Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Kallikrein 4 (hK4) and prostate-specific antigen (PSA) are associated with the loss of E-cadherin and an epithelial-mesenchymal transition (EMT)-like effect in prostate cancer cells.

Prostate-specific antigen (PSA) and the related kallikrein family of serine proteases are current or emerging biomarkers for prostate cancer detection and progression. Kallikrein 4 (KLK4/hK4) is of particular interest, as KLK4 mRNA has been shown to be elevated in prostate cancer. In this study, we now show that the comparative expression of hK4 protein in prostate cancer tissues, compared with benign glands, is greater than that of PSA and kallikrein 2 (KLK2/hK2), suggesting that hK4 may play an important functional role in prostate cancer progression in addition to its biomarker potential. To examine the roles that hK4, as well as PSA and hK2, play in processes associated with progression, these kallikreins were separately transfected into the PC-3 prostate cancer cell line, and the consequence of their stable transfection was investigated. PC-3 cells expressing hK4 had a decreased growth rate, but no changes in cell proliferation were observed in the cells expressing PSA or hK2. hK4 and PSA, but not hK2, induced a 2.4-fold and 1.7-fold respective increase, in cellular migration, but not invasion, through Matrigel, a synthetic extracellular matrix. We hypothesised that this increase in motility displayed by the hK4 and PSA-expressing PC-3 cells may be related to the observed change in structure in these cells from a typical rounded epithelial-like cell to a spindle-shaped, more mesenchymal-like cell, with compromised adhesion to the culture surface. Thus, the expression of E-cadherin and vimentin, both associated with an epithelial-mesenchymal transition (EMT), was investigated. E-cadherin protein was lost and mRNA levels were significantly decreased in PC-3 cells expressing hK4 and PSA (10-fold and 7-fold respectively), suggesting transcriptional repression of E-cadherin, while the expression of vimentin was increased in these cells. The loss of E-cadherin and associated increase in vimentin are indicative of EMT and provides compelling evidence that hK4, in particular, and PSA have a functional role in the progression of prostate cancer through their promotion of tumour cell migration.

Self injurious behaviour in Tourette syndrome: correlates with impulsivity and impulse control.

BACKGROUND: Self injurious behaviour (SIB), the deliberate, repetitive infliction of self harm, is present in a wide variety of neuropsychiatric disorders, including Tourette syndrome (TS). Although SIB occurs in up to 60% of individuals with TS, and can cause significant clinical impairment and distress, little is known about its aetiology. OBJECTIVE: This study examined the relationship between SIB and other behavioural features that commonly co-occur with TS in nearly 300 subjects with TS participating in three genetic studies. SIB, obsessions, compulsions, tic severity, attention deficit hyperactivity disorder related impulsivity, risk taking behaviours, and rages were systematically assessed in all subjects. METHODS: Using logistic regression, a best fit model was determined for both mild to moderate SIB and severe SIB. RESULTS: Mild/moderate SIB in TS was correlated with the presence of obsessive and compulsive symptoms such as the presence of aggressive obsessions or violent or aggressive compulsions, and with the presence of obsessive-compulsive disorder and overall number of obsessions. Severe SIB in TS was correlated with variables related to affect or impulse dysregulation; in particular, with the presence of episodic rages and risk taking behaviours. Both mild/moderate and severe SIB were also correlated with tic severity. CONCLUSIONS: This study suggests that mild/moderate and severe SIB in TS may represent different phenomena, which has implications for clinical management of these symptoms.

Co-expression of GH and GHR isoforms in prostate cancer cell lines.

Prostate cancer is a significant cause of morbidity and mortality in Western males. While it is known that androgens play a central role in prostate cancer development and progression, other hormones and growth factors are also involved in prostate growth. Insulin-like growth factor-I (IGF-I) plasma levels have been associated with prostate cancer risk, and growth hormone (GH), a major factor regulating IGF levels, also appears to have a role in prostate cancer cell growth. Most significantly, GH has been shown to increase the rate of cell proliferation in prostate cancer cell lines. We have now demonstrated the co-expression of GH and GH receptor (GHR) mRNA isoforms in the ALVA41, PC3, DU145, LNCaP prostate cancer cells by reverse transcription polymerase chain reaction. Sequence analysis has confirmed that these cell lines express the pituitary form of GH mRNA and also the placental mRNA isoform. These prostate cancer cell lines also express the full-length mRNA for the GHR and the exon 3 deleted isoform. We have also demonstrated the presence of GH and GHR proteins in these cell lines by immunohistochemistry. GH expression has not been described previously in human prostate cancer cells. The co-expression of GH and its receptor would enable an autocrine-paracrine pathway to exist in the prostate that would be capable of stimulating prostate growth, either directly via the GHR or indirectly via IGF production. The GH axis in the prostate could therefore be an important additional target for the future development of prostate cancer therapies.

Structure-function relationships for inhibitors of beta-amyloid toxicity containing the recognition sequence KLVFF.

Beta-amyloid (Abeta), the primary protein component of Alzheimer's plaques, is neurotoxic when aggregated into fibrils. We have devised a modular strategy for generating compounds that inhibit Abeta toxicity. These compounds contain a recognition element, designed to bind to Abeta, linked to a disrupting element, designed to interfere with Abeta aggregation. On the basis of this strategy, a hybrid peptide was synthesized with the sequence KLVFF (residues 16-20 of Abeta) as the recognition element and a lysine hexamer as the disrupting element; this compound protects cells in vitro from Abeta toxicity [Pallitto, M. M., et al. (1999) Biochemistry 38, 3570]. To determine if the length of the disrupting element could be reduced, peptides were synthesized that contained the KLVFF recognition element and a sequence of one to six lysines as disrupting elements. All compounds enhanced the rate of aggregation of Abeta, with the magnitude of the effect increasing as the number of lysines in the disrupting element increased. The greatest level of protection against Abeta toxicity was achieved with compounds containing disrupting elements of three or more lysines in sequence. A peptide with an anionic disrupting element, KLVFFEEEE, had activity similar to that of KLVFFKKKK, in both cellular toxicity and biophysical assays, whereas a peptide with a neutral polar disrupting element, KLVFFSSSS, was ineffective. Protective compounds retained activity even at an inhibitor:Abeta molar ratio of 1:100, making these some of the most effective inhibitors of Abeta toxicity reported to date. These results provide critical insight needed to design more potent inhibitors of Abeta toxicity and to elucidate their mechanism of action.

Cultural influences on diagnosis and perception of Tourette syndrome in Costa Rica.

BACKGROUND AND OBJECTIVES: Tourette syndrome (TS) is a neuropsychiatric disorder in which the pattern of symptom presentation can vary greatly between individuals. Although globally described, TS has not been well characterized in many parts of the world. Differences in individual and cultural perceptions of TS may impact its expression and recognition in some countries, confounding the identification of affected individuals. This study examines the phenomenology and presentation of TS in Costa Rica. METHOD: Clinical data on 85 Costa Rican subjects with TS (aged 5-29 years) initially recruited for a genetic study between 1996 and early 2000 were obtained by direct interview and review of medical records. RESULTS: The clinical characteristics of TS were similar to that found elsewhere. The gender ratio was 4.6:1, the mean age of onset was 6.1 years, and 20% of subjects had coprolalia. However, the perceived impact of TS was different. Many subjects denied that their TS caused impairment or distress, even when objective evidence of impairment was available. CONCLUSIONS: TS in Costa Rica is phenomenologically similar to TS seen in other parts of the world, but differs in perceived impairment. In other countries where cultural forces affect disease definition, close scrutiny of symptom expression and possible adjustment of phenotype definition may be important.

Depressed mood during pregnancy and the puerperium: clinical recognition and implications for clinical practice.

Mild to moderate depression is common among women during the first 3 months postpartum. The authors studied 20 normal pregnant women in the hope of finding valid predictors of postpartum mood disorder. The subjects rated their level of emotions and various depressive symptoms at 26 and 36 weeks of pregnancy and filled out a brief questionnaire about the emotional circumstances of their pregnancy. The mood scales were repeated at 2 days and 6 weeks postpartum, along with a clinical interview. The antepartum mood scale identified women with postpartum depression and differentiated this condition from the more common, transient postpartum blues. Certain psychosocial variables also predicted postpartum distress. The authors discuss the implications of these findings, emphasizing the feasibility and necessity of routine screening for mood disturbances in prenatal and puerperal women.

Stimulant medications precipitate Tourette's syndrome.

Following treatment with stimulant medications for symptoms of attention deficit disorder, Gilles de la Tourette's syndrome occurred in 15 patients. Early signs of Tourette's syndrome may be difficult to distinguish from hyperactive and attention disordered symptoms, leading the clinician to consider treatment with stimulants. In these Tourette's-susceptible patients, stimulants may exacerbate severe motor and phonic tics, requiring discontinuation of administration of stimulants and institution of haloperidol therapy for tic control. Clinical evaluation for tics and Tourette's syndrome in children and their families should precede and dictate use of stimulant medications in children.

Stimulant medications precipitate Tourette's syndrome.

Following treatment with stimulant medications for symptoms of attention deficit disorder, Gilles de la Tourette's syndrome occurred in 15 patients. Early signs of Tourette's syndrome may be difficult to distinguish from hyperactive and attention disordered symptoms, leading the clinician to consider, treatment with stimulants. In these Tourette's-susceptible patients, stimulants may exacerbate severe motor and phonic tics, requiring discontinuation of administration of stimulants and institution of haloperidol therapy for tic control. Clinical evaluation for tics and Tourette's syndrome in children and their families should precede and dictate use of stimulant medications in children.

Thyroid hormone in autistic children.

Thyroid hormone plays an important role in the pre- and postnatal development and function of the central nervous system. Disturbances in thyroid hormone regulation have been hypothesized in childhood autism. We evaluated blood indices of thyroid function, including serum thyroxine, triiodothyronine, and thyroid-stimulating hormone, in a large population of autistic children. No differences were found between autistic and normal children.

Detection of phenylketonuria in autistic and psychotic children.

Sixty-five children with pervasive developmental disturbance (autism and atypical childhood psychosis) were screened by standard urinary amino acid detection testing methods. Three of the children showed abnormalities in these screening tests, leading to the diagnosis of phenylketonuria. This was verified by repeated urinary testing and blood phenylalanine determinations. The children with phenylketonuria were treated with low-phenylalanine diets and have shown improvement in functioning and developmental level since treatment. Urinary genetic screening should be a standard test for all children being evaluated for serious developmental disturbances of childhood.

Quantitation of Neisseria gonorrhoeae from women with gonorrhea.

The number of infecting organisms has been shown to be an important variable in animal models of infection with Neisseria gonorrhoeae. This variable may also be important in the natural transmission of gonorrhea in humans. The number of gonococci in the cervicovaginal area of women with gonorrhea is unknown, as are the effects of certain physiologic or therapeutic variables on the number of gonococci. In this study a semiquantitative technique for the enumeration of N. gonorrhoeae was used; 10 ml of phosphate-buffered saline was directed against the cervix and vaginal wall, and the number of colony-forming units (cfu) of N. gonorrhoeae in the aspirate was determined. The number of N. gonorrhoeae recovered ranged from 4.0 X 10(2) to 1.8 X 10(7) cfu. The geometric mean number was 1.45 X 10(5) cfu, with a standard deviation of 1.04 X 10(1) cfu. Statistical analyses showed that the number of gonococci was not influenced by the use of oral contraceptives, concurrent infection with Trichomonas vaginalis and/or Corynebacterium (Haemophilus)vaginalis, time of douche prior to examination, or phase of the menstrual cycle at which the women were examined. The results indicated a wide range in the number of N. gonorrhoeae recoverable by vaginal irrigation but failed to define the reason for this variability.