Annual Review of Medicine - Volume 60, 2009

This review focuses on sublingual immunotherapy (SLIT), toll-like receptor-9 (TLR-9) vaccines using cytosine phosphorothioate guanosine (CpG)–allergen conjugates, and anti-IL-5 as novel immunomodulating therapies in allergy. At present, all three approaches are investigational in the United States and require further study to determine their safety and effectiveness. SLIT provides a novel oral route of administering an allergen to induce tolerance to inhaled allergens. Studies of SLIT in allergic rhinitis demonstrate that it reduces symptoms and medication use and is associated with a low incidence of systemic allergic reactions. Initial phase II studies with TLR-9 vaccines conjugated to a ragweed allergen demonstrate that they reduce symptoms of allergic rhinitis during the ragweed season. Anti-IL-5 is effective as a corticosteroid-sparing agent in the hypereosinophilic syndrome. It has not shown benefit in moderate asthmatics with persistent symptoms but may reduce aspects of airway remodeling in asthma.

Hypereosinophilic syndrome is a heterogeneous group of rare disorders characterized by marked blood or tissue eosinophilia resulting in a wide variety of clinical manifestations. Although the existence of clinical subtypes (or variants) of HES has been appreciated for some time, the recent characterization of some of these variants at the molecular and immunologic levels has demonstrated dramatic differences in disease pathogenesis, response to treatment, and prognosis depending on the etiology of the eosinophilia. This, together with the availability of novel targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, has fundamentally altered the approach to the diagnosis and treatment of HES.

The presence and consequences of resistance to drugs used for the treatment of tuberculosis have long been neglected. The recent detection and recognition of widespread multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis have raised interest and concern among clinicians and public health authorities globally. In this article, we describe the current global status of drug-resistant tuberculosis. We discuss the development of resistance, current management, and strategies for control.

A number of inherited disorders result in renal cyst development. The most common form, autosomal dominant polycystic kidney disease (ADPKD), is a disorder most often diagnosed in adults and caused by mutation in PKD1 or PKD2. The PKD1 protein, polycystin-1, is a large receptor-like protein, whereas polycystin-2 is a transient receptor potential channel. The polycystin complex localizes to primary cilia and may act as a mechanosensor essential for maintaining the differentiated state of epithelia lining tubules in the kidney and biliary tract. Elucidation of defective cellular processes has highlighted potential therapies, some of which are now being tested in clinical trials. ARPKD is the neonatal form of PKD and is associated with enlarged kidneys and biliary dysgenesis. The disease phenotype is highly variable, ranging from neonatal death to later presentation with minimal kidney disease. ARPKD is caused by mutation in PKHD1, and two truncating mutations are associated with neonatal lethality. The ARPKD protein, fibrocystin, is localized to cilia/basal body and complexes with polycystin-2. Rare, syndromic forms of PKD also include defects of the eye, central nervous system, digits, and/or neural tube and highlight the role of cilia and pathways such as Wnt and Hh in their pathogenesis.

The association between renal dysplasia and minor malformations of the external ear is weak. However, there is a remarkable list of syndromes that link the kidney to the inner ear. To organize these seemingly disparate syndromes, we cluster representative examples into three groups: (a) syndromes that share pathways regulating development; (b) syndromes involving dysfunction of the primary cilium, which normally provides critical information to epithelial cells about the fluid in which they are bathed; (c) syndromes arising from dysfunction of specialized proteins that transport ions and drugs in and out of the extracellular fluid or provide structural support.

Serotonin is perhaps best known as a neurotransmitter that modulates neural activity and a wide range of neuropsychological processes, and drugs that target serotonin receptors are used widely in psychiatry and neurology. However, most serotonin is found outside the central nervous system, and virtually all of the 15 serotonin receptors are expressed outside as well as within the brain. Serotonin regulates numerous biological processes including cardiovascular function, bowel motility, ejaculatory latency, and bladder control. Additionally, new work suggests that serotonin may regulate some processes, including platelet aggregation, by receptor-independent, transglutaminase-dependent covalent linkage to cellular proteins. We review this new “expanded serotonin biology” and discuss how drugs targeting specific serotonin receptors are beginning to help treat a wide range of diseases.

Autism is a common childhood neurodevelopmental disorder with strong genetic liability. It is not a unitary entity but a clinical syndrome, with variable deficits in social behavior and language, restrictive interests, and repetitive behaviors. Recent advances in the genetics of autism emphasize its etiological heterogeneity, with each genetic susceptibility locus accounting for only a small fraction of cases or having a small effect. Therefore, it is not surprising that no unifying structural or neuropathological features have been conclusively identified. Given the heterogeneity of autism spectrum disorder (ASD), approaches based on studying heritable components of the disorder, or endophenotypes, such as language or social cognition, provide promising avenues for genetic and neurobiological investigations. Early intensive behavioral and cognitive interventions are efficacious in many cases, but autism does not remit in the majority of children. Therefore, development of targeted therapies based on pathophysiologically and etiologically defined subtypes of ASD remains an important and achievable goal of current research.

Although philosophers and cognitive neuroscientists have struggled to define human consciousness, physicians can identify and assess its two clinical dimensions: wakefulness and awareness. A comatose patient has neither wakefulness nor awareness; a patient in a vegetative state has wakefulness without awareness; and a minimally conscious patient has both, but awareness is impaired. Syndromes of unconsciousness have established diagnostic criteria, but they encompass a spectrum of severity of brain damage and have indistinct boundaries. Functional neuroimaging using PET and fMRI have provided a new and complementary way to assess consciousness. Several recent provocative studies suggest that fMRI in unresponsive patients may detect evidence of conscious awareness when a careful neurological examination cannot. If these findings are verified by future studies, functional neuroimaging technologies will alter clinical practices concerning the diagnosis, classification, and prognosis of unconscious patients, and will lead to a greater understanding of the biology of human consciousness.

The purpose of the psychiatric hospital changed dramatically during the twentieth century. Formerly the primary location for psychiatric treatment, the hospital now plays a more circumscribed role within a community-based system of care. Crisis stabilization, safety, and a focus on rapid discharge are the critical components of the acute inpatient stay. Subspecialized units focus on geriatrics, children, adolescents, dual diagnosis (substance abuse and mental illness), trauma disorders, eating disorders, and forensics. When integrated with the general medical system and a comprehensive base of community-delivered day treatment, residential sevices, and outpatient services, psychiatric hospitalization is a humane alternative to long-term institutional care.

Surgical mortality varies widely across hospitals and surgeons, more so than would be predicted by chance alone or differences in case mix. Although a large body of research has suggested the importance of procedure volume, clinical mechanisms underlying variation in surgical mortality remain largely unknown. Payers, policy makers, and professional organizations have implemented a variety of large-scale strategies aimed at improving outcomes. Selective referral, process compliance, and outcomes measurement reflect different philosophies on how best to improve surgical quality and have distinct advantages and disadvantages. The optimal strategy may depend on both the clinical context (e.g., which procedure) and political realities.

MRI-guided focused ultrasound (MRgFUS) surgery is a noninvasive thermal ablation method that uses magnetic resonance imaging (MRI) for target definition, treatment planning, and closed-loop control of energy deposition. Integrating FUS and MRI as a therapy delivery system allows us to localize, target, and monitor in real time, and thus to ablate targeted tissue without damaging normal structures. This precision makes MRgFUS an attractive alternative to surgical resection or radiation therapy of benign and malignant tumors. Already approved for the treatment of uterine fibroids, MRgFUS is in ongoing clinical trials for the treatment of breast, liver, prostate, and brain cancer and for the palliation of pain in bone metastasis. In addition to thermal ablation, FUS, with or without the use of microbubbles, can temporarily change vascular or cell membrane permeability and release or activate various compounds for targeted drug delivery or gene therapy. A disruptive technology, MRgFUS provides new therapeutic approaches and may cause major changes in patient management and several medical disciplines.

In the practice of internal medicine, the value of genetic testing in common (mono)genetic diseases such as familial hemochromatosis, hypercholesterolemia, Mediterranean fever, and thrombophilia is limited. The genotype insufficiently predicts the phenotype because of the powerful effects of other modifying genes, environmental influences, and lifestyle factors. Many common diseases, including diabetes mellitus, osteoporosis, and cardiovascular disease, have strong genetic influences but are called complex genetic traits. The underlying genetic factors are currently investigated using new molecular tools such as genome-wide association studies, analyzing up to 500,000 markers in huge numbers of patients. Many new (often unexpected) markers have been identified, and in many instances their functional significance is unknown. Genomic profiles play a rapidly growing role in the field of pharmacogenomics. A number of recently identified pharmacogenomic biomarkers are helpful to predict drug-related toxic effects.

The International HapMap Project produced a genome-wide database of human genetic variation for use in genetic association studies of common diseases. The initial output of these studies has been overwhelming, with over 150 risk loci identified in studies of more than 60 common diseases and traits. These associations have suggested previously unsuspected etiologic pathways for common diseases that will be of use in identifying new therapeutic targets and developing targeted interventions based on genetically defined risk. Here we examine the development and application of the HapMap to genome-wide association (GWA) studies; present and future technologies for GWA research; current major efforts in GWA studies; successes and limitations of the GWA approach in identifying polymorphisms related to complex diseases; data release and privacy polices; use of these findings by clinicians, the public, and academic physicians; and sources of ongoing authoritative information on this rapidly evolving field.

Life expectancy has increased dramatically in the United States and in much of the world in recent years and decades. The factors underlying this increase are incompletely understood and are undoubtedly complex. A question that drives current research is whether life expectancy can be further extended using current knowledge of modifiable risk factors. A still more challenging research focus is on the possibility that life expectancy might be further increased through knowledge gained from studies of the basic biology of aging and its genetic and environmental modifiers.

There is an intense interplay between HIV and the immune system, and the literature is replete with studies describing various immunological phenomena associated with HIV infection. Many of these phenomena seem too broad in scope to be attributable either to HIV-infected cells or to the HIV-specific immune response. Recently, a more fundamental understanding of how HIV affects various T cells and T cell compartments has emerged. This review covers the role of immune activation in HIV immunopathogenesis, how that activation could be mediated directly by HIV replicating within and damaging the gut mucosal barrier, how HIV affects multiple T cell functions and phenotypes, and how chronic HIV replication induces immune modulatory pathways to negatively regulate certain functions in HIV-specific T cells.

The fact that human immunodeficiency virus (HIV) causes a deadly disease in humans whereas its simian counterparts, the simian immunodeficiency viruses (SIVs), are virtually nonpathogenic in their natural hosts remains a fundamental mystery of modern medicine. Arguably, the pathogenesis of HIV infection will remain poorly understood until the mechanisms responsible for the AIDS resistance of natural SIV hosts are fully explained. Over the past few years, some key features of natural SIV infections have been described in studies conducted predominantly in sooty mangabeys (SMs), African green monkeys (AGMs), and mandrills. Natural SIV hosts are able to avoid the chronic, generalized immune system activation that is associated with disease progression in HIV-infected individuals and have evolved to down-modulate the expression of CCR5 on CD4⁺ T cells. Better elucidation of the mechanisms underlying the lack of disease progression of natural SIV infections holds promise for the design of novel preventive and therapeutic approaches to HIV infection.