Frequency of the Common MYH Mutations (G382D and Y165C) in MMR Mutation Positive and Negative HNPCC Patients

Recently mutations in the MYH gene have been associated with a milder form of adenomatous polyposis which is characterized by a variable level of colonic polyps ranging from a few to several hundred. In the context of HNPCC it is not unusual to identify patients with a smattering of polyps. The MYH gene product is involved in DNA repair and indeed the hMSH2/hMSH6 complex (both genes being essential elements of the DNA mismatch repair pathway) is required to stimulate MYH activity. We reasoned that because of the clinical similarity of a subset of HNPCC patients to those described with MYH mutations and the role of the hMSH2/hMSH6 complex in the activation of MYH protein that MYH mutations may account for a small proportion of HNPCC patients. In a study of 442 HNPCC patients we identified MYH mutations at the same frequency as that expected in the general population. Nevertheless, two HNPCC families were identified harbouring biallelic changes in MYH

The Association of the COMT V158M Polymorphism with Endometrial/Ovarian Cancer in HNPCC Families Adhering to the Amsterdam Criteria

Catechol-O-methyltransferase (COMT) is vital for the conjugation of catechol estrogens that are produced during oestrogen metabolism. The efficiency of this process varies due to a polymorphism in COMT, which changes valine to methionine (V158M). The Met genotypes slow the metabolism of catechol oestrogens, which are agents that are capable of causing DNA damage through the formation of DNA adducts and reactive oxygen species (ROS) production. The slower metabolism of catechol oestrogens results in there being a higher circulating concentration of these oeastrogens and consequently greater probability of DNA damage. To determine whether metabolic inefficiencies of oeastrogen metabolism are associated with the development of malignancy in hereditary non-polyposis colorectal cancer (HNPCC), we studied the V158M polymorphism in COMT in a large cohort of 498 HNPCC patients from Australia and Poland that were either mutation positive (n = 331) or negative (n = 167) for mismatch repair (MMR) gene mutations (hMLH1 or hMSH2). HNPCC is a familial predisposition to colorectal cancer (CRC) and extracolonic cancers that include endometrial cancer

Impaired phagocytosis of apoptotic cells by macrophages in chronic granulomatous disease is reversed by IFN-γ in a nitric oxide-dependent manner

Immunodeficiency in chronic granulomatous disease (CGD) is well characterized. Less understood are exaggerated sterile inflammation and autoimmunity associated with CGD. Impaired recognition and clearance of apoptotic cells resulting in their disintegration may contribute to CGD inflammation. We hypothesized that priming of macrophages (Ms) with IFN-γ would enhance impaired engulfment of apoptotic cells in CGD. Diverse M populations from CGD (gp91(phox)(-/-)) and wild-type mice, as well as human Ms differentiated from monocytes and promyelocytic leukemia PLB-985 cells (with and without mutation of the gp91(phox)), demonstrated enhanced engulfment of apoptotic cells in response to IFN-γ priming. Priming with IFN-γ was also associated with increased uptake of Ig-opsonized targets, latex beads, and fluid phase markers, and it was accompanied by activation of the Rho GTPase Rac. Enhanced Rac activation and phagocytosis following IFN-γ priming were dependent on NO production via inducible NO synthase and activation of protein kinase G. Notably, endogenous production of TNF-α in response to IFN-γ priming was critically required for inducible NO synthase upregulation, NO production, Rac activation, and enhanced phagocytosis. Treatment of CGD mice with IFN-γ also enhanced uptake of apoptotic cells by M in vivo via the signaling pathway. Importantly, during acute sterile peritonitis, IFN-γ treatment reduced excess accumulation of apoptotic neutrophils and enhanced phagocytosis by CGD Ms. These data support the hypothesis that in addition to correcting immunodeficiency in CGD, IFN-γ priming of Ms restores clearance of apoptotic cells and may thereby contribute to resolution of exaggerated CGD inflammation

MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer

Background: Approximately 10% of Lynch syndrome families have a mutation in MSH6 and fewer families have a mutation in PMS2. It is assumed that the cancer incidence is the same in families with mutations in MSH6 as in families with mutations in MLH1/MSH2 but that the disease tends to occur later in life, little is known about families with PMS2 mutations. This study reports on our findings on mutation type, cancer risk and age of diagnosis in MSH6 and PMS2 families. Methods: A total of 78 participants (from 29 families) with a mutation in MSH6 and 7 participants (from 6 families) with a mutation in PMS2 were included in the current study. A database of de-identified patient information was analysed to extract all relevant information such as mutation type, cancer incidence, age of diagnosis and cancer type in this Lynch syndrome cohort. Cumulative lifetime risk was calculated utilising Kaplan-Meier survival analysis. Results: MSH6 and PMS2 mutations represent 10.3% and 1.9%, respectively, of the pathogenic mutations in our Australian Lynch syndrome families. We identified 26 different MSH6 and 4 different PMS2 mutations in the 35 families studied. We report 15 novel MSH6 and 1 novel PMS2 mutations. The estimated cumulative risk of CRC at age 70 years was 61% (similar in males and females) and 65% for endometrial cancer in MSH6 mutation carriers. The risk of developing CRC is different between males and females at age 50 years, which is 34% for males and 21% for females. Conclusion: Novel MSH6 and PMS2 mutations are being reported and submitted to the current databases for identified Lynch syndrome mutations. Our data provides additional information to add to the genotype-phenotype spectrum for both MSH6 and PMS2 mutations

Association of health related quality of life domains with daytime sleepiness among elderly recipients of long-term services and supports

Excessive daytime sleepiness (EDS) is prevalent in older adults; however, data are lacking that examine EDS across living environments. The aims of this secondary data analysis were to identify the prevalence and predictors of EDS among older adults receiving long-term services and supports (LTSS) in assisted living communities (ALCs), nursing homes (NHs), and the community. Participants (n = 470) completed multiple measures including daytime sleepiness. Logistic regression modeling was used to identify EDS predictors. Participants were primarily female and white with a mean age of 81 ± 9 years. The overall prevalence of EDS was 19.4%; the prevalence differed across living environment. Older adults in ALCs and NHs had higher odds of EDS than those living in the community. Also, depressive symptoms and number of bothersome symptoms predicted EDS. Upon admission for LTSS, evaluating older adults, especially those in ALCs and NHs, for depression and bothersome symptoms may reveal modifiable factors of EDS

Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn

PURPOSE: To determine the prevalence of persistent pulmonary hypertension of the newborn (PPHN) among infants whose mothers were exposed to antidepressants in the third trimester of pregnancy compared to the prevalence among infants whose mothers were not exposed to antidepressants in the third trimester. METHODS: A retrospective study was conducted using the automated databases of four health plans participating in the HMO Research Network Center for Education and Research on Therapeutics. Women who delivered an infant in a hospital from 1 January 1996 through 31 December 2000 were identified. The administrative databases were used to identify full-term infants whose mothers received an antidepressant during the third trimester of pregnancy and unexposed infants whose mothers did not receive an antidepressant during the third trimester. Hospitalization data were used to identify diagnoses or procedure codes potentially indicative of PPHN. RESULTS: Among 1104 infants exposed to antidepressants in the third trimester and a matched sample of 1104 unexposed infants, five infants were classified by the expert reviewers as having PPHN. Among those infants whose mothers were exposed to selective serotonin reuptake inhibitors (SSRIs) in the third trimester, the prevalence of PPHN was 2.14 per 1000 (95% confidence interval (CI) 0.26, 7.74), while the prevalence among infants whose mothers were not exposed was 2.72 per 1000 (95%CI 0.56, 7.93). CONCLUSIONS: We did not find an association between SSRI use in late pregnancy and PPHN. Limitations of the present study, including the small number of confirmed cases, suggest further research in this area may be warranted