Perinatal fluoxetine exposure results in social deficits and reduced monoamine oxidase gene expression in mice.

Perinatal antidepressant drug exposure increases risk for autism spectrum disorder, yet the molecular and neurobehavioral effects of maternal antidepressant drug use on offspring remain poorly understood. In this study, we administered the selective serotonin reuptake inhibitor (SSRI) fluoxetine non-invasively to female mice throughout gestation and early lactation, and then examined social interaction behaviors in offspring. In addition, we measured whole brain gene expression levels of monoamine oxidase A (MAOA), the primary metabolizing enzyme for serotonin. We found deficits in sociability and social novelty-seeking behavior in the juvenile offspring of SSRI-treated mice, and these behaviors persisted into young adulthood. Furthermore, we found decreased MAOA expression in the brains of offspring of SSRI-treated mice. Our findings suggest that exposure to antidepressants during the prenatal and early postnatal period may negatively affect social development. Moreover, reduced MAOA expression may play a role in the mechanistic pathway linking SSRI exposure and behavioral deficits symptomatic of autism.

Microparticle subpopulations are potential markers of disease progression and vascular dysfunction across a spectrum of connective tissue disease.

OBJECTIVE: Microparticles (MPs) are membrane-bound vesicles derived from vascular and intravascular cells such as endothelial cells (EMPs) and platelets (PMPs). We investigated EMP and PMP numbers across a spectrum of autoimmune rheumatic diseases (AIRDs) with the aim of comparing the levels of, and relationship between, EMPs and PMPs. METHODS: Patients with Systemic Lupus Erythematosus (SLE) (n = 24), Systemic Sclerosis (SSc) (n = 24), Primary Raynauds Phenomenon (RP) (n = 17) and "other CTD" (n = 15) (Primary Sjogrens Syndrome, UCTD or MCTD) as well as 15 healthy controls were recruited. EMPs and PMPs were quantified using flow cytometry. Associations between MP levels and objective functional vascular assessments were evaluated. RESULTS: SLE patients had significantly higher EMPs compared with healthy controls and SSc patients. Higher PMP levels were noted in SSc and primary RP when compared to healthy controls and 'other CTD' patients. A modest correlation was noted between EMP and PMP levels in healthy controls (Spearman r = 0.6, p = 0.017). This relationship appeared stronger in SLE (r = 0.72, p < 0.0001) and other CTD patients (r = 0.75, p < 0.0001). The association between EMPs and PMPs was notably less strong in SSc (r = 0.45, p = 0.014) and RP (r = 0.37, p = 0.15). A significantly lower EMP/PMP ratio was detected in SSc/RP patients in comparison to both healthy controls and SLE/other CTD patients. Higher EMP and PMP levels were associated with higher digital perfusion following cold challenge in SSc. In contrast, higher PMP (but not EMP) levels were associated with lower digital perfusion at both baseline and following cold challenge in primary RP. Higher PMP levels were associated with greater endothelial-independent dilation in patients with SLE. CONCLUSION: MP populations differ across the spectrum of AIRDS, possibly reflecting differences in vascular cell injury and activation. MP levels are associated with functional assessments of vascular function and might have a role as novel vascular biomarkers in AIRDs. SIGNIFICANCE AND INNOVATIONS: Levels of circulating endothelial and platelet microparticles differ between SSc/primary RP compared with SLE and other CTDs (UCTD, MCTD and Primary Sjogrens). MP release may occur within different vascular sites across these disease groups (macrovascular and microvascular). The association between circulating MP levels and objective assessment of macro- and microvascular dysfunction within these disease areas suggests that MPs might have a useful role as novel circulating biomarkers of vascular disease within the CTDs.

Endothelial microparticles: Pathogenic or passive players in endothelial dysfunction in autoimmune rheumatic diseases?

Autoimmune rheumatic diseases are characterised by systemic inflammation and complex immunopathology, with an increased risk of cardiovascular disease, initiated by endothelial dysfunction in a chronic inflammatory environment. Endothelial microparticles (EMPs) are released into the circulation from activated endothelial cells and may therefore, reflect disease severity, vascular and endothelial dysfunction, that could influence disease pathogenesis via autocrine/paracrine signalling. The exact function of EMPs in rheumatic disease remains unknown, and this has initiated research to elucidate EMP composition and function, which may be determined by the mode of endothelial activation and the micro environment. To date, EMPs are thought to play a role in angiogenesis, thrombosis and inflammation by transferring specific proteins and microRNAs (miRs) to target cells. Here, we review the mechanisms underlying the generation and composition of EMPs and the clinical and experimental studies describing the involvement of EMPs in rheumatic diseases, since we have previously shown endothelial dysfunction and an elevated risk of cardiovascular disease are characteristics in systemic lupus erythematosus. We will also discuss the potential of EMPs as future biomarkers of cardiovascular risk in these diseases.

Influenza and pneumococcal vaccination and varicella status in inflammatory arthritis patients.

Patients with inflammatory arthritis are at increased risk of vaccine preventable infections. This risk is increased by immunomodulatory therapies. Vaccination for influenza and pneumococcal disease reduces the risk. Severe cases of varicella infection have occurred in patients on biologic therapies. We sought to identify vaccination rates for commonly acquired infections and to ascertain varicella immune status in patients with inflammatory arthritis. 100 patients with inflammatory arthritis were administered a standardised questionnaire. Data collected included age, diagnosis, vaccination history, history of varicella, treatment and the presence of other indications for vaccination. 58 patients (58%) had not received the influenza vaccine in the past year. Only 19 patients (19%) had ever received pneumococcal vaccine. Anti TNF use did not predict vaccination (p = .46). An increasing number of co morbid conditions predicted both pneumococcal (p < 0.003) and influenza vaccine (p < 0.03) administration. Nineteen patients (19%) gave no history of varicella infection, none having had varicella titres checked pre treatment. Immunisation rates in patients with inflammatory arthritis on immunosuppressive therapies are low. Immunisation schedules should be available for each patient during rheumatology and general practice consultations.

Verbal self-regulation over time in preschool children at risk for attention and behavior problems.

This study is a prospective, longitudinal attempt to explore behavioral self-regulation, private speech, and speech-action coordination in a sample of behaviorally at-risk preschool children. Preschoolers (N = 72) were classified at age 3 years into a behaviorally at-risk group or a comparison group on the basis of preschool teacher behavioral ratings. Children were videotaped on four different occasions across the span of almost 2 years as they completed problem-solving tasks, and private speech, task performance, executive functioning, and speech-action coordination were analyzed. Children identified 2 years earlier as being hard to manage were at risk for continued behavior problems at elementary school entry. Behaviorally at-risk children consistently used more spontaneous private speech than comparison children across all observations. Both groups of children demonstrated a pattern of increasing silence with task success over time. No group differences were observed in children's speech-action coordination at age 5 years. Intraindividual developmental changes in private speech for both groups were associated with task performance, speech-action coordination, and executive functioning at age 5, but not with teacher- and parent-reported problem behavior.

Dermatologist and electrologist perspectives on laser procedures by nonphysicians.

BACKGROUND: As hair removal technology continues to evolve and new equipment comes to market, conflicts may develop between dermatologists and electrologists regarding the professional control and use of these devices. METHODS: A total of 1004 Fellows of the American Academy of Dermatology and 719 electrologists from the southern United States were anonymously surveyed about clinical laser procedures (CLPs). RESULTS: Compared to electrologists, dermatologists were more likely to support clinical laser regulations that placed licensed physicians in control (P =.001) and preferred that a delegating physician be physically present on the premises when CLPs were performed (P =.001). If a laser device was invented for permanent hair removal that was identical to traditional needle/probe electrolysis in every respect except energy type ("laser fiberoptic probe," LFP), electrologists were more likely than dermatologists to support independent use of this device by electrologists (P =.001). A greater percentage of electrologists from Texas, a state without electrolysis licensing, were more likely to support the unlicensed use of the LFP and CLPs than electrologists from states requiring electrolysis licensing. CONCLUSIONS: These data are consistent with previously published literature and permit a greater understanding of the multiple attitudinal, regulatory, and ethical issues involved when considering delegated and independent CLPs by electrologists.

Mother-child interaction, private speech, and task performance in preschool children with behavior problems.

The purpose of the present study was to explore patterns of mother-child interaction, children's private speech use, and behavioral self-regulation among a sample of preschool children identified by their preschool teachers as evidencing behavior problems. Forty preschoolers were classified into two groups (behaviorally at-risk and a matched comparison group) on the basis of teacher ratings of impulsivity, inattention, and hyperactivity. Children completed a magnet board puzzle task once in collaboration with their mother and once individually, and maternal and child speech and behavior were coded from videotapes. Although there were no group differences in children's behavior or speech during the collaborative session, nor were there differences in children's individual task performance or on-task attention, mother-child interaction involving behaviorally at-risk children was characterized by more other-regulation, negative control, less praise, and less physical withdrawal over time, compared to interactions involving comparison children. Behaviorally at-risk children, compared to controls, used more overt, task-relevant private speech during individual problem solving. Partially internalized private speech use among at-risk preschoolers was positively associated with task performance. Group differences rather than similarities prevailed in terms of the relations between maternal behavior, child speech, and child performance.

Beach holiday sunburn: the sunscreen paradox and gender differences.

A survey about sunbathing practices was performed on a summer holiday weekend at a Galveston beach. The likelihood of sunburn increased with increasing duration of sun exposure, with 100% of subjects experiencing sunburn after exposure > or = 4.5 hours. Men exhibited a significantly higher frequency of sunburn, employed fewer sun-protective measures, and demonstrated less knowledge concerning sun safety information and skin cancer than women. This information suggests a need for greater educational efforts directed toward changing public attitudes about preventing sunburn, especially those of men, that currently lead to high-risk sunbathing behavior.

Characterization of an intron splice enhancer that regulates alternative splicing of human GH pre-mRNA.

Splicing of pre-mRNA transcripts is regulated by consensus sequences at intron (intervening sequence, IVS) boundaries and the branch site. In vitro studies have shown that the small introns of some genes also require intron splice enhancers (ISE) to modulate splice site selection. An autosomal dominant form of isolated GH deficiency (IGHD-II) is caused by mutations in IVS3 of the GH-1 gene that cause exon 3 (E3) skipping, resulting in truncated hGH products that prevent secretion of normal hGH. Interestingly, some of these IGHD-II mutations perturb an ISE that is buried in IVS3. We localized this ISE by quantitating the effects of deletions within IVS3 on E3 skipping. The importance of individual nucleotides to ISE function was determined by analyzing the effects of point mutants and additional deletions. Our results show that (i) an ISE with a G2X1-4G3motif resides in IVS3 of GH-1; (ii) both runs of Gs are required for ISE function; (iii) a single copy of the ISE regulates E3 skipping and (iv) ISE function can be modified by an adjacent AC element. Our findings reveal a new mechanism by which mutations can cause inherited human endocrine disorders and suggest that (i) ISEs may regulate splicing of transcripts of other genes and (ii) mutations of these ISEs or of the trans -acting factors that bind them may cause other genetic disorders.

A novel mechanism of aberrant pre-mRNA splicing in humans.

Eukaryotic pre-mRNA splicing is regulated by consensus sequences at the intron boundaries and branch site. Recently, Sirand-Pugnet et al. reported the importance of an additional intronic sequence, an (A/U)GGG repeat in chicken beta-tropomyosin that is a binding site for a protein required for spliceosome assembly. Interestingly, we have detected mutations in IVS3 of the human growth hormone (GH) gene that affect a putative, homologous consensus sequence and which also perturb splicing. In a series of dominant-negative GH mutations that cause exon skipping, we found two mutations that do not occur within the 5' and 3' splice sites, or branch consensus sites. The first mutation is a G-->A transition of the 28th base (+28G-->A) of and the second deletes 18 bp (del+28-45) of IVS3 of the human GH gene. These mutations segregated with autosomal dominant GH deficiency in both kindreds and no other allelic GH gene changes were detected. RT-PCR amplification of transcripts from expression vectors containing the +28G-->A or del+28-45 alleles yielded products showing a >10-fold preferred use of alternative splicing, similar to findings previously reported for IVS3 donor site mutations. Both mutations are located 28 bp downstream from the 5' splice site and examination of the sequences perturbed revealed an intronic XGGG repeat similar to the repeat found to regulate mRNA splicing in chicken beta-tropomyosin. Interestingly, the XGGG repeats involved in our mutations exhibit homologous spacing to those in a so-called 'winner' RNA sequence. Binding of A1 heterogeneous nuclear ribonucleoprotein (hnRNP) by 'winner' sequences in pre-mRNA transcripts is thought to play an important role in pre-mRNA packaging and transport as well as 5' splice site selection in pre-mRNAs that contain multiple 5' splice sites. Our findings suggest that (i) XGGG repeats may regulate alternative splicing in the human GH gene and (ii) mutations of these repeats cause GH deficiency by perturbing alternative splicing. Mutations of homologous intron sequences may underlie other human diseases.