Cancer of the female breast. Improving the public's health through early detection

Decision makers who represent the public need to understand the extent of the breast cancer problem, the potential for improvement, and the actions needed to achieve this potential. Informed, dedicated physicians, individually and collectively, are instrumental and can be most effective leaders in this process. There are several evidences of the fine tradition of the medical profession to advocate practices and policies in the interest of the best health of our patients. The North Carolina Medical Society recently adopted a position statement encouraging the provision of screening mammograms and pap smears by both private and self-insured third party payors; the North Carolina Academy of Family Practice recently adopted a position statement urging priority be placed on allocating resources for efficacious preventive services; the multiple specialty organizations developed the widely recognized national guidelines for early breast cancer detection; and the ACR continues its efforts to assure quality mammography services. To the end that this paper has informed and stimulated further sharing, discussion or debate about the extent of the breast cancer problem, the potential for improvement, and the actions needed to achieve this potential, it has accomplished its purpose. To the end that the physician community acts to improve early breast cancer detection, we will have fulfilled the common purpose that binds us as physicians to one another and to the people we are privileged and bound to serve.     

The voltage gated potassium channel KCNQ2 and idiopathic generalized epilepsy.

Mutations in the voltage gated potassium channel gene KCNQ2 and the homologous gene KCNQ3 have been found to cause a rare monogenic subtype of idiopathic generalized epilepsy, the benign familial neonatal convulsions. Recently, the heteromeric KCNQ2/KCNQ3 channel was found to contribute to the native M-current, one of the most important regulators of neuronal excitability. By performing a systematic mutation scan of the coding region and an association study involving a frequent Thr752Asn substitution polymorphism, we, therefore, investigated whether allelic variation of the KCNQ2 gene confers susceptibility to common subtypes of idiopathic generalized epilepsy. Our results do not provide evidence that allelic variation of the KCNQ2 gene contributes a common and relevant effect to the pathogenesis of common subtypes of idiopathic generalized epilepsy.     

Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy

Genetic predisposition plays a major role in the etiology of idiopathic epilepsies. The common epilepsy syndromes display a complex pattern of inheritance, with an unknown number of genes contributing to seizure susceptibility. During the last decade linkage studies have narrowed down several candidate regions for susceptibility loci of idiopathic epilepsies. Several lines of evidence point to the existence of an epilepsy susceptibility gene on chromosome 15q14. Evidence for linkage to this region has thus been reported for juvenile myoclonic epilepsy, common subtypes of idiopathic generalized epilepsy (IGE), in addition to the EEG trait 'centrotemporal spikes' in families with rolandic epilepsy. The chromosomal region 15q14 harbours several candidate genes that are involved in the regulation of neuronal excitability. One of the most promising candidate genes is the brain-expressed potassium chloride cotransporter KCC3, given that this class of ion transporter has been implicated in the regulation of neuronal chloride activity. We therefore performed a mutation analysis of KCC3 in the index patients of 23 IGE-families as well as of 16 families with rolandic epilepsy which where selected by positive evidence for linkage to D15S165. Four novel single nucleotide exchanges (SNPs) were identified, none of which change the coding sequence. These results do not support a major role for KCC3 in the etiology of rolandic epilepsy or common subtypes of IGE.     

Physical Activity Patterns Among U.S. Adults with and without Serious Psychological Distress

Objective

A physically active lifestyle is recommended for overall health—both physical and mental. Serious psychological distress (SPD) is associated with adverse health behaviors. We compared patterns of physical activity (PA) among adults with and without SPD using current public health guidelines for PA and examined whether adults with SPD were physically active at recommended levels.

Methods

We used data from the 2009 Behavioral Risk Factor Surveillance System (BRFSS) to assess SPD using the Kessler 6 (K6) scale of nonspecific psychological distress and PA categories based on the 2008 U.S. Department of Health and Human Services guidelines. Complete data were available for 78,886 adults in 16 states that used an optional BRFSS mental illness and stigma module containing the K6 scale. We performed multiple logistic regression analyses to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs).

Results

The unadjusted prevalence of SPD was 3.9% (95% CI 3.6, 4.2), and the age-adjusted prevalence of SPD was 3.8% (95% CI 3.5, 4.1). After adjusting for age, sex, race/ethnicity, education, employment, body mass index, smoking status, and heavy drinking, adults with SPD were significantly less likely to be physically active at recommended levels than adults without SPD. PRs were attenuated but remained significant after further adjustment for limitations to PA.

Conclusion

Adults with SPD are less likely to meet current PA recommendations than adults without SPD, highlighting the need for targeted interventions.Serious psychological distress (SPD), while not indicative of a specific mental illness, is associated with anxiety and mood disorders.^1,2 In 2012, the U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) compared National Survey on Drug Use and Health (NSDUH) mental health data with other data sources.³ SAMHSA reported that the estimated prevalence of past-year SPD was 10.2% using the 2009 NSDUH. The estimated prevalences of past-year serious mental illness and any mental illness (i.e., ≥1 mental disorder excluding substance abuse) were 4.8% and 19.9%, respectively, using NSDUH data, and 5.8% and 24.8%, respectively, using National Comorbidity Survey Replication data.^3,4 Past 30-day estimates of SPD were 3.1% using National Health Interview Survey (NHIS) data, 4.6% using NSDUH data, and 4.8% using Medical Expenditure Panel Survey (MEPS) data.³SPD is frequently comorbid with chronic physical conditions and disabilities, resulting in an increased risk for adverse health outcomes and premature death.^5–7 In addition, SPD is highly associated with adverse health behaviors, such as smoking, physical inactivity, and substance abuse.^8–11 The economic costs of mental disorders are substantial. While an estimated 6.2% of U.S. health-care spending is attributed to mental disorders,¹² the true cost of these disorders is elusive, as they are mainly indirect, such as increased work absenteeism and decreased productivity, increased risk of unemployment and subsequent reliance on social services disability income, and other adverse consequences (e.g., reduced educational attainment, homelessness, and incarceration).^13,14The overall health benefits of physical activity (PA) are well known.^11,15–23 In 2008, the U.S. Department of Health and Human Services (HHS) published revised PA recommendations informed by the most recent scientific evidence available. These new public health guidelines recommend a physically active lifestyle not only for physical health but also for mental health.²³ Similarly, many organizations have recognized the intertwined relationship between mental and physical health, especially the role PA has in improving and maintaining mental health.^{11,15,17–22,24–26} For example, the American Psychiatric Association''s (APA''s) clinical practice guidelines include PA as an initial treatment modality in patients with mild depressive disorder, and as an adjunct therapy for patients no matter the severity of depression.^17,22 Given the comprehensive health benefits of PA, further elucidation of the PA patterns among adults with SPD is needed to establish a baseline and to inform public health strategies; primary care collaborative care models; and clinical protocols designed to prevent adverse health outcomes, treat mental disorders, and improve the quality of life among this population.Thus, this study had two goals: (1) to compare the PA patterns of adults with and without SPD and (2) to examine whether adults with SPD are physically active in accordance with the 2008 HHS PA guidelines.     

Mutation screening of the CHRNA4 and CHRNB2 nicotinic cholinergic receptor genes in Alzheimer's disease.

Potential genomic changes leading to decreased nicotine binding, crucial for cognitive dysfunction in Alzheimer's disease (AD), have not yet been studied. A search for mutations of the genes coding for the most widely distributed nicotinic receptor subtype alpha4beta2 (CHRNA4/CHRNB2) has been performed in AD patients by screening the coding regions of both genes by single strand conformation analysis and heteroduplex analysis of fibroblast-derived genomic DNA. Polymorphisms in CHRNA4, none of which led to amino acid changes in the predicted sequence, were found in three patients. Although the other receptor subunits have yet to be screened, it appears likely that the reduction of nicotine binding sites in AD is not due to genomic changes.     

An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first, and to date only, idiopathic epilepsy for which a specific mutation has been found. A missense mutation in the critical M2 domain of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4) has been recently identified in one large Australian pedigree. Here we describe a novel mutation in the M2 domain of the CHRNA4 gene in a Norwegian family. Three nucleotides (GCT) were inserted at nucleotide position 776 into the coding region for the C-terminal end of the M2 domain. Physiological investigations of the receptor reconstituted with the mutated CHRNA4 subunit reveal that this insertion does not prevent the receptor function but increases its apparent affinity for ACh. In addition, this mutant receptor shows a significantly lower calcium permeability that, at the cellular level, may correspond to a loss of function. Comparison of the two mutations identified so far in families with ADNFLE illustrates that different mutations can result in similar phenotypes.      

Independent occurrence of the CHRNA4 Ser248Phe mutation in a Norwegian family with nocturnal frontal lobe epilepsy

PURPOSE: To describe the clinical features of a family from Northern Norway in which autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is associated with a Ser248Phe amino acid exchange in the second transmembrane domain of the neuronal nicotinic acetylcholine receptor alpha4 subunit (CHRNA4). We also tested for evidence of a de novo mutation or founder effect by comparing haplotypes with the original Australian family where the Ser248Phe mutation was first described. METHODS: Clinical details were obtained from 19 family members. Personal interviews and genetic analysis were carried out in 17. Parts of the coding region of CHRNA4 were sequenced, and two known polymorphisms (bp555/FokI, bp594/CfoI) were typed by restriction analysis. RESULTS: Eleven individuals had ADNFLE. The haplotypes of the mutation-carrying alleles of affected individuals from the Northern Norwegian and the Australian ADNFLE family are different. The phenotypic expressions are remarkably similar. CONCLUSIONS: The Ser248Phe mutation occurred independently in both families. Given the rarity of the disease, this suggests that not only the position of a mutation in the coding sequence but also the type of an amino acid exchange is important for the etiology of ADNFLE. The phenotypic similarity of these two families with different genetic backgrounds suggests that the Ser248Phe mutation largely determines the phenotype, with relatively little influence of other background genes.