Gene expression and levels of IL-6 and TNFα in PBMCs correlate with severity and functional class in patients with chronic heart failure.

BACKGROUND: Evidence shows that proinflammatory cytokines are important determinants of assessment of severity and prognosis of chronic heart failure (CHF). AIMS: We investigated whether peripheral expression of the proinflammmatory factors, TNF-α and IL-6 can predict variable of clinical assessment of patients with CHF. METHODS: In this report, we used real-time PCR assay to compare relative gene expression of TNFα and IL-6 in PBMC from CHF patients with various heart diseases (n = 42, EF < 45%, NYHA I to IV) and matched healthy control subjects (n = 42).We also determined the TNFα and IL-6 concentrations of cell culture supernatant of PBMCs with ELISA. RESULTS: There was a significant negative correlation between gene expression of TNFα and LVEF(r = 0.4, p < 0.05). Patients with CHF had increased gene expression of TNFα and IL-6 in PBMCs (p < 0.05). They also had elevated the supernatant levels of these cytokines in cultured PBMCs (p < 0.001). Levels of TNFα and IL-6 were increased in ischemic heart disease compared to non-ischemic heart disease. There was a positive correlation between TNFα and IL-6 levels in CHF patients and severity of CHF in patients. Levels of these cytokines were higher in patients with NYHA III-IV than in NYHA I-II and normal subjects. CONCLUSIONS: Results of this study indicate that peripheral expression of proinflammatory cytokines, TNF-α and IL-6, is important indicators of severity and prognosis in patients with chronic heart disease.

FOXP3, RORγt and IL-10 cytokine profile in chronic heart failure.

BACKGROUND: Distinct subsets of T cells play crucial regulatory roles in inflammatory processes of chronic heart failure (CHF). Retinoic acid receptor-related orphan receptor-γt (Ror-γt) and Forkhead box P3 (Foxp3) have been defined as the "master regulators" of Th17 cells and Treg cells, respectively. At the same time, anti-inflammatory cytokines such as IL-10 may neutralize inflammation in CHF. The current study was designed to compare FOXP3, RORγt and IL-10 protein expression in the blood and IL-10 in supernatant PBMCs in CHF patients versus normal subjects. PATIENTS AND METHODS: Our study population consisted of 42 patients with CHF in four different function classes and 42 healthy subjects who served as controls. RNA extraction and cDNA synthesis was performed and mRNA expression for genes FOXP3, RORγt, IL-10 was determined by RT-PCR. The amount of IL-10 protein in supernatant of PBMCs was measured by ELISA technique. RESULTS: There was no significant difference in FOXP3, RORγt, IL-10 protein expression and supernatant PBMCs IL-10 in CHF patients as compared to control. The level of Foxp3 was significantly lower in CHF patients with ischemic vs non-ischemic cause (p = 0.04). DISCUSSION: Although inflammation plays a central role in the pathophysiology of CHF, the roles of FOXp3, RORγt, and IL-10 remain to be determined (Tab. 3, Ref. 33).

Association of interleukin 1 gene cluster and interleukin 1 receptor gene polymorphisms with ischemic heart failure.

BACKGROUND: Proinflammatory cytokines have been known to play a considerable part in the pathomechanisms of chronic heart failure (CHF). Given the importance of proinflammatory cytokines in the context of the failing heart, we assessed whether the polymorphisms of interleukin (IL)-1 gene cluster, including IL-1α, IL-1ß, and IL-1 receptor antagonist (IL-1RA) and IL-1R gene are predictors of CHF due to ischemic heart disease. METHODS: Forty- three patients with ischemic heart failure were recruited in this study as patients group and compared with 140 healthy unrelated control subjects. Using polymerase chain reaction with sequence-specific primers method, the allele and genotype frequency of 5 single nucleotide polymorphisms (SNPs) within the IL-1α (-889), IL-1ß (-511, +3962), IL-1R (psti 1970), and IL-1RA (mspa1 11100) genes were determined. RESULTS: The frequency of the IL-1ß -511/C allele was significantly higher in the patient group compared to that in the control group (p = 0.031). The IL-1ß (-511) C/C genotype was significantly overrepresented in patients compared to controls (p = 0.022). CONCLUSIONS: Particular allele and genotype in IL-1ß gene were overrepresented in patients with ischemic heart failure, possibly affecting the individual susceptibility to this disease (Tab. 1, Ref. 27).

Long-term follow-up of ninety eight Iranian patients with primary immune deficiency in a single tertiary centre

PURPOSE: The aim was to describe the clinical manifestations, complications and long-term outcome of a cohort of Iranian patients with primary immune deficiency (PID). METHOD: We retrospectively studied the demographic, clinical and immunological characteristics of the PID patients in a single tertiary centre, from January 1989 to July 2014. The patients were classified according to the International Union of Immunological Societies Expert Committee on PID. RESULTS: 98 patients were diagnosed with and followed-up for 15 disorders. The mean age at onset and diagnosis and the diagnostic delay were 8±10, 14.2±13.1 and 6.1±7 years, respectively. Parental consanguinity rate was 57%. Predominantly Antibody Deficiency was the most common diagnosis (n=63), followed by congenital defects of phagocytes (n=16), combined immunodeficiencies (n=12), well defined syndromes (n=4) and defects in innate immunity (n=3). Recurrent sinopulmonary infection was the most common presentation. Active infections were treated appropriately, in addition to prophylactic therapy with IVIG and antimicrobials. Not all the patients were compliant with prophylactic regimens due to cost and unavailability. One SCID patient underwent successful bone marrow transplantation. The total mortality rate was 19% during the follow-up period (7.8±7.6 years). The mean age of living patients at the time of study was 23±11.7 years. CONCLUSIONS: Physicians awareness of PID has been rising dramatically in Iran, ensuring an increasing number of patients being diagnosed and treated. More effective treatment services, including health insurance coverage and drug availability are needed to improve the outcome of PID patients

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Long-term follow-up of ninety eight Iranian patients with primary immune deficiency in a single tertiary centre.

PURPOSE: The aim was to describe the clinical manifestations, complications and long-term outcome of a cohort of Iranian patients with primary immune deficiency (PID). METHOD: We retrospectively studied the demographic, clinical and immunological characteristics of the PID patients in a single tertiary centre, from January 1989 to July 2014. The patients were classified according to the International Union of Immunological Societies Expert Committee on PID. RESULTS: 98 patients were diagnosed with and followed-up for 15 disorders. The mean age at onset and diagnosis and the diagnostic delay were 8±10, 14.2±13.1 and 6.1±7 years, respectively. Parental consanguinity rate was 57%. Predominantly Antibody Deficiency was the most common diagnosis (n=63), followed by congenital defects of phagocytes (n=16), combined immunodeficiencies (n=12), well defined syndromes (n=4) and defects in innate immunity (n=3). Recurrent sinopulmonary infection was the most common presentation. Active infections were treated appropriately, in addition to prophylactic therapy with IVIG and antimicrobials. Not all the patients were compliant with prophylactic regimens due to cost and unavailability. One SCID patient underwent successful bone marrow transplantation. The total mortality rate was 19% during the follow-up period (7.8±7.6 years). The mean age of living patients at the time of study was 23±11.7 years. CONCLUSIONS: Physicians awareness of PID has been rising dramatically in Iran, ensuring an increasing number of patients being diagnosed and treated. More effective treatment services, including health insurance coverage and drug availability are needed to improve the outcome of PID patients.

Study of SH2D1A gene mutation in paediatric patients with B-cell lymphoma

BACKGROUND: X-linked lymphoproliferative disease (XLP) is an often fatal inherited immunodeficiency disorder characterised by fulminant infectious mononucleosis, acquired haemophagocytic lymphohistiocytosis, dysgammaglobulinaemia and malignant lymphoma. Given the paucity of data on the genetic stratification of XLP gene mutations in paediatric patients diagnosed with B-cell lymphoma, we sought to determine the existence of such association in the present study. METHODS: We studied 20 male subjects diagnosed with non-Hodgkin B-cell lymphoma. RESULTS: Eleven patients had laboratory evidence of EBV infection by serology and quantitative PCR. The SH2D1A gene analysis was negative in all patients. CONCLUSIONS: This is the first study to analyse the SH2D1A gene mutations in Iranian paediatric patients diagnosed with lymphoma. Although we could not demonstrate such an association in our cohort of patients, larger, multi-centre studies are required to extend and confirm our early finding

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Study of SH2D1A gene mutation in paediatric patients with B-cell lymphoma.

BACKGROUND: X-linked lymphoproliferative disease (XLP) is an often fatal inherited immunodeficiency disorder characterised by fulminant infectious mononucleosis, acquired haemophagocytic lymphohistiocytosis, dysgammaglobulinaemia and malignant lymphoma. Given the paucity of data on the genetic stratification of XLP gene mutations in paediatric patients diagnosed with B-cell lymphoma, we sought to determine the existence of such association in the present study. METHODS: We studied 20 male subjects diagnosed with non-Hodgkin B-cell lymphoma. RESULTS: Eleven patients had laboratory evidence of EBV infection by serology and quantitative PCR. The SH2D1A gene analysis was negative in all patients. CONCLUSIONS: This is the first study to analyse the SH2D1A gene mutations in Iranian paediatric patients diagnosed with lymphoma. Although we could not demonstrate such an association in our cohort of patients, larger, multi-centre studies are required to extend and confirm our early findings.

Soluble CD26 and CD30 levels in patients with common variable immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by decreased serum immunoglobulin levels and increased susceptibility to recurrent bacterial infections. There is increasing evidence that the type 1 helper T cell (T(H)1)/T(H)2 cell balance is shifted towards a T(H) 1-type immune response in patients with CVID. This study was performed to measure levels of soluble CD26 (sCD26) and CD30 (sCD30) as plausible markers of a dysregulated immune response in a group of patients with CVID. METHODS: Twenty-five patients with CVID and 20 age- and sex-matched controls were enrolled in this study. A sandwich enzyme-linked immunosorbent assay was used to measure serum sCD26 and sCD30 levels. RESULTS: The mean (SD) serum sCD26 level was significantly higher in patients with CVID than in controls (88.47 [59.82] ng/mL vs 28.31 [25.61] ng/mL, P = .001). Serum sCD30 levels were also significantly higher in patients with CVID than in controls (196.37 [169.71] ng/mL vs 30.72 [12.98] ng/mL, P < .001). Analysis of serum sCD30 levels in association with different clinical variables indicated that patients with splenomegaly and malignancy had significantly higher levels than patients without these disorders. However, serum sCD30 levels did not differ with bronchiectasis or autoimmunity. CONCLUSIONS: The presence of increased serum levels of sCD26 and sCD30 in patients with CVID suggests that CVID patients have a polarized immune response towards a T(H)1-like phenotype, whereas the association between high levels of these markers and disease severity suggests that the soluble form could be used as a prognostic tool in CVID.

Soluble CD26 and CD30 Levels in Patients With Common Variable Immunodeficiency

Antecedentes: La inmunodeficiencia común variable (IDCV) constituye un grupo heterogéneo de alteraciones caracterizado por una disminución en el nivel de inmunoglobulinas séricas y un incremento en la susceptibilidad para sufrir infecciones bacterianas recurrentes. Existen evidencias que confirman que los pacientes con IDCV muestran una alteración del balance Th1/Th2 hacia una respuesta tipo Th1. En este estudio cuantificamos los niveles de CD26 soluble (sCD26) y CD30 (sCD30) como posibles marcadores de una respuesta inmune alterada en un grupo de pacientes con IDCV. Métodos: Se incluyeron 25 pacientes con IDCV y controles con edad y sexo similar, a los que se cuantificó mediante un ELISA los niveles de CD26 soluble y CD30. Resultados: Los niveles medios de sCD26 en pacientes con IDCV fueron 88.47±59.82 ng/mL, significativamente más altos que en los controles 28.31±25.61 ng/mL (p =0.001). Los niveles de sCD30 en pacientes con IDCV fueron también mayores que en los controles (196.37±169.71 ng/mL vs. 30.72±12.98 ng/mL, p <0.001). El análisis de los niveles de sCD30 en asociación con diferentes variables clínicas indicaron que los pacientes con esplenomegalia y neoplasias eran más altos en comparación con los que no presentaban estas asociaciones. No se encontraron asociaciones de los niveles de sCD30 con la presencia de bronquiectasias o autoinmunidad. Conclusiones: La elevación de sCD26 y sCD30 en pacientes con IDCV podría sugerir la hipótesis de una respuesta inmune polarizada al fenotipo Th1, y la asociación de niveles elevados de estos marcadores con la severidad de la enfermedad puede involucrar a estos marcadores como una herramienta útil en el pronóstico de la IDCV (AU)

Background: Common variable immunodefi ciency (CVID) is a heterogeneous group of disorders characterized by decreased serum immunoglobulin levels and increased susceptibility to recurrent bacterial infections. There is increasing evidence that the type 1 helper T cell (TH1)/TH2 cell balance is shifted towards a TH1-type immune response in patients with CVID. This study was performed to measure levels of soluble CD26 (sCD26) and CD30 (sCD30) as plausible markers of a dysregulated immune response in a group of patients with CVID. Methods: Twenty-five patients with CVID and 20 age- and sex-matched controls were enrolled in this study. A sandwich enzyme-linked immunosorbent assay was used to measure serum sCD26 and sCD30 levels. Results: The mean (SD) serum sCD26 level was significantly higher in patients with CVID than in controls (88.47 [59.82] ng/mL vs 28.31 [25.61] ng/mL, P=.001). Serum sCD30 levels were also significantly higher in patients with CVID than in controls (196.37 [169.71] ng/mL vs 30.72 [12.98] ng/mL, P<.001). Analysis of serum sCD30 levels in association with different clinical variables indicated that patients with splenomegaly and malignancy had significantly higher levels than patients without these disorders. However, serum sCD30 levels did not differ with bronchiectasis or autoimmunity. Conclusions: The presence of increased serum levels of sCD26 and sCD30 in patients with CVID suggests that CVID patients have a polarized immune response towards a TH1-like phenotype, whereas the association between high levels of these markers and disease severity suggests that the soluble form could be used as a prognostic tool in CVID (AU)

Evaluation and treatment of ADHD.

Symptoms of attention-deficit/hyperactivity disorder (ADHD) are present in as many as 9 percent of school-age children. ADHD-specific questionnaires can help determine whether children meet diagnostic criteria for the disorder. The recommended evaluation also includes documenting the type and severity of ADHD symptoms, verifying the presence of normal vision and hearing, screening for comorbid psychologic conditions, reviewing the child's developmental history and school performance, and applying objective measures of cognitive function. The stimulants methylphenidate and dextroamphetamine remain the pharmacologic agents of first choice for the management of ADHD. These agents are equally effective in improving the core symptoms of the disorder, but individual children may respond better to one stimulant medication than to another. Achievement of maximal benefit may require titration of the initial dosage and dosing before breakfast, before lunch and in the afternoon. The family physician should tailor the treatment plan to meet the unique needs of the child and family. Psychosocial, behavioral and educational strategies that enhance specific behaviors may improve educational and social functioning in the child with ADHD.

T cell receptor rearrangements in various S49 lymphoma sublines.

The S49 cell lines are a unique series of tumor sublines isolated from a single BALB/c thymoma. Several different sublines were previously isolated from non-mutagenized cells using pharmacologic agents that would select for different stages of thymic development. In this report we show that all seven of the sublines studied express TL class I Ag confirming their derivation from immature thymocytes. This uniform TL expression is in contrast to the previously characterized locus-specific shut off of Kd,Dd, and/or LdAg by various S49 sublines. Furthermore, S49 sublines were found to display disparate CD4/CD8 expression. Whereas the unselected subline is a CD4+/CD8+ double positive, each of the selected sublines is singly positive for either CD4 or CD8. All seven sublines were found to be CD3+ and express alpha beta TCR heterodimers. To establish whether the S49 sublines have a monoclonal or polyclonal origin, their TCR rearrangements were compared. Based on the detection of identical but unusual TCR gamma rearrangements and similarity of the alpha and beta rearrangements, we propose that the S49 sublines probably had a monoclonal origin. However, significant differences between the TCR alpha and beta gene rearrangement were observed, suggesting that these sublines have undergone further differentiation at TCR loci in addition to CD4/CD8 and MHC loci. Evidence is presented that much of this phenotypic diversity preceded their in vitro selection.

Relationship of MMPI dependency and dominance scale scores to staff's ratings, diagnoses, and demographic data for day-treatment clients.

Scores on the MMPI Dominance (Do) and Dependency (Dy) scales of day-treatment clients were correlated with staff's ratings, age, sex, diagnosis, length of time in day treatment, and level of independent living. A total of 72 subjects, 36 men and 36 women between the ages of 20 and 65 years, completed the MMPI. Day-treatment staff were asked to rate the dependent and dominant characteristics of each subject on a unipolar adjective checklist of 20 10-point scales. Pearson product-moment correlations indicated significant associations between the two scales, between subjects' scores and staff's ratings, and between scores and age. Analysis of variance showed that (a) Dy scale T-scores were significantly higher than Do scale T-scores, (b) women scored higher on Dy and men scored higher on Do, (c) depressed subjects scored higher on Dy than did other diagnostic groups, (d) apartment dwellers scored lower on Dy than did subjects living in either group homes or with their families, and (e) Dy and Do scores did not vary with length of time in day treatment.

Locus-specific regulation of Kd, Dd, and Ld class I genes in the BALB/c S49 lymphoma sublines.

The S49 tumor sublines are variants isolated from a single parent BALB/c tumor which demonstrate locus-specific shut-off of their Kd, Dd, and/or Ld surface molecules. Four phenotypically different sublines were characterized: wild-type (Kd Dd Ld)+, a null phenotype (Kd Dd Ld)-, and two intermediates (Kd Dd)+ (Ld)- and (Kd)+ (Dd, Ld)-. Nonexpressed class I Ag were not induced with IFN-gamma even though the expressed antigens were found to be appropriately responsive. Southern blot analysis using probes specific for the 5', exonic or 3' portions of the Kd, Dd, and Ld genes indicated that these S49 sublines have no major chromosomal aberrancies. Northern blot analysis of RNA from each S49 subline using locus-specific oligonucleotide probes revealed message only for the expressed Ag. Thus, the locus-specific shut-off of class I expression in these tumors appears to be acting at the transcriptional level. RNase protection analysis confirmed this result and furthermore demonstrated that the repression is exquisitely specific for the Kd, Dd, and Ld genes as other "class I-like" messages were detected in each cell line. These findings are discussed in the context of the various cis- and trans-acting mechanisms that have been proposed to regulate class I expression.

Radioimmunoassay of free beta-subunit of human chorionic gonadotropin as a prognostic test for persistent trophoblastic disease in molar pregnancy.

A new radioimmunoassay system was established with a monoclonal antibody (1E5) that distinguishes the free beta-subunit of human chorionic gonadotropin in the presence of intact human chorionic gonadotropin, showing only 0.23% cross-reactivity with the intact human chorionic gonadotropin molecule and virtually no cross-reactivity with other glycoprotein hormones or their beta-subunits. Serum samples, taken at initial diagnosis from nine patients with hydatidiform mole and spontaneous remission and 12 patients with subsequent progression to persistent trophoblastic disease, were assayed for free and total levels of the beta-subunit of human chorionic gonadotropin. The assay results were expressed as a ratio of nanograms of free beta-subunit per 1000 mIU of total beta-subunit. Eight of nine patients with mole and spontaneous remission had a ratio value less than 4 whereas 10 of 12 patients with subsequent persistent disease had a ratio value greater than 4. Statistical analysis with chi 2 showed a highly significant correlation of high ratios with eventual progressive disease (p = 0.0009). This study suggests that excessive production of the free beta-subunit of human chorionic gonadotropin may identify patients with a high likelihood of developing persistent trophoblastic disease.