Kelli Williamson

Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease

Background: The vast majority of the parkin mutations previously identified have been found in individuals with juvenile or early onset PD. Previous screening of later onset PD cohorts has not identified substantial numbers of parkin mutations. Methods: Families with at least two siblings with PD were ascertained to identify genes contributing to PD susceptibility. Screening of the parkin gene, by both quantitative PCR and exon sequencing, was performed in those families with either early onset PD (age onset ≤50 years) or positive lod score with a marker in intron 7 of the parkin gene. Results: A total of 25 different mutations in the parkin gene were identified in 103 individuals from 47 families. Mutations were found in both parkin alleles in 41 of the individuals, whereas a single mutation in only one of the two parkin alleles was observed in 62 individuals. Thirty-five of the subjects (34%) with a parkin mutation had an age at onset of 60 years or above with 30 of these 35 (86%) having a detectable mutation on only one parkin allele. Few significant clinical differences were observed among the individuals with two, one, or no mutated copies of the parkin gene. Conclusion: Mutations in the parkin gene occur among individuals with PD with an older age at onset (≥60 years) who have a positive family history of the disease. In addition, the clinical findings of parkin-positive individuals are remarkably similar to those without mutations.

Significant Linkage of Parkinson Disease to Chromosome 2q36-37

Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility.

Rasagiline improves quality of life in patients with early Parkinson's disease

The objective of this study was to determine the effects of rasagiline as monotherapy on quality of life (QOL) in patients with early Parkinsons disease (PD). Rasagiline, a potent, second‐generation, irreversible, selective monoamine oxidase B inhibitor improves PD symptoms in patients with early PD. Patients with early untreated PD were randomly assigned to once‐daily rasagiline 1 mg/day, rasagiline 2 mg/day, or placebo in a 6‐month, double‐blind trial (n = 404). At the end of 6 months, patients entered the preplanned, active‐treatment phase in which those receiving 1 mg/day and 2 mg/day of rasagiline continued on their previously assigned dosages and those receiving placebo switched to rasagiline 2 mg/day, while maintaining blinding to treatment assignments. QOL was measured with the Parkinsons Disease Quality of Life questionnaire (PDQUALIF) at 0, 14, 26, and 52 weeks after randomization. Analysis of the change in PDQUALIF scores from baseline to 6 months showed adjusted treatment effects (with 95% confidence interval) favoring rasagiline over placebo of −2.91 units (−5.19, −0.64, P = 0.01) for the 1 mg/day group and −2.74 units (−5.02, −0.45, P = 0.02) for the 2 mg/day. Subscore analysis attributed most of this benefit to the self‐image/sexuality domain. At 12 months (n = 266), with all groups receiving rasagiline for at least 6 months, no significant differences in PDQUALIF scores were seen between groups. Rasagiline improved QOL compared with placebo. This QOL improvement appears to be accounted for primarily by the symptomatic benefit of rasagiline.

Evaluation of the role of Nurr1 in a large sample of familial Parkinson's disease.

Parkinsons disease (PD) is a common neurodegenerative disorder in humans with wide variability in the age of disease onset. Although the disease has been thought previously to occur sporadically in most patients, there is increasing evidence of a genetic contribution to the disorder. Recently, a polymorphic variant within intron 6 of the Nurr1 gene was reported to be associated with sporadic and familial PD. In an effort to identify susceptibility genes for PD, we have collected 783 PD patients from 372 families and 397 healthy controls from 217 families. PD patients and healthy controls were genotyped for the intron 6 insertion polymorphism by BseRI restriction endonuclease digestion. No significant difference in either homozygosity or heterozygosity for the 7048G7049 (IVS6 1361 +16insG) polymorphism was detected in the PD patient cohort as compared with the panel of healthy controls. Moreover, direct sequencing of exon 1 of the Nurr1 gene in PD patients failed to detect either of the two recently reported Nurr1 mutations identified in a small subset of a PD patient cohort. Taken together, these data suggest that genetic alteration at the Nurr1 locus is not a significant risk factor for the development of Parkinsons disease in our large sample of familial PD patients.

Screening for domestic violence: practice patterns, knowledge, and attitudes of physicians in Arizona

Objectives: Victims of domestic violence presenting for health care are frequently referred to medical specialists, but little is known about domestic violence screening among specialists. The aim of this study was to evaluate attitudes and behaviors concerning domestic violence of all physicians in Arizona. Methods: A cross-sectional survey of 2,244 physicians from 13 medical specialties describes domestic violence screening practices, attitudes, and behaviors of practicing physicians in Arizona. Results: Among 976 respondents, 56% reported prior education on domestic violence screening; 50.5% rarely or never screen their female patients for domestic violence; and 52% reported their competence for providing treatment for victims as poor to fair. Physicians from emergency medicine, psychiatry, obstetrics/gynecology, and family practice reported higher rates of domestic violence education, screening, awareness of services, and competence at treating victims. Physical medicine/rehabilitation, anesthesiology/pain control, surgical subspecialty, medicine subspecialty, general surgery, and orthopedic physicians scored lowest on these characteristics. Conclusions: Differences in attitudes and behaviors regarding domestic violence screening were noted among specialty groups. Customizing physician training based on these findings may be beneficial.

Additive Inhibitory Effects of Progesterone and Sodium Nitroprusside on Uterine Contractility During Pregnancy

Progesterone (P4) and nitric oxide (NO) suppress uterine contractility (CTX). This study compares the effects of P4 to sodium nitroprusside (SNP, an NO donor) and their combination on human CTX of term/preterm and labor/nonlabor tissues. Uterine tissues (n = 128) from women (n = 28) undergoing Cesarean were suspended in organ baths. Tissues (n ≥ 6/group) were treated with vehicle, P4, SNP, or combinations. A subset of tissues (n ≥ 2/group) from term/preterm ± labor and nonpregnant patients was analyzed with P4 alone. Analysis of variance (ANOVA) was used for statistical differences (P < .05). The combination of P4 with SNP significantly suppresses CTX (% inhibition of −127.1 ± 14.5) to the levels lower than with either P4 (−20.1 ± 8.6) or SNP alone (−72.0 ± 11.2). Suppression of P4 is similar in term, preterm, and nonpregnant tissues, with increased sensitivity in laboring tissues. This indicates that P4 or SNP alone may be used for preterm labor and their combination may be more successful.