Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed afterdepolarizations due to increased propensity to Ca2+ waves.

AIMS: Mutations in cardiac ryanodine receptors (RyR2s) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), characterized by risk of polymorphic ventricular tachyarrhythmias and sudden death during exercise. Arrhythmias are caused by gain-of-function defects in RyR2, but cellular arrhythmogenesis remains elusive. METHODS AND RESULTS: We recorded endocardial monophasic action potentials (MAPs) at right ventricular septum in 15 CPVT patients with a RyR2 mutation (P2,328S, Q4,201R, and V4,653F) and in 12 control subjects both at baseline and during epinephrine infusion (0.05 microg/kg/min). At baseline 3 and during epinephrine infusion, four CPVT patients, but none of the control subjects, showed delayed afterdepolarizations (DADs) occasionally coinciding with ventricular premature complexes. In order to study the underlying mechanisms, we expressed two types of mutant RyR2 (P2,328S and V4,653F) causing CPVT as well as wild-type RyR2 in HEK 293 cells. Confocal microscopy of Fluo-3 loaded cells transfected with any of the three RyR2s showed no spontaneous subcellular Ca(2+) release events at baseline. Membrane permeable cAMP analogue (Dioctanoyl-cAMP) triggered subcellular Ca(2+) release events as Ca(2+) sparks and waves. Cells expressing mutant RyR2s showed spontaneous Ca(2+) release events at lower concentrations of cAMP than cells transfected with wild-type RyR2. CONCLUSION: CPVT patients show DADs coinciding with premature action potentials in MAP recordings. Expression studies suggest that DADs are caused by increased propensity of abnormal RyR2s to generate spontaneous Ca(2+) waves in response to cAMP stimulation. Increased sensitivity of mutant RyR2s to cAMP may explain the occurrence of arrhythmias during exercise or emotional stress in CPVT.     

The corpus luteum of the guinea pig. Fine structure at the time of maximum progesterone secretion and during regression

This report describes the fine structure of guinea pig luteal cells during the period of maximum progesterone secretion and throughout involution, in ovaries that have been fixed by perfusion, a technique that provides optimal preservation of steroid-secreting tissues. Smooth endoplasmic reticulum (smooth ER), a prominent organelle in these cells, is particularly well preserved by this method of fixation. During the time of maximal progesterone secretion, luteal cells contain abundant tubules and cisternae of smooth ER, many mitochondria, a well-developed Golgi complex and some lipid droplets. This fine structural picture is consistent with active steroidogenesis. Autophagy plays an important role in the regression of luteal cells in the corpus luteum. The onset of luteolysis is marked by the appearance of structurally complex autophagic vacuoles, one of which has not been described previously in luteal cells. This autophagic vacuole seems to originate from GERL (Golgi-endoplasmic reticulum-lysosomes) as a cup-shaped structure, which subsequently increases in size and complexity. Regressing luteal cells also contain increased numbers of both dense bodies (lysosomes) and lipid droplets, and exhibit changes in nuclear and mitochondrial morphology. In contrast to previous reports in the literature, changes in the morphology of smooth ER were not observed as a characteristic feature of involution in corpora lutea of guinea pigs in the present study. Advanced regression of luteal cells is characterized by multiple fusion of lipid droplets and a decrease in the amount of smooth ER. Another mechanism active in the breakdown of the corpus luteum is the phagocytosis of luteal cells by macrophages. Although present at all stages, macrophages are most abundant in older corpora lutea, where they often surround dead or dying luteal cells.     

Smoking, alcohol use, and physical activity: a 13-year longitudinal study ranging from adolescence into adulthood.

PURPOSE: To assess the associations among smoking, alcohol use, and physical activity, and to assess how the health behaviors predict changes in other health behaviors from adolescence to adulthood. METHODS: Subjects were the participants of the North Karelia Youth Project study from six schools in Eastern Finland. At the baseline in 1978 they were 13-year-olds (n = 903) and in the last of the six surveys in 1993 they were 28-year-olds. This study uses the data from three surveys in which the participants were 15-, 21-, and 28-year olds. The response rate was 71% in the last survey. Data were analysed by SPSS software. RESULTS: Smoking prevalence was highest at the age of 21 years and alcohol use at the age of 28 years. The prevalence of leisure-time physical activity did not change much over time. Smoking and alcohol use correlated positively for each survey. Smoking correlated negatively with leisure-time physical activity. The best predictors for each health behavior were the same behaviors measured before, but smoking had the strongest level of continuity. In addition, alcohol use at the age of 15 years predicted smoking at the ages of 21 years and 28 years, but smoking in adolescence did not predict alcohol use in adulthood. CONCLUSIONS: Smoking was associated with both alcohol use and physical activity and therefore has a central role among health behaviors. Smoking and alcohol use were particularly clearly related from adolescence to adulthood. Smoking behavior was the most constant behavior.     

Potential case of gynecomastia in mummified remains of an early modern period northern finnish vicar

We report possibly the oldest evidence of gynecomastia in mummified human remains. Computed tomography was performed on the mummified remains of an early 17th century Northern Finnish vicar. The examination of the scans revealed large bilateral subareolar irregular masses resembling female mammary glands. The nearly septuagenarian vicar appears to have had gynecomastia, as it is a common condition in elderly men, and is sometimes associated with obesity. Gynecomastia is the most likely explanation for these findings. Clin. Anat. 31:641–644, 2018. © 2018 Wiley Periodicals, Inc.     

A 13-year follow-up of Finnish patients with Salla disease

Background

Salla disease (SD) is a rare lysosomal storage disorder leading to severe intellectual disability. SD belongs to the Finnish disease heritage, and it is caused by mutations in the SLC17A5 gene. The aim of the study was to investigate the course of neurocognitive features of SD patients in a long-term follow-up.

Methods

Neuropsychological and neurological investigations were carried out on 24 SD patients, aged 16–65 years, 13 years after a similar examination.

Results

The survival analysis showed excess mortality among patients with SD after the age of 30 years. The course of the disease was progressive, but follow-up of SD patients revealed that motor skills improved till the age of 20 years, while mental abilities improved in most patients till 40 years of age. Verbal comprehension skills did not diminish during the follow-up, but productive speech deteriorated because of dyspraxia and dysarthria. Motor deficits were marked. Ataxia was prominent in childhood, but it was replaced by athetotic movements during the teens. Spasticity became more obvious with age especially in severely disabled SD patients.

Conclusions

Younger SD patients performed better in almost every task measuring mental abilities that then seem to remain fairly constant till early sixties. Thus, the results indicate better prognosis in cognitive skills than earlier assumed. There is an apparent decline in motor skills after the age of 20 years. The early neurocognitive development predicts the later course of motor and cognitive development.     

Plasminogen activator inhitor-1 associates with cardiovascular risk factors in healthy young adults in the Cardiovascular Risk in Young Finns Study

AimsHypofibrinolysis displayed by elevated serum plasminogen activator inhibitor 1 (PAI-1) level has been associated with cardiovascular disease (CVD) and its risk factors such as obesity and insulin resistance. However, no studies have examined associations between PAI-1 and CVD risk factors in healthy subjects. We examined associations between serum PAI-1, ultrasound markers of atherosclerosis and CVD risk factors and whether PAI-1 improves prediction of atherosclerosis over known risk factors in a cohort of asymptomatic adults.MethodsWe analyzed PAI-1 and CVD risk factors and assessed carotid intima-media thickness (cIMT), distensibility (CDist) and the presence of a carotid atherosclerotic plaque and flow-mediated dilation (FMD) ultrasonographically for 2202 adults (993 men and 1,209 women, aged 30–45 years) participating in the ongoing longitudinal cohort study, The Cardiovascular Risk in Young Finns Study. High cIMT was defined as >90th percentile and/or carotid plaque and low CDist and low FMD as <20th percentile.ResultsIn bivariate analyses, PAI-1 correlated directly with cIMT and the risk factors: blood pressure, BMI, waist and hip circumference, alcohol use, total and LDL-cholesterol, triglycerides, glomerular filtration rate, high-sensitivity CRP and glucose (all P < 0.005). PAI-1 was higher in men and increased with age. Inverse correlation was observed with CDist, HDL-cholesterol and adiponectin in both sexes, with testosterone and sex hormone binding globulin in men and with creatinine and oral contraceptive use in women (P < 0.005). Independent direct associations were observed between PAI-1 and waist circumference, serum triglycerides, insulin, alcohol use and age and inverse with serum creatinine, HDL-cholesterol and adiponectin. PAI-1 did not improve estimation of high cIMT, low CDist and low FMD over conventional risk factors (P for difference in area under curve ≥ 0.37).ConclusionPAI-1 was independently associated with several known CVD risk factors, especially obesity markers, in both men and women. However, addition of PAI-1 to known risk factors did not improve cross-sectional prediction of high cIMT, low CDist and low FMD suggesting that PAI-1 is not a clinically important biomarker in early atherosclerosis.     

Hip prosthesis introduction and early revision risk: A nationwide population-based study covering 39,125 operations

A report is made of experience with the conservative treatment of old scaphoid fractures and pseudarthroses. The bandaging technique practised for this is of decisive importance and consists of a non-upholstered plaster cast enclosing all the fingers, so that complete immobilisation of the fragments is achieved. On average Ibis is maintained for 3–4½ months. Even with unfavourable initial conditions such as a small ulnar fragment healing is obtained. Cases with severe, deforming articular metamorphoses, considerable unevenness of the fracture surfaces and dislocation of the fragments are not suited to conservative therapy.