Progressive Degeneration and Adaptive Excitability in Dopamine D1 and D2 Receptor-Expressing Striatal Neurons Exposed to HIV-1 Tat and Morphine.

The striatum is especially vulnerable to HIV-1 infection, with medium spiny neurons (MSNs) exhibiting marked synaptodendritic damage that can be exacerbated by opioid use disorder. Despite known structural defects in MSNs co-exposed to HIV-1 Tat and opioids, the pathophysiological sequelae of sustained HIV-1 exposure and acute comorbid effects of opioids on dopamine D1 and D2 receptor-expressing (D1 and D2) MSNs are unknown. To address this question, Drd1-tdTomato- or Drd2-eGFP-expressing reporter and conditional HIV-1 Tat transgenic mice were interbred. MSNs in ex vivo slices from male mice were assessed by whole-cell patch-clamp electrophysiology and filled with biocytin to explore the functional and structural effects of progressive Tat and acute morphine exposure. Although the excitability of both D1 and D2 MSNs increased following 48 h of Tat exposure, D1 MSN firing rates decreased below control (Tat-) levels following 2 weeks and 1 month of Tat exposure but returned to control levels after 2 months. D2 neurons continued to display Tat-dependent increases in excitability at 2 weeks, but also returned to control levels following 1 and 2 months of Tat induction. Acute morphine exposure increased D1 MSN excitability irrespective of the duration of Tat exposure, while D2 MSNs were variably affected. That D1 and D2 MSN excitability would return to control levels was unexpected since both subpopulations displayed significant synaptodendritic degeneration and pathologic phospho-tau-Thr205 accumulation following 2 months of Tat induction. Thus, despite frank morphologic damage, D1 and D2 MSNs uniquely adapt to sustained Tat and acute morphine insults.

Platelet reactivity influences clot structure as assessed by fractal analysis of viscoelastic properties.

Despite the interwoven nature of platelet activation and the coagulation system in thrombosis, few studies relate both analysis of protein and cellular parts of coagulation in the same population. In the present study, we use matched ex vivo samples to determine the influences of standard antiplatelet therapies on platelet function and use advanced rheological analyses to assess clot formation. Healthy volunteers were recruited following fully informed consent then treated for 7 days with single antiplatelet therapy of aspirin (75 mg) or prasugrel (10 mg) or with dual antiplatelet therapy (DAPT) using aspirin (75 mg) plus prasugrel (10 mg) or aspirin (75 mg) plus ticagrelor (90 mg). Blood samples were taken at day 0 before treatment and at day 7 following treatment. We found that aspirin plus prasugrel or aspirin plus ticagrelor inhibited platelet responses to multiple agonists and reduced P-selectin expression. Significant platelet inhibition was coupled with a reduction in fractal dimension corresponding to reductions in mean relative mass both for aspirin plus prasugrel (-35 ± 16% change, p = 0.04) and for aspirin plus ticagrelor (-45 ± 14% change, p = 0.04). Aspirin alone had no effect upon measures of clot structure, whereas prasugrel reduced fractal dimension and mean relative mass. These data demonstrate that platelets are important determinants of clot structure as assessed by fractal dimension (df) and that effective platelet inhibition is associated with a weaker, more permeable fibrin network. This indicates a strong association between the therapeutic benefits of antiplatelet therapies and their abilities to reduce thrombus density that may be useful in individual patients to determine the functional relationship between platelet reactivity, eventual clot quality, and clinical outcome. df could represent a novel risk stratification biomarker useful in individualizing antiplatelet therapies.

Endocannabinoids in brain plasticity: Cortical maturation, HPA axis function and behavior.

Marijuana use during adolescence has reached virtually every strata of society. The general population has the perception that marijuana use is safe for mature people and therefore is also safe for developing adolescents. However, both clinical and preclinical research shows that marijuana use, particularly prior to age 16, could have long-term effects on cognition, anxiety and stress-related behaviors, mood disorders and substance abuse. These effects derive from the role of the endocannabinoid system, the endogenous cannabinoid system, in the development of cortex, amygdala, hippocampus and hypothalamus during adolescence. Endocannabinoids are necessary for normal neuronal excitation and inhibition through actions at glutamate and GABA terminals. Synaptic pruning at excitatory synapses and sparing of inhibitory synapses likely results in changes in the balance of excitation/inhibition in individual neurons and within networks; processes which are necessary for normal cortical development. The interaction between prefrontal cortex (PFC), amygdala and hippocampus is responsible for emotional memory, anxiety-related behaviors and drug abuse and all utilize the endogenous cannabinoid system to maintain homeostasis. Also, endocannabinoids are required for fast and slow feedback in the normal stress response, processes which mature during adolescence. Therefore, exogenous cannabinoids, such as marijuana, have the potential to alter the course of development of each of these major systems (limbic, hypothalamic-pituitary-adrenal (HPA) axis and neocortex) if used during the critical period of brain development, adolescence. This article is part of a Special Issue entitled SI: Adolescent plasticity.

Assessment of platelet function in patients with stroke using multiple electrode platelet aggregometry: a prospective observational study.

BACKGROUND: There is a link between high on-treatment platelet reactivity (HPR) and adverse vascular events in stroke. This study aimed to compare multiple electrode platelet aggregometry (MEA), in healthy subjects and ischaemic stroke patients, and between patients naive to antiplatelet drugs (AP) and those on regular low dose AP. We also aimed to determine prevalence of HPR at baseline and at 3-5 days after loading doses of aspirin. METHODS: Patients with first ever ischaemic stroke were age and sex-matched to a healthy control group. Three venous blood samples were collected: on admission before any treatment given (baseline); at 24 h and 3-5 days after standard treatment. MEA was determined using a Mutliplate® analyser and agonists tested were arachidonic acid (ASPI), adenosine diphosphate (ADP) and collagen (COL). RESULTS: Seventy patients (mean age 73 years [SD 13]; 42 men, 28 women) were age and sex-matched to 72 healthy subjects. Thirty-three patients were on antiplatelet drugs (AP) prior to stroke onset and 37 were AP-naive. MEA results for all agonists were significantly increased in AP-naive patients compared to healthy subjects: ADP 98 ± 31 vs 81 ± 24, p < 0.005; ASPI 117 ± 31 vs 98 ± 27, p < 0.005; COL 100 ± 25 vs 82 ± 20, p < 0.005. For patients on long term AP, 33% (10/30) of patients were considered aspirin-resistant. At 3-5 days following loading doses of aspirin, only 11.1% were aspirin resistant based on an ASPI cut-off value of 40 AU*min. CONCLUSIONS: Many patients receiving low dose aspirin met the criteria of aspirin resistance but this was much lower at 3-5 days following loading doses of aspirin. Future studies are needed to establish the causes of HPR and potential benefits of individualizing AP treatment based on platelet function testing.

The effect of sepsis and its inflammatory response on mechanical clot characteristics: a prospective observational study.

PURPOSE: Sepsis and its progression are known to have a major influence on the coagulation system. Current coagulation tests are of limited use when assessing coagulation in sepsis patients. This study aims to assess the potential for a new functional biomarker of clot microstructure, fractal dimension, to identify changes in the mechanical properties of clot microstructure across the sepsis spectrum (sepsis, severe sepsis and septic shock). METHODS: A total of 100 patients that presented acutely to a large teaching hospital were included in this prospective observational study (50 sepsis, 20 severe sepsis and 30 septic shock) against a matched control of 44 healthy volunteers. Fractal analysis was performed, as well as standard markers of coagulation, and six plasma markers of inflammation. RESULTS: Fractal dimension was significantly higher in the sepsis and severe sepsis groups than the healthy control (1.78 ± 0.07 and 1.80 ± 0.05, respectively vs 1.74 ± 0.03) (p < 0.001), indicating a significant increase in mechanical clot strength and elasticity consistent with a hypercoagulable state. Conversely, fractal dimension was significantly lower in septic shock (1.66 ± 0.10, p < 0.001), indicating a significant reduction in mechanical clot strength and functionality consistent with a hypocoagulable state. This corresponded with a significant increase in the inflammatory response. CONCLUSIONS: This study confirms that clot microstructure is significantly altered through the various stages of sepsis. Of particular importance was the marked change in clot development between severe sepsis and septic shock, which has not been previously reported.

Altered clot microstructure detected in obstructive sleep apnoea hypopnoea syndrome.

Abnormal clot microstructure plays a pivotal role in the pathophysiology of thromboembolic diseases. Assessing the viscoelastic properties of clot microstructure using novel parameters, Time to Gel Point (T GP ), Fractal Dimension (d f ) and clot elasticity (G׳ GP ) could explain the increased cardiovascular and thromboembolic events in patients with Obstructive Sleep Apnoea Hypopnea Syndrome (OSAHS). We wanted to compare T GP , d f , and G׳ GP and their diurnal variation in OSAHS and symptomatic comparators. thirty six patients attending a sleep disturbed breathing clinic with symptoms of OSAHS were recruited. T GP , d f and G׳ GP were measured alongside standard coagulation screening, thrombin generation assays, and platelet aggregometry at 16:00 h and immediately after an in-patient sleep study at 07:30 h. OSAHS group had significantly lower afternoon d f than comparators (1.705±0.033 vs. 1.731±0.031, p<0.05). d f showed diurnal variation and only in the OSAHS group, being significantly lower in the afternoon than morning (p<0.05). Diurnal changes in d f correlated with 4% DR, even after controlling for BMI (r=0.37, p=0.02). The lower d f in the afternoon in OSAHS suggests a partial compensatory change that may make up for other pro-clotting abnormalities/hypertension during the night. The change to the thrombotic tendency in the afternoon is biggest in severe OSAHS. d f Shows promise as a new microstructural indicator for abnormal haemostasis in OSAHS.

Sex and age specific effects of delta-9-tetrahydrocannabinol during the periadolescent period in the rat: The unique susceptibility of the prepubescent animal.

Adolescents who use marijuana are more likely to exhibit anxiety, depression, and other mood disorders, including psychotic-like symptoms. Additionally, the age at onset of use and the stress history of the individual can affect responses to cannabis. To examine the effect of early life experience on adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we exposed adolescent (postnatal day (P) 29-38) male and female rats, either shipped from a supplier or born in our vivarium, to once daily injections of 3mg/kg THC. Our findings suggest that males are more sensitive to the anxiolytic and antidepressant effects of THC, as measured by the elevated plus maze (EPM) and forced swim test (FST), respectively, than females. Exposure to the FST increased plasma corticosterone levels, regardless of drug treatment or origin and females had higher levels than males overall. Shipping increased THC responses in females (acoustic startle habituation) and in males (latency to immobility in FST). No significant effects of THC or shipping on pre-pulse inhibition were observed. Due to differences in timing of puberty in males and females during the P29-38 period of THC treatment, we also dosed female rats between P21-30 (pre-puberty) and male rats between P39-48 (puberty). Pre-pubertal animals showed reductions in anxiety on the EPM, an effect that was not seen in animals treated during puberty. These results suggest that both sexes are more susceptible to changes in emotional behavior when THC exposure occurs just prior to the onset of puberty. Within the animals dosed from P29-38, THC increased cannabinoid receptor 1 (CB1R) mRNA expression and tended to decrease CP55,940 stimulated [35S]GTPγS binding in the central amygdala only of females. Therefore, early stress enhances THC responses in males (in FST) and females (ASR habituation), THC alters CB1R expression and function in females only and prepubescent rats are generally more responsive to THC than pubertal rats. In summary, THC and stress interact with the developing endocannabinoid system in a sex specific manner during the peri-pubertal period.

Fractal dimension (df) as a new structural biomarker of clot microstructure in different stages of lung cancer.

Venous thromboembolism (VTE) is common in cancer patients, and is the second commonest cause of death associated with the disease. Patients with chronic inflammation, such as cancer, have been shown to have pathological clot structures with modulated mechanical properties. Fractal dimension (df) is a new technique which has been shown to act as a marker of the microstructure and mechanical properties of blood clots, and can be performed more readily than current methods such as scanning electron microscopy (SEM). We measured df in 87 consecutive patients with newly diagnosed lung cancer prior to treatment and 47 matched-controls. Mean group values were compared for all patients with lung cancer vs controls and for limited disease vs extensive disease. Results were compared with conventional markers of coagulation, fibrinolysis and SEM images. Significantly higher values of df were observed in lung cancer patients compared with controls and patients with extensive disease had higher values than those with limited disease (p< 0.05), whilst conventional markers failed to distinguish between these groups. The relationship between df of the incipient clot and mature clot microstructure was confirmed by SEM and computational modelling: higher df was associated with highly dense clots formed of smaller fibrin fibres in lung cancer patients compared to controls. This study demonstrates that df is a sensitive technique which quantifies the structure and mechanical properties of blood clots in patients with lung cancer. Our data suggests that df has the potential to identify patients with an abnormal clot microstructure and greatest VTE risk.

Influence of antenatal physical exercise on haemodynamics in pregnant women: a flexible randomisation approach.

BACKGROUND: Normal pregnancy is associated with marked changes in haemodynamic function, however the influence and potential benefits of antenatal physical exercise at different stages of pregnancy and postpartum remain unclear. The aim of this study was therefore to characterise the influence of regular physical exercise on haemodynamic variables at different stages of pregnancy and also in the postpartum period. METHODS: Fifty healthy pregnant women were recruited and randomly assigned (2 × 2 × 2 design) to a land or water-based exercise group or a control group. Exercising groups attended weekly classes from the 20th week of pregnancy onwards. Haemodynamic assessments (heart rate, cardiac output, stroke volume, total peripheral resistance, systolic and diastolic blood pressure and end diastolic index) were performed using the Task Force haemodynamic monitor at 12-16, 26-28, 34-36 and 12 weeks following birth, during a protocol including postural manoeurvres (supine and standing) and light exercise. RESULTS: In response to an acute bout of exercise in the postpartum period, stroke volume and end diastolic index were greater in the exercise group than the non-exercising control group (p = 0.041 and p = 0.028 respectively). Total peripheral resistance and diastolic blood pressure were also lower (p = 0.015 and p = 0.007, respectively) in the exercise group. Diastolic blood pressure was lower in the exercise group during the second trimester (p = 0.030). CONCLUSIONS: Antenatal exercise does not appear to substantially alter maternal physiology with advancing gestation, speculating that the already vast changes in maternal physiology mask the influences of antenatal exercise, however it does appear to result in an improvement in a woman's haemodynamic function (enhanced ventricular ejection performance and reduced blood pressure) following the end of pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02503995. Registered 20 July 2015.

Sex-specific alterations in hippocampal cannabinoid 1 receptor expression following adolescent delta-9-tetrahydrocannabinol treatment in the rat.

Marijuana use by adolescents has been on the rise since the early 1990s. With recent legalization and decriminalization acts passed, cannabinoid exposure in adolescents will undoubtedly increase. Human studies are limited in their ability to examine underlying changes in brain biochemistry making rodent models valuable. Studies in adult and adolescent animals show region and sex specific downregulation of the cannabinoid 1 (CB1) receptor following chronic cannabinoid treatment. However, although sex-dependent changes in behavior have been observed during the drug abstinence period following adolescent cannabinoid exposure, little is known about CB1 receptor expression during this critical time. In order to characterize CB1 receptor expression following chronic adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we used [(3)H] CP55,940 binding to assess CB1 receptor expression in the dentate gyrus and areas CA1, CA2, and CA3 of the hippocampus in both male and female adolescent rats at both 24h and 2 weeks post chronic THC treatment. Consistent with other reported findings, we found downregulation of the CB1 receptor in the hippocampal formation at 24h post treatment. While this downregulation persisted in both sexes following two weeks of abstinence in the CA2 region, in females, this downregulation also persisted in areas CA1 and CA3. Expression in the dentate gyrus returned to the normal range by two weeks. These data suggest that selective regions of the hippocampus show persistent reductions in CB1 receptor expression and that these reductions are more widespread in female compared to male adolescents.

The changes in clot microstructure in patients with ischaemic stroke and the effects of therapeutic intervention: a prospective observational study.

BACKGROUND: Stroke is the second largest cause of death worldwide. Hypercoagulability is a key feature in ischaemic stroke due to the development of an abnormally dense clot structure but techniques assessing the mechanics and quality of clot microstructure have limited clinical use. We have previously validated a new haemorheological technique using three parameters to reflect clot microstructure (Fractal Dimension (d f )) ex-vivo, real-time clot formation time (T GP ) and blood clot strength (elasticity at the gel point (G'GP)). We aimed to evaluate these novel clotting biomarkers in ischaemic stroke and changes of clot structure following therapeutic intervention. METHODS: In a prospective cohort study clot microstructure was compared in ischaemic stroke patients and a control group of healthy volunteers. Further assessment took place at 2-4 hours and at 24 hours after therapeutic intervention in the stroke group to assess the effects of thrombolysis and anti-platelet therapy. RESULTS: 75 patients (mean age 72.8 years [SD 13.1]; 47 male, 28 female) with ischaemic stroke were recruited. Of the 75 patients, 32 were thrombolysed with t-PA and 43 were loaded with 300 mg aspirin. The following parameters were significantly different between patients with stroke and the 74 healthy subjects: d f (1.760 ± .053 versus 1.735 ± 0.048, p = 0.003), TGP (208 ± 67 versus 231 ± 75, p = 0.05), G'GP (0.056 ± 0.017 versus 0.045 ± 0.014, p < 0.0001) and fibrinogen (3.7 ± 0.8 versus 3.2 ± 0.5, p < 0.00001). There was a significant decrease in d f (p = 0.02), G'GP (p = 0.01) and fibrinogen (p = 0.01) following the administration of aspirin and for d f (p = 0.003) and fibrinogen (p < 0.001) following thrombolysis as compared to baseline values. CONCLUSION: Patients with ischaemic stroke have denser and stronger clot structure as detected by d f and G'GP. The effect of thrombolysis on clot microstructure (d f ) was more prominent than antiplatelet therapy. Further work is needed to assess the clinical and therapeutic implications of these novel biomarkers.

Fractal dimension: a novel clot microstructure biomarker use in ST elevation myocardial infarction patients.

OBJECTIVES: Changes in clot microstructure are increasingly implicated in the pathology of atherosclerosis although most data are from techniques in the remote laboratory using altered blood. We validate the novel biomarker Gel Point in STEMI patients and assess therapeutic interventions. Gel Point marks the transition of blood from a visco-elastic liquid to visco-elastic solid and is rapidly measured using unadulterated blood. The Gel Point provides measurements of three parameters to reflect clot microstructure (fractal dimension (df)), real-time clot formation time (TGP) and blood clot strength (elasticity at the Gel Point (G'GP)). METHODS: We prospectively recruited 38 consecutive patients with STEMI undergoing primary percutaneous coronary intervention (pPCI). Venous blood samples were collected on admission, after pPCI and 24 h after admission for assessment of the new biomarkers, standard coagulation tests and scanning electron microscopy (SEM). RESULTS: df after pPCI was lower than df on admission (mean 1.631 [SD 0.063] vs 1.751 [0.052], p < 0.000001) whereas df at 24 h was similar to that on admission. G'GP also showed similar trend to df (p < 0.001). TGP was prolonged at after-PCI measurement compared with admission (median 854 s [IQR 581-1801] vs 217 [179-305], p < 0.00001). Changes in the values of df and G'GP were consistent with changes in the SEM images of the mature clot. CONCLUSIONS: We characterise Gel Point derived markers of clot microstructure in patients admitted with emergency arterial thrombosis. This point of care test can potentially be used to assess the efficacy of therapeutic interventions by measuring changes in clot microstructure.

A new biomarker quantifies differences in clot microstructure in patients with venous thromboembolism.

This study compared patients with venous thromboembolism (VTE) to non-VTE patients using a biomarker of clot microstructure (df ) and clot formation time (TGP ). df was the only marker that identified a significant difference (P < 0·001) between the VTE (n = 60) and non-VTE cohorts (n = 69). The 'abnormal' clot microstructures in the VTE patients suggests either inadequate response to anticoagulant therapy or the presence of a procoagulant state not detected by other markers of coagulation (i.e., International Normalized Ratio). Furthermore, elevated values of df in first time VTE patients who later develop a secondary event indicates that df may identify those at risk of recurrence.

Low-educated women have an increased risk of gestational diabetes mellitus: the Generation R Study.

AIMS: To investigate whether maternal educational level is associated with gestational diabetes mellitus (GDM), and to what extent risk factors for GDM mediate the effect of educational level. METHODS: We examined data of 7,511 pregnant women participating in a population-based cohort study in Rotterdam, the Netherlands. The highest achieved education was categorized into four levels. Diagnosis of GDM was retrieved from delivery records. Odds ratios (OR) of GDM were calculated for levels of education, adjusting for confounders and potential mediators. Mediators were selected according to Baron and Kenny's causal step approach. RESULTS: Adjusted for ethnicity, age, family history of diabetes and parity, women in the lowest educational level were three times more likely to develop GDM than women in the highest level (OR 3.07; 95 % CI 1.37, 6.89). Selected mediators were alcohol use and body mass index (BMI). Additional adjustment for alcohol use attenuated the OR to 2.54 (95 % CI 1.11, 5.78). The individual addition of BMI attenuated the OR to 2.35 (95 % CI 1.03, 5.35). All mediators together explained 51 % (95 % CI -122, -25) of the association between low education and GDM. CONCLUSIONS: Low maternal educational level is associated with GDM, which is mainly due to higher rates of overweight and obesity. In order to reduce the higher rates of GDM, and consequently type 2 diabetes among women in low socioeconomic subgroups, prevention and intervention strategies need to be focused on reducing the rates of overweight and obesity before pregnancy.

Influence of somatic state on cardiovascular measurements in pregnancy.

Normal pregnancy causes marked changes in cardiac and haemodynamic function but there is continuing debate about the patterns of 'normal' change. We believe that this lack of consensus is in large part caused by inappropriate assessment conditions. This study aimed to assess physiological data obtained from pregnant women during multiple steady-states and during between-state changes. The study was a longitudinal characterization of apparently healthy pregnant women aged >18 years with assessments at three antenatal stages (12-16, 26-28 and 34-36 weeks) and at 12 weeks following birth. Cardiovascular and heart rate variability (HRV) measures were quantified non-invasively during a range of states including postural manoeuvre, exercise and respiratory regulation. Cardiovascular and HRV variables were influenced by pregnancy in specific ways: (1) steady-state values were influenced differently to state-change responses; (2) cardiac output (CO) increased progressively throughout pregnancy in all states except supine rest; (3) the ΔCO response to the supine-standing manoeuvre was particularly sensitive to pregnancy stage; (4) blood pressure was unaffected by pregnancy; (6) ΔCO and ΔSBP (systolic blood pressure) were enhanced from mid-pregnancy onwards; (7) ΔHRV responses to state changes were markedly and progressively influenced by pregnancy. This study indicates that cardiovascular function in pregnant women is best quantified during at least one physical state change (in particular during the supine-to-standing manoeuvre) and that assessment during supine rest is inadequate for quantifying antenatal physiological function.

Moderate-intensity running causes intervertebral disc compression in young adults.

BACKGROUND: Decreased intervertebral disc (IVD) volume can result in diminished load-carrying capacity of the spinal region. Although moderate-intensity running is generally advocated for apparently healthy adults, running causes a loss in stature that is thought to reflect IVD compression. The aim of this investigation was to use magnetic resonance imaging (MRI) to quantify the influence of moderate-intensity treadmill running on IVD height and volume in the thoracic and lumbar regions of the vertebral column. METHODS: A clinic-based repeated-measures design was used in eight healthy young asymptomatic adults. After preliminary measurements and familiarization (day 1), participants reported to the clinic on two further occasions. MRI scans and stature measurements were completed at baseline (day 2), preexercise (day 3), and after 30 min of moderate-intensity treadmill running (postexercise, day 3). Mean height and volume were derived for all thoracic and lumbar IVDs from digitized MRIs, and stature was determined with a stadiometer. RESULTS: Moderate-intensity running resulted in 6.3% ± 0.9% reduction in mean IVD height and 6.9% ± 1.0% reduction in calculated IVD volume. The day-to-day variation in mean IVD height and volume were 0.6% ± 0.6% and 0.4% ± 0.6%, respectively. CONCLUSIONS: This is the first study to quantify the influence of moderate-intensity running on IVD height and volume. Changes in IVD height and volume were observed throughout the thoracic and lumbar vertebral regions. These findings suggest that future studies evaluating the influence of various loading activities and recovery techniques on IVD structure should consider thoracic as well as lumbar regions of the spine.

Children of low socioeconomic status show accelerated linear growth in early childhood; results from the Generation R Study.

OBJECTIVES: People of low socioeconomic status are shorter than those of high socioeconomic status. The first two years of life being critical for height development, we hypothesized that a low socioeconomic status is associated with a slower linear growth in early childhood. We studied maternal educational level (high, mid-high, mid-low, and low) as a measure of socioeconomic status and its association with repeatedly measured height in children aged 0-2 years, and also examined to what extent known determinants of postnatal growth contribute to this association. METHODS: This study was based on data from 2972 mothers with a Dutch ethnicity, and their children participating in The Generation R Study, a population-based cohort study in Rotterdam, The Netherlands (participation rate 61%). All children were born between April 2002 and January 2006. Height was measured at 2 months (mid-90% range 1.0-3.9), 6 months (mid-90% range 5.6-11.4), 14 months (mid-90% range 13.7-17.9) and 25 months of age (mid-90% range 23.6-29.6). RESULTS: At 2 months, children in the lowest educational subgroup were shorter than those in the highest (difference: -0.87 cm; 95% CI: -1.16, -0.58). Between 1 and 18 months, they grew faster than their counterparts. By 14 months, children in the lowest educational subgroup were taller than those in the highest (difference at 14 months: 0.40 cm; 95% CI: 0.08,0.72). Adjustment for other determinants of postnatal growth did not explain the taller height. On the contrary, the differences became even larger (difference at 14 months: 0.61 cm; 95% CI: 0.26,0.95; and at 25 months: 1.00 cm; 95% CI: 0.57,1.43) CONCLUSIONS: Compared with children of high socioeconomic status, those of low socioeconomic status show an accelerated linear growth until the 18th month of life, leading to an overcompensation of their initial height deficit. The long-term consequences of these findings remain unclear and require further study.

Early respiratory morbidity in a multicultural birth cohort: the Generation R Study.

Ethnic disparities in the prevalence of asthma symptoms in children have been described. We evaluated to what extent the association between ethnic background and respiratory symptoms during the first 2 years of life could be explained by the mediating effect of risk factors for respiratory morbidity. The Generation R Study is a multiethnic, population-based birth cohort study. Pre and postnatal risk factors for respiratory morbidity were prospectively assessed by questionnaires. Information about ethnicity was available for 5,684 infants. The associations between ethnic background and lower respiratory symptoms at 12 and 24 months were evaluated with log-binomial regression models. Relative risks and 95 % confidence intervals (RR [95 % CI]) were computed for Cape Verdean, Moroccan, Antillean, Surinamese and Turkish ethnicity with Dutch ethnicity as the reference category. We found an increased risk of lower respiratory symptoms at 24 months in Antillean infants (1.32 [95 % CI 1.12-1.57]) that was mediated by early postnatal exposures (pets keeping, siblings, breastfeeding, daycare attendance, smoke exposure). Turkish infants also had an increased risk of lower respiratory symptoms at 12 and 24 months (1.14 [95 % CI 1.02-1.27] and 1.21 [95 % CI 1.07-1.38], respectively), partly explained by previous morbidity (eczema, infections and upper respiratory symptoms). There were no differences for Cape Verdean, Moroccan or Surinamese, as compared to Dutch infants. Hence, ethnic background was associated with respiratory symptoms during the first 2 years of life and this association was largely explained by mediating effects of known pre and postnatal risk factors for respiratory morbidity.

Prenatal tetrahydrocannabinol (THC) alters cognitive function and amphetamine response from weaning to adulthood in the rat.

Research suggests that not only is marijuana use prevalent among women of reproductive age, but a significant number of women continue to use marijuana and its derivatives throughout pregnancy. Many studies have shown, in both humans and animals, that marijuana exposure during adolescence and adulthood is detrimental to normal cognition and memory. In this study, we examined the effects of daily intravenous injections of 0.15 mg/kg Δ(9)-tetrahydrocannabinol (THC), given to pregnant dams throughout gestation, on cognitive function in the offspring. Offspring were exposed to three tests: a passive avoidance test at postnatal day (PND) 22, an active place avoidance test at PND 45, and an attention task at PND 60, which assessed learning and long-term memory, spatial working memory and prediction, and attention, respectively. Other offspring were also given a 1mg/kg amphetamine challenge at PND 60. Passive avoidance testing showed that prenatal THC had no effect on acquisition but interfered with consolidation during retention testing. The active place avoidance task showed no treatment-related effects on acquisition but a significant treatment effect was observed in reversal performance in males. The attention task showed that a smaller percentage of THC-exposed rats completed the test, although the failure rate of both groups was quite high. Finally, THC exposed animals, both male and female, showed a dampened locomotor response to amphetamine, but females were more active than males overall. These results suggest that prenatal THC exposure has effects on certain aspects of cognitive function in rats from weaning to adulthood. These effects suggest that prenatal marijuana exposure could also alter cognitive function in humans and therefore have an impact on school performance and dampen responses to psychostimulants as well.

Norepinephrine mediates contextual fear learning and hippocampal pCREB in juvenile rats exposed to predator odor.

Predator odors induce unconditioned fear in the young animal and provide the opportunity to study the mechanisms underlying unlearned and learned fear. In the current study, cat odor produced unlearned, innate fear in infant (postnatal age 14; PN14) and juvenile (PN26) rats, but contextual fear learning occurred only in juveniles. It was hypothesized that contextual fear learning in juveniles is mediated by norepinephrine. Consistent with this hypothesis, pre-training injection of the ß-adrenergic antagonist propranolol reduced the unlearned fear response while post-training injection inhibited contextual fear learning in juvenile rats exposed to cat odor. We suggest that NE mediates the formation of contextual fear memories by activation of the transcription factor CREB in the hippocampus in juveniles but not in infants. Levels of phosphorylated CREB (pCREB) were increased in the dorsal and ventral hippocampi of juvenile rats exposed to cat odor. These levels were not increased in infants or juveniles exposed to a control odor. Further, propranolol blocked these increases in pCREB. In conclusion, although innate fear occurs within the neonatal period, contextual fear learning is a relatively late-occurring event, is hippocampal dependent, and mediated by norepinephrine.