Depression as a spreading adjustment disorder of monoaminergic neurons: a case for primary implication of the locus coeruleus

A model for the pathophysiology of depression is discussed in the context of other existing theories. The classic monoamine theory of depression suggests that a deficit in monoamine neurotransmitters in the synaptic cleft is the primary cause of depression. More recent elaborations of the classic theory also implicitly include this postulate, other theories of depression frequently prefer to depart from the monoamine-based model altogether. We suggest that the primary defect emerges in the regulation of firing rates in brainstem monoaminergic neurons, which brings about a decrease in the tonic release of neurotransmitters in their projection areas, an increase in postsynaptic sensitivity, and concomitantly, exaggerated responses to acute increases in the presynaptic firing rate and transmitter release. It is proposed that the initial defect involves, in particular, the noradrenergic innervation from the locus coeruleus (LC). Dysregulation of the LC projection activities may lead in turn to dysregulation of serotonergic and dopaminergic neurotransmission. Failure of the LC function could explain the basic impairments in the processing of novel information, intensive processing of irrational beliefs, and anxiety. Concomitant impairments in the serotonergic neurotransmission may contribute to the mood changes and reduction in the mesotelencephalic dopaminergic activity to loss of motivation, and anhedonia. Dysregulation of CRF and other neuropeptides such as neuropeptide Y, galanin and substance P may reinforce the LC dysfunction and thus further weaken the adaptivity to stressful stimuli.     

Natural variation of rice strigolactone biosynthesis is associated with the deletion of two MAX1 orthologs

Rice (Oryza sativa) cultivar Azucena—belonging to the Japonica subspecies—exudes high strigolactone (SL) levels and induces high germination of the root parasitic plant Striga hermonthica. Consistent with the fact that SLs also inhibit shoot branching, Azucena is a low-tillering variety. In contrast, Bala, an Indica cultivar, is a low-SL producer, stimulates less Striga germination, and is highly tillered. Using a Bala × Azucena F6 population, a major quantitative trait loci—qSLB1.1—for the exudation of SL, tillering, and induction of Striga germination was detected on chromosome 1. Sequence analysis of the corresponding locus revealed a rearrangement of a 51- to 59-kbp stretch between 28.9 and 29 Mbp in the Bala genome, resulting in the deletion of two cytochrome P450 genes—SLB1 and SLB2—with high homology to the Arabidopsis SL biosynthesis gene, MAX1. Both rice genes rescue the Arabidopsis max1-1 highly branched mutant phenotype and increase the production of the SL, ent-2′-epi-5-deoxystrigol, when overexpressed in Bala. Furthermore, analysis of this region in 367 cultivars of the publicly available Rice Diversity Panel population shows that the rearrangement at this locus is a recurrent natural trait associated with the Indica/Japonica divide in rice.The root parasitic Striga spp. parasitize on roots of crops in tropical and subtropical areas. The species typically parasitize cereals, including economically important crops such as maize, sorghum, millet, and rice (1). The parasitic relationship is dependent on the ability of the parasite to detect the host, which is mediated by the perception of strigolactones (SLs), molecules exuded by the host into the rhizosphere, by the seeds of the parasite (2). SLs are also signaling molecules for the establishment of the symbiosis with arbuscular mycorrhizal (AM) fungi (3) that help the plant to improve nutrient uptake. Under low phosphate availability, SL exudation into the rhizosphere is strongly enhanced, hence promoting AM symbiosis (4). As a negative consequence, however, agricultural areas with poor soils and low fertilizer input are strongly affected by Striga (1, 4). In addition to their rhizosphere role, SLs also function as plant hormones inhibiting shoot branching and modulating root architecture (5–7), also in response to phosphate deficiency (8, 9). SL biosynthesis or signaling mutants have increased axillary bud outgrowth, resulting in a bushy and dwarf phenotype (10). Biosynthesis of SLs proceeds through isomerization of β-carotene by β-CAROTENE ISOMERASE (D27), followed by cleavage by CAROTENOID CLEAVAGE DIOXYGENASE 7 (CCD7) and CAROTENOID CLEAVAGE DIOXIGENASE 8 (CCD8), which results in the formation of carlactone (11–16). The gene(s) responsible for the conversion of carlactone to a SL has/have not been identified, although MORE AXILLARY GROWTH 1 (MAX1), encoding a cytochrome P450 (CYP) in Arabidopsis, has been suggested to be a candidate (8, 11, 17, 18). SL signaling is mediated by an F-Box protein (MAX2 in Arabidopsis; D3 in rice) and an α/β-hydrolase protein (D14) (5, 6, 19, 20).In the present study, molecular genetics was used to further elucidate the SL biosynthetic pathway. We had observed that the rice cultivars Bala and Azucena differ greatly in SL biosynthesis and susceptibility to Striga infection. The Bala × Azucena F₆ recombinant inbred line (RIL) population was used to map quantitative trait loci (QTL) related to SLs. A major QTL was detected explaining most of the variation in the concentrations of all five SLs detected in rice exudates. This locus was also detected as a QTL for rice–Striga interaction in a previous study that used the same population (21). Here we show that the QTL is due to a rearrangement of a 51- to 59-kbp stretch between 28.9 and 29.0 Mbp of chromosome 1 in the Bala genome. This rearrangement results in the deletion of two CYP genes, which we show are orthologs of the Arabidopsis MAX1. The rearrangement of this locus is a recurrent natural trait, observed in several rice cultivars.     

Value of "functional" magnetic resonance imaging in the diagnosis of ligamentous affection at the craniovertebral junction

Introduction

Objective of this investigation was to evaluate the rotational mobility at the craniocervical junction and changes in the width of the subarachnoid space during head rotation in healthy volunteers using Magnetic Resonance Imaging (MRI).

Materials and Methods

In 30 healthy volunteers axial 3 mm Half-Fourier Acquisition Single-Shot Turbo Spin-Echo (HASTE) sequences were obtained with the subject's head in neutral position, and in maximal rotation to the left and right respectively. All MRI examinations were evaluated by two neuroradiologists in consensus. The ranges of axial rotation at C0–C2 as well as the width of the subarachnoid space in neutral, and in maximal rotated position were measured. Student's t-tests were used to compare group differences.

Results

Total range of right-to-left-rotation at C0–C2 was 59–183° with mean rotation to the right and left side of 70° (±12.7°) and 75° (±13.0°). Difference between degrees of rotation to both sides was on average 4.9° (±7.1°) with a significantly greater rotational range to the left compared to the right. In neutral position, distance between the dura and the ventral wall of the cervical spinal cord was 1.6–4.2 mm. In active rotation interface between dura and myelon was evident in 19 volunteers with unilateral contact in 7, and bilateral contact in 12 cases.

Conclusions

High variablity of rotational mobility at the craniocervical junction and attenuation of width of the subarachnoid space during head rotation are frequent findings in an asymptomatic population. Our results indicate that the assessment of these parameters is of limited diagnostic value in patients with whiplash-associated disorders.     

Intergenerational Cardiovascular Disease Risk Factors Involve Both Maternal and Paternal BMI

OBJECTIVE

To examine the association between parental BMI and offspring cardiovascular disease (CVD) risk factors.

RESEARCH DESIGN AND METHODS

The study comprised 940 children (9.5 ± 0.4 years) and 873 adolescents (15.5 ± 0.5 years). Parental weight and height were reported by the mother and the father, and BMI was calculated. CVD risk factors included total (sum of five skinfolds) and central (waist circumference) body fat, blood pressure, cardiorespiratory fitness, insulin sensitivity, total cholesterol, HDL cholesterol, triglycerides, and fibrinogen.

RESULTS

Maternal and paternal BMI were positively associated with total and central fatness in offspring (P < 0.001). BMIs of both parents were significantly related to fibrinogen levels (P < 0.02), but these associations disappeared when controlling for fatness. There was a positive relationship between maternal and paternal BMI and waist circumference in the offspring regardless of total adiposity and height (P < 0.001). Maternal BMI was negatively associated with offspring cardiorespiratory fitness independently of fatness (P < 0.02). These relationships persisted when overweight descendants were excluded from the analysis. There were no significant associations between parental BMI and the other CVD risk factors.

CONCLUSIONS

Both maternal and paternal BMI increase CVD risk factors of their offspring, characterized by total and central body fat, and higher maternal BMI was associated with poorer cardiorespiratory fitness. Our findings give further support to the concept that adiposity in parents transmits susceptibility to CVD risk to descendants, which is detectable even in the absence of overweight in offspring.Parental obesity substantially increases the risk of obesity in offspring through genetic, biological, or environmental influences (1). The fetal overnutrition hypothesis suggests that maternal obesity and/or gestational diabetes may predispose offspring to increased adiposity in adulthood (2). Human studies showed a greater influence of maternal than paternal BMI on offspring adiposity (3,4). In contrast, others suggested that the contribution of the mother and the father on both prenatal and postnatal programming of intergenerational obesity may be similar according to the genomic imprinting (5).Most of the studies focused on the relationships of maternal and paternal BMI with their offspring BMI provided contradictory results (3,6,7), and only one study compared the association of maternal and paternal BMI with total body fat in the offspring (8). Whether the parental BMI-offspring body fat relationship applies to other established cardiovascular disease (CVD) risk factors remains to be elucidated.Excess adiposity leads to increased CVD risk factors and biological pathway alterations as insulin resistance, dyslipemia, hypertension, systemic inflammation, and low cardiorespiratory fitness (9). Therefore, the parental BMI-offspring CVD risk factor relationship may be influenced by the offspring body composition.The European Youth Heart Study (EYHS) provides an opportunity to better understand the parental-descendant aggregation of CVD factors by controlling for other potential confounding factors that could mediate in this relationship. Therefore, the aim of this study was to determine the association between both maternal and paternal BMI and the offspring CVD risk factors including total and central body fat, cardiorespiratory fitness, insulin sensitivity, blood pressure, blood lipids, and fibrinogen. We also examined the role of offspring adiposity in this relationship.     

An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunity

Type I IFNs were discovered as the primary antiviral cytokines and are now known to serve critical functions in host defense against bacterial pathogens. Accordingly, established mediators of IFN antiviral activity may mediate previously unrecognized antibacterial functions. RNase-L is the terminal component of an RNA decay pathway that is an important mediator of IFN-induced antiviral activity. Here, we identify a role for RNase-L in the host antibacterial response. RNase-L^−/− mice exhibited a dramatic increase in mortality after challenge with Bacillus anthracis and Escherichia coli; this increased susceptibility was due to a compromised immune response resulting in increased bacterial load. Investigation of the mechanisms of RNase-L antibacterial activity indicated that RNase-L is required for the optimal induction of proinflammatory cytokines that play essential roles in host defense from bacterial pathogens. RNase-L also regulated the expression of the endolysosomal protease, cathepsin-E, and endosome-associated activities, that function to eliminate internalized bacteria and may contribute to RNase-L antimicrobial action. Our results reveal a unique role for RNase-L in the antibacterial response that is mediated through multiple mechanisms. As a regulator of fundamental components of the innate immune response, RNase-L represents a viable therapeutic target to augment host defense against diverse microbial pathogens.     

Echocardiographic assessment of the different left ventricular geometric patterns in middle-aged men and women in Tallinn

The aim of this study was to determine the association of left ventricular (LV) geometry with sex, age, arterial hypertension and obesity in Tallinn. In a framework of a population study for cardiovascular risk factors, echocardiography was carried out in 325 men and 398 women (69.3% of all 1043 participants aged 35-59) in 1999-2001. Left ventricular hypertrophy was defined if left ventricular mass (LVM), LVM/height and LVM/body surface area were 294 g, 163 g/m and 150 g/m2 in men, and 198 g, 121 g/m and 120 g/m2 in women, respectively. LV geometry was analysed according to four types generally recognized (with regard to relative wall thickness > 0.45). The prevalence of concentric hypertrophy was similar in men and women: 7.7% and 9.1%. The prevalence of eccentric hypertrophy was significantly higher in women than in men (33.3% vs 4.9%). Concentric remodelling was also found in women more often than in men (9.5 vs 5.5%; p < 0.05). Regardless of sex and age, concentric hypertrophy was never found in participants with blood pressure < 140/90. In hypertensives, there was a tendency for age-related increase of concentric hypertrophy prevalence: the latter was higher in women than in men: 39.1% vs 25.5%; p < 0.05. In examinees with BMI < 30, this type of LV geometry was seldom found: in 3.1% of men and 5.0% of women; p < 0.05. In obese persons, it increased with age, reaching 26.5% in men and 21.2% in women (p < 0.05). The prevalence of eccentric hypertrophy in men increased with age, and with hypertension and obesity. The prevalence of concentric remodelling in men was not related to BMI; it was significantly more often found in older age groups and in hypertensives. In women, the prevalence of eccentric hypertrophy and concentric remodelling was not related to age, hypertension or obesity.     

Arterial hypertension,left ventricular geometry and QT dispersion in a middle-aged Estonian female population

The aim of the present study was to determine the prevalence of Left ventricular hypertrophy (LVH) and different left ventricular (LV) geometric patterns in the middle-aged women population of Tallinn, to assess the relationship between LV geometry, age, blood pressure and LV repolarization duration and inhomogeneity. A random sample of the population, 482 women aged 35-59, was examined in the framework of a cardiovascular risk factors survey for the WHO/CINDI programme years 1999-2000. Patients with valvular pathology, primary cardiomyopathy, atrial fibrillation, bundle branch blocks and flat T wave on electrocardiography (ECG) were excluded; 398 (82.2%) of the participants underwent echocardiography (Echo) and standard 12-lead ECG at rest and were included in the study. LVH was defined if left ventricular mass (LVM), LVM/height and LVM/BSA were >198 g, >121 g/m and > 120 g/m2, respectively. Arterial hypertension was determined in 23.1% of the women. The prevalence of arterial hypertension was three times higher in those aged 50-59 than in those aged 40-49 (37.4% vs 13.2%; p < 0.05). Different geometric patterns were found as follows: concentric hypertrophy in 9.1%; eccentric hypertrophy 33.9%; concentric remodelling 9.5% and normal geometry 47.5% of the participants. Concentric hypertrophy was found exclusively in hypertensive women and increased with age. No age-related eccentric hypertrophy and concentric remodelling differences were found, either in the normotensive or in the hypertensive group. Prolonged QT dispersion--a marker of increased myocardial electrical instability, was associated with LVH and arterial hypertension and was related mostly to concentric hypertrophy in hypertensives.     

Stress-protection action of beta-phenyl(GABA): involvement of central and peripheral type benzodiazepine binding sites

Forced swimming stress caused a significant increase in the density of central type benzodiazepine binding sites in rat cerebral cortex and hippocampus. The number of peripheral type benzodiazepine binding sites was also enhanced on blood platelets. The affinity of neither central nor peripheral type benzodiazepine binding sites was changed considerably after swimming stress. Pretreatment of rats with beta-(phenyl)GABA (100 mg/kg), a GABAB agonist, almost completely eliminated the described changes of the both types of benzodiazepine binding sites caused by swimming stress. In an elevated plus-maze model of anxiety beta-(phenyl)GABA itself was inactive but like diazepam effectively counteracted the behavioural effects of DMCM, a beta-carboline derivative with anxiogenic properties. The possible involvement of benzodiazepine receptors in the mechanism of action of beta-(phenyl)GABA is discussed.     

Alterations in brain cholecystokinin receptors in suicide victims.

Cholecystokinin (CCK) and benzodiazepine receptor binding characteristics were analyzed in the brain tissue samples from 19 suicide victims and 23 control cases. In the frontal cortex, significantly higher apparent number of CCK receptors and affinity constants were found in the series of suicide victims. These differences between suicides and controls were present in similar proportions when the suicide cases with depressive syndrome or violent or non-violent means of self-killing were compared to matched controls. However, when the samples were split into subgroups consisting of persons either below or over the age of 60 years, significant differences in the CCK receptor characteristics in the frontal cortex were observed only between younger suicides and controls. Furthermore, the younger suicide victims had a higher density of CCK receptors in the cingulate cortex, whereas in older suicides the value was lower as compared to age-matched controls. No difference in benzodiazepine receptor binding was found between control and suicide groups. The results of this investigation suggest that CCK-ergic neurotransmission is linked to self-destructive behaviour, probably through its impact on anxiety and adaptational deficits.