Effect of glucocorticoid monotherapy on pulmonary function and survival in Japanese patients with scleroderma-related interstitial lung disease

BackgroundScleroderma-related interstitial lung disease (SSc-ILD) is a chronic, progressive condition that is characterized by a restrictive ventilator defect. Cyclophosphamide (CYC), with or without glucocorticoid, effectively alters the course of SSc-ILD. However, the effect of glucocorticoid monotherapy remains unclear.MethodsSeventy-one patients with SSc-ILD were classified into 2 groups: 21 in the treatment group (glucocorticoid monotherapy [n=14] or immunosuppressive agents [n=7]) and 50 in the non-treatment group. Their backgrounds and prognoses were analyzed retrospectively. We also classified these patients into survival (n=55) and non-survival (n=16) groups to assess prognostic factors.ResultsThe median follow-up period was 9.8 years. The treatment group had a greater proportion of patients with diffuse systemic sclerosis or respiratory symptoms than the non-treatment group. The treatment group's annual change in forced vital capacity (FVC) compared to baseline, which was 170.4 mL (157.8 mL for the glucocorticoid monotherapy subgroup and 191.3 mL for the immunosuppressive agent subgroup), was better than that of the non-treatment group, ?60.8 mL (p<0.01). Still, in terms of 5- and 10-year survival, there was no statistically significant difference between these groups. No incidence of SSc renal crisis was reported in the treatment group. The non-survival group included more patients with pulmonary hypertension than the survival group, but multivariate analysis showed no other statistically significantly difference between these groups.ConclusionsSimilar to CYC, glucocorticoid alone improved pulmonary function of Japanese SSc-ILD patients, suggesting that this monotherapy is a good alternative when CYC is contraindicated.     

The efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis

BackgroundLymphangioleiomyomatosis (LAM) is a rare disease caused by dysregulated activation of the mammalian target of rapamycin (mTOR). Sirolimus, an inhibitor of mTOR, has been reported to decrease the size of angiomyolipomas and stabilize pulmonary function in patients with LAM. However, the optimal dose for the treatment of LAM remains unclear.MethodsWe conducted a retrospective, observational study of 15 patients with LAM who underwent sirolimus therapy for more than 6 months. The efficacy was evaluated by reviewing the patients' clinical courses, pulmonary function and chest radiologic findings before and after the initiation of sirolimus treatment.ResultsAll patients had blood trough levels of sirolimus lower than 5 ng/mL. Sirolimus treatment improved the annual rates of change in FVC and FEV₁ in the 9 patients who were free from chylous effusion (FVC, ?101.0 vs. +190.0 mL/y, p=0.046 and FEV₁, ?115.4 vs. +127.8 mL/y, p=0.015). The remaining 7 patients had chylous effusion at the start of sirolimus treatment; the chylothorax resolved completely within 1?5 months of treatment in 6 of these cases. These results resembled those of previous studies in which blood trough levels of sirolimus ranged from 5 to 15 ng/mL.ConclusionsLow-dose sirolimus (trough level, 5 ng/mL or less) performed as well as the higher doses used previously for improving pulmonary function and decreasing chylous effusion in patients with LAM.     

Impact of Sleep Duration on Obesity and the Glycemic Level in Patients With Type 2 Diabetes: The Fukuoka Diabetes Registry

OBJECTIVE

Few studies are currently available regarding the influence of sleep duration on glycemic control in diabetic patients. The objective of the current study was to examine the relationship between sleep duration, obesity, and the glycemic level in type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

A total of 4,870 Japanese type 2 diabetic patients aged ≥20 years were divided into six groups according to their self-reported sleep duration: less than 4.5 h, 4.5–5.4 h, 5.5–6.4 h, 6.5–7.4 h, 7.5–8.4 h, and more than 8.5 h. The associations of sleep duration with obesity and the HbA_1c levels were examined in a cross-sectional manner.

RESULTS

The HbA_1c levels showed a quadratic association with sleep duration; namely, a shorter or longer sleep duration was associated with a higher level compared with a sleep duration of 6.5–7.4 h (P for quadratic trend <0.001). This association remained significant after adjusting for potential confounders, including the total energy intake and depressive symptoms. Furthermore, additional adjustments for obesity, which also showed a U-shaped relationship with sleep duration, did not attenuate the U-shaped sleep-HbA_1c association. A significant interaction between sleep duration and age or the use of insulin was observed for the HbA_1c levels.

CONCLUSIONS

Sleep duration was shown to have U-shaped associations with obesity and the HbA_1c levels in type 2 diabetic patients, independent of potential confounders, and therefore may be an important modifiable factor for the clinical management of patients with type 2 diabetes.An increasing prevalence of type 2 diabetes and its complications, including macro- and microvascular diseases, is a growing public health concern in both developing and developed countries (1). This is probably because of population growth, aging, and the increasing prevalence of obesity, which results from environmental factors such as urbanization, physical inactivity, and the increased consumption of food. More recently, it has been reported that the habitual sleep duration has decreased (2) as a result of the modern lifestyle and 24-h society, and epidemiological evidence has suggested that this is associated with adverse consequences such as obesity or weight gain (3,4), hypertension (5), cardiovascular diseases (6,7), and increased mortality (6). The negative impacts of prolonged sleep duration on these outcomes have also been described (3–7), thus suggesting that there is a U-shaped relationship between sleep duration and health disorders. A possible association between an inadequate sleep duration and the development of type 2 diabetes among nondiabetic subjects has been described as well (8–14), but epidemiological evidence concerning the relationship between sleep duration and glycemic control or obesity among diabetic patients is scarce (15–17). Furthermore, to the best of our knowledge, no study has so far examined this relationship among diabetic patients in Asia, despite the fact that racial differences have been suggested in the association between sleep and diabetes (12,18). In this context, the objective of the current study was to investigate the association of sleep duration with the HbA_1c levels, as well as with obesity, which is the major factor related to poor glycemic control, among Japanese type 2 diabetic patients.     

Correlation between Transient Hypotension and Exclusively Exercise-induced Symptoms of Two-to-One Atrioventricular Block

A 62-year-old woman with activity-dependent two-to-one atrioventricular block (2:1AVB) and a normal left ventricular ejection fraction was referred to our department for the evaluation of exclusively exercise-induced marked symptoms. The treadmill test helped establish a clear correlation between 2:1AVB and symptoms. The test results demonstrated that exercise-induced marked symptoms were attributed to abrupt transient hypotension combined with relative bradycardia, probably due to increased diastolic mitral and tricuspid regurgitation because of 2:1AVB during moderate-to-heavy exercise. After pacemaker implantation for 2:1AVB, the symptoms and transient hypotension disappeared, and her exercise capacity improved.     

Fetal pancreatic Langerhans islets size in pregnancies with metabolic disorders

Objective: Metabolic disorders are a pandemic and increasing health problem. Women of childbearing age may also be affected, thus an abnormal metabolism may interfere with pregnancy short- and long-term outcomes, harming both mother and child. In the context of an abnormal maternal and intrauterine metabolic milieu the development of fetal organs, including pancreas, may be affected.

Aim: To investigate the effects of pregnancy metabolic disorders on the morphology of pancreatic Langerhans islets in human late-third trimester stillborn fetuses.

Methods: Samples from fetal pancreas underwent a quantitative histological evaluation to detect differences between pregnancy with (cases, n?=?9) or without (controls, n?=?6) abnormal metabolism.

Results: Results show that the islets size increases in fetuses from dysmetabolic pregnancies and that this increment is related to both beta-cell hyperplasia and hypertrophy. Moreover, according to pregnancy and fetal metabolic disorders, a threshold of abnormal size of the islets has been identified. Above this threshold the size of fetal pancreatic Langerhans islets should be considered excessively increased.

Conclusion: The study suggests that an accurate fetal pancreas analysis supplies an important tool in stillborn fetus, to discover metabolic disturbances that should be kept in mind and managed in future pregnancies.     

Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells

Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK.     

Analysis of oxygen transport and oxygen utilization combined

We propose a model which combines oxygen transport system from blood to tissue with oxygen utilization system at the tissue.The model consists of 3 equations; the relationship between tissue P_{O 2} (Pts_{O 2}) and O₂ utilization (Vrc_{O 2}), diffusion from vessel to tissue, and Fick equation. This model has two advantages. First, it is self-consistent. Varying Vrc_{O 2} varies the oxygen transport. Second, it enables to analyze the effects of various factors of oxygen transport/utilization on other factors.We applied this model to the brain tissue. Following values were assumed. Critical tissue P_{O 2} (Pcrit_{O 2}) 2mmHg; oxygen utilization above this level 3ml·min^–1·100g^–1; diffusion coefficient from blood vessel to tissue (D) 0.2ml·min^–1·mmHg^–1·100g^–1; cerebral blood flow (CBF) 50ml·min^–1·100g^–1; hemoglobin 15g·100ml^–1. Hill equation was used for oxygen dissociation curve with n of 2.7 and P50 of 27.0mmHg.From these, the following values were obtained; Pv_{O 2}, Pts_{O 2} and Vrc_{O 2}. The changes were analyzed for the 5 input values, Pa_{O 2}, CBF, D, P50 and Hb, changing from zero to their respective normal values. A reduction of a single parameter down to 50% of normal barely affected oxygen utilization. A further reduction resulted in significant oxygen utilization. Under conditions studied, a decrease in P50 reduced oxygen utilization faster than that in any other parameters.(Suwa K: Analysis of oxygen transport and oxygen utilization combined. J Anesth 6: 51–56, 1992)