01 mg/kg, in association with regulation of IL-1ß and IL-10 concentrations. As therapy, anti-IFNγ fragments were protective only when initiated 24 h after CLP. CONCLUSIONS: Delicate modulation of IFNγ at the correct timing, even when the septic process has begun, is an exciting alternative to explore in the treatment of sepsis.

Erosive arthritis in systemic lupus erythematosus is associated with high serum C-reactive protein and anti-cyclic citrullinated peptide antibodies.

Predictors for erosive arthritis in systemic lupus erythematosus (SLE) are poorly understood. We performed a pilot, descriptive case-series study to identify whether different biomarkers differentiate SLE patients from those additionally developing erosive arthritis. Median C-reactive protein (CRP) concentration in erosive arthritis was 14.5 mg/L (IQR, 6.6-19.4), but only 0.8 (0.45-7.37, p = 0.01) in non-erosive. Anti-cyclic citrullinated peptide antibodies (anti- CCP) were also associated with erosive arthritis (60 vs. 0% , p = 0.02; OR = 18.2, 0.66-495). Serum IL-6, IFNgamma, IL-4 and IL-10 tended to be higher in erosive arthritis, although none attained statistical significance. A negative correlation between IL-6 and CRP was found in non-erosive arthritis ( r-0.60). High CRP and anti-CCP may be useful serological markers for an erosive arthritis pattern among SLE patients.

Mechanical deformation inhibits IL-10 and stimulates IL-12 production by mouse calvarial osteoblasts in vitro.

The skeleton is continuously remodelled throughout life, a process that is orchestrated by cells of the osteoblast lineage. Remodelling involves a complex network of cell-cell signalling involving systemic hormones, locally produced cytokines, growth factors and the mechanical environment of the cells. Here, we report on the effect of mechanically-induced strain on the synthesis by mouse calvarial osteoblasts in monolayer culture of IL-10 and IL-12, two cytokines that inhibit osteoclast formation in bone marrow cultures; IL-10 also suppresses osteoblast differentiation suggesting a role for both cytokines in bone physiology. A tensile strain was applied to the cells intermittently for 6s, every 90s, for 2-96h. After 2-h culture, supernatants from deformed cells contained significantly less IL-10 than control cultures. In contrast, mechanical deformation had a stimulatory effect on IL-12 synthesis; however, by 48h both had returned to control levels. These data suggest that IL-10 and IL-12 can be added to the growing list of mechanical stress-responsive genes. The down-regulation of IL-10 and stimulation of IL-12 further suggests that the initial response of the cells to mechanical deformation was an osteogenic one.

Antibiotic misuse in diarrhea. A household survey in a Mexican community.

A survey of 1659 households in a periurban community in Mexico City was carried out to assess the frequency of and risk factors for inappropriate antimicrobial therapy in acute diarrhea. The housewife was interviewed to obtain information of the occurrence of diarrhea or use of an antibiotic in the previous 2 weeks by any member of the family. An antibiotic was used in 37% or 287 diarrheal episodes although only in 5% of all episodes was this therapy indicated, based on the presence of gross blood in stools. Patients seen by a physician were 6 times more likely to be treated with an antibiotic compared to those who did not consult a physician (p < 0.001). Self-medication was associated with a higher risk of using an inadequate drug or dose (in 72% of treated episodes) and of following treatment for less than 5 days (in 66% of treated episodes). Other risk factors significantly and independently associated with antibiotic misuse were: an increased number of stools (odds ratio [OR] = 1.21; 95% confidence interval [CI] = 1.04, 1.41), bloody diarrhea (OR = 19.04; 95% CI = 2.52, 160.90) and family crowding (OR = 2.07; 95% CI = 1.17, 3.63). These findings support future community-oriented educational interventions aimed at improving physician prescribing practices and patient compliance behavior in order to achieve a more rational use of antibiotics.

Reliable serology of Taenia solium cysticercosis with antigens from cyst vesicular fluid: ELISA and hemagglutination tests.

New levels of reproducibility and sensitivity have been achieved in the detection of anticysticercus antibodies in human sera by using cysticercus vesicular fluid as the source of antigens for both ELISA and hemagglutination assays. Reproducibility both between tests on a serum and between similar sera was significantly improved over typical results using antigens from whole parasite extracts. Sera collected from uninfected individuals in endemic areas gave somewhat elevated values over those collected in nonendemic areas. This necessitated the use of a higher threshold in endemic areas to avoid false positives. With the threshold appropriate for a nonendemic area, both ELISA and hemagglutination were sensitive enough to detect infection in 95% of cases. With the threshold value for sera from an endemic area, these sensitivities were reduced to 80%-90%. A prominent 103-Kd protein of vesicular fluid, not related to antigen B, elicited the strongest antibody response in neurocystercotic patients.

Low risk of invasive amebiasis in cyst carriers. A longitudinal molecular seroepidemiological study.

A seroepidemiological study of a household cohort, using both clinical observational and molecular criteria was conducted in a periurban area endemic for E. histolytica infection. This longitudinal study was undertaken to determine the risk of asymptomatic cyst carriers to develop invasive illness. Zymodeme patterns of strains isolated from these patients were correlated both with the clinical presentation of disease and with the serological response against the M-17 ameba antigen and further compared with that found in 16 proven cases of amebic liver abscess. From a total of 163 housewives screened, 39, (24%) were asymptomatic cyst carriers; 31 of them (index cases) and 114 members of their households remained in the study over an 8 month follow-up period to detect ameba infection and illness. Of the household members at risk, 46 (40%) became infected within 6 weeks. None of the index or secondary cases developed ameba-related symptoms and cyst excretion followed a chronic persistent, intermittent, or transient pattern over the period of the study. Amebas were recovered and zymodemes determined in 19 of 71 (27%) cyst carriers. Ameba shed from each of these 19 carriers exhibited nonpathogenic zymodeme 1, except for one index case where zymodeme 2 was recovered in one sampling, and returned to zymodeme 1 in subsequent samples. Of 48 of 71 cyst carriers studied, antibodies to crude E. histolytica antigen were detected by ELISA in 16 (31%); antibodies to the M-17 fusion protein were found in 8 (16%) by ELISA and in 2 (4%) by Western-Blot (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Antibiotic use in a periurban community in Mexico: a household and drugstore survey.

In developing countries, antibiotics are the most common drugs sold, and some data suggest that they are frequently misused. In order to describe the pattern of antibiotic use in a periurban community in Mexico City, 1659 randomly-selected households were visited and an interview with the housewife was carried out. Six local drugstores also were selected at random. A social worker made six visits to each pharmacy, observed the events during the purchase of the drug and applied a structured questionnaire to the customer immediately after the transaction. Of 8279 individuals, 425 (5%) said that they had used at least one antimicrobial in the preceding 2 weeks and antibiotics were the majority (29%) of the drug sales. The main perceived reasons for drug use were acute respiratory tract ailments and gastroenteritis. Interviewees reported that antibiotic therapy was given in 27% of respiratory diseases and in 37% of all diarrheal episodes. The drugs most commonly reported were: penicillins, erythromycin, metronidazole, neomycin, cotrimoxazole and tetracyclines. While self-medication and drug purchases without medical prescription were common, the majority of antibiotics were prescribed by a physician. Approximately two thirds of individuals using an antibiotic said they had used it for less than 5 days and 72% of the purchases were for insufficient quantities of drugs. Our data suggest that antibiotics are frequently misused and they support the need to assess the determinants of self-medication, health-seeking behavior and physician prescribing practices. The need for effective educational programs to improve prescribers' decisions is stressed.

Thymus-related cellular immune mechanisms in sex-associated resistance to experimental murine cysticercosis (Taenia crassiceps).

The role of sex, thymus, and cellular immune mechanisms in mouse resistance to experimental cysticercosis with Taenia crassiceps was studied in male and female susceptible mice treated with cyclophosphamide, as well as in mice neonatally thymectomized and passively transferred with T-enriched lymphoid cells. High doses of cyclophosphamide increased delayed hypersensitivity and resistance of mice of both sexes without affecting antibody production. Neonatal thymectomy diminished resistance in both sexes but depressed delayed hypersensitivity in females only, without significantly affecting antibody response in either sex. Passive transfer of T-enriched lymphoid cells to thymectomized mice restored resistance to control levels without greatly affecting delayed hypersensitivity. Thus, our results indicate that cell-associated immune mechanisms are implicated in resistance to murine cysticercosis with T. crassiceps. Because neonatal thymectomy nearly equalized the intensity of infection of female and male mice, it is argued that the thymus is importantly involved in the interaction between gonads and the immune system in the control of this cysticercosis.

A role for 17-beta-estradiol in immunoendocrine regulation of murine cysticercosis (Taenia crassiceps).

In experimental murine cysticercosis caused by Taenia crassiceps, parasite reproduction is favored by thymectomy or by orchidectomy, and restricted by ovariectomy. Hormonal reconstitution experiments showed that 17-beta-estradiol increases parasite numbers whereas 5-alpha-dihydrotestosterone was ineffective. Parasite numbers decreased with increments in cellular immunity but were insensitive to antibody levels. A possible immunoendocrinological interaction involving estrogen as a depressor of cellular immunity is envisaged in the control of cysticercosis.

Shift from an early protective Th1-type immune response to a late permissive Th2-type response in murine cysticercosis (Taenia crassiceps).

In early stages of experimental murine cysticercosis caused by Taenia crassiceps, there is a clear but transient Th1-type immune response (characterized by high levels of interleukin [IL]-2, interferon-gamma, concanavalin A, and antigen specific response, delayed-type hypersensitivity, and immunoglobulin [Ig]G2a antibodies) that associates with a low rate of parasite reproduction. As time of infection progresses an energic and more permanent Th2-type response follows (characterized by high levels of IL-4, IL-6, IL-10, IgG2b, and IgG1 antibodies) that in turn associates with an increment in the rate of parasite reproduction. The sequential activation of Th1-type and Th2-type responses in murine cysticercosis would appear to favor progressively parasite reproduction, explaining the long time residence and the massive parasite intensity reached in chronic infections.

[Immune response or tolerance. Cellular selection by the thymus]. / Respuesta inmune o tolerancia. La selección celular en el timo.

There is currently a very active research on the mechanisms that give rise to the cell selection of lymphocyte precursors by the thymus. This selection is basic for the process of formation of the repertoire of T cells with which an organism is potentially capable of developing an immune response to a foreign antigen, and not doing so when encountering its own antigens. This work pretends to detail some recent advances in the knowledge of the process by which cells are positively or negatively selected by the thymus, to give rise to the T cell repertoire of an individual.

LPS pretreatment by the oral route protects against sepsis induced by cecal ligation and puncture. Regulation of proinflammatory response and IgM anti-LPS antibody production as associated mechanisms.

OBJECTIVE: To explore the efficacy of prophylactic oral lipopolysaccharide (LPS) in sepsis induced by cecal ligation and puncture (CLP). MATERIAL: Male Balb/c mice. LPS serotype O55: B5 TREATMENT: Mice were treated every 4 days for a total of 5 times with 50 mug of LPS by intraperitoneal (IP) or oral (O) routes. Treatment was stopped one week prior to CLP. Control (C) groups received the vehicle orally, and sham (S) groups were used as reference. METHODS: Histopathology was performed to determine inflammation in liver and lung. Serum cytokines were measured by ELISA, and TNFalpha tissue expression by RTPCR. Antibodies against LPS were measured by ELISA. RESULTS: Administration of LPS by the oral route significantly increased survival (p<0.05) of mice in association with a reduction of Kupffer cells in liver, pulmonary edema in lung, shorter or delayed TNFalpha expression in target organs, a trend to decreased IFN gamma and increased IL-10 serum levels, and a notable increase in the production of specific IgM anti-LPS antibodies. CONCLUSIONS: LPS by oral route protected against CLP. The underlying mechanisms could be the modulation of the proinflammatory response and an increased production of IgM anti-LPS antibodies.

Anti-tumor necrosis factor alpha F(ab')2 antibody fragments protect in murine polymicrobial sepsis: concentration and early intervention are fundamental to the outcome.

BACKGROUND: Negative results are frequent using anti-TNFalpha antibodies in sepsis models and clinical trials. METHODS AND RESULTS: Different prophylactic doses of anti-TNFalpha F(ab')2 antibody fragments were compared for the prevention of death by sepsis induced by cecal ligation and puncture (CLP) in mice. High (10 mg/kg) and very low (0.01 and 0.1 mg/kg) concentrations of anti-TNFalpha antibody fragments were not the most adequate for treating polymicrobial sepsis, since they did not significantly improve survival. To the contrary, intermediate doses (1 mg/kg) significantly protected the challenged animals. Protective activity was also observed when administration of the antibody fragments was initiated early (up to 30 min) after CLP. CONCLUSIONS: These results suggest that in processes where excessive production of cytokines is involved, the aim should be to return them to their physiologically acting range but not to inhibit their production. The timing of initiating therapy should also be considered in order to maximize the possible benefits.

[The use of antibiotics in a community of Mexico City. I. A household survey]. / Uso de antibióticos en una comunidad de la Ciudad de México. I. Encuesta domiciliaria.

Based on previous community-oriented studies an irrational use of antibiotics, particularly in developing countries, has been suggested. In order to describe the pattern of antibiotic use in a periurban community in Mexico City, 1659 randomly selected households were visited and an interview to the housewife was carried out. Of 8279 individuals 425 (5%) had used at least one antimicrobial in the preceding two weeks. Main perceived reasons for drug use were: respiratory tract ailments (58%) and acute diarrhea (25%). Antibiotic therapy was given in 27% of respiratory diseases and in 37% of all diarrheal episodes. Most commonly used drugs were: penicillins (43%), erythromycin (13%), metronidazole (9%), neomycin (6%), cotrimoxazole (6%) and tetracyclines (6%). While self-medication was common (19%) the majority of antibiotics were prescribed by a physician (81%). Approximately two thirds of individuals using an antibiotic did it for less than five days. Our data suggest a frequent misuse of antibiotics and support the future assessment, in this community, of physician prescribing practices, the determinants of self-medication as well as the impact of this drug use on the selection of resistant bacterial strains.

[Antibiotic consumption in a community of Mexico City. II. Survey of purchases at pharmacies]. / Uso de antibióticos en una comunidad de la Ciudad de México. II. Encuesta de compras en farmacias.

In developing countries, antibiotics are the most common sales of drugs and it has been suggested that their irrational use leads to the emergence of resistant bacteria. In order to assess the purchase of antimicrobials in a peri-urban community in Mexico City six local drug stores were randomly selected. A social worker made five visits to each pharmacy and she observed the events during the purchase of the drug and applied a structured questionnaire to the customer immediately after the transaction. Antibiotics were the majority (29%) of the drug sales. Of all purchasers of an antibiotic 43% did it without medical prescription and 72% answered that a physician had influenced on the purchase. Duration of the antibiotic therapy was specified in one out of three prescriptions that were examined and only in 28% of the sales the purchase was enough for a treatment duration of more than four days. More information, from similar surveys in drug stores in other settings, is needed to support the reinforcement of actions to control the sales of antibiotics in the community.

Susceptibility to Trypanosoma cruzi is modified by a previous non-related infection.

Helminth infections are frequently massive, chronic and strong inductors of Th2-type cytokines. This implies that infection by such parasites could alter the susceptibility to subsequent infections by other pathogens, particularly intracellular parasites. We therefore explored whether a persistent infection, caused by Taenia crassiceps cysticerci, in BALB/c mice could affect susceptibility to a later infection by Trypanosoma cruzi. We found that the presence of the cysticerci indeed modified the immune response and the susceptibility to T. cruzi, and that these modifications depended on the time-course evolution of the initial infection. Coinfection with the protozoan in the early stages of the helminth infection, induced a delay on the onset of parasitaemia, early specific production of IFN-gamma and high specific production of IL-4. A significant increase in susceptibility to T. cruzi was observed only when mice were coinfected in late stages when the helminth load is greater and a Th2 type response against it is predominant. The in vitro specific response to T. cruzi antigens was then characterized by low levels of both IFN-gamma and IL-4. These findings suggest that chronic helminth infections could potentially have a significant influence over the immune response and hence susceptibility to other pathogens.