Dependence of cytoplasmic calcium transients on the membrane potential in isolated nerve endings of the guinea pig

The relation of changes in internal, free Ca2+, measured with arsenazo III, to the membrane potential, measured with the cyanine dye di-S-C2(5) or 86Rb+ distribution ratio, was studied in isolated guinea pig cortical nerve endings. Depolarization of the plasma membrane with veratridine or gramicidin as well as addition of ionophore A23187 led to an increase in cytosolic Ca2+. Only the response to veratridine was inhibited by tetrodotoxin. The dependence of the depolarization-induced increase in intraterminal, free Ca2+ on the membrane potential between about -50 to 0 mV was sigmoidal. A maximal increase in cytosolic Ca2+ was reached when the membrane potential was depolarized from the resting level, about -64 mV, to about -40 mV. These results show that in isolated nerve endings the activation of voltage-sensitive Ca2+ channels concomitantly leads to an increase in cytosolic, free Ca2+. Comparison of the results of the present study with the previous electrophysiological observations indicate that Ca2+ channels in synaptosomes, presynaptic nerve terminals of the squid giant synapse and cardiac cells have essentially similar voltage dependency.     

Serum high density lipoprotein cholesterol,alcohol, and coronary mortality in male smokers.

OBJECTIVE--To determine whether the increase in mortality from coronary heart disease with high concentration (> 1.75 mmol/l) of high density lipoprotein cholesterol could be due to alcohol intake. DESIGN--Cohort study. SETTING--Placebo group of the alpha tocopherol, beta carotene cancer prevention (ATBC) study of south western population in Finland. PARTICIPANTS--7052 male smokers aged 50-69 years enrolled to the ATBC study in the 1980s. MAIN OUTCOME MEASURES--The relative and absolute rates adjusted for risk factors for clinically or pathologically verified deaths from coronary heart disease for different concentrations of high density lipoprotein cholesterol with and without stratification for alcohol intake. Similar rates were also calculated for different alcohol consumption groups. RESULTS--During the average follow up period of 6.7 years 258 men died from verified coronary heart disease. Coronary death rate steadily decreased with increasing concentration of high density lipoprotein cholesterol until a high concentration. An increase in the rate was observed above 1.75 mmol/l. This increase occurred among those who reported alcohol intake. Mortality was associated with alcohol intake in a J shaped dose response, and those who reported consuming more than five drinks a day (heavy drinkers) had the highest death rate. Mortality was higher in heavy drinkers than in non-drinkers or light or moderate drinkers in all high density lipoprotein categories from 0.91 mmol/l upward. CONCLUSIONS--Mortality from coronary heart disease increases at concentrations of high density lipoprotein cholesterol over 1.75 mmol/l. The mortality was highest among heavy drinkers, but an increase was found among light drinkers also.     

A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo

Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphorylation and O-GlcNAc modification of tau and reductions in O-GlcNAc levels on tau in AD brain offers motivation for the generation of potent and selective inhibitors that can effectively enhance O-GlcNAc in vertebrate brain. We describe the rational design and synthesis of such an inhibitor (thiamet-G, K(i) = 21 nM; 1) of human O-GlcNAcase. Thiamet-G decreased phosphorylation of tau in PC-12 cells at pathologically relevant sites including Thr231 and Ser396. Thiamet-G also efficiently reduced phosphorylation of tau at Thr231, Ser396 and Ser422 in both rat cortex and hippocampus, which reveals the rapid and dynamic relationship between O-GlcNAc and phosphorylation of tau in vivo. We anticipate that thiamet-G will find wide use in probing the functional role of O-GlcNAc in vertebrate brain, and it may also offer a route to blocking pathological hyperphosphorylation of tau in AD.     

Lower conditioning leisure-time physical activity in young adults born preterm at very low birth weight

Background

Adults born preterm at very low birth weight (VLBW, <1500 g) have elevated levels of risk factors for cardiovascular diseases and type 2 diabetes. Preliminary observations suggest that this could partly be explained by lower rates of physical activity. The aim of this study was to assess physical activity in healthy young adults born preterm at very low birth weight compared with term-born controls.

Methodology/Principal Findings

We studied 94 unimpaired young adults, aged 21–29 years, born at VLBW and 101 age-, sex-, and birth hospital-matched term-born controls from one regional center in Southern Finland. The participants completed a validated 30-item 12-month physical activity questionnaire and the NEO-Personality Inventory based on the Big Five taxonomy, the most commonly used classification of personality traits. Yearly frequency, total time, total volume and energy expenditure of conditioning and non-conditioning leisure-time physical activity (LTPA) and commuting physical activity were compared between VLBW and term-born subjects. A subset of participants underwent dual-energy x-ray absorptiometry for body composition measurement. Data were analyzed by multiple linear regression. Compared with controls, VLBW participants had lower frequency [−38.5% (95% CI; −58.9, −7.7)], total time [−47.4% (95% CI; −71.2, −4.1)], total volume [−44.3% (95% CI; −65.8, −9.2)] and energy expenditure [−55.9% (95% CI; −78.6, −9.4)] of conditioning LTPA when adjusted for age, sex, body mass index, smoking, parental education and personality traits. Adjusting for lean body mass instead of body mass index attenuated the difference. There were no differences in non-conditioning LTPA or commuting physical activity.

Conclusions/Significance

Compared with term-born controls, unimpaired VLBW adults undertake less frequent LTPA with lower total time and volume of exercise resulting in lower energy expenditure. Differences in personality that exist between the VLBW and term-born groups do not seem to explain this association.     

Activity changes of inorganic pyrophosphatase of Streptococcus faecalis during batch culture

The state of inorganic pyrophosphatase (EC 3.6.1.1) from Streptococcus faecalis ATCC 8043 was studied in different phases of batch culture. The degree of inactivation (i.e. the ratio of activities observed before and after incubation at 37 degrees C without cysteine) was highest, and the degree of activation (i.e. the ratio of activities after and before incubation in the presence of cysteine) was lowest, in samples taken during the early-exponential growth phase. During the various phases of batch culture, the specific activity before incubation and the degree of inactivation changed in parallel, whereas the specific activity observed after incubation remained nearly constant. During the early-exponential phase of growth almost all the enzyme was in the high-activity form, whereas during the stationary phase the highly active and the less active forms existed in equal amounts. These findings suggest that inorganic pyrophosphatase in S. faecalis is synthesized constitutively and is primarily regulated at the level of activity.     

Early Life Stress and Physical and Psychosocial Functioning in Late Adulthood

Background

Severe stress experienced in early life may have long-term effects on adult physiological and psychological health and well-being. We studied physical and psychosocial functioning in late adulthood in subjects separated temporarily from their parents in childhood during World War II.

Methods

The 1803 participants belong to the Helsinki Birth Cohort Study, born 1934–44. Of them, 267 (14.8%) had been evacuated abroad in childhood during WWII and the remaining subjects served as controls. Physical and psychosocial functioning was assessed with the Short Form 36 scale (SF-36) between 2001 and 2004. A test for trends was based on linear regression. All analyses were adjusted for age at clinical examination, social class in childhood and adulthood, smoking, alcohol intake, physical activity, body mass index, cardiovascular disease and diabetes.

Results

Physical functioning in late adulthood was lower among the separated men compared to non-separated men (b = −0.40, 95% confidence interval [95% CI]: −0.71 to −0.08). Those men separated in school age (>7 years) and who were separated for a duration over 2 years had the highest risk for lower physical functioning (b = −0.89, 95% CI: −1.58 to −0.20) and (b = −0.65, 95% CI: −1.25 to −0.05), respectively). Men separated for a duration over 2 years also had lower psychosocial functioning (b = −0.70, 95% CI: −1.35 to −0.06). These differences in physical and psychosocial functioning were not observed among women.

Conclusion

Early life stress may increase the risk for impaired physical functioning in late adulthood among men. Timing and duration of the separation influenced the physical and psychosocial functioning in late adulthood.     

Maternal Use of Selective Serotonin Reuptake Inhibitors and Lengthening of the Umbilical Cord: Indirect Evidence of Increased Foetal Activity—A Retrospective Cohort Study

BackgroundAntenatal depression affects up to 19% of pregnant women. Some of these women are also in need of antidepressant treatment. Nevertheless, the impact of maternal antidepressant treatment and prenatal depression on the course of pregnancy, foetal development and delivery outcomes is not fully understood.MethodsWe analysed data from 24 818 women who gave birth at Kuopio University Hospital between 2002–2012. Logistic regression analysis was used to estimate associations between the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and the progression of pregnancy, development of the foetus and delivery outcomes.ResultsAltogether, 369 (1.5%) women used SSRIs. A regression model adjusted for age, overweight, nulliparity, prior termination, miscarriages, smoking, maternal alcohol consumption, chronic illness and polyhydramnion showed that pregnant women exposed to SSRI medication had significantly lower Apgar scores at 1 minute (p < 0.0001) and 5 minutes (p < 0.0001) and more admissions to the neonatal intensive care unit (p < 0.0001) than unexposed pregnant women. In addition, exposed newborns had longer umbilical cords (p < 0.0001) than non-exposed newborns.ConclusionIn addition to the previously known associates with maternal SSRI exposure, such as lowered Apgar scores, SSRI exposure appeared to be associated with increased umbilical cord length. The observation related to increased umbilical cord length may be explained by an SSRI-induced increase in the movements of the developing foetus.     

Comparative assessment of inorganic pyrophosphate and pyrophosphatase levels of Escherichia coli, Clostridium pasteurianum, and Clostridium thermoaceticum

Abstract Pyrophosphatase (PP_iase) specific activities were much higher in anaerobic cultures of Escherichia coli (0.54 units) than in Clostridium pasteurianum (0.067 units) and Clostridium thermoaceticum (0.017 units) (1 unit = 1 μ mole PP_i hydrolyzed/min per mg cell dry wt.), and were fairly constant throughout the growth of all three organisms. Conversely, intracellular levels of pyrophosphate (PP_i) were very low and constant in E. coli throughout growth (0.3 mM), while those of C. pasteurianum and C. thermoaceticum were higher (1.44 and 0.8 mM, respectively) and peaked sharply during mid log-phase of growth. PP_iase and intracellular PP_i remained relatively constant in E. coli when grown aerobically or anaerobically, and when growth was in medium containing PP_i as the sole source of supplemental phosphorus.