Purpose: Until recently the role of germline genetics in prostate cancer care was not well defined. While important questions remain, we reviewed the current understanding of germline genetic alterations related to prostate cancer. We discuss the clinical implications for genetic counseling, genetic testing, early detection and treatment in men with these mutations. Materials and Methods: We searched PubMedÒ for English language articles published since 2001 with the key words "germline mutations," "BRCA," "family history" or "prostate cancer genetics." We also used relevant data from websites, including the Centers for Medicare and Medicaid Services, National Comprehensive Cancer NetworkÒ, Bureau of Labor Statistics and National Society of Genetic Counselors websites. Results: A number of germline mutations in DNA damage repair genes (BRCA1, BRCA2, CHEK2, ATM and PALB2) and in DNA mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) can drive the development of prostate cancer. Careful genetic counseling coupled with multipanel gene testing can help identify men with these mutations and provide enhanced understanding of the disease risk. Cascade testing of family members can then have an impact extending well beyond the index patient. In men with a pathogenic germline mutation the optimal early detection paradigm is not well defined. Data from the IMPACT study (ClinicalTrials.gov NCT00261456) that the cancer detection rate is substantially elevated in BRCA1 and BRCA2 carriers at prostate specific antigen greater than 3 ng/ml has helped establish the importance of close prostate specific antigen screening in these men. Additionally, BRCA2 and likely other DNA damage repair mutations are associated with aggressive disease, although it is not yet clear how this impacts localized disease management. However, there is strong evidence that patients with metastatic, castration resistant prostate cancer who have DNA damage repair defects respond positively to targeting PARP enzymes. In many cancers there is also evidence that patients with an increased tumor mutational burden, such as in Lynch syndrome, are particularly sensitive to immune checkpoint inhibitors. Conclusions: Emerging evidence supports the implementation of germline genetic counseling and testing as a key component of prostate cancer management. Further research is needed to elucidate the clinical significance of lesser known germline mutations and develop optimal screening, early detection and treatment paradigms in this patient population.
Background:Severe crouch gait in adolescent cerebral palsy is a difficult problem to manage. The patients develop loading of patellofemoral joint, leading to pain, gait deviation, excessive energy expenditure and progressive loss of function. Patella alta and avulsion of patella are the other complications. Different treatment options have been described in the literature to deal with this difficult problem. We evaluated outcome of supracondylar femoral extension osteotomy (SCFEO) and patellar tendon advancement (PTA) in the treatment of crouch gait in patients with cerebral palsy.Materials and Methods:Fourteen adolescents with crouch gait were operated by SCFEO and PTA. All subjects were evaluated pre and postoperatively. Clinical, radiographic, observational gait analysis and functional measures were included to assess the changes in knee function.Results:Cases were followed up to 3 years. The patients walked with increased knee extension and improvement in quadriceps muscle strength. Knee pain was decreased and improvements in functional mobility and radiologic improvement were found.Conclusion:SCFEO and PTA for adolescent crouch gait is effective in improving knee extensor strength, reducing knee pain and improving function.
printing of pelvic fracture urethral injuries-fusion of technology and urethroplasty.
The dopamine transporter (DAT) plays an integral role in dopamine neurotransmission through the clearance of dopamine from the extracellular space. Dysregulation of DAT is central to the pathophysiology of numerous neuropsychiatric disorders and as such is an attractive therapeutic target. DAT belongs to the solute carrier family 6 (SLC6) class of Na+/Cl− dependent transporters that move various cargo into neurons against their concentration gradient. This review focuses on DAT (SCL6A3 protein) while extending the narrative to the closely related transporters for serotonin and norepinephrine where needed for comparison or functional relevance. Cloning and site-directed mutagenesis experiments provided early structural knowledge of DAT but our contemporary understanding was achieved through a combination of crystallization of the related bacterial transporter LeuT, homology modeling, and subsequently the crystallization of drosophila DAT. These seminal findings enabled a better understanding of the conformational states involved in the transport of substrate, subsequently aiding state-specific drug design. Post-translational modifications to DAT such as phosphorylation, palmitoylation, ubiquitination also influence the plasma membrane localization and kinetics. Substrates and drugs can interact with multiple sites within DAT including the primary S1 and S2 sites involved in dopamine binding and novel allosteric sites. Major research has centered around the question what determines the substrate and inhibitor selectivity of DAT in comparison to serotonin and norepinephrine transporters. DAT has been implicated in many neurological disorders and may play a role in the pathology of HIV and Parkinson’s disease via direct physical interaction with HIV-1 Tat and α-synuclein proteins respectively.
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