Endobronchial valve deployment in severe α‐1 antitrypsin deficiency emphysema: a case series

Introduction: Patients with end‐stage emphysema because of α‐1 antitrypsin (AAT) deficiency represent a challenging clinical management problem, and studies of volume reduction therapy to date have largely excluded these patients. We report the outcome of bronchoscopic volume reduction with the insertion of Emphasys endobronchial valves (Emphasys Medical, Redwood City, CA, USA) in six patients with end‐stage emphysema because of AAT deficiency. Case Series: Of 51 patients with end stage emphysema referred for transplantation, we studied six patients with AAT deficiency and utilized the BODE index and lung allocation score for survival estimation. Measurements and Main Results: The forced expiratory volume in 1 s improved from a median of 0.575 L to 0.905 L (P = 0.028). There was a median reduction in total lung capacity (TLC) of 0.61 L. The residual volume /TLC fell from 74.0% to 58.4%. Before treatment, four patients had a BODE index of greater than eight units, which correlates with a 4‐year survival of 18%. After treatment, two patients improved their BODE index to below seven units, which correlates with an estimated 4‐year survival of over 50%. Conclusions: The data from this case series suggest that this intervention may provide bridging therapy to subsequent transplantation for younger AAT patients with end‐stage emphysema. Please cite this paper as: Tuohy MM, Remund KF, Hilfiker R, Murphy DT, Murray JG and Egan JJ. Endobronchial valve deployment in severe α‐1 antitrypsin deficiency emphysema: a case series. Clin Respir J 2013; 7: 45–52.     

Comparison of three α‐glucosidase inhibitors for glycemic control and bodyweight reduction in Japanese patients with obese type 2 diabetes

Aims/Introduction

α‐Glucosidase inhibitors (αGIs) are widely used for the primary treatment of type 2 diabetes. We compared the clinical effects of three αGIs (miglitol, acarbose and voglibose) in patients with obese type 2 diabetes.

Materials and Methods

Japanese patients (n = 81) with obese type 2 diabetes (body mass index [BMI] ≥25 kg/m²) were enrolled in this multicenter, open‐label study. The participants were randomized into the miglitol (n = 18), acarbose (n = 22), voglibose (n = 19) or control (n = 22) groups. Glycemic control (fasting blood glucose and glycated hemoglobin [HbA1c]), bodyweight, BMI, serum insulin, serum lipids (low‐density lipoprotein and high‐density lipoprotein cholesterol, and triacylglycerols) and adipocytokines (leptin and adiponectin) were evaluated every 4 weeks for 12 weeks.

Results

In the miglitol group, HbA1c was improved significantly from the baseline at all points. The changes in HbA1c at 8 and 12 weeks from baseline were greater in the miglitol group than the control group. The voglibose group showed significant improvements in HbA1c at 12 weeks. Bodyweight and BMI were decreased significantly in the miglitol group. In addition, significant correlations were observed between the decrements in HbA1c and bodyweights over 12 weeks in the miglitol (r = 0.759, P < 0.001) and voglibose groups (r = 0.667, P = 0.002). Serum lipid and adipocytokine levels were not altered in any groups.

Conclusions

αGIs, especially miglitol, can effectively control blood glucose and bodyweight in obese type 2 diabetes. This study was registered with UMIN (no. UMIN000006465).     

α‐thalassaemia masked by β gene defects and a new polyadenylation site mutation on the α2‐globin gene

We report three examples of chronic anaemia involving complex combinations of α‐ and β‐globin gene defects. The first case had a potential Hb H disease caused by the classic SEA/RW deletions masked by Hb E [β26(B8)Glu→Lys] in the homozygous state. The second had an unusual Hb H disease caused by compound heterozygosity for two different α2 polyadenylation site mutations masked by a β‐thalassaemia heterozygosity. The third had an intermediate α‐thalassaemia with considerable anaemia caused by an as yet unknown polyadenylation site (AATAAA>AATAAC) mutation in combination with a common RW deletion masked by a common Hb C [β6(A3)Glu→Lys] heterozygosity. Diagnostic methods, genotype/phenotype correlations and the chance of overlooking these combinations during risk assessment in a multiethnic society are discussed.     

Relationship between soluble CD40 ligand and γ‐glutamyltransferase concentrations in non‐drinking,young Type 1 diabetic individuals

Aims To assess the association between circulating levels of soluble CD40 ligand (sCD40L), an emerging cardiovascular risk factor, and γ‐glutamyltransferase (GGT) activity concentrations in Type 1 diabetic subjects. Methods Plasma concentrations of sCD40L and GGT activity, a marker of liver dysfunction, were measured in 54 non‐smoking, non‐drinking, young Type 1 diabetic patients, who were free of diagnosed cardiovascular disease. Results When participants were grouped according to tertiles of GGT, plasma sCD40L concentrations steadily increased across GGT tertiles (P = 0.007 for trend). Similarly, plasma sCD40L concentrations were positively correlated with plasma GGT levels in the whole group of participants (r = 0.532; P < 0.0001). In multivariate linear regression analysis, plasma GGT activity levels were positively associated with sCD40L (standardized beta coefficient = 0.342; P = 0.027) independently of age, gender, diabetes duration, glycated haemoglobin, total cholesterol and systolic blood pressure. Further adjustment for the presence of diabetic retinopathy and microalbuminuria did not appreciably attenuate this association. Conclusions Our findings suggest that there is a strong, graded, relationship between plasma GGT activity and sCD40L concentrations in non‐smoking, non‐drinking, young Type 1 diabetic individuals. This association appears to be independent of numerous confounding factors. Further studies are required to confirm the reproducibility of these results.     

Peripheral T cell receptors αβ and γδ in patients with Hodgkin's lymphoma

Antigen recognition by T cells is determined by an antigen specific T cell receptor (TCR). Two heterodimeric TCR structures associated with CD3 have been defined: TCR αβ and TCR γδ. TCR αβ and its function are well described but the role of TCR γδ in normal and lymphoproliferative disorders is not well established. In newly diagnosed or relapsed/refractory Hodgkin's disease (HD), a disease associated with defective T cell functions and increased sIL-2R, We determined levels of seven TCR αβ variable regions [βV5(a), βV5(b), βV6(a), βV12(a), αβV(a), αV2(a)] and TCR γδ by using monoclonal antibodies (MCA). TCR γδ levels did not show any difference, but several variable regions of the TCR αβ differed when groups are compared with each other and the control group.     

A novel binding site for the native hepatic acute‐phase protein α1‐antitrypsin expressed on the human hepatoma cell line HepG 2 and intestinal cell line Caco 2

Abstract: Aims/Background:α1‐antitrypsin (α1‐AT) is a hepatic acute phase protein which predominantly inhibits neutrophil elastase. Besides this major function, we have also previously shown that α1‐AT markedly increased H‐ferritin mRNA expression and ferritin synthesis in the human hepatoma cell line HepG 2. These actions suggest that α1‐AT might interact with HepG 2 cells via a specific cell surface binding site. Methods and Results: Using radio‐labelled native α1‐AT, we observed saturable binding to HepG 2 cells with a dissociation constant (Kd) of 63.3±6.9 nM and a maximal density of binding sites (Bmax) of 0.34 ±0.05 pmol/10⁶ cells equivalent to 195800±29200 sites/cell. The binding of [¹²⁵I]α1‐AT was time dependent with a calculated association rate constant of 9.22±1.84×10⁴×M^?1×min^?1. Binding was highly specific since other acute phase proteins or protease inhibitors failed to block binding. Although α1‐AT‐trypsin, α1‐AT‐elastase and the pentapeptide FVYLI, the minimal binding sequence for the SEC receptor, increased [¹²⁵I]α1‐AT binding, in long term experiments these complexes failed to influence the number of α1‐AT binding sites. Specific, saturable binding of [¹²⁵I]α1‐AT was also found on the human intestinal epithelial Caco 2 cells, but not on fibroblast or leukaemic cell lines. Conclusion: These experiments demonstrate a specific, high affinity binding site for native α1‐AT on HepG 2 and Caco 2 cells, cell lines derived from tissues involved in the acute phase response.     

Difference between old and young adults in contribution of β‐cell function and sarcopenia in developing diabetes mellitus

Aims/Introduction

To investigate the difference in contributing factors in developing diabetes between old and young adults.

Materials and Methods

Subjects with recent‐onset diabetes were selected from a nationwide survey data and classified according to age: elderly (age ≥75 years), middle‐age (age 45–64 years) and young (age 25–39 years). The homeostasis model assessment of insulin resistance and β‐cell function were calculated. Sarcopenia was assessed using dual‐energy X‐ray absorptiometry.

Results

The prevalence of recent‐onset diabetes was 13.5%, 8.0%, and 1.4% in patients aged ≥75 years (unweighted n = 1,082), 45–64 years (unweighted n = 6,532), and 25–39 years (unweighted n = 5,178), respectively. Homeostasis model assessment of β‐cell function along with homeostasis model assessment of insulin resistance showed increasing trends as onset age increased in recent‐onset diabetes (P for trend < 0.001 in both). Elderly‐onset diabetic patients had significantly higher homeostasis model assessment of β‐cell function and homeostasis model assessment of insulin resistance compared with the middle‐age‐onset group (P < 0.001 and 0.014, respectively). Multivariate analysis showed that sarcopenia was significantly associated with recent‐onset diabetes only in patients aged ≥75 years (odds ratio [OR] 2.478, 95% confidence interval [CI] 1.379–4.452) but not in patients aged 45–64 years. In the middle‐age group, abdominal obesity (OR 2.933, 95% CI 2.086–4.122), hypertriglyceridemia (OR 1.529, 95% CI 1.078–2.169]) and low high‐density lipoprotein cholesterolemia (OR 1.930, 95% CI 1.383–2.695) were associated with recent‐onset diabetes.

Conclusions

Elderly‐onset diabetic patients had higher insulin resistance and relatively preserved β‐cell function compared with middle‐age‐onset patients. Sarcopenia might play a more important role in developing diabetes in the elderly population.     

Melatonin attenuates TNF‐α and IL‐1β expression in synovial fibroblasts and diminishes cartilage degradation: Implications for the treatment of rheumatoid arthritis

The hormone melatonin has many properties, including antioxidant, anti‐inflammatory, and immunomodulatory effects. Melatonin has been demonstrated to be beneficial in several inflammatory autoimmune diseases, but its effects in rheumatoid arthritis (RA) remain controversial. We sought to determine how melatonin regulates inflammation in RA. We found that melatonin dose‐dependently inhibits tumor necrosis factor‐α (TNF‐α) and interleukin (IL)‐1β expression through the PI3K/AKT, ERK, and NF‐κB signaling pathways. We also identified that melatonin inhibits TNF‐α and IL‐1β production by upregulating miR‐3150a‐3p expression. Synovial tissue specimens from RA patients and culture of human rheumatoid fibroblast‐like synoviocytes confirmed that the MT1 receptor is needed for the anti‐inflammatory activities of melatonin. Importantly, melatonin also significantly reduced paw swelling, cartilage degradation, and bone erosion in the collagen‐induced arthritis mouse model. Our results indicate that melatonin ameliorates RA by inhibiting TNF‐α and IL‐1β production through downregulation of the PI3K/AKT, ERK, NF‐κB signaling pathways, as well as miR‐3150a‐3p overexpression. The role of melatonin as an adjuvant treatment in patients with RA deserves further clinical studies.