Non-invasive ventilation during arm exercise and ground walking in patients with chronic hypercapnic respiratory failure

Background and objective:   People with chronic hypercapnic respiratory failure (HRF) often have a ventilatory limitation to exercise with difficulty performing activities of daily living. Although non-invasive ventilation (NIV) appears to reduce the ventilatory limitation and improve exercise performance in people with severe COPD, the effect of NIV during functional activities such as unsupported arm exercise (UAE) and ground walking in people with chronic HRF is unclear.
Methods:   Seventeen patients with chronic HRF (PaCO₂ 52.1 ± 5.3 mm Hg) performed a series of UAE tests, and 15 patients (PaCO₂ 51.7 ± 3.8 mm Hg) performed a series of endurance shuttle walk tests, with and without NIV in a randomized cross-over design.
Results:   NIV during UAE increased endurance time by a mean of 91 s (95% confidence interval (CI): 10–172, P  = 0.031) and reduced dyspnoea by a mean of 2.3 on the Borg scale (95% CI: 1.0–3.7, P  = 0.002) compared with exercise without NIV. There was a non-significant increase in walking endurance time with NIV during exercise (119 s, 95% CI: −17 to 254, P  = 0.081); however, isotime dyspnoea was unchanged compared with walking without NIV (−1.0, 95% CI: −3.0 to 1.0, P  = 0.29).
Conclusion:   NIV during UAE increased endurance time and reduced dyspnoea compared with exercise without NIV in patients with chronic HRF. Investigation of the role of NIV as an adjunct to UAE training is warranted. In contrast, NIV during ground walking did not improve exercise capacity. However, the pressure support provided may have been inadequate as dyspnoea was not reduced.     

Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis

Background and objective:   Although pulmonary rehabilitation is effective for patients with COPD, its efficacy in patients with IPF is unknown. The purpose of this study was to evaluate the effects of pulmonary rehabilitation in IPF.
Methods:   Thirty patients diagnosed with IPF, according to the consensus statement, were randomly assigned to the rehabilitation group or the control group. The pulmonary rehabilitation mainly consisted of a 10-week programme of exercise training. Pulmonary function, blood gas analysis, 6MWD, dyspnoea rating with the baseline dyspnoea index and health-related quality of life score on the St George's Respiratory Questionnaire were evaluated at baseline and after the programme.
Results:   Assessment of efficacy was carried out on 13 patients who completed the programme and 15 patients in the control group. There were no significant effects of the programme on measures of pulmonary function, values of arterial blood gas analysis or dyspnoea rating. Although there were some differences in the baseline 6MWD and total health-related quality of life score which were not statistically significant, marked improvements were observed in the 6MWD (mean difference 46.3 m (95% CI: 8.3–84.4), P  < 0.05) and the total health-related quality of life score (−6.1 (95% CI: −11.7 to −0.5), P  < 0.05).
Conclusions:   Pulmonary rehabilitation improves both exercise capacity and health-related quality of life in patients with IPF.     

Plasma HCV-RNA decline in the first 48 h identifies hepatitis C virus mono-infected but not HCV/HIV-coinfected patients with an undetectable HCV viral load at week 4 of peginterferon-alfa-2a/ribavirin therapy

Summary.  During peginterferon-alfa-2a/ribavirin therapy, plasma hepatitis C virus (HCV)-RNA decreases with a rapid first phase and a slower second phase. We compared the viral load decrease and slope in the first 48 h in patients with a rapid viral response (RVR, i.e. HCV-RNA < 50 IU/mL at week 4) with patients not achieving an RVR. From 23 HCV-infected (14 mono-infected and nine HCV/HIV-coinfected) genotype 1 or 4 positive peginterferon-alfa-2a/ribavirin-treated patients, plasma HCV-RNA was determined at baseline, 48 h, weeks 1, 2, 4, 8, 12, 48 and 72. The HCV viral load decrease (Δ0–48), the slope (λ₁) and the efficiency factor (ε) were determined in the first 48 h after the start of therapy. Five (36%) HCV mono-infected patients and three (33%) HIV/HCV-coinfected patients achieved an RVR whereas six (43%) HCV mono-infected patients and five (56%) HIV/HCV-coinfected patients reached a sustained viral response (SVR). In contrast to HIV/HCV-coinfected patients, five HCV mono-infected patients with an RVR showed both a larger Δ0–48 and steeper λ₁ (−1.77log₁₀ IU/mL ± 0.66 and −2.04/day ± 0.76) compared to nine non-RVR patients (−0.66log₁₀ IU/mL ± 0.39; P  = 0.019 and −0.76/day ± 0.41; P  = 0.019). When divided by SVR, a greater Δ0–48 and steeper λ₁ were also seen in both HCV mono-infected and HIV/HCV-coinfected patients. Thus, in the first 48 h after the start of therapy, HCV mono-infected patients with an RVR have a larger viral load decrease, steeper viral slope and a higher efficiency factor as compared with non-RVR patients.     

Association between angiotensin-converting enzyme gene polymorphisms and exercise performance in patients with COPD

Background and objective:   Recent studies have shown that polymorphisms of the angiotensin-converting enzyme (ACE) gene are closely associated with pulmonary disorders. The ACE gene is involved in the regulation of inflammatory reactions to lung injury, respiratory drive, erythropoiesis and tissue oxygenation. The hypothesis for this study was that the ACE gene may be associated with the ventilatory response to exercise and the aerobic work efficiency of skeletal muscle in patients with COPD.
Methods:   Sixty-one Chinese Han COPD patients and 57 healthy control subjects performed incremental cardiopulmonary exercise testing on a cycle ergometer. ACE genotypes were determined using PCR amplification.
Results:   Resting lung function and blood gas index were not significantly different among the three ACE genotype COPD groups. Similarly, there were no significant differences in AT, maximal O₂ uptake, maximal O₂ pulse, maximal dyspnoea index, ventilatory response (ΔVE/ΔVCO₂), O₂ cost of ventilation (VO₂/W/VE), end-tidal partial pressure of carbon dioxide at maximal exercise and maximal SaO₂ among the three ACE genotype COPD patients. Maximal work load and aerobic work efficiency were higher in the COPD group with the II genotype than in those with the ID or DD genotype. There were no significant differences in resting lung function and cardiopulmonary exercise testing parameters among the three ACE genotype control groups.
Conclusions:   The ACE gene may be involved in the regulation of skeletal muscle aerobic work efficiency, but is not associated with the ventilatory responses to exercise in COPD patients.     

Effects of oxygen on exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease

Background and objective: The results of studies on the oxygen response in patients with COPD should provide important clues to the pathophysiology of exertional dyspnoea. We investigated the exercise responses to hyperoxia in relation to dyspnoea profile, as well as cardiopulmonary, acidotic and sympathetic parameters in 35 patients with stable COPD (mean FEV₁ 46% predicted). Methods: This was a single‐blind trial, in which patients breathed 24% O₂ or compressed air (CA) in random order during two incremental cycle exercise tests. Results: PaO₂ and PaCO₂ were higher (P < 0.0001 and P < 0.05, respectively) at each exercise point while patients were breathing 24% O₂ compared with CA. At a standardized time point near peak exercise, use of O₂ resulted in reduced plasma lactate and plasma noradrenaline concentrations (P < 0.01). Peak minute ventilation/indirect maximum voluntary ventilation was similar while breathing 24% O₂ and CA. At peak exercise, the dyspnoea score, pH and plasma noradrenaline concentrations were similar while breathing 24% O₂ and CA. The dyspnoea—ratio (%) of Δoxygen uptake (peak minus resting oxygen uptake) curve reached a break point that occurred at a similar exercise point while breathing 24% O₂ or CA. Conclusions: Regardless of whether they breathed CA or 24% O₂, patients with COPD did not develop ventilatory compensation for exertional acidosis, and the pH values measured were similar. Hyperoxia during a standardized exercise protocol did not alter the pattern of exertional dyspnoea in these patients, compared with breathing CA, although hyperoxia resulted in miscellaneous effects.     

Cough-reflex sensitivity to inhaled capsaicin in COPD associated with increased exacerbation frequency

Background and objective:   The causes of exacerbations in COPD patients are poorly understood. This study examined the association between cough-reflex sensitivity in patients with stable COPD and the frequency of subsequent exacerbations.
Methods:   The sampling frame for cases and controls for this study was patients attending a hospital outpatient clinic. cough-reflex sensitivity was evaluated using the log concentration of capsaicin causing five or more coughs (log C₅). Subsequent COPD exacerbations were identified prospectively via symptom-based diaries over a 12-month period.
Results:   The study group comprised 45 COPD subjects and 10 controls. Mean log C₅ was lower in the COPD group than in the control group (0.97 (95% confidence interval (CI): 0.76–1.18) versus 1.26 (95% CI: 0.81–1.71), P  = 0.095). In the COPD group, log C₅ was negatively correlated with serum CRP level ( r  = −0.36, P  = 0.02) and significantly associated with the exacerbation frequency ( r  = −0.38, P  = 0.01). Stepwise multiple regression analysis showed that cough-reflex sensitivity was significantly associated with exacerbation frequency ( r ² = 0.15, P  = 0.01).
Conclusions:   Hypersensitivity of the cough reflex to inhaled capsaicin might reflect airway inflammation in stable COPD patients, which predisposes to frequent exacerbations.     

Urinary bile acid sulfate levels in patients with hepatitis C virus-related chronic liver diseases

Aim:  Urinary bile acids are mainly conjugated with sulfuric acid, and urinary sulfated bile acid (USBA) levels in hepatobiliary diseases have been reported. However, the relationship between USBA and fasting serum total bile acid (TBA) has not been studied in hepatobiliary diseases. In the present study, we measured USBA levels in patients with hepatitis C virus-related chronic liver diseases, and the relationship between TBA and various laboratory tests was studied.
Methods:  USBA was measured using an automatic assay kit in 66 patients with chronic hepatitis and 28 patients with liver cirrhosis, and its relationship between TBA and various laboratory tests was studied.
Results:  The median USBA level was 10.7 µmol/g creatinine in patients with chronic hepatitis and 41.1 µmol/g creatinine in liver cirrhosis ( P  = 0.000). More patients with chronic hepatitis had elevated USBA levels (61%) compared to TBA level (39%) ( P  = 0.002). USBA level was well correlated with TBA (r_s = 0.680), and negatively correlated with albumin (r_s = −0.488), prothrombin time (r_s = −0.385) and platelet counts (r_s = −0.394). In patients with liver cirrhosis, USBA was significantly elevated in Child–Pugh class B compared to Child–Pugh class A ( P  = 0.036).
Conclusion:  Although the metabolic pathways of USBA and TBA are different, these levels correlated very well, and USBA is considered to be a useful indicator of hepatic function like TBA in patients with chronic hepatitis C.     

Acute effects of hyperoxia on resting pattern of ventilation and dyspnoea in COPD

Background and objective:   Hyperoxia has been shown to reduce resting ventilation, hyperinflation and dyspnoea in patients with severely hypoxaemic COPD. This study assessed the effects of hyperoxia on these resting measures in patients with COPD of varying disease severity and characterized those patients who responded.
Methods:   Measurements of dyspnoea (Borg score), oxyhaemoglobin saturation (SpO₂), inspiratory capacity (IC), minute ventilation, tidal volume, breathing and cardiac frequency were performed at rest in 51 patients with COPD while they breathed air and 44% oxygen, in a randomized double-blinded fashion.
Results:   Hyperoxia induced significant reductions in cardiac frequency and dyspnoea and a significant increase in SpO₂. No significant change was noted in IC for the group overall, and there was substantial inter-subject variation in this measurement. No significant changes were found in ventilation, and there was no correlation between change in dyspnoea and change in IC. In patients with moderate to severe airflow obstruction (FEV₁ < 70% predicted), a significant association was found between the degree of airflow obstruction and change in IC induced by hyperoxia.
Conclusions:   Hyperoxia improved dyspnoea but did not significantly alter resting pulmonary hyperinflation in a group of patients with COPD of varying severity. However, in a subset patients with moderate to severe airflow obstruction a relationship existed between the severity of airflow obstruction and volume response to hyperoxia.     

Air trapping: The major factor limiting diaphragm mobility in chronic obstructive pulmonary disease patients

Background and objective:   Patients with COPD can have impaired diaphragm mechanics. A new method of assessing the mobility of the diaphragm, using ultrasound, has recently been validated. This study evaluated the relationship between pulmonary function and diaphragm mobility, as well as that between respiratory muscle strength and diaphragm mobility, in COPD patients.
Methods:   COPD patients with pulmonary hyperinflation ( n  = 54) and healthy subjects ( n  = 20) were studied. Patients were tested for pulmonary function, maximal respiratory pressures and diaphragm mobility using ultrasound to measure the craniocaudal displacement of the left branch of the portal vein.
Results:   COPD patients had less diaphragm mobility than did healthy individuals (36.5 ± 10.9 mm vs 46.3 ± 9.5 mm, P  = 0.001). In COPD patients, diaphragm mobility correlated strongly with pulmonary function parameters that quantify air trapping (RV: r  = −0.60, P  < 0.001; RV/TLC: r  = −0.76, P  < 0.001), moderately with airway obstruction (FEV₁: r  = 0.55, P  < 0.001; airway resistance: r  = −0.32, P  = 0.02) and weakly with pulmonary hyperinflation (TLC: r  = −0.28, P  = 0.04). No relationship was observed between diaphragm mobility and respiratory muscle strength (maximal inspiratory pressure: r  = −0.11, P  = 0.43; maximal expiratory pressure: r  = 0.03, P  = 0.80).
Conclusion:   The results of this study suggest that the reduction in diaphragm mobility in COPD patients is mainly due to air trapping and is not influenced by respiratory muscle strength or pulmonary hyperinflation.     

The relationship of glycaemic control and triglycerides in patients with diabetes mellitus: a PreCIS Database Study

Aims:  A common therapeutic approach in patients with type 2 diabetes mellitus who have elevated triglycerides (TGs) is to treat the hyperglycaemia before specifically targeting high TG. The aims of the current study were (i) to determine whether there was a relationship between glycated haemoglobin (HgbA1c) and TG levels at the baseline visit and (ii) to analyse the relationship between ΔHgbA1c and ΔTG after treatment.
Methods:  Among 650 consecutive diabetic patients seen in the Cleveland Clinic Preventive Cardiology Department, 372 had both baseline and post-treatment HgbA1c and TG values. We analysed the relationship between baseline HgbA1c and TG as well as between the change in HgbA1c and the change in TG. For analysis, patients were divided into nine groups by tertiles of HgbA1c (≤6.6, 6.7–7.8 and >7.8%) and TG (≤1.75, 1.76–3.89 and >3.89 mmol/l) at baseline.
Results:  At baseline, there was a small correlation between HgbA1c and TG (r² = 0.051; p < 0.001). For the entire group, there was a significant correlation between ΔHgbA1c and ΔTG from baseline to follow-up (r² = 0.077; p < 0.001). Analyses by tertiles showed that ΔTG were only associated with changes in two groups: HgbA1c tertile 3 (>7.8%) and TG tertiles 2 (r² = 0.24; p < 0.0001) and 3 (r² = 0.187; p = 0.003). For every 1% change in the top tertile HgbA1c, there was a 9.3% change in TG (tertile 2) and a 9.8% change in TG (tertile 3).
Conclusions:  These observations suggest that for patients with diabetes mellitus and elevated TG, the effect of HgbA1c reduction has limited effects on TG reduction. Patients may benefit from TG-specific therapy initiated earlier rather than waiting to see effects of glycaemic control.     

Lipohypertrophy: does it matter in daily life? A study using a continuous glucose monitoring system

Aims:  To use continuous glucose monitoring (CGMS) to compare glucose profiles in people with type 1 diabetes following injection of insulin into an area affected by lipohypertrophy vs. an area not affected by lipohypertrophy.
Methods:  Eight patients with type 1 diabetes underwent 72 h of CGMS while following a standardized diet and injecting all insulin either into an area with or without lipohypertrophy. Patients underwent two testing periods in random order, separated by 4 days. On day 1 of each test subjects were admitted for measurement of insulin and plasma glucose levels immediately prior to, and hourly for 4 h following, a standardized lunch.
Results:  Insulin area under the curve (AUC)_{0–4 h} was similar for both test periods; 656; interquartile range (IQR): 518–1755 (normal tissue) vs. 602; IQR: 382–1436 (lipohypertrophic tissue), z  = 1.7, p = 0.09. There was also no difference in the median time to maximal insulin concentration (Time_max 2 h; IQR: 2–3 h; z  = 0.6; p = 0.6). There was a 37.5% increase in mean plasma glucose levels following a standardized meal; however this was not significant between sites (AUC_{0–4 h} t  = −1.7; p = 0.1). Moreover, there was no difference in CGMS profiles (AUC_{1–72 h} t  = −0.9; p = 0.4) across the 72-h monitoring period. Overall the prevalence of hypoglycaemia (CGMS readings < 4 mmol/l) was similar between injection sites (11.6 vs. 10.6%, p = 0.1).
Conclusion:  The pharmacokinetic and pharmacodynamic effect of injecting into lipohypertrophic tissue is small in comparison to the usual clinical variation observed with insulin injections.     

Transferring to insulin detemir from NPH insulin or insulin glargine in type 2 diabetes patients on basal-only therapy with oral antidiabetic drugs improves glycaemic control and reduces weight gain and risk of hypoglycaemia: 14-week follow-up data from PREDICTIVE

Aim:  The aim of this study was to evaluate the safety and efficacy of insulin detemir in type 2 diabetes patients previously receiving NPH insulin (NPH group, n = 175) or insulin glargine (glargine group, n = 118) in combination with oral antidiabetic drugs (OADs).
Methods:  Patients were transferred to insulin detemir, while the OAD regimen and number of injections remained the same. The incidence of serious adverse drug reactions, including major hypoglycaemia, and haemoglobin A_1c (HbA_1c), fasting glucose, within-patient fasting glucose variability and body weight change were measured at 14 weeks.
Results:  Glycaemic control improved in both NPH (HbA_1c = −0.2%, p < 0.05; fasting glucose −1.0 mmol/l, p < 0.0001) and glargine (HbA_1c = −0.6%, p < 0.0001; fasting glucose −1.4 mmol/l, p < 0.0001) groups, including a reduction in fasting glucose variability (p < 0.01 for both). The incidence of total and nocturnal hypoglycaemia was reduced in both NPH and glargine groups. The incidence of major hypoglycaemia was low and did not change significantly during the follow-up period. Mean body weight was significantly reduced in the NPH (−0.7 kg, p < 0.01) and glargine (−0.5 kg, p < 0.05) groups.
Conclusions:  These results indicate that in type 2 diabetes, transferring from other basal insulins to insulin detemir in combination with OADs was associated with improvements in glycaemic control, which were accompanied by a reduced risk of hypoglycaemia and a reduction in body weight.     

Hepcidin Regulation in Wild-Type and Hfe Knockout Mice in Response to Alcohol Consumption: Evidence for an Alcohol-Induced Hypoxic Response

Background /Aims:  Expression of Hamp1 , the gene encoding the iron regulatory peptide hepcidin, is inappropriately low in HFE-associated hereditary hemochromatosis and Hfe knockout mice ( Hfe ^−/− ). Since chronic alcohol consumption is also associated with disturbances in iron metabolism, we investigated the effects of alcohol consumption on hepcidin mRNA expression in Hfe ^−/− mice.
Methods:  Hfe ^−/− and C57BL/6 (wild-type) mice were pair-fed either an alcohol liquid diet or control diet for up to 8 weeks. The mRNA levels of hepcidin and ferroportin were measured at the mRNA level by RT-PCR and protein expression of hypoxia inducible factor-1 alpha (HIF-1α) was measured by western blot.
Results:  Hamp1 mRNA expression was significantly decreased and duodenal ferroportin expression was increased in alcohol-fed wild-type mice at 8 weeks. Time course experiments showed that the decrease in hepcidin mRNA was not immediate, but was significant by 4 weeks. Consistent with the genetic defect, Hamp1 mRNA was decreased and duodenal ferroportin mRNA expression was increased in Hfe ^−/− mice fed on the control diet compared with wild-type animals and alcohol further exacerbated these effects. HIF-1α protein levels were elevated in alcohol-fed wild-type animals compared with controls.
Conclusion:  Alcohol may decrease Hamp1 gene expression independently of the HFE pathway possibly via alcohol-induced hypoxia.     

Association between CRHR1 polymorphism and improved lung function in response to inhaled corticosteroid in patients with COPD

Background and objective:   Inhaled corticosteroids are used to treat COPD and asthma. An association between sequence variants in the corticotrophin-releasing hormone receptor 1 ( CRHR1 ) gene and improved lung function in asthmatics treated with inhaled corticosteroids was reported recently. This study investigated the association between the change in lung function in response to inhaled corticosteroids and single-nucleotide CRHR1 polymorphisms in patients with COPD.
Methods:   COPD patients ( n  = 87) with a positive smoking history were recruited from the pulmonary clinics of 11 hospitals in Korea. Patients were treated with fluticasone propionate and salmeterol for 12 weeks and lung function was measured at baseline and after the 12-week treatment. Eighty-four of the 87 subjects were successfully genotyped.
Results:   Seventy-one patients with the wild-type GG genotype and 13 patients with the heterozygous GT genotype in rs242 941 were evaluated. After 12-week treatment, the change in FEV₁ was significantly higher in patients with wild-type GG genotype (6.0 ± 0.8% of predicted FEV₁) than in GT heterozygotes (−0.8 ± 1.8, P  = 0.003).
Conclusions:   Improved FEV₁ following inhaled corticosteroid and a long-acting β2-agonist was associated with CRHR1 genetic polymorphism in patients with COPD.     

Lower risk of hypoglycemia with insulin detemir than with neutral protamine hagedorn insulin in older persons with type 2 diabetes: a pooled analysis of phase III trials

OBJECTIVES: To compare the safety and efficacy of insulin detemir with that of neutral protamine Hagedorn (NPH) insulin in older (aged ≥65) and younger (aged 18–64) persons with type 2 diabetes mellitus (DM).
DESIGN: Pooled, post hoc analysis of data from three open-label, randomized studies.
SETTING: Three multinational Phase III trials.
PARTICIPANTS: Four hundred sixteen older and 880 younger persons with DM, treated for 22 to 26 weeks with basal insulin plus mealtime insulin or oral agents.
MEASUREMENTS: Hemoglobin A_1c (HbA_1c), fasting plasma glucose, glucose variability, hypoglycemic episodes.
RESULTS: Mean treatment difference for HbA_1c (insulin detemir–NPH insulin) indicated that insulin detemir was not inferior to NPH insulin for both age groups (0.035%, 95% confidence interval (CI)=−0.114–0.183 and 0.100%, 95% CI=−0.017–0.217, for older and younger persons, respectively). Relative risk of all hypoglycemic episodes (insulin detemir/NPH insulin) was 0.59 (95% CI-0.42–0.83) for older persons and 0.75 (95% CI-0.59–0.96) for younger persons. Adverse events were similar between treatments. Fasting plasma glucose was similar between treatments (mean treatment difference 0.97 mg/dL, 95% CI=−8.01–9.95, and 4.69 mg/dL, 95% CI=−2.30–11.67, for older and younger persons, respectively). Mean treatment difference for weight was −1.02 kg (95% CI −1.61 to −0.42) and −1.13 (95% CI −1.58 to −0.69) for older and younger persons, respectively.
CONCLUSION: Previously reported benefits of insulin detemir, particularly less hypoglycemia and less weight gain, compared with NPH insulin, were the same for older and younger persons with DM at similar levels of HbA_1c.     

SRD5B1 gene analysis needed for the accurate diagnosis of primary 3-oxo-Δ4-steroid 5β-reductase deficiency

Background and Aim:  We encounter hyper-3-oxo-Δ⁴ bile aciduria in patients with severe cholestatic liver disease or fulminant liver failure during the neonatal period. However, simply by bile acid analysis, it is difficult to distinguish hyper-3-oxo-Δ⁴ bile aciduria from primary 3-oxo-Δ⁴-steroid 5β-reductase deficiency.
Methods:  To determine whether 3-oxo-Δ⁴-steroid 5β-reductase ( SRD5B1 ) gene analysis is required for the accurate diagnosis of 3-oxo-Δ⁴-steroid 5β-reductase deficiency, we evaluated the laboratory data, bile acid analysis and SRD5B1 gene analysis from six patients with hyper-3-oxo-Δ⁴ bile aciduria.
Results:  Based upon the results, four patients who had developed neonatal liver failure were diagnosed as having neonatal hemochromatosis. Two patients with chronic cholestasis were diagnosed as having primary 3-oxo-Δ⁴-steroid 5β-reductase deficiency by SRD5B1 gene analysis. The SRD5B1 gene in these two patients had a heterozygous mutation, G737A (Gly 223 Glu) in one patient and C217T (Arg 50 stop) in the other.
Conclusions:  Based upon our limited data, we conclude that SDR5B1 gene analysis is required for the accurate diagnosis of 3-oxo-Δ⁴-steroid 5β-reductase deficiency. Moreover, we think that it is important to elucidate whether there is a heterozygous or a compound heterozygous mutation of the SRD5B1 gene in our two patients.     

G-substrate gene promoter SNP (−1323T>C) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: Intra-familial association study in an eight-generation hyperlipidemic kindred

Background:   Plasma lipid and lipoprotein generally reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity.
Methods:   In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH, to examine possible genetic modification of lipoprotein phenotype by 'modifier locus'. G-substrate (GSBS) is an endogenous substrate for cGMP-dependent protein kinase. We carried out an intrafamilial correlation analysis of modifier effect of −1323T>C substitution in the GSBS gene among 85 LDLR-mutation carriers and 75 non-carriers.
Results:   In the LDLR - mutation carriers, the plasma cholesterol levels were highest among −1323C homozygotes (mean ± SD = 454 ± 101 mg/dL), lowest among −1323T homozygotes (mean ± SD, 307 ± 72 mg/dL) and intermediate among −1323T/C heterozygotes (mean ± SD, 314 ± 62 mg/dL; P  = 0.015). Similarly, in the LDLR-mutation carriers, the plasma triglyceride levels were highest among −1323C homozygotes (mean ± SD, 371 ± 381 mg/dL), lowest among −323T homozygotes (mean ± SD, 171 ± 94 mg/dL), and intermediate among −1323T/C heterozygotes (mean ± SD, 218 ± 130 mg/dL; P  = 0.003). No such gene-interactive effect was observed among non-carriers of the LDLR-mutation.
Conclusion:   These results indicate a significant modification of the phenotype of FH with defective LDLR allele, by GSBS-1323C allele in the kindred studied.     

Age-related changes in plasma androgen levels and their association with cardiovascular risk factors in male Japanese office workers

Aim:   To assess the age-related change in plasma androgen levels in healthy middle-aged men and whether any clinical parameters are associated with the hormonal change.
Methods:   The study was comprised of male Japanese office-workers aged 40–64 years, who had undergone an annual health check-up in 2002 and 2007 (96 and 76 men, respectively). Body mass index and blood pressure were measured, and serum concentration of lipids, glucose and uric acid in addition to plasma total testosterone, free testosterone and dehydroepiandrosterone sulfate (DHEA-S) levels were determined in the morning after an overnight fast. The 5-year hormonal changes and their associations with clinical parameters were analyzed in 33 men who repeated the examination at both check-ups. The cross-sectional associations of hormonal levels with clinical parameters were also investigated.
Results:   Age was negatively associated with free testosterone ( r  = −0.399, P  < 0.001 in 2002; r  = −0.458, P  < 0.001 in 2007) and DHEA-S ( r  = −0.233, P  = 0.02 in 2002; r  = −0.336, P  < 0.01 in 2007) but not with total testosterone, while the 5-year changes of free testosterone and DHEA-S levels were not significant and showed no associations with major cardiovascular risk factors. Cross-sectionally, after adjustment for age, linear regression analysis showed a positive association between free testosterone and blood hemoglobin and a negative association between total testosterone and serum uric acid.
Conclusion:   In Japanese middle-aged men, 5-year androgen decline is too subtle to detect, and endogenous androgen levels seem to have relatively weak association with cardiovascular risk profiles.     

Neutrophil elastase activity in acute lung injury and respiratory distress syndrome

Background and objective:   Neutrophil elastase (NE) may play a key role in the development of acute lung injury (ALI) or ARDS. NE activity (NEA) was measured in patients with ALI treated with a selective NE inhibitor.
Methods:   NEA and NE-α1-antitrypsin (NE-AT) complex were measured in plasma before, during and after the administration of the selective NE inhibitor, sivelestat, in 32 patients with a diagnosis of ALI or ARDS. NEA index (NEAI) was calculated as NEA/NE-AT. The sequential organ failure assessment (SOFA) score and the ratio PaO₂/fraction of inspired oxygen (FiO₂) were measured.
Results:   NEA and NE-AT was raised in all patients. Sivelestat reduced NEAI and NEA ( P  < 0.01 for both) but not NE-AT and NEA, and NEAI returned to pretreatment levels. NEA correlated closely with NE-AT before, but not after treatment. No relationship was observed between these indices and SOFA score or PaO₂/FiO₂ ratio.
Conclusions:   Sivelestat reduced NEA and NEAI in patients with ALI or ARDS suggesting NE inhibition. A larger study is needed to determine the relationship of NEA, NE-AT and NEAI with the outcome of ALI/ARDS.     

Association of a single-nucleotide polymorphism in the promoter region of leukemia inhibitory factor receptor gene with low bone mineral density in adult women

Background:   Osteoporosis is believed to result from the interaction among multiple environmental and genetic determinants that regulate bone-mineral density (BMD).
Methods:   To investigate a potentially predisposing genetic factor in the onset of osteoporosis, we looked for a possible association between BMD in adult Japanese women and known polymorphisms in the leukemia inhibitory factor receptor gene (LIFR).
Results:   An association analysis of chromosomes from 384 volunteer subjects revealed significant correlation between the −603T > C variant of LIFR and radial BMD ( r  = 0.11, P  = 0.032) in this test population. Comparisons of mean values of adjusted radial BMD among separate genotypic groups implied an allelic dosage effect, because homozygous carriers of T alleles of that SNP had the highest adjusted BMDs (0.403 ± 0.054 g/cm²); women homozygous for the C-allele had the lowest (0.373 ± 0.042 g/cm²), and heterozygous individuals had intermediate scores (0.394 ± 0.056 g/cm²).
Conclusion:   This polymorphism in LIFR may be an important determinant of predisposition to postmenopausal osteoporosis.