Change in the membranous lipid composition accelerates lipid peroxidation in young rat hearts subjected to 2 weeks of hypoxia followed by hyperoxia.

BACKGROUND: The effects of chronic hypoxia on cardiac membrane fatty acids and on lipid peroxidation were examined, as well as the effect of l-carnitine (LCAR), which suppresses lipid peroxidation, on this process. METHODS AND RESULTS: Four-week-old Sprague-Dawley rats were exposed to 10% oxygen for 14 days ("Hypoxia"), and then to 100% oxygen for 12 h (O2). LCAR (200 mg/kg) was administered by intraperitoneal injection daily for 2 weeks. Fatty acid composition, malondialdehyde (MDA) as a lipid peroxidation product, and antioxidants (superoxide dismutase (SOD), glutathione peroxidase and catalase) were measured. The concentration of linoleic acid was lower, and that of docosahexaenoic acid, which has more double bonds than linoleic acid, was increased in hypoxic hearts. SOD activity decreased in hypoxia, whereas MDA was unchanged, but significantly increased in "Hypoxia"+O2. LCAR reduced the increase in MDA, and had no effect on SOD activity or fatty acid composition. The administration of LCAR caused an increase in the ventricular levels of acetylcarnitine. CONCLUSIONS: These results suggest that chronic hypoxia changes the cardiac fatty acid composition of juvenile rats to fatty acids that contain more double-bonds and reduce SOD activity, and that lipid peroxidation was augmented by exposure to oxygen.     

Two de novo mutations in the AR gene cause the complete androgen insensitivity syndrome in a pair of monozygotic twins

The androgen insensitivity syndrome (AIS) is the most common cause of male undermasculinization and is typically caused by mutations in the AR gene. Affected individuals may exhibit either complete external feminization (complete AIS) or a partial phenotype (partial AIS). Here we describe monozygotic twins diagnosed with complete AIS who each possess two substitutions (C-->G at position 2930 and T-->C at position 2955, both in exon 7), leading to Phe(856)Leu and Ser(865)Pro mutations, respectively. Neither parent was found to be a carrier for these mutations, indicating that the double mutation arose de novo. Both mutations were recreated by site-directed mutagenesis and compared functionally with the wild-type receptor. The Phe(856)Leu mutation did not affect androgen binding when expressed in COS-1 cells, nor did this mutation decrease androgen-dependent trans-activation in transfected HeLa cells. However, the Ser(865)Pro mutation completely ablated androgen binding and trans-activation. In this study we demonstrate that the replacement of serine by proline at position 865 is sufficient in itself to cause complete AIS in these twins. Analyses of nuclear receptor structures suggest that this mutation is likely to perturb the conformation of helix 10/11, which plays a role in ligand binding, dimerization, and receptor activation. To our knowledge this is the first confirmed instance of AIS (complete or partial) due to an AR mutation occurring in twins. Furthermore, the phenotype was associated with two mutations that were both novel in nature.     

Plasma Exchange Therapy to Reduce Mortality in Japanese Patients With Diffuse Alveolar Hemorrhage and Microscopic Polyangiitis

Diffuse alveolar hemorrhage (DAH) is well known as a serious complication of microscopic polyangiitis (MPA). We examined the effectiveness of plasma exchange (PLEX) therapy to reduce mortality in Japanese DAH patients with MPA. This retrospective, double‐center, observational cohort study included 20 DAH patients with MPA who were admitted to Juntendo University Hospital or Juntendo Koto Geriatric Medical Center between April 1998 and March 2018. The primary outcome was non–disease‐specific mortality. The 1‐year survival rate of patients with PLEX therapy (N = 4) was higher than that of patients with conventional therapy (N = 16, 75% and 13%, respectively, P = 0.037). Higher values of the 1996 Five‐Factor Score (FFS) and 2009 FFS were associated with increased mortality, with hazard ratios of 2.29 (P = 0.040) and 2.41 (P = 0.043), respectively, by Cox univariate analysis. We investigated PLEX therapy for reducing mortality in DAH patients with MPA, and the 1996 FFS and 2009 FFS were both independent prognostic factors.     

Association of sleep‐disordered breathing with decreased cognitive function among patients with dementia

Sleep is known to be essential for proper cognitive functioning. Sleep disturbance, especially respiratory disturbance during sleep, is a risk factor for the development of dementia. However, it is not known whether hypopnoea during sleep is related to severity of cognitive function in patients already diagnosed with dementia. Considering the high prevalence of sleep problems in aged people, it is important to determine if hypopnoea during sleep contributes to dementia. In addition, it would be desirable to develop a feasible method for objectively evaluating sleep in patients with dementia. For this purpose, a simple sleep recorder that employs single or dual bioparameter recording, which is defined as a type‐4 portable monitor, is suitable. In this study, a type‐4 sleep recorder was used to evaluate respiratory function during sleep in 111 patients with dementia, and data suggesting a possible relationship with cognitive function levels were examined. Multivariate logistic regression was used to investigate the association of severity of dementia with sleep‐disordered breathing, age, diabetes, dyslipidaemia and hypertension. It was found that the respiratory disturbance index was associated with severity of cognitive dysfunction in our subjects. Furthermore, patients younger than 80 years were more susceptible to lower cognitive function associated with sleep‐disordered breathing than patients 80 years old or over, because an increase in the respiratory disturbance index was associated with deteriorated cognitive function only in the former age group. These results suggest that proper treatment of sleep apnea is important for the preservation of cognitive function, especially in patients with early‐stage dementia.