Polymorphisms of the Dopamine Transporter Gene

Attention deficit-hyperactivity disorder (ADHD) is a very common and heterogeneous childhood-onset psychiatric disorder, affecting between 3% and 5% of school age children worldwide. Although the neurobiology of ADHD is not completely understood, imbalances in both dopaminergic and noradrenergic systems have been implicated in the origin and persistence of core symptoms, which include inattention, hyperactivity, and impulsivity. The role of a genetic component in its etiology is strongly supported by genetic studies, and several investigations have suggested that the dopamine transporter gene (DAT1; SLC6A3 locus) may be a small-effect susceptibility gene for ADHD. Stimulant medication has a well-documented efficacy in reducing ADHD symptoms. Methylphenidate, the most prescribed stimulant, seems to act mainly by inhibiting the dopamine transporter protein and dopamine reuptake. In fact, its effect is probably related to an increase in extracellular levels of dopamine, especially in brain regions enriched in this protein (i.e. striatum). It is also important to note that dopamine transporter densities seem to be particularly elevated in the brain of ADHD patients, decreasing after treatment with methylphenidate. Altogether, these observations suggest that the dopamine transporter does play a major role in ADHD. Among the several polymorphisms already described in the SLC6A3 locus, a 40 bp variable number of tandem repeats (VNTR) polymorphism has been extensively investigated in association studies with ADHD. Although there are some negative results, the findings from these reports indicate the allele with ten copies of the 40 bp sequence (10-repeat allele) as the risk allele for ADHD. Some investigations have suggested that this polymorphism can be implicated in dopamine transporter gene expression in vitro and dopamine transporter density in vivo, even though it is located in a non-coding region of the SLC6A3 locus. Despite all these data, few studies have addressed the relationship between genetic markers (specifically the VNTR) at the SLC6A3 locus and response to methylphenidate in ADHD patients. A significant effect of the 40 bp VNTR on response to methylphenidate has been detected in most of these reports. However, the findings are inconsistent regarding both the allele (or genotype) involved and the direction of this influence (better or worse response). Thus, further investigations are required to determine if genetic variation due to the VNTR in the dopamine transporter gene is able to predict different levels of clinical response and palatability to methylphenidate in patients with ADHD, and how this information would be useful in clinical practice.     

Late second trimester assessment of pyelectasis (SERP) to predict pediatric urological outcome is improved by checking additional features.

OBJECTIVE: Counseling for pyelectasis in the late 2nd trimester is usually based only upon assessing the antero-posterior (AP) width of the renal pelvis. We hypothesized that checking additional features would better predict postnatal outcome. STUDY DESIGN: Ultrasound (<24 weeks gestational age (GA)) and newborn outcome data collected prospectively since 1986 were analyzed retrospectively. We determined if outcome predictions in kidneys with a sonographically evident renal pelvis (SERP), which had evaluation of additional features (e.g., renal and bladder lengths, presence of a dilated ureter or dilated calyces) are more accurate than those that did not have these features. RESULTS. There were 286 fetuses studied with pediatric follow-up of an average of 6.5 years. There were 338 exams providing 459 ultrasound images with SERP. Additional features were not assessed in 183 fetuses; however 103 fetuses did have evaluation of additional features. These features were categorized as abnormal (92) or as normal (11). Fetuses with SERP and abnormal additional features required extensive urological care or died 6.1 times more often than fetuses in which additional features were not examined (p < 0.001) and 12.9 times more often when additional features were normal (p < 0.001). CONCLUSION: Fetal kidneys with SERP (<24 weeks GA) and an abnormal additional ultrasound feature had extensive pediatric care significantly more often than when such features were not evaluated or were normal.     

Differential effects of environmental enrichment on behavior and learning of male and female Ts65Dn mice,a model for Down syndrome

We have assessed the effects of enriched environment (EE) upon behavioral and cognitive performances of partially trisomic Ts65Dn (TS) mice and their control (CO) littermates. Enriched environment was applied to pups for 7 weeks after weaning. Circadian spontaneous activity (actimetry), exploratory behavior (hole board), activity in the open field and spatial memory (Morris Water Maze, repeated acquisition and cued paradigms) were analyzed in 86 female and 75 male mice, starting 15 days after completing enrichment. For each gender, mice were distributed in non-enriched and enriched control and trisomic groups. Enriched environment reduced in trisomic females and enhanced in trisomic males' circadian activity. Exploratory behavior was increased by enrichment in all groups, regardless of gender or presence of trisomy. In the Morris Water Maze, a significant improvement of the spatial memory was observed in enriched-control females, but not in enriched-control male mice, as assessed by distances traveled. Performances in the four groups of control animals were also consistently and significantly better than those of matching trisomic mice. In the acquisition trials, enrichment improved performance in trisomic female animals, but deteriorated in trisomic male mice. In all groups, changes in escape latencies and distances induced by enrichment were accounted for by changes in the total time spent in the periphery of the pool, indicating changes in learning strategy. Working memory was the function more affected by enrichment. It is concluded that enriched environment induces behavioral and learning changes in trisomic mice, although gender plays a significant modulatory role.     

Opsonization of apoptotic cells by autologous iC3b facilitates clearance by immature dendritic cells,down-regulates DR and CD86, and up-regulates CC chemokine receptor 7

Immature dendritic cells (iDCs) do not mature after uptake of apoptotic cells and may play a role in the induction of peripheral tolerance to self antigens derived from apoptotic material. The integrins, alphavbeta3, alphavbeta5, and the scavenger receptor, CD36, have been shown to mediate uptake of apoptotic cells by iDCs. However, it is not known whether the complement system, also takes part in this process. In this study we investigated the ability of iDCs to bind to apoptotic cells opsonized by iC3b. Monocyte-derived dendritic cells were offered apoptotic Jurkat cells opsonized by autologous iC3b and labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanineperchlorate. A significant increase (P < 0.001) in the amount of cleared apoptotic cells was seen at low ratios. Despite increased efficiency of uptake, interaction between iC3b-opsonized apoptotic cells and iDCs down-regulated the expression of major histocompatibility complex class II, CD86, CC chemokine receptor (CCR)2, CCR5, and beta2-integrins (P < 0.001), and up-regulated expression of CCR7 (P < 0.001). In addition, iDC maturation responses to CD40L and lipopolysaccharide were significantly inhibited. We conclude that opsonization of apoptotic cells by iC3b induces tolerant iDCs that are able to migrate to lymph nodes.     

Ekbom's sydrome and spasmodic torticollis: case report

The Ekbom's syndrome, also known as delirium of parasitic infestation, acarophobia, delusional parasitosis, psychogenic parasitosis, is a disease of rare occurrence. Generally it is characterized by the firm conviction of the patients to be infected by worms that come out of the skin, usually from the scalp or even from the mouth, from the eyes or from the genital region. Most of the patients are elderly and female, and with frequent social isolation. Some cases are associated with organic diseases as hyperthyroidism, diabetes, cortical lesion, intoxication by medicines. To our knowledge the association between delusional parasitosis with spasmodic torticollis was not described in literature. We report the case of a 72-year-old-woman with delusional parasitosis associated with spasmodic torticollis.     

Lithium ions modulate the expression of VMAT2 in rat brain

Recent work has indicated that lithium (at 1 mM, a concentration that is efficacious in the treatment of manic-depressive disorders) modulates the level of vesicular monoamine transporter 1 (VMAT1) mRNA in PC12 cells as a function of the differentiation status of these cells. To ascertain whether VMAT expression in neurons is sensitive to lithium, in vivo, rats were fed a lithium-supplemented diet for 21 days (which raised serum lithium to 0.98+/-0.1 mM). Northern analysis revealed an overall increase (199+/-27%) of the neuronal VMAT isoform (VMAT2) in rat brain after lithium. However, in situ hybridization analysis revealed regional differences in the effects of lithium. Thus, VMAT2 mRNA increased by 50-100% over control in the raphe nuclei, ventral tegmental area, and substantia nigra of rats fed the lithium diet. Concomitantly, VMAT2 mRNA declined by about 50% in the locus coeruleus. Because VMAT2 is expressed in neurons that are strongly implicated in regulating mood and behavior, these data support the hypothesis that alterations of VMAT2 expression contribute to the therapeutic effects of lithium in psychiatric disorders.     

Prevalence rate and correlates of depressive symptoms in older individuals: the Veneto Study

BACKGROUND: Depressive symptoms (DS) are very common in elders, particularly among women, and their prevalence rates vary widely across countries. METHODS: A random sample of noninstitutionalized men (n = 867) and women (n = 1531), aged 65 years and older, from the Veneto region, northeastern Italy, were interviewed and participated in a brief physical examination in their homes. The prevalence rates of DS and the associated physical, social, and psychological factors were analyzed. RESULTS: The overall prevalence rate of DS was 58% in women and 34% in men (p <.0001), but there was no significant trend with age. Women were at higher risk of DS (OR = 1.63) than men, even after adjusting for traditional risk factors, such as fair-poor self-rated health, sleep disturbances and use of sleep medications, lack of support from social and family network, and physical and cognitive impairment. CONCLUSIONS: This study provides evidence that older women more frequently report DS than men, independently from the presence of traditional risk and associated factors. Cultural and lifestyle factors throughout life might explain this gender difference.     

Expression and dendritic mRNA localization of GABAC receptor rho1 and rho2 subunits in developing rat brain and spinal cord

The cellular distribution of GABAC receptor rho1 and rho2 subunits in the rat central nervous system remains controversial. We investigated how these subunits were distributed in cerebellum, hippocampus and spinal cord at postnatal day 1, 7 or in adult life. We found that in the adult cerebellum rho1 and rho2 mRNAs were expressed in Purkinje cells and basket-like cells only. In the hippocampus both subunits were expressed throughout the CA1 pyramidal layer, dentate gyrus and scattered interneurons with maximum staining intensity at P7. In the adult hippocampus in situ staining was predominantly found on interneurons. GABAC antibody labelling in P7 and adult hippocampus was largely overlapping with the in situ staining. Western blot analysis showed GABAC receptor in retina, ovary and testis. In the spinal cord the rho2 signal was consistently stronger than rho1 with overlapping expression patterns. At P1, the most intensely labelled cells were the motoneurons while on P7 and adult sections, interneurons and motoneurons were likewise labelled. On spinal neurons both rho1 and rho2 mRNAs showed somatodendritic localization, extending out for >100 microm with punctate appearance especially in adult cells. A similar spinal distribution pattern was provided with polyclonal antibody labelling, suggesting close correspondence between mRNA and protein compartmentalization. Electrophysiological experiments indicated that P1 spinal motoneurons did possess functional GABAC receptors even though GABAC receptors played little role in evoked synaptic transmission. Our results suggest a pattern of rho1 and rho2 subunit distribution more widespread than hitherto suspected with strong developmental regulation of subunit occurrence.