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41.
Genetic analysis provides specific etiologic information about disease that cannot be deduced by clinical and pathologic investigations alone. Two large families have been characterized with multi-system degeneration: rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration (PPND) and disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC). Linkage analysis identified a locus, wld, on-17q21-22 that is responsible for DDPAC. Analysis of a PPND family shows that PPND is also due to a gene on 17q21-22. Comparison of genealogic, clinical, diagnostic, and pathologic data shows that DDPAC and PPND are distinct disorders suggesting two different mutations in wld. Literature review identifies many kindreds with multi-system degeneration that may be allelic. 相似文献
42.
German-Canadian family (family A) with parkinsonism, amyotrophy, and dementia - Longitudinal observations 总被引:2,自引:0,他引:2
Wszolek ZK Vieregge P Uitti RJ Gasser T Yasuhara O McGeer P Berry K Calne DB Vingerhoets FJ Klein C Pfeiffer RF 《Parkinsonism & related disorders》1997,3(3):125-139
Etiology of Parkinson's disease (PD), amyotrophy lateral sclerosis (ALS), and Alzheimer's disease (AD) remains uncertain. Environmental factors probably play a role, but genetic influences may predispose certain individuals to develop each of these major neurodegenerative disorders. We describe our longitudinal observations concerning a Canadian family traced to Northern Germany. Autosornal dominant inheritance has been established. Affected members present with L-dopa responsive parkinsonism and amyotrophy. In the German portion of the family some individuals displayed only dementia or focal dystonia. Linkage analysis studies performed with polymorphic markers associated with 13 candidate genes provided no significant evidence for linkage with any of the genes examined. Positron emission tomography with [(18)F]-6-fluoro-L-dopa (FD) and [su11C]-raclopride (raclopride) of one affected subject revealed reduced striatal FD uptake particularly in putamen, and an increased raclopride striatum/background ratio. Postmortem levels of dopamine and its metabolites were greatly reduced in caudate and putamen of two patients. There was substantial neuronal loss in the substantia nigra and the presence of abundant eosinophilic granules (different than Lewy bodies) in surviving neurons. One of them also showed mild loss of anterior horn cells, while another showed abundant senile plaques and some neurofibrillary tangles in distribution and intensity typical of mild to moderate AD. Our report further describes this unique family with a combination of clinical features of PD, ALS, and AD. By studying kindreds like this we may learn more about the pathophysiology of sporadic forms of PD, ALS, or even AD. 相似文献
43.
Nicholas J. Giacalone William U. Shipley Rebecca H. Clayman Andrzej Niemierko Michael Drumm Niall M. Heney Marc D. Michaelson Richard J. Lee Philip J. Saylor Matthew F. Wszolek Adam S. Feldman Douglas M. Dahl Anthony L. Zietman Jason A. Efstathiou 《European urology》2017,71(6):952-960
Background
Tri-modality therapy (TMT) is a recognized treatment strategy for selected patients with muscle-invasive bladder cancer (MIBC).Objective
Report long-term outcomes of patients with MIBC treated by TMT.Design, setting, and participants
Four hundred and seventy-five patients with cT2–T4a MIBC were enrolled on protocols or treated as per protocol at the Massachusetts General Hospital between 1986 and 2013.Intervention
Patients underwent transurethral resection of bladder tumor followed by concurrent radiation and chemotherapy. Patients with less than a complete response (CR) to chemoradiation or with an invasive recurrence were recommended to undergo salvage radical cystectomy.Outcome measurements and statistical analysis
Disease-specific survival (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method.Results and limitations
Median follow-up for surviving patients was 7.21 yr. Five- and 10-yr DSS rates were 66% and 59%, respectively. Five- and 10-yr OS rates were 57% and 39%, respectively. The risk of salvage cystectomy at 5 yr was 29%. In multivariate analyses, T2 disease (OS hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.44–0.75, DSS HR: 0.51, 95% CI: 0.36–0.73), CR to chemoradiation (OS HR: 0.61, 95% CI: 0.46–0.81, DSS HR: 0.49, 95% CI: 0.34–0.71), and presence of tumor-associated carcinoma in situ (OS HR: 1.56, 95% CI: 1.17–2.08, DSS HR: 1.50, 95% CI: 1.03–2.17) were significant predictors for OS and DSS. When evaluating our cohort over treatment eras, rates of CR improved from 66% to 88% and 5-yr DSS improved from 60% to 84% during the eras of 1986–1995 to 2005–2013, while the 5-yr risk of salvage radical cystectomy rate decreased from 42% to 16%.Conclusions
These data demonstrate high rates of CR and bladder preservation in patients receiving TMT, and confirm DSS rates similar to modern cystectomy series. Contemporary results are particularly encouraging, and therefore TMT should be discussed and offered as a treatment option for selected patients.Patient summary
Tri-modality therapy is an alternative to radical cystectomy for patients with muscle-invasive bladder cancer, and is associated with comparable long-term survival and high rates of bladder preservation. 相似文献44.
45.
46.
Ischemia-reperfusion injury caused by vascular clamping contributes to the decline in glomerular filtration rate following partial nephrectomy. Ischemia is the main modifiable factor that determines postoperative kidney function, and it is likely that a harmless duration of ischemia does not exist. Each additional minute of warm ischemia increases the odds of acute renal failure, severe chronic kidney disease (CKD) and end-stage renal disease. Our experience comparing partial nephrectomy with and without clamping in solitary kidneys suggests that renovascular clamping is the only statistically significant determinant of postoperative renal dysfunction. Studies comparing partial nephrectomy with and without clamping demonstrate that ischemia is associated with a risk of acute renal failure, advanced CKD, and renal replacement therapy. Oncologic outcomes and complications in partial nephrectomy without clamping are similar to those with clamping. Even in complex lesions, partial nephrectomy without vascular clamping is preferable when feasible. 相似文献
47.
Puschmann A Verbeeck C Heckman MG Soto-Ortolaza AI Lynch T Jasinska-Myga B Opala G Krygowska-Wajs A Barcikowska M Uitti RJ Wszolek ZK Ross OA 《Parkinsonism & related disorders》2011,17(5):376-378
A role for the immune system in the pathogenesis of Parkinson's Disease (PD) has previously been suggested. A recent genome-wide association (GWA) study identified an association between one single nucleotide polymorphism (SNP) in the human leucocyte antigen (HLA) region (HLA-DRA rs3129882) and PD in a population of American patients with European ancestry. In that study, the minor rs3129882 allele (G) was associated with an increased risk of PD under an additive model. Due to the increased likelihood of obtaining false positive results in GWA studies compared to studies conducted based on a hypothesis-driven approach, repeated validation of findings from GWA studies are necessary. Herein, we evaluated the association between rs3129882 and PD in three different Caucasian patient-control series (combined 1313 patients and 1305 controls) from the US, Ireland, and Poland. We observed no association (OR: 0.96, P = 0.50) between rs3129882 and PD when analyzing our data under an additive or dominant model. In contrast, when examined under a recessive model, the GG genotype was observed to be protective in the Irish (OR: 0.55, P = 0.008), Polish (OR: 0.67, P = 0.040) and combined (OR: 0.75, P = 0.006) patient-control series. In view of these diverging results, the exact role of genetic variation at the HLA region and susceptibility to PD remains to be resolved. 相似文献
48.
49.
Carles Vilariño-Güell Christian Wider Owen A. Ross Barbara Jasinska-Myga Jennifer Kachergus Stephanie A. Cobb Alexandra I. Soto-Ortolaza Bahareh Behrouz Michael G. Heckman Nancy N. Diehl Claudia M. Testa Zbigniew K. Wszolek Ryan J. Uitti Joseph Jankovic Elan D. Louis Lorraine N. Clark Alex Rajput Matthew J. Farrer 《Neurogenetics》2010,11(4):401-408
Genetic variation in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was recently associated with an increased risk of developing essential tremor (ET) and Parkinson disease (PD). Herein, we performed a comprehensive study of LINGO1 and its paralog LINGO2 in ET and PD by sequencing both genes in patients (ET, n?=?95; PD, n?=?96) and by examining haplotype-tagging single-nucleotide polymorphisms (tSNPs) in a multicenter North American series of patients (ET, n?=?1,247; PD, n?=?633) and controls (n?=?642). The sequencing study identified six novel coding variants in LINGO1 (p.S4C, p.V107M, p.A277T, p.R423R, p.G537A, p.D610D) and three in LINGO2 (p.D135D, p.P217P, p.V565V), however segregation analysis did not support pathogenicity. The association study employed 16 tSNPs at the LINGO1 locus and 21 at the LINGO2 locus. One variant in LINGO1 (rs9652490) displayed evidence of an association with ET (odds ratio (OR)?=?0.63; P?=?0.026) and PD (OR?=?0.54; P?=?0.016). Additionally, four other tSNPs in LINGO1 and one in LINGO2 were associated with ET and one tSNP in LINGO2 associated with PD (P?<?0.05). Further analysis identified one tSNP in LINGO1 and two in LINGO2 which influenced age at onset of ET and two tSNPs in LINGO1 which altered age at onset of PD (P?<?0.05). Our results support a role for LINGO1 and LINGO2 in determining risk for and perhaps age at onset of ET and PD. Further studies are warranted to confirm these findings and to determine the pathogenic mechanisms involved. 相似文献