Annual Review of Medicine - Volume 62, 2011

The medical management of women at an increased risk of breast cancer has substantially changed over the past few years, with improvements in screening, cancer prevention, and treatment, and is best defined for women with mutations in BRCA1 and BRCA2. Screening techniques, such as breast magnetic resonance imaging, enable early detection of cancers in high-risk women. Prophylactic salpingo-oophorectomy has been demonstrated to decrease the risk of breast and ovarian cancers, as well as mortality in BRCA1/2 mutation carriers. Most recently, there have been considerable strides in the treatment of cancers in BRCA1/2 mutation carriers. Breast cancer patients with BRCA1/2 mutations treated with systemic therapy do not appear to have excess toxicity, and have similar relapse-free and overall survival compared to noncarriers. Preclinical and early clinical research suggests that specific classes of chemotherapy may be more effective in mutation carriers. PARP inhibitors represent a novel therapeutic strategy that exploits the weaknesses of BRCA1/2-associated malignancies.

Although safe and effective agents are currently available to treat osteoporosis, fragility fractures remain a significant problem worldwide. Recent improvements in the understanding of the cellular, biochemical, and molecular pathways of bone biology have led to the development of newer agents to treat osteoporosis, which may lead to further improvements in outcomes. In this review, we summarize the most recent advances in the field, including new modes of administration of existing drug classes, various approaches to combination therapy, and drugs with novel mechanisms of action to treat osteoporosis.

The molecular elucidation of two human skeletal dysplasias revealed that they are caused by an increase or a decrease in the synthesis of serotonin by enterochromaffin cells of the gut. This observation revealed a novel and powerful endocrine means to regulate bone mass. Exploiting these findings in the pharmacological arena led to the demonstration that inhibiting synthesis of gut-derived serotonin could be an effective means to treat low-bone-mass diseases such as osteoporosis.

Alpha-1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children. The primary pathological issue is a point mutation that renders an abundant hepatic secretory glycoprotein prone to altered folding and a tendency to polymerize and aggregate. However, the expression of serious liver damage among homozygotes is dependent on genetic and/or environmental modifiers. Several studies have validated the concept that endogenous hepatic pathways for disposal of aggregation-prone proteins, including the proteasomal and autophagic degradative pathways, could play a key role in the variation in hepatic damage and be the target of the modifiers. Exciting recent results have shown that a drug that enhances autophagy can reduce the hepatic load of aggregated protein and reverse fibrosis in a mouse model of this disease.

The hepatic peptide hormone hepcidin is the principal regulator of iron absorption and its tissue distribution. Pathologically increased hepcidin concentrations cause or contribute to iron-restrictive anemias including anemias associated with inflammation, chronic kidney disease and some cancers. Hepcidin deficiency results in iron overload in hereditary hemochromatosis and ineffective erythropoiesis. The hepcidin-ferroportin axis is the principal regulator of extracellular iron homeostasis in health and disease, and is a promising target for the diagnosis and treatment of iron disorders and anemias.

Novel, culture-independent, molecular and metagenomic techniques have provided new insight into the complex interactions between the mammalian host and gut microbial species. It is increasingly evident that gut microbes may shape the host metabolic and immune network activity and ultimately influence the development of obesity and diabetes. We discuss the evidence connecting gut microflora to obesity and to type 1 and type 2 diabetes, and we present recent insights into potential mechanisms underlying this relationship: increased nutrient absorption from the diet, prolonged intestinal transit time, altered bile acid entero-hepatic cycle, increased cellular uptake of circulating triglycerides, enhanced de novo lipogenesis, reduced free fatty acid oxidation, altered tissue composition of biologically active polyunsaturated fatty acid, chronic low-grade inflammation triggered by the endotoxin toll-like receptor 4 axis, and altered intestinal barrier function.

The importance of bidirectional brain-gut interactions in gastrointestinal (GI) illness is increasingly recognized, most prominently in the area of functional GI syndromes such as irritable bowel syndrome (IBS), functional dyspepsia, and functional chest pain. The brain receives a constant stream of interoceptive input from the GI tract, integrates this information with other interoceptive information from the body and with contextual information from the environment, and sends an integrated response back to various target cells within the GI tract. This system is optimized to assure homeostasis of the GI tract during physiological perturbations and to adapt GI function to the overall state of the organism. In health, the great majority of interoceptive information reaching the brain is not consciously perceived but serves primarily as input to autonomic reflex pathways. In patients with functional abdominal pain syndromes, conscious perception of interoceptive information from the GI tract, or recall of interoceptive memories of such input, can occur in the form of constant or recurrent discomfort or pain. This is often associated with alterations in autonomic nervous system output and with emotional changes. A model is proposed that incorporates reported peripheral and central abnormalities in patients with IBS, extrapolates similar alterations in brain-gut interactions to patients with other chronic abdominal pain syndromes, and provides novel treatment targets.

Cognitive therapy is a system of psychotherapy with a powerful theoretical infrastructure, which has received extensive empirical support, and a large body of research attesting to its efficacy for a wide range of psychiatric and medical problems. This article provides a brief overview of the conceptual and practical components of cognitive therapy and highlights some of the empirical evidence regarding its efficacy. Cognitive therapy (often labeled generically as cognitive behavior therapy) is efficacious either alone or as an adjunct to medication and provides a prophylaxis against relapse and recurrence.

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism.

The brain is the key organ of stress processes. It determines what individuals will experience as stressful, it orchestrates how individuals will cope with stressful experiences, and it changes both functionally and structurally as a result of stressful experiences. Within the brain, a distributed, dynamic, and plastic neural circuitry coordinates, monitors, and calibrates behavioral and physiological stress response systems to meet the demands imposed by particular stressors. These allodynamic processes can be adaptive in the short term (allostasis) and maladaptive in the long term (allostatic load). Critically, these processes involve bidirectional signaling between the brain and body. Consequently, allostasis and allostatic load can jointly affect vulnerability to brain-dependent and stress-related mental and physical health conditions. This review focuses on the role of brain plasticity in adaptation to, and pathophysiology resulting from, stressful experiences. It also considers interventions to prevent and treat chronic and prevalent health conditions via allodynamic brain mechanisms.

Inadequate sleep and sleep disorders have important adverse consequences on multiple systems. This review covers three areas: (a) Genetic determinants of sleep disorders. Common gene variants with small effects have been identified for both restless legs syndrome and narcolepsy with cataplexy. Rare variants with large effects have been found in familial phase advance syndrome and in subjects with short sleep durations. (b) Obstructive sleep apnea (OSA). OSA is an oxidative stress disorder. Prospective cohort studies show an increased risk of cardiovascular events in patients with untreated severe OSA. (c) The impact of sleep disorders on obesity and diabetes. Inadequate sleep results in changes in insulin resistance and in hormone levels leading to increases in appetite. Hence, inadequate sleep is associated with development of obesity. OSA is also an independent risk factor for insulin resistance; treatment of OSA can improve insulin sensitivity.

We have identified a brain-based endophenotype for major depressive disorder (MDD) that includes thinning of the cortex of the lateral aspect of the right hemisphere and the medial aspect of the left, as well as bilateral hypoplasia of frontal and parietal white matter. The endophenotype status of these abnormalities is supported by their presence in a multigenerational cohort of persons who themselves do not have MDD but who are at increased familial risk for developing the illness. Those who have the endophenotype but who are not ill nevertheless still suffer from inattention and poor visual memory for social stimuli in direct proportion to the magnitude of cortical thinning and white matter hypoplasia within the endophenotype. Identification of this endophenotype and its cognitive correlates provides targets for devising new preventive and therapeutic interventions for MDD.