RESUMO
Genetic testing of an Irish kindred identified an exonic nucleotide substitution c.1664T>C (p.Leu555Pro) in the MLH1 mismatch repair (MMR) gene. This previously unreported variant is classified as a "variant of uncertain significance" (VUS). Immunohistochemical (IHC) analysis and microsatellite instability (MSI) studies, genetic testing, a literature and online MMR mutation database review, in silico phenotype prediction tools, and an in vitro MMR activity assay were used to study the clinical significance of this variant. The MLH1 c.1664T>C (p.Leu555Pro) VUS co-segregated with three cases of classic Lynch syndrome-associated malignancies over two generations, with consistent loss of MLH1 and PMS2 protein expression on IHC, and evidence of the MSI-High mutator phenotype. The leucine at position 555 is well conserved across a number of species, and this novel variant has not been reported as a normal polymorphism in the general population. In silico and in vitro analyses suggest that this variant may have a deleterious effect on the MLH1 protein and abrogate MMR activity. Evidence from clinical, histological, immunohistochemical, and molecular genetic data suggests that MLH1 c.1664T>C (p.Leu555Pro) is likely to be the pathogenic cause of Lynch syndrome in this family.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Trifosfatases/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Mutação/genética , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adenosina Trifosfatases/metabolismo , Adulto , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento , Análise Multivariada , Proteína 1 Homóloga a MutL , Estadiamento de Neoplasias , Proteínas Nucleares/metabolismo , Linhagem , Fenótipo , Prognóstico , Adulto JovemRESUMO
BACKGROUND: This paper reviews current research on workplace violence in the USA and offers suggestions concerning the roles that mental health professionals with forensic expertise can play in this expanding field. AIMS: To clarify the role of the mental health professional in evaluating issues related to workplace violence. METHOD: Manual and computer literature searches were performed. RESULTS: The incidence of reported workplace violence is on the rise and can be devastating beyond the immediate injury. Forensically oriented mental health professionals can assist companies by providing pre-employment screenings, fitness-for-duty evaluations and threat assessment by using the results of current research on potentially violent individuals. CONCLUSIONS: With the growing interest in workplace violence come many opportunities for mental health professionals to assist companies in assessment, intervention and prevention.
Assuntos
Psiquiatria Legal , Violência/prevenção & controle , Local de Trabalho , Humanos , Serviços de Saúde Mental/organização & administração , Seleção de Pessoal , Prática Profissional , Projetos de Pesquisa , Estados Unidos , Violência/estatística & dados numéricosRESUMO
We evaluated auditory working memory in 41 HIV-seropositive (HIV+) and 37 HIV-seronegative (HIV-) male drug users, employing a modified version of the Letter-Number Span Task developed by Gold and colleagues. We added a control condition to the standard task in order to evaluate more directly the contribution of the processing component to the working memory deficits with the effects of storage demands minimized. HIV+ subjects performed significantly more poorly compared to controls on an index of working memory processing derived from raw scores obtained under the two testing conditions. These findings are consistent with our previous reports that HIV-related working memory deficits are evident across multiple informational domains; further, the deficit appears to involve multiple-component functions of working memory. Converging findings from recent working memory studies and from primate and neuroimaging investigations suggest that functional abnormalities of prefrontal cortex should receive greater emphasis in models of neurocognitive aspects of HIV-1 infection, which have typically emphasized "subcortical" deficits.