Associations between psychological distress in adolescence and menstrual symptoms across life: Longitudinal evidence from the 1970 British Cohort Study.

PURPOSE: This study aimed to investigate the association between psychological distress (PD) at age 16 and menstrual symptoms experienced across women's life. METHODS: Up to 2584 females from the 1970 British Cohort Study, a study of individuals born within one week in 1970, were included. PD at age 16 was measured with the 12-item General Health Questionnaire. Three categories were derived: low PD (<11), moderate PD (11-15), and severe PD (>15). Five menstrual health symptoms were self-reported at each age (16, 30 and 42 years). Binomial logistic regressions examined associations between PD at age 16 and each individual symptom, adjusted for age of menarche, sleep and appetite problems, physical activity levels and socioeconomic position. RESULTS: The most prevalent symptoms were "pain" (61 %), "painful period" (10 %) and "heavy period" (33 %) at ages 16, 30 and 42, respectively. At age 16, those with severe PD were more likely to experience depression (OR: 2.92; 95% CI: 2.31, 3.70)), irritability (1.67; 1.33, 2.11), menstrual pain (1.34; 1.01, 1.80), and headaches (1.29; 1.02, 1.63). A weak association was found between severe PD at age 16 and pre-menstrual tension at age 30 (1.72; 1.01, 2.83). At age 42, those with severe PD at age 16 were more likely to experience pre-menstrual tension (1.89; 1.46, 2.44), painful periods (1.64; 1.27, 2.11), and heavy periods (1.28; 1.00, 1.62). DISCUSSION: Menstruating females with higher levels of PD in adolescence have an increased risk of menstrual symptoms across adolescence, early and mid-adulthood. Our findings suggest the need to consider early-life psychological interventions to improve women's menstrual experiences across their reproductive years.

Is cardiorespiratory fitness associated with cognitive outcomes in mid-adulthood? Findings from the 1958 British birth cohort.

Identifying causal factors to intervene on to delay age-related declines in cognitive function is urgently needed. We examined associations between non-exercise testing cardiorespiratory fitness (NETCRF; estimated using sex, age, body mass index, resting heart rate, and physical activity) at 45 years and cognitive function outcomes (immediate and delayed verbal memory; verbal fluency; visual processing speed) at 50 years in 8130 participants from the 1958 British birth cohort. In unadjusted models, higher NETCRF was associated with better cognitive function across all outcomes. When adjusted for confounding factors, associations disappeared. In this cohort, associations between 45 years NETCRF and 50 years cognitive function likely result from confounding factors.

Associations between sporting physical activity and cognition in mid and later-life: Evidence from two cohorts.

Evidence has linked sporting leisure time physical activity (sporting-LTPA) to healthy cognition throughout adulthood. This may be due to the physiological effects of physical activity (PA), or to other, psychosocial facets of sport. We examined associations between sporting-LTPA and cognition while adjusting for device-measured PA volume devoid of context, both in midlife (N = 4041) participants from the 1970 British Cohort Study and later-life (N = 957) participants from the British Regional Heart Study. Independent of device-measured PA, we identified positive associations between sporting-LTPA and cognition. Sports with team/partner elements were strongly positively associated with cognition, suggesting LTPA context may be critical to this relationship.

Associations between the composition of daily time spent in physical activity, sedentary behaviour and sleep and risk of depression: Compositional data analyses of the 1970 British cohort Study.

BACKGROUND: The benefits of moderate to vigorous physical activity(MVPA) in lowering depression risk are well established, but there is mixed evidence on sleep, sedentary behaviour(SB), and light-intensity physical activity(LIPA). These behaviours are often considered in isolation, neglecting their behavioural and biological interdependences. We investigated how time spent in one behaviour relative to others was associated with depression risk. METHODS: We included 4738 individuals from the 1970 British Cohort study (age 46 wave). Depression status was ascertained using self-reported doctor visits and prescribed anti-depressant use. MVPA, LIPA, SB and sleep were ascertained using thigh-worn accelerometers worn consecutively for 7 days. Compositional logistic regression was used to examine associations between different compositions of time spent in movement behaviours and depression. RESULTS: More time spent in MVPA, relative to SB, sleep or LIPA, was associated with a lower risk of depression. When modelling reallocation of time (e.g. replacing time in one behaviour with another), replacing sleep, SB or LIPA with MVPA time was strongly associated with lower depression risk. Reallocating time between SB, sleep or LIPA had minimal to no effect. LIMITATIONS: Data was cross-sectional, therefore causality cannot be inferred. Accelerometers do not capture SB context (e.g. TV watching, reading) nor separate biological sleep from time spent in bed. CONCLUSIONS: Displacing any behaviour with MVPA was associated with a lower risk of depression. This study provides promising support that increasing MVPA, even in small doses, can have a positive impact on prevention, mitigation and treatment of depression.

Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy.

Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report 2 patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2, an accessory subunit of complex I. The first patient was initially diagnosed with a primary systemic carnitine deficiency associated with a homozygous variant in SLC22A5, but also exhibited developmental regression and cystic leukoencephalopathy, and an additional diagnosis of complex I deficiency was suspected. Biochemical analysis confirmed a complex I deficiency, and whole-exome sequencing revealed a homozygous mutation in NDUFA2 (c.134A>C, p.Lys45Thr). Review of a biorepository of patients with unsolved genetic leukoencephalopathies who underwent whole-exome or genome sequencing allowed us to identify a second patient with compound heterozygous mutations in NDUFA2 (c.134A>C, p.Lys45Thr; c.225del, p.Asn76Metfs*4). Only 1 other patient with mutations in NDUFA2 and a different phenotype (Leigh syndrome) has previously been reported. This is the first report of cystic leukoencephalopathy caused by mutations in NDUFA2.

Alignment and scaling of large-scale fluctuations in the solar wind.

We investigate the dependence of solar wind fluctuations measured by the Wind spacecraft on scale and on the degree of alignment between oppositely directed Elsasser fields. This alignment controls the strength of the nonlinear interactions and, therefore, the turbulence. We find that at scales larger than the outer scale of the turbulence the Elsasser fluctuations become on average more antialigned as the outer scale is approached from above. Conditioning structure functions using the alignment angle reveals turbulent scaling of unaligned fluctuations at scales previously believed to lie outside the turbulent cascade in the "1/f range." We argue that the 1/f range contains a mixture of a noninteracting antialigned population of Alfvén waves and magnetic force-free structures plus a subdominant population of unaligned cascading turbulent fluctuations.

Overexpression of NGF ameliorates ethanol neurotoxicity in the developing cerebellum.

Transgenic mice overexpressing NGF in the central nervous system under the control of the glial fibrillary acidic protein (GFAP) promoter were exposed to ethanol via vapor inhalation on postnatal days 4 and 5 (P4-5), the period of maximal cerebellar Purkinje cell sensitivity to ethanol. Wild-type controls were exposed in a similar manner. There were no differences in body weight or size following these procedures, but the transgenic brain weights at this age were significantly greater than wild-type controls. In the wild-type animals, a significant 33.3% ethanol-mediated loss of Purkinje cells in lobule I was detected via unbiased three-dimensional stereological counting on P5. In the GFAP-NGF transgenic animals, however, the 17.6% difference in Purkinje cell number in control and ethanol-exposed animals was not significant. There was a similar difference in Purkinje cell density in both groups, which did reach statistical significance (-32.7% in wild-type ethanol-treated animals, -17% in transgenic ethanol-exposed animals). These results suggest that endogenous overexpression of neurotrophic factors, which have previously been shown to protect against ethanol neurotoxicity in culture, can serve a similar protective function in the intact animal.

Effect of neonatal ethanol exposure on parvalbumin-expressing GABAergic neurons of the rat medial septum and cingulate cortex.

This study was performed to determine the long-term effects of ethanol exposure during the brain growth spurt (postnatal days 4-10) on the number of parvalbumin-immunoreactive (PA+) GABAergic neurons in the adult (P60) rat medial septum and anterior cingulate cortex. Significant loss of neurons within each of these populations has previously been demonstrated following prenatal ethanol exposure. In the present study, no significant differences in the number of PA+ neurons were found in either the medial septum or the cingulate cortex when control and ethanol-exposed animals were compared. The cellular densities and volumetric measures in both brain regions were also similar in the two groups. We speculate that compensatory up-regulative mechanisms may have accounted for the protection of the PA neuronal populations in these two areas following the early neonatal exposure.

Ethanol-induced alterations in the expression of neurotrophic factors in the developing rat central nervous system.

Neonatal rats were exposed to ethanol throughout gestation, or during the early postnatal period (postnatal days 4-10 (P4-10)), and enzyme-linked immunoabsorbent assays were subsequently conducted in order to assess nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) protein content in hippocampus, septum, cortex/striatum and cerebellum. These determinations revealed that following prenatal ethanol treatment, there were significant ethanol-induced increases in NGF in P1 cortex/striatum, but no changes in any of the three neurotrophic factors (NTFs) in the other brain regions. Cortex/striatal NGF protein returned to control levels by P10. Following early postnatal exposure, BDNF was elevated in hippocampus and cortex/striatum (assessed on P10), and NGF was also enhanced in cortex/striatum at this age. Hippocampal and cortex/striatal BDNF returned to control levels by P21, but cortex/striatal NGF levels remained enhanced at this age. This NTF did not differ in ethanol and control animals by P60, however. The possible significance of elevated levels of NTFs as a function of ethanol exposure is discussed, and it is speculated that while such alterations could play a protective role, increases in these substances during critical developmental periods could also prove to be deleterious, and could even contribute to certain of the neuropathologies which have been observed following developmental ethanol exposure.

Amelioration of ethanol-induced neurotoxicity in the neonatal rat central nervous system by antioxidant therapy.

BACKGROUND: The cerebellum of the neonatal rat is highly susceptible to ethanol, with profound loss of Purkinje cells resulting from even brief exposure during the first postnatal week. Developmental ethanol exposure previously has been shown to induce free radicals/oxidative stress processes and/or down-regulate protective antioxidants. In an earlier study, we found antioxidants protected against ethanol neurotoxicity in a tissue culture environment. The present study was designed to determine whether similar protection could be manifested in the intact animal. METHODS: Neonatal rats were administered a liquid diet via intragastric intubation on postnatal days 4 and 5 (P4-P5), the peak period of ethanol sensitivity in the developing cerebellum. The diet consisted of milk formula with 12% ethanol, the isocaloric substitution of maltose-dextrin for ethanol, or ethanol plus the antioxidant vitamin E. Unbiased three-dimensional counting was utilized to analyze Purkinje cell numbers and density within defined volumes from these animals on P5. RESULTS: These determinations revealed a substantial loss of Purkinje cells in the ethanol-treated animals compared to controls (approximately 30-44%), but this loss was prevented by the inclusion of vitamin E (601U/100 ml) in the diet. A lower concentration of the antioxidant (301U/100 ml) was not effective in this regard, however. CONCLUSIONS: These results suggest that ethanol-related cerebellar damage during this early postnatal period may be related to oxidative stress processes or the insufficiency of protective antioxidants. Thus, antioxidant treatment may represent a possible therapy for preventing or ameliorating the central nervous system (CNS) damage seen in the fetal alcohol syndrome.

Ethanol-induced alterations in neurotrophin expression in developing cerebellum: relationship to periods of temporal susceptibility.

BACKGROUND: The developing cerebellum has been shown to be profoundly affected by exposure to ethanol and to exhibit a temporal pattern of vulnerability. Cerebellar Purkinje cells are particularly susceptible to ethanol on postnatal day 4 or day 5 (P4-5), whereas this population is much less vulnerable to similar ethanol insult slightly later in the postnatal period (P7-9). The purpose of the study was to determine whether differential alterations in neurotrophic factors might be associated with this differential susceptibility. METHODS: Neonatal rats were exposed to ethanol via vapor inhalation, and enzyme-linked immunoabsorbent assays were subsequently conducted to assess cerebellar nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 protein content. These analyses were made after ethanol exposure during the period of maximal cerebellar ethanol sensitivity (postnatal days 4-5 [P4-51), during a period of much lower sensitivity (P7-8), and during the entire "brain growth spurt" (P4-10). RESULTS: These determinations revealed a significant ethanol-induced decrease in cerebellar nerve growth factor after exposure on P4-5 but not after exposure on P7-8 or P4-10. No significant changes in brain-derived neurotrophic factor or neurotrophin-3 were found with any of the exposure paradigms. CONCLUSIONS: These results suggest that alterations in nerve growth factor, which has previously been shown to support cerebellar Purkinje and granule cells, may be a mechanism contributing to the early ethanol susceptibility within these neuronar populations.

Insulin-induced insulin receptor substrate-1 degradation is mediated by the proteasome degradation pathway.

Insulin receptor substrate (IRS) proteins are important intracellular molecules that mediate insulin receptor tyrosine kinase signaling. A decreased content of IRS proteins has been found in insulin-resistant states in animals, humans, and cultured cells under various conditions. However, the molecular mechanism that controls cellular levels of IRS proteins is unknown. We report that chronic insulin treatment induces the degradation of IRS-1, but not IRS-2, protein in cultured cells. The insulin-induced degradation of IRS-1 can be prevented by pretreatment with lactacystin, a specific inhibitor for proteasome degradation. These data demonstrate, for the first time, that insulin-induced degradation of IRS-1 is mediated by the proteasome degradation pathway. IRS-2 can escape from the insulin-induced proteasome degradation, suggesting the existence of specific structural requirements for this degradation process.

TNF-alpha and insulin, alone and synergistically, induce plasminogen activator inhibitor-1 expression in adipocytes.

Obesity is associated with hyperinsulinemia and elevated concentrations of tumor necrosis factor-alpha (TNF-alpha) in adipose tissue. TNF-alpha has been implicated as an inducer of the synthesis of plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of fibrinolysis, mediated by plasminogen activators in cultured adipocytes. To identify mechanism(s) through which TNF-alpha induces PAI-1, 3T3-L1 preadipocytes were differentiated into adipocytes and exposed to TNF-alpha for 24 h. TNF-alpha selectively increased the synthesis of PAI-1 without increasing activity of plasminogen activators. Both superoxide (generated by xanthine oxidase plus hypoxanthine) and hydrogen peroxide were potent inducers of PAI-1, and hydroxyl radical scavengers completely abolished the TNF-alpha induction of PAI-1. Exposure of adipocytes to TNF-alpha or insulin alone over 5 days increased PAI-1 production. These agonists exert synergistic effects. Results obtained suggest that TNF-alpha stimulates PAI-1 production by adipocytes, an effect potentiated by insulin, and that adipocyte generation of reactive oxygen centered radicals mediates the induction of PAI-1 production by TNF-alpha. Because induction of PAI-1 by TNF-alpha is potentiated synergistically by insulin, both agonists appear likely to contribute to the impairment of fibrinolytic system capacity typical in obese, hyperinsulinemic patients.

Vitamin E and beta-carotene protect against ethanol combined with ischemia in an embryonic rat hippocampal culture model of fetal alcohol syndrome.

Neurodevelopmental damage can occur as a result of in utero exposure to alcohol. Oxidative stress processes are one of many proposed mechanisms thought to contribute to nervous system dysfunction characterized in fetal alcohol syndrome (FAS). Therefore, this study examined neuroprotective effects of antioxidant supplementation during ethanol (EtOH) treatment (0, 200, 400, 800 or 1600 mg/dl) combined with concomitants of EtOH exposure: acute (2-h) ischemia (aISCH) and chronic (16-h) hypoglycemia (cHG). The antioxidants vitamin E and beta-carotene protected embryonic hippocampal cultures against 0-1600 mg/dl EtOH/aISCH/cHG treatments. In addition, neuronal viability, as measured by MTT ((3,4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; 5 mg/ml)), was equal to untreated cultures when supplemented with vitamin E or beta-carotene at 0-800 mg/dl or 0-200 mg/dl EtOH/aISCH/cHG, respectively. These in vitro studies mirror potential in utero ethanol-exposed CNS conditions and may lead to therapeutic strategies targeted at attenuating neurodevelopmental FAS-related deficits.

The antioxidants vitamin E and beta-carotene protect against ethanol-induced neurotoxicity in embryonic rat hippocampal cultures.

Fetal alcohol syndrome is characterized by numerous nervous system anomalies with the developing hippocampus being highly vulnerable. Other conditions can result from maternal ethanol consumption including oxidative stress. Critical antioxidants, such as vitamin E, can be decreased and antioxidative defenses altered. Gestational day 18 rat hippocampal cultures were exposed to ethanol ranging from 400 to 2400 mg/dl (16 h). MTT assays assessed neurotoxicity. Viability was decreased dose dependently. Supplementation with vitamin E or beta-carotene afforded neuroprotection against all ethanol concentrations. Vitamin E completely ameliorated neuronal loss following 400 and 800 mg/dl ethanol. Vitamin E increased survival to 95%, 79%, 66%, and 75% during 1600, 1800, and 2000 and 2400 mg/dl ethanol compared to nonethanol treatment. Vitamin E increased viability by 38%, 23%, 12%, and 29% at 1600, 1800, 2000, and 2400 mg/dl compared to non-vitamin E-supplemented, ethanol treatment. beta-Carotene completely ameliorated cell loss from 400 mg/dl ethanol and increased survival by 18% at 1600 mg/dl and 12% at 2000 mg/dl. This study demonstrates in vitro antioxidative neuroprotection against developmental ethanol exposure and suggests that nutritional therapies incorporating antioxidants may help protect against deleterious fetal effects from maternal alcohol abuse.

BDNF and NGF afford in vitro neuroprotection against ethanol combined with acute ischemia and chronic hypoglycemia.

Consumption of alcohol during pregnancy can result in central nervous system deficits in infants ranging from fetal alcohol effects to fetal alcohol syndrome. Changes in cerebral metabolism causing ischemic in utero conditions can also result from ethanol (EtOH). Growth factors have been shown to ameliorate ischemic damage and EtOH-induced neurotoxicity. However, using an in vitro model system of fetal alcohol effects/fetal alcohol syndrome, this study examines the neuroprotective effects of nerve growth factor, brain-derived neurotrophic factor, or glial cell line derived neurotrophic factor against EtOH treatment (0, 200, 400, 800, or 1, 600 mg/dl) combined with acute ischemia (2-hour hypoxia in EtOH-containing glucose-free media) followed by chronic hypoglycemia (16-hour glucose deprivation in EtOH-containing media). 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays assessed relative neurotoxicity. Glial cell derived neurotrophic factor was not neuroprotective. Nerve growth factor protected against ischemia/hypoglycemia combined with 0-1,600 mg/dl EtOH. Brain-derived neurotrophic factor protected against ischemia/hypoglycemia combined with 0-800 mg/dl EtOH. These studies demonstrate marked growth factor neuroprotection against a myriad of conditions encountered by developing EtOH-exposed fetuses.

Myofibroblasts in diffuse alveolar damage of the lung.

The myofibroblast is an ultrastructurally and metabolically distinctive connective tissue cell identified as a key participant in tissue remodeling in human granulation tissue, organ fibrosis, and the fibroblastic host response to malignant neoplasms. In this study of myofibroblasts in human lung diffuse alveolar damage (DAD), we identified 36 autopsy cases in which DAD could be histologically documented. DAD is known to progress from initial injury through an exudative, proliferative, and terminal fibrotic phase. In the exudative phase (16 cases), myofibroblasts expressing alpha-smooth muscle actin (alpha-SMA) are found in the septa and less frequently in hyaline membranes. In the proliferative phase (18 cases), many myofibroblasts in septa, hyaline membranes, and intra-alveolar fibroplasia express alpha-SMA. The alpha-SMA phenotype should be used in additional studies of myofibroblast differentiation, replication, and apoptosis. A better understanding of the biology of this cell type should offer new therapy for patients with DAD.

Age-related changes in [3H]MK-801 binding in the Fischer 344 rat brain.

In this study we tested the hypothesis that the efficacy of L-glutamate to stimulate [3H]MK-801 binding to the NMDA receptor/channel complex is altered as a function of aging. L-Glutamate, or related excitatory amino acid (EAA), is the endogenous neurotransmitter of the NMDA receptor/channel complex. These studies examined the efficacy and potency with which L-glutamate produces receptor activation, channel opening and subsequent MK-801 binding as a function of increasing age by comparing dose-response curves (EC50 and Emax) from 6-, 12-, and 24-month-old F-344 rats. The number of NMDA receptors, as determined by [3H]MK-801 binding in the presence of a saturating concentration of L-glutamate, was reduced in the inner frontal cortex, entorhinal cortex and the lateral striatum in aged rats when compared with young adults. When a range of L-glutamate concentrations were used, differences in Emax were noted in the same brain regions in addition to several others in aged and middle-aged animals when compared with young-adult animals. No changes in EC50 values were noted in any of the brain regions at either age when compared with young-adults.

A comparative study of ethanol, hypoglycemia, hypoxia and neurotrophic factor interactions with fetal rat hippocampal neurons: a multi-factor in vitro model developmental ethanol effects.

Fetal alcohol syndrome (FAS) is characterized by numerous central nervous system anomalies, with the hippocampus being particularly vulnerable to developmental ethanol exposure. In addition to direct ethanol neurotoxicity, other conditions resulting from maternal ethanol consumption, such as hypoglycemia and hypoxia, may also contribute to FAS. The present study used a tissue culture system to model multiple conditions which may relate to in vivo FAS, and assessed their relative neurotoxicity with MTT assays. Gestational day 18 rat hippocampal cultures were exposed to varying ethanol concentrations, glucose withdrawal-induced hypoglycemic (gwHG, 16 h) or acute hypoxic (aHP, 2 h) conditions alone, as well as to co-treatments with ethanol and gwHG or aHP. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have previously been shown to ameliorate ethanol-, hypoglycemia- and hypoxia-induced neurotoxicity. Therefore, their neuroprotective potential, along with ciliary neurotrophic factor (CNTF), was examined. Neuronal viability was reduced dose-dependently by ethanol, alone or with hypoglycemia or hypoxia. Ethanol + gwHG or aHP was not uniformly additive. NGF treatment provided the most extensive neuroprotection, being effective against ethanol (200 and 400 mg/dl), gwHG, and aHP, alone and combined. BDNF afforded similar protection, but not against ethanol + gwHG. CNTF protected only against aHP. CNTF + BDNF, previously shown to act synergistically, protected against ethanol + aHP up to 800 mg/dl ethanol, but not, paradoxically, against ethanol alone, gwHG, or ethanol + gwHG, all conditions BDNF alone protected against. This study demonstrated that several neurotrophic factors are capable of mitigating neurotoxicity associated with ethanol, hypoglycemia and hypoxia.