Fibroproliferative activity in patients with immune thrombocytopenia (ITP) treated with thrombopoietic agents

This study assessed the grade of bone marrow (BM) fibrosis and its association with a seromarker for collagen-III formation and fibrosis-related cytokines in 25 immune thrombocytopenia (ITP) patients treated with thrombopoietin receptor agonists (Tpo-RA) who had at least one BM biopsy. Assessment of 8 pre- and on-treatment BM biopsies revealed statistically significant increases in reticulin. Reticulin in biopsies performed after a median of 1·4 years of treatment was graded: MF-0 in 3 (12%), MF-1 in 19 (76%), MF-2 in 2 (8%) and MF-3 in 1 (4%). No cytogenetic or flow-cytometric abnormalities were detected. Median pretreatment Procollagen III N-propeptide (PIIINP) (6·6 μg/l) was significantly higher than on-treatment levels (5·6 μg/l); both were higher than controls (3·4 μg/l; P < 0·001). PIIINP was negatively correlated with treatment duration (r = -0·49) suggesting a decelerated reticulin production over time. There was a trend towards an association between grade of reticulin and PIIINP. Transforming growth factor (GF)-beta and basic-Fibroblast GF were not different between patients and controls but Hepatocyte GF (HGF), an anti-fibrotic cytokine, was significantly elevated in patients. In conclusion, low-grade BM reticulin fibrosis is seen in most ITP patients on Tpo-RA. The novel findings of decreasing PIIINP and elevated HGF need further investigation to explore their significance in BM fibrogenesis.     

Cytokine Gene Polymorphisms in Iranian Patients with Beta-Thalassemia Major

Background: β-thalassemia as a hereditary disease is defined as defective synthesis of   β-globin chains, resulting in erythropoiesis abnormalities and severe anemia. Different studies have shown that cytokines and cytokine gene polymorphisms play a major role in the pathogenesis of   β-thalassemia. Single nucleotide polymorphisms (SNPs) within the promoter region or other regulatory sequences of cytokine genes lead to overall production of cytokines.   Objective: To analyze the genetic profile of Th1 and Th2 cytokines in Iranian patients with   β-thalassemia major. Methods: Allelic and genotype frequencies of cytokine genes were determined in 30 thalassemia patients and 40 healthy subjects using PCR-SSP assay. Allele and genotype frequencies were calculated and compared with those of normal controls.   Results: The results of our study show a significant decrease in A allele at position UTR 5644 IFN-   γ, G alleles at position -238 TNF-   α and 166 IL-2, and C allele at position -590 IL-4. TGF- β   haplotype TG/TG increased whereas TGF-β haplotype CG/CG and IL-10 haplotype GCC/ACC decreased significantly in all patients.   Conclusion: Data of this investigation suggest that variations among cytokine gene polymorphisms may contribute to the disease susceptibility. A finding which needs to be fairly clarified in other ethnic groups.     

Perioperative immunonutrition ameliorates the postoperative immune depression in patients with gastrointestinal system cancer (prospective clinical study in 42 patients)

Cancer surgery is a major challenge for patients to develop immune depression in postoperative period. Several cytokines can depress immune cell subpopulations. Increased cytokine response after surgery is assumed to arise mainly from lipooxygenase pathway acting on membrane arachidonic acid. Therefore; investigators focused their efforts to alter the membrane fatty acid profile by changing the nutritional regimen with epsilon-3 fatty acid supplementation and encouraging results were obtained after surgery. Despite the theoretical and clinical advantage of enteral nutrition many surgeons remain committed to parenteral nutrition for feeding of patients due to maintain bowel rest and fear of anastomosis leakage at the postoperative period. Several studies investigating role of the postoperative immunonutrition reported that beneficial immunological changes were associated with reduction of infectious complications. Interestingly; these findings were observed at least five days after the surgery in which the highest incidence of complications was seen. In this prospective study including 42 patients eligible for curative gastric or colon cancer surgery; we investigated the beneficial effect of enteral immunonutrition (EEN) compared to total parenteral hyperalimentation (TPN) beginning from the preoperative period. Cortisol and CRP levels as stress parameters significantly increased one day after surgery in both groups but they rapidly returned to (on POD1) preoperative baseline level in EEN group whereas these values remained high in the TPN group. Additionally a significant decrease in natural killer (NK) cells and CD8+ levels were observed in both groups. However they recovered on POD3 in EEN group and on POD6 in TPN group. CD4+ subset remained almost same as preoperative value in the TPN group whereas it increased from (%) 40.14 to 46.40, 51.29 and 54.7 on PO 6th hr, POD3 and POD6 in the EEN group. Our findings suggest that preoperative nutrition via the enteral route provided better regulation of postoperative immune system restoration than parenteral nutrition. On the basis of our findings we recommend enteral immunonutrition to be started at the preoperative period rather than postoperatively before a major operation whenever the enteral route is feasible.     

Hepatic disease in patients with the acquired immune deficiency syndrome (AIDS)

The spectrum of liver disease in patients with acquired immune deficiency syndrome (AIDS) and the clinical impact of diagnostic percutaneous liver biopsy in this population were evaluated by a retrospective review of hepatic histology, clinical features and laboratory data in 85 patients (26 biopsies, 59 autopsies). Only 1 (3.8%) biopsy and 9 (15%) postmortem livers were histologically normal. Macrosteatosis and nonspecific portal inflammation were the most common histologic abnormalities. Intrahepatic AIDS-specific opportunistic infections or malignancies were detected in 42% of both biopsy and autopsy groups, with Mycobacterium avium-intracellulare the most frequent pathogen seen. Kaposi's sarcoma, although not detected on biopsy, was the most common postmortem AIDS-related hepatic finding. Intrahepatic lymphoma, cytomegalovirus hepatitis and hepatic mycoses were less frequently observed. In general, hepatic involvement represented part of a previously diagnosed, widely disseminated disease process, and liver biopsy led to new AIDS-specific diagnoses in only two patients. We conclude that while liver biopsy is a useful diagnostic tool in selected patients with AIDS, the information provided by biopsy rarely influences therapy or leads to improved survival.     

Functions of macrophages in the immune system (author's transl)

With respect to our present knowledge about the functions of macrophages in relation to the immune responses the most important functions include elimination and processing of the antigen; antigen presentation and induction of immune response; immune regulation by several inhibitory and activating factors; binding of T cell products, which regulate B cell functions (helper and suppressor factors); helper cell induction; cytotoxicity, bactericide and tumoricide activities after stimulation by T cells. In the present time most research activities are directed to the interactions of T cells and macrophages. These interactions depend mainly from genetically determined structures of the cell membranes (Ia antigens).     

The use of intravenous immunoglobulin (endobulin) in patients with immune thrombocytopenia

Six adults were treated for chronic immune thrombocytopenia (ITP) with high dose intravenous immunoglobulin (ENDOBULIN). Five patients were evaluable. In four patients the platelet associated IgG (PAIgG) levels were increased. All four responded to i.v. Ig and two subsequently underwent splenectomy. One patient had normal PAIgG and had no response to i.v. Ig. Endobulin is useful in the treatment of chronic ITP and is followed in some patients by a prolonged response. High levels of PAIgG may predict a favourable outcome.     

Assessment of three activity questionnaires in patients with heart failure

The activity questionnaire most frequently used in heart failure, the New York Heart Association Classification, does not correlate well with peak oxygen uptake. The correlation of this variable with other activity questionnaires was analyzed in 83 patients (69 with heart failure and 14 control patients), 61.5 11 years old, who were interviewed and classified according to the Canadian Cardiovascular Society Classification. The Dyspnea-Fatigue Index and functional capacity according to the Specific Activity Questionnaire were determined for each patient. Subsequently, the treadmill cardiopulmonary exercise test (Naughton) was performed and the following correlations with peak oxygen uptake were found: Canadian Cardiovascular Society, r = 0.39; Dyspnea-Fatigue Index, r = 0.44; Specific Activity Questionnaire, r = 0.38. p < 0.001 for all three. The Dyspnea-Fatigue Index yielded the best correlation, although it was only slightly better than the Canadian Cardiovascular Society Classification, which is easier to obtain.     

Depression and increased myocardial ischemic activity in patients with ischemic heart disease

Background

Depression is relatively common in patients with ischemic heart disease (IHD) and is associated with increased risk of mortality and morbidity. However, the mechanisms by which depression adversely affects clinical outcomes of patients with IHD are unknown. This study examined the relationship between depression and myocardial ischemia during mental stress testing and during daily living in patients with stable IHD.

Methods and results

The Center for Epidemiological Studies-Depression scale (CES-D) was administered to 135 patients with IHD to evaluate depressive symptoms. Radionuclide ventriculography was used to evaluate the occurrence of left ventricular wall motion abnormality (WMA) during mental stress and exercise testing. Forty-eight-hour ambulatory electrocardiography was used to assess myocardial ischemia during daily living. The mean CES-D score was 8.2 (SD 7.4, range 0-47) with a median of 7. Logistic regression models using restricted cubic splines revealed a curvilinear relation among CES-D scores and the probability of ischemia. For patients with CES-D scores ≤19 (81.5% of study population), a 5-point increment in the CES-D score was associated with roughly a 2-fold increase in the likelihood of ischemia during mental stress. For patients with CES-D scores >19, the relation among scores and ischemia during mental stress tended to be inversely related, but the portion of the sample is very small. Similar patterns of results were noted for CES-D scores and ischemia during daily life.

Conclusions

Patients with mild to moderate depressive symptoms (CES-D scores ≤19) are more likely to exhibit myocardial ischemia during mental stress testing and during daily living. Myocardial ischemia may be one mechanism by which depression increases the risk of mortality and morbidity in patients with IHD. The observed inverse association between higher level of depressive symptoms and ischemic activity needs to be further assessed in large samples.     

Assessment of humoral immune response in patients with chronic hepatitis C virus infection

Hepatitis C infection is a major public health problem worldwide. Hepatitis C virus (HCV) infection has been identified as a major causative agent of post-transfusion hepatitis. The host immune response to HCV infection is composed of both non- specific immune response, including interferon (IFN) production and natural killer (NK) cell activity and a virus-specific immune response, including humoral and cellular components. Susceptibility to infection has been related to immunological disturbances. Several studies have provided experimental evidence of disorders of both cellular and humoral immunity. Humoral Immunity is dependent mainly on immunoglobulins and little data are available about serum immunoglobulin values in chronic hepatitis C. The present study aimed to evaluate humoral immune response by measuring the concentration of serum immunoglobulin isotypes (IgG, IgM, IgA) and IgG-subclasses level (IgG1-4) in chronic hepatitis C patients and healthy controls. This study included 50 patients with chronic hepatitis C. All of them had positive serum anti-HCV antibodies, positive serum HCV-RNA by PCR, and histologically-proven chronic hepatitis. The results were compared with 25 healthy controls. Total IgG, IgA and IgM were assayed by nephelometry. IgG subclasses were assayed using human IgG subclasses enzyme immunoassay. Serum protein electrophoresis was performed in agarose gel. The results showed that no significant difference in serum immunoglobulin levels were found among patients with chronic hepatitis C of minimal liver damage( Knodell index < or =3) and patients with mild liver disease (Knodell index > 3). A significant increase in total serum IgG, IgG1 and IgG2 levels were found in patients with chronic hepatitis than in healthy controls but no difference was found in IgG3 and IgG4 in both patients and controls. Mean serum IgM was increased in patients with HCV infection compared with healthy controls. No significant difference was found in IgA level in both the patients and healthy controls. Our data revealed an increase of humoral immune response in chronic hepatitis C infection. This is evidenced by an elevation in serum immunoglobulin isotypes; IgG and its subclasses IgG1 and IgG2 and IgM. These findings may provide some new insights into the antibody response to HCV.     

Biological therapy and the immune system in patients with chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells that has been recognized as a disease responsive to immunotherapy. Despite the huge success of the tyrosine kinase inhibitors (TKIs), CML remains for the most part incurable, probably due to treatment resistance of leukemic stem cells, which are responsible for rapid disease relapse after discontinuation of therapy. Only allogeneic stem cell transplantation enables disease eradication. In addition to the Bcr-Abl1 oncoprotein, TKIs also inhibit off-target kinases (e.g. c-kit, Src, Tec), some of them having physiological functions in immune responses. In vitro studies have implied immunomodulatory effects of TKIs and interferon-alpha (IFN-α), but comprehensive information from in vivo analyses is missing. This review summarizes the recent advances in the field of immunology of CML, including basic information about leukemia-associated antigens and peptide vaccines, that could lead to the incorporation of TKIs and IFN-α in future therapeutic, potentially curative, interventions for CML.     

Correlation of disease activity with circulating immune complexes (C1QbA) and complement breakdown products (C3D) in patients with systemic lupus erythematosus

Summary Most biologic effects of immune complexes are mediated through the activation of the complement system. The relationship between lupus disease activity and the presence of C₃ breakdown products (C_3d) and circulating immune complexes (CIC) as demonstrated with the C_1q binding assay (C_1qbA), was evaluated. Nearly all 13 systemic lupus erythematosus (SLE) patients had a stable disease course in this prospective study, nevertheless, in each patient the profiles of the serologic parameters were quite different. Despite the small number of investigated patients (13), it is concluded that irrespective of the disease activity, the serologic parameters could be either positive or negative. No relationship could be obtained between disease activity and the presence of C_3d and/or CIC. Nor was there any evidence that the presence of CIC would indicate increased levels of C₃ breakdown products (C_3d). This observation argues against a pathogenetic significance of CIC detected by the C_1qbA in SLE. In conclusion, the supposed link between the presence of CIC, consumption and activation of the complement system, and the activity of SLE needs further study.     

Neutropenia in Iranian patients with primary immunodeficiency disorders

Neutropenia may occur in some of the primary immunodeficiency disorders. We reviewed the records of 56 neutropenic patients. The most common disorders were Shwachman-Diamond syndrome, cyclic neutropenia, Kostmann disease, Chediak-Higashi syndrome, hyper IgM syndromes, severe combined immunodeficiency, hyper IgE syndrome, and common variable immunodeficiency.