Ultrastructural Pathology of the Heart in Patients with ß-Thalassaemia Major

Renal AL-amyloidosis is usually lambda-light-chain-related, particularly lambda type 6. Kappa-light-chain-related renal amyloidosis is a rare entity. Relatively few cases have been reported in the literature. The pathologic findings in some of these cases may mimic other disease processes. It is important to recognize the different morphologic expressions of this entity in order to render the right diagnosis. The authors discuss one such case in which the initial pathologic impression was erroneous and, upon further studies, including ultrastructural immunogold labeling, the diagnosis of kappa-light-chain-related renal amyloidosis was established.     

Long-Acting β- Agonist Treatment in Patients with Persistent Asthma Already Receiving Inhaled Corticosteroids

International guidelines recommend that long-acting β-agonists should be considered in patients who are symptomatic despite moderate doses of inhaled corticosteroids. When combined with inhaled corticosteroids they improve asthma symptoms and lung function and reduce exacerbations. The evidence suggests that they are well tolerated. However, they are less effective than inhaled corticosteroids as monotherapy and should not be used alone, although the addition of a long-acting β-agonist may permit a small reduction in the corticosteroid dose. Both salmeterol and formoterol appear equally effective in improving asthma control. Formoterol, however, has a rapid onset of action and is now being promoted for the relief of acute asthma symptoms. Both drugs provide prolonged protection against exercise-induced bronchospasm. However, this effect rapidly diminishes with continuous therapy and if this is the main aim of treatment, intermittent use may be preferable. When compared with alternative treatments, inhaled long-acting β-agonists are more effective in controlling asthma symptoms than either theophylline or antileukotriene agents. Bambuterol, an oral prodrug of terbutaline, appears to be as effective as the inhaled long-acting β-agonists and has the advantage of once daily oral administration. However, the inhaled long-acting β-agonists are less likely to have systemic adverse effects. There are theoretical concerns that regular β-agonist treatment may lead to tolerance and a failure to respond to emergency asthma treatment. While there is no doubt that tolerance occurs, there is currently little evidence that this is a clinical problem. Insights into pharmacological as well as therapeutic interactions between inhaled corticosteroids and β-agonists are providing justification for their use in combination. Guidelines for the management of patients with chronic persistent asthma are likely to require modification to reflect these developments.     

Biomarkers Guided Treatment Strategies in Adult Patients with Asthma: Ready for the Clinical Field?

Archivum Immunologiae et Therapiae Experimentalis - Asthma is a chronic inflammatory airways disorder mainly characterized by heterogeneity. In the more severe forms, a discordance often exists...     

Treosulfan-Thiotepa-Fludarabine–Based Conditioning Regimen for Allogeneic Transplantation in Patients with Thalassemia Major: A Single-Center Experience from North India

Hematopoietic stem cell transplantation (HSCT) is the definite treatment for patients with thalassemia major. A busulfan (Bu) and cyclophosphamide (Cy)–based regimen has been the standard myeloablative chemotherapy, but it is associated with higher treatment-related toxicity, particularly in patients classified as high risk by the Pesaro criteria. Treosulfan-based conditioning regimens have been found to be equally effective and less toxic. Consequently, we analyzed the safety and efficacy of treosulfan/thiotepa/fludarabine (treo/thio/flu)-based conditioning regimens for allogeneic HSCT in patients with thalassemia major between February 2010 and September 2012. We compared those results retrospectively with results in patients who underwent previous HSCT with a Bu/Cy/antithymocyte globulin (ATG)–based conditioning regimen. A treo/thio/flu-based conditioning regimen was used in 28 consecutive patients with thalassemia major. The median patient age was 9.7 years (range, 2-18 years), and the mean CD34⁺ stem cell dose was 6.18 × 10⁶/kg. Neutrophil and platelet engraftment occurred at a median of 15 days (range, 12-23 days) and 21 days (range, 14-34 days), respectively. Three patients developed veno-occlusive disease, 4 patients developed acute graft-versus-host disease (GVHD), and 2 patients had chronic GVHD. Treatment-related mortality (TRM) was 21.4%. Two patients experienced secondary graft rejection. We compared these results with results in patients who underwent previous HSCT using a Bu/Cy/ATG-based conditioning regimen. Twelve patients were treated with this protocol, at a median age of 7.2 years (range, 2-11 years). One patient had moderate veno-occlusive disease, 2 patients developed acute GVHD, 2 patients had chronic GVHD, and 2 patients experienced graft rejection. There was no TRM in this group. We found no significant differences between the 2 groups (treo/thio/flu vs Bu/Cy/ATG) in terms of the incidence of acute GVHD, chronic GVHD, TRM, and graft failure, although a trend toward higher TRM was seen with the treo/thio/flu regimen.     

Clinical Experience of Interferon Alfa-2a Treatment for Refractory Uveitis in Beh?et's Disease

Behçet''s disease (BD) involves multisystem vasculitis of unknown origin. Ocular manifestations of BD mostly include bilateral panuveitis and retinal vasculitis, which are very challenging to treat. Interferon alfa-2a (IFN) has been recently introduced for treating refractory Behçet uveitis, mainly in Germany and Turkey. Nonetheless, there is so far no consensus about the ideal treatment regimen of IFN for Behçet uveitis. We report our experience of IFN treatment in five Korean BD patients with refractory uveitis. All patients complained of oral ulcers; one patient had a positive pathergy test and 2 showed the presence of HLA-B51. Immunosuppressive agents used prior to IFN treatment included cyclosporine and methotrexate. The IFN treatment was commenced with a dose of 6-9 MIU/day for 7 days, adjusted according to individual ocular manifestations, tapered down to 3 MIU three times in a week, and then discontinued. All patients showed positive response to IFN treatment; 50% of them showed complete response without additional major ocular inflammation during the follow-up period. Other BD symptoms also improved after IFN treatment in most cases. After treatment, the relapse rate and the required dose of oral corticosteroid were decreased in most cases, showing a significant steroid-sparing effect. However, the visual acuity was not improved in most cases due to irreversible macular sequelae. Despite the small sample size of this study, we suggest that, in Korean patients, IFN is an effective treatment modality for BD uveitis as was observed in German and Turkish patients.     

Impact of β-Globin Mutations on Outcome of Matched Related Donor Hematopoietic Stem Cell Transplantation for Patients with β-Thalassemia Major

The clinical outcome of hematopoietic stem cell transplantation (HSCT) for patients with β-thalassemia major (β-TM) can be affected by several factors. We investigated the influence of β-globin gene mutation in patients with β-TM on the clinical outcome of HSCT and conducted a prospective study of consecutive β-TM patients who underwent allogeneic HSCT at our center. Among 87 included patients, 62 (71%) had homozygous and 25 (29%) had compound heterozygous β-globin gene mutations. Intervening sequence II-1 appeared to be the most common mutation, with an occurrence rate of 33% in β-globin alleles. With a median follow-up of 12 months, the thalassemia-free survival and overall survival probabilities were 83% (standard error, 4%) and 90% (standard error, 3%), respectively. Overall survival was not found to be associated with the β-globin gene mutation status, but thalassemia-free survival was significantly improved in patients with homozygous mutations compared with patients with compound heterozygous mutations in univariate (91.2% versus 64.0%, P = .009) and multivariable (hazard ratio, 3.83; P = .014) analyses. This is the first report on the impact of β-globin mutation status on the outcome of β-TM after allogeneic HSCT and helps to better illustrate the course and prognosis of β-TM after transplantation.     

Treatment with Natalizumab in Relapsing–Remitting Multiple Sclerosis Patients Induces Changes in Inflammatory Mechanism

Natalizumab is a widely accepted drug for the relapsing–remitting subtype of multiple sclerosis (RRMS). The present longitudinal exploratory study in RRMS patients analyzes the effects of natalizumab treatment on the levels of pro-inflammatory and anti-inflammatory cytokine protein levels and also the frequency and suppressor function of regulatory T cells. Flow cytometry was used to determine cytokines and regulatory T cell frequency while regulatory T cell suppressor function was assayed in vitro at different time-points after starting with natalizumab. Results showed serum levels of pro-inflammatory interferon gamma and interleukin (IL)-12p70, as well as anti-inflammatory IL-4 and IL-10, were elevated just a few hours or days after first IV infusion of natalizumab. Interestingly, other cytokines like IL-5 or IL-13 were also elevated while pro-inflammatory IL-17, IL-2, and IL-1β increased only after a long-term treatment, suggesting different immune mechanisms. In contrast, we did not observe any effect of natalizumab treatment on regulatory T cell frequency or activity. In conclusion, these results suggest natalizumab has other immunological effects beyond VLA-4 interaction and inhibition of CNS extravasation, the relevance of which is as yet unknown and warrants further investigation.     

Increased Expressions of Integrin Subunit β1, β2 and β3 in Patients with Acute Infection

Objective: Our previous studies have shown that integrin subunits β1, β2 and β3 were the core proteins of venous thrombi and potential useful biomarker of venous thromboembolism (VTE). Patients with acute infection have a high risk of VTE. In this study we explored that is there any relevance between core proteins and acute infection.Methods: A total of 230 patients (112 females) with clinically proven acute infection in the emergency unit were recruited into this study, meanwhile 230 patients without acute infection matched in sex and age were recruited as control group. Flow cytometry was done to measure the expressions of blood integrin β1, β2, β3 and cellular immunity (CD3, CD4, CD8, CD4/CD8, CD16CD56 and CD19). The association degree between increased core proteins and acute infection was analyzed by calculating the relative risk (RR).Results: The expression of integrin β1, β2 and β3 was markedly increased in patients with acute infection (P=0.000, 0.000 and 0.015, respectively). The relative risk ratio (RR) of increased integrin β1, β2 and β3 in acute infection patients was 1.424 (95%CI: 1.156-1.755, P=0.001), 1.535 (95%CI: 1.263-1.865, P=0.000) and 1.20 (95%CI: 0.947-1.521, P=0.148), respectively. Combined integrin β1, β2 and β3 analysis showed that the relative risk ratio (RR) of increased in patients with acute infection was 2.962 (95%CI: 1.621-5.410, P=0.001), and this relative risk (RR) rise to 3.176 (95%CI: 1.730-5.829, P=0.000) in patients with respiratory tract infection (RTI).Conclusion: As the core proteins of venous thrombi, integrinβ1, β2 and β3 were markedly increased expression in patients with acute infection, which maybe explain the increased risk of VTE in acute infection patients. A weakened immune system could be the basic condition of VTE occurrence.     

Dynamics of Cognitive Impairments in Patients with Parkinson’s Disease Receiving L-DOPA Treatment

Neuroscience and Behavioral Physiology - Objectives. To assess the dynamics of cognitive impairment (CI) in patients with Parkinson’s disease (PD) during L-DOPA treatment. Materials and...     

Unrelated Donor Peripheral Blood Stem Cell Transplantation for Patients with β-Thalassemia Major Based on a Novel Conditioning Regimen

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only available curative treatment for patients with β-thalassemia major (β-TM). However, the problem of finding a suitable sibling donor with well-matched human leukocyte antigens is still a major obstacle to curing these patients. With the progress in high-resolution HLA typing technology and supportive care, outcomes after allogeneic HSCT from an HLA well-matched unrelated donor (UD) now approach those of well-matched sibling donors. However, UD HSCT is hampered by an increased risk of graft-versus-host disease and transplant-related mortality. Here we report the outcome of transplantation in patients with β-TM using a novel WZ-14-TM transplant protocol, based on cyclophosphamide, intravenous busulfan, fludarabine, and antithymocyte globulin, in our center. Forty-eight patients between 2 and 11 years of age with β-TM received HLA well-matched UD peripheral blood stem cell transplantation following the WZ-14-TM protocol. All of the transplanted patients achieved donor engraftment. The incidences of grade II to IV acute and chronic graft-versus-host disease were 8.3% and 8.3%, respectively. The overall survival and thalassemia-free survival rates were both 100%. This encouraging result suggests that the WZ-14-TM protocol is a feasible and safe conditioning regime for patients with β-TM undergoing UD HSCT.     

Elevation of Bioactive Transforming Growth Factor-β in Serum from Patients with Chronic Fatigue Syndrome

The level of bioactive transforming growth factor- (TGF-) was measured in serum from patients with chronic fatigue syndrome (CFS), healthy control subjects, and patients with major depression, systemic lupus erythematosis (SLE), and multiple sclerosis (MS) of both the relapsing/remitting (R/R) and the chronic progressive (CP) types. Patients with CFS had significantly higher levels of bioactive TGF- levels compared to the healthy control, major depression, SLE, R/R MS, and CP MS groups (P < 0.01). Additionally, no significant differences were found between the healthy control subjects and any of the disease comparison groups. The current finding that TGF- is significantly elevated among patients with CFS supports the findings of two previous studies examining smaller numbers of CFS patients. In conclusion, TGF- levels were significantly higher in CFS patients compared to patients with various diseases known to be associated with immunologic abnormalities and/or pathologic fatigue. These findings raise interesting questions about the possible role of TGF- in the pathogenesis of CFS.     

Treatment with double dose of omeprazole increases β-endorphin plasma level in patients with coronary artery disease

Introduction

The proton pump inhibitor empirical trial, besides the analysis of symptoms, is the main method in the diagnosis of gastro-oesophageal reflux disease-related chest pain. β-Endorphin acts as an endogenous analgesia system. The aim of the study was verify whether β-endorphin plasma level is affected by omeprazole administration and influences the severity of anginal symptoms and outcome of the “omeprazole test” in patients with coronary artery disease (CAD) and chest pain of suspected non-cardiac origin.

Material and methods

Omeprazole was administered to 48 patients with CAD in a randomized, placebo-controlled, crossover study design. At the beginning of the study, and again after the 14-day omeprazole and placebo treatment, the β-endorphin plasma concentration was determined.

Results

The level of plasma β-endorphin after the administration of omeprazole was significantly greater than at the start of the study and following the placebo. Responders to omeprazole had an average lower β-endorphin plasma concentration than subjects who failed to respond to this therapy. Subjects with symptoms in class III (according to the Canadian Cardiovascular Society classification) after omeprazole administration had a greater β-endorphin plasma level than subjects in class II for anginal symptom severity.

Conclusions

Fourteen-day therapy with a double omeprazole dose significantly increases the β-endorphin plasma concentration in patients with CAD. Circulating β-endorphin does not seem to be involved in the mechanism for the “omeprazole test” outcome, although an individually different effect on pain threshold cannot be excluded.     

Less-Than-Standard Treatment in Rectal Cancer Patients: Which Patients Are at Risk?

ObjectiveGuidelines recommend that patients with non-metastatic rectal cancer receive surgery and adjuvant chemotherapy and/or radiation therapy (XRT) after surgery (especially if stage II and III). Studies reported that 90% of stage II and III patients received surgery, and 70% received adjuvant treatment. In states where socioeconomics and limited medical resources may hinder treatment, cancer care is understudied. The objective is to describe initiation and completion of rectal cancer treatment in Alabama.MethodsMedicare claims were obtained for 675 stage I to III rectal cancer patients diagnosed in 1999–2003, enrolled in fee-for-service Medicare, and with at least 9 months of follow-up. Logistic regressions were used to identify significant differences by sex, age, and race in the likelihood of initiating treatment and receiving an incomplete course of chemotherapy or XRT (< 120 days of chemotherapy and < 28 days of XRT).ResultsOverall, 90% received surgery, of which 43% received some adjuvant treatment. Among stage II to III patients, 58.8% received adjuvant treatment. Except for patients aged 75 years and greater being less likely to start chemotherapy, there were no significant differences in initiation by age, sex, and race. Depending on concurrent administration of chemotherapy and XRT, 29% to 35% received incomplete chemotherapy, and 16% to 23% incomplete XRT. Women were more likely to have incomplete chemotherapy than men.ConclusionsAdjuvant treatment was less than reported in previous studies. Treatment initiation and completion did not differ across demographic factors. Future studies should explore reasons why older rectal cancer patients in Alabama are less likely to receive recommended treatment.     

Differences in Clinical Manifestations and Outcomes between Adult and Child Patients with Henoch-Sch?nlein Purpura

We aimed to investigate differences in clinical manifestations and outcomes between adult and child patients with Henoch-Schönlein purpura (HSP), and to analyze the factors associated with poor prognosis for HSP nephritis. This retrospective 10-yr study enrolled 160 patients with HSP who visited Severance Hospital. Purpura was mostly detected in lower extremities, but purpura in upper extremities was more frequently observed in adults than children (41.7% vs 19.3%). Children had a greater frequency of arthralgia (55.4% vs 27.1%), while adults had a greater frequency of diarrhea (20% vs 1.6%). Anemia, elevated C-reactive protein, and level of IgA were more frequently observed in adults (25% vs 7.1%, 65.6% vs 38.4%, 26.3% vs 3.5%). Renal involvement in adults was more severe than in children (79.2% vs 30.4%). Chronic renal failure showed a significant difference in outcomes of HSP between adults (10.4%) and children (1.8%) after a follow up period of an average of 27 months. Furthermore, renal insufficiency at diagnosis was significantly related to the progression to chronic renal failure. Our results showed several differences in the clinical features of HSP between adults and children. Adults with HSP had a higher frequency of renal insufficiency and worse renal outcomes than children. Renal insufficiency at diagnosis might be of predictive value for the progression to chronic renal failure in HSP patients.

Graphical Abstract

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The Transforming Growth Factor β1/Interleukin-31 Pathway Is Upregulated in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure and Is Associated with Disease Severity and Survival

The transforming growth factor β1/interleukin-31 (TGF-β1/IL-31) pathway plays an important role in the process of cell injury and inflammation. The purpose of this work was to explore the role of the TGF-β1/IL-31 pathway in the cytopathic process of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). The quantitative serum levels of TGF-β1, IL-9, IL-10, IL-17, IL-22, IL-23, IL-31, IL-33, and IL-35 were analyzed among chronic hepatitis B (CHB) patients (n = 17), ACLF patients (n = 18), and normal control (NC) subjects (n = 18). Disease severity in patients with ACLF was assessed using the model for end-stage liver disease (MELD) and Child-Pugh scores. Serum TGF-β1 levels were strongly positively correlated with IL-31 in all subjects, and both of them were positively correlated with IL-17, IL-22, and IL-33. In CHB and ACLF patients, serum levels of TGF-β1 and IL-31 were both increased significantly compared with those in NC subjects and positively correlated with total bilirubin (TBil) and alpha-fetoprotein (AFP) levels. ACLF patients showed the highest levels of TGF-β1 and IL-31, which were positively correlated with Child-Pugh scores. Furthermore, the recovery from the liver injury in CHB was accompanied by decreased TGF-β1 and IL-31 levels. More importantly, serum levels of TGF-β1 and IL-31 were markedly upregulated in ACLF nonsurvivors, and IL-31 displayed the highest sensitivity and specificity (85.7% and 100.0%, respectively) in predicting nonsurvival of ACLF patients. Increasing activity of the TGF-β1/IL-31 pathway is well correlated with the extent of liver injury, disease severity, and nonsurvival of ACLF patients, while reducing activity is detected along the recovery from liver injury in CHB, suggesting its potential role in the pathogenesis of liver injury during chronic HBV infection.     

A “Carboxyl Terminal” Clinical R Adioim Muno Assay for Parathyroid Hormone with Apparent Recognition Preference for the Intact Hormone

A radioimmunoassay for Parathyroid Hormone which is used in a clinical setting was characterized by (1) immunoreactivity with various synthetic fragments of the hormone, (2) serum parathyroid hormone response to oral calcium intake in normocalcemic calcium stone-formers, and (3) ability to detect fragments of parathyroid hormone secreted by abnormal human parathyroid tissue in vitro. Although almost all of the recognition sites for the antiserum were within the 53–84 carboxyl terminal amino acid sequence of the hormone, the radioimmunoassay mainly detected the “intact” hormone rather than the carboxyl terminal fragment(s) which most “carboxyl-terminal” assays of parathyroid hormone are claimed to preferentially detect. Differences in tertiary structure between the intact hormone and its fragments probably account for the relative inability of this antiserum to detect the carboxyl terminal fragment(s). (KEY WORDS: Parathyroid Hormone radioimmunoassay, PTH immunoheterogeneity).     

TNF-α -857C>T Genotype is Predictive of Clinical Response after Treatment with Definitive 5-Fluorouracil/cisplatin-based Chemoradiotherapy in Japanese Patients with Esophageal Squamous Cell Carcinoma

Background: Genotypes of tumor necrosis factor alpha (TNF-α) and its surface receptors, TNFRSF1A and TNFRSF1B, have been examined in terms of the progression, metastasis, clinical efficacy, and prognosis of various cancers; however, little is known about their effects on clinical outcome in patients with esophageal squamous cell carcinoma (ESCC). In this study, TNF-α and TNFRSF1A genotypes were retrospectively evaluated in terms of predicting clinical response, long-term survival, and severe acute toxicities in 46 male Japanese ESCC patients treated with definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT).Methods: A course consisted of the continuous infusion of 5-FU at 400 mg/m²/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m²/day on days 1 and 8, and radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course being repeated after a 2-week interval. The TNF-α -1031T>C (rs1799964), -863C>A (rs1800630), -857C>T (rs1799724), -308G>A (rs1800629), -238G>A (rs361525), TNFRSF1A -609G>T (rs4149570), and 36A>G (rs767455) genotypes were evaluated.Results: The TNF-α -857C>T genotype was found to be predictive of clinical response, i.e., complete response or not (P = 0.010, Fisher''s exact test), but had no effect on long-term survival (CC^-857 vs. CT^-857 + TT^-857, P = 0.072, Fisher''s exact test, P = 0.070, Log-rank test).Conclusions: The TNF-α -857C>T genotype was found to be predictive of clinical response and was more likely to predict long-term survival in Japanese ESCC patients receiving definitive 5-FU/CDDP-based CRT. Further clinical investigations with a larger number of patients or experiments in vitro should be performed to assess the predictive value of this genotype following CRT.