Annual Review of Medicine - Volume 49, 1998

Some of the recent advances in our knowledge of immune recognition have provided new tools to circumvent or reverse some of the major disadvantages of allogeneic bone marrow transplantation (BMT). The pretransplant conditioning regimen produces a major defect in the immune system that greatly favors the occurrence of life-threatening infections, caused particularly by Epstein-Barr virus and cytomegalovirus. However, adoptive transfer of virus-specific cytotoxic T lymphocytes can reconstitute specific immunity and/or cure viral disease in immunocompromised post-BMT patients. The other major drawback of allogeneic BMT is graft-versus-host disease (GVHD). Although potentially detrimental, it is closely associated with an antileukemia reaction (graft-versus- leukemia, GVL). The most direct evidence of the GVL effect has been provided by the efficacy of donor leukocyte infusions (DLI). DLI can induce long-lasting remissions, especially in patients with chronic myeloid leukemia who relapse post-BMT. Although allogeneic cell therapy should still be considered a “naive” form of immunotherapy, work in progress on the identification of leukemia-specific antigens will improve the outcome and enlarge its applications.

Functional brain imaging techniques, which permit noninvasive measures of neurophysiology and neuroreceptor binding, are powerful and sensitive tools for research aimed at elucidating the pathophysiology of major depression. The application of these technologies in depression research has produced several studies of resting cerebral blood flow (BF) and glucose metabolism in subjects imaged during various phases of illness and treatment. This review examines these data and the principles relevant to their interpretation and discusses the insights they provide into the anatomical correlates of depression. Within the anatomical networks implicated in emotional processing by other types of evidence, these BF and metabolic data demonstrate that major depression is associated with reversible, mood state–dependent, neurophysiological abnormalities in some structures and irreversible, trait-like abnormalities in other structures. In some of the regions in which trait-like abnormalities appear, abnormal metabolic activity appears at least partly related to the anatomical abnormalities identified in magnetic resonance imaging (MRI) studies of depression.

Abdominal aortic aneurysms (AAA) may now be treated by endovascular placement of an arterial graft. These grafts are inserted through the femoral artery and then secured to the aorta above and below the aneurysm. The procedure reduces the risk of many perioperative complications and reduces hospital costs and length of stay. Several FDA-approved clinical trials are currently in progress with a variety of different devices. None is available for general use at this time. Overall, more than 800 grafts have now been placed, with a primary success rate of greater than 80%. Several complications have been reported, but the incidence of complications has generally decreased as proficiency has improved. The most troublesome problem has been leak of blood around the graft with continued risk of aneurysm rupture; therefore, follow-up CT scans and clinical examinations are mandatory to allow for appropriate treatment. Future modifications of current devices and techniques for delivery can be expected to reduce the incidence of currently identified problems. Endovascular grafting for AAA offers important potential advantages over conventional repair and may become increasingly important in the management of patients who have an abdominal aortic aneurysm.

Clostridium difficile infection is associated with broad-spectrum antibiotic therapy and is the most common cause of infectious diarrhea in hospital patients. Pathogenic strains of C. difficile produce two protein exotoxins, toxin A and toxin B, which cause colonic mucosal injury and inflammation. Infection may be asymptomatic, cause mild diarrhea, or result in severe pseudomembranous colitis. Diagnosis depends on the demonstration of C. difficile toxins in the stool. The first step in management is to discontinue the antibiotic that caused diarrhea. If diarrhea and colitis are severe or persistent, oral metronidazole is the treatment of choice. Oral vancomycin is also effective, but it is more expensive than metronidazole and its widespread use may encourage the proliferation of vancomycin-resistant nosocomial bacteria. Diarrhea and colitis usually improve within three days after a patient starts taking metronidazole or vancomycin, but 20% suffer a relapse of diarrhea when these agents are discontinued.

The development of genetic and serological markers of autoimmune Type I diabetes has allowed us to begin to identify subjects at risk for the development of Type I diabetes. Assessment of these variables can assign risk to subjects and permit the implementation of immune intervention trials in an attempt to alter the course of pre-diabetes. This review discusses relevant aspects of the genetics and diagnosis of pre-diabetes, and both current and future clinical trials that are attempting to prevent the full expression of clinical diabetes in these individuals.

Angiogenesis, the recruitment of new blood vessels, is an essential component of the metastatic pathway. These vessels provide the principal route by which tumor cells exit the primary tumor site and enter the circulation. For many tumors, the vascular density can provide a prognostic indicator of metastatic potential, with the highly vascular primary tumors having a higher incidence of metastasis than poorly vascular tumors. Tumor angiogenesis is regulated by the production of angiogenic stimulators including members of the fibroblast growth factor and vascular endothelial growth factor families. In addition, tumors may activate angiogenic inhibitors such as angiostatin and endostatin that can modulate angiogenesis both at the primary site and at downstream sites of metastasis. The potential use of these and other natural and synthetic angiogenic inhibitors as anticancer drugs is currently under intense investigation. Such agents may have reduced toxicity and be less likely to generate drug resistance than conventional cytotoxic drugs. Clinical trials are now underway to develop optimum treatment strategies for antiangiogenic agents.

Genetic predisposition is responsible for 5–10% of all breast cancer, and a much larger percent of early-onset disease. Within the past few years, a number of genes associated with a high risk of breast cancer have been identified, including BRCA1, BRCA2, p53, and the Cowden disease gene PTEN/MMAC1. These genes appear to function as tumor suppressors, and although their mutation frequency in the general population is low, certain populations have a carrier frequency of up to 1% for particular BRCA1 and BRCA2 mutations. The isolation of these genes is likely to provide important insight into the pathogenesis of human cancer. The clinical application of these molecular discoveries raises controversial issues regarding presymptomatic testing for patients suspected of harboring cancer predisposing mutations.

Benditt's observation of the monoclonal origin of the atherosclerotic lesion has been controversial because it appeared to conflict with conventional wisdom. A new method based on a polymerase chain reaction amplification of the DNA of an X-inactivated gene from microdissected tissue confirms that Benditt was correct. However, this monoclonal expansion can also be found in nonatherosclerotic intima and media. These new data suggest that plaque clonality may represent expansion of preexisting patches of cells arising during development of the media. This developmental view does not conflict with other recent evidence that plaque expansion is associated with mutation or viral events. However, if plaques arise from patches, then early developmental mechanisms may be critical to the later evolution of the lesions.

The familial pattern of recurring pain and early death seen so often among those affected by sickle cell disease has been long recognized within African cultures, though its first clear description in Western medical literature did not appear until 1910 (1). Although most common in persons of African ancestry, the mutation giving rise to the sickle gene arose independently in several locations where malaria was prevalent (2), traveled with migrating populations, and is now widely distributed among regions and ethnic groups. Recognizing the qualitative abnormality of sickle hemoglobin as a prototype, Pauling & Castle established the notion of a molecular disease (3). Ironically, while the biochemistry and molecular biology of sickle cell disease has been intensively investigated, research into patient care has been limited in scope until recently. Prospective study of large patient groups diagnosed at birth is now providing insight into the disease's natural history and facilitating investigational treatments. Newborn diagnosis, combined with study of new drugs, cytokines, surgical procedures, and a more proactive utilization of transfusion is leading to greatly improved care and survival. Life expectancy is increasing (4) but adults are experiencing more complications of chronic organ dysfunction. A few patients have been cured by stem-cell transplantation, but difficult problems will continue to limit its application.

Dyspepsia, defined as “pain or discomfort centered in the upper abdomen” is reported by one in four adults in Western societies. The most important causes are non-ulcer (functional) dyspepsia, peptic ulcer, gastroesophageal reflux, and, rarely, gastric cancer. Persons with heartburn alone are not considered to have dyspepsia. The division of dyspepsia into symptom-based subgroups (ulcer-like, dysmotility-like, reflux-like, and unnspecified dyspepsia) has proven to be of doubtful value for the clinician, as it has a low predictive value for identifying the causes of dyspepsia. Upper endoscopy remains the “gold standard” test; ultrasound and blood tests have a low yield. The role of Helicobacter pylori in peptic ulcer disease is well known, but the clinical role of the infection in non-ulcer dyspepsia remains very controversial. In uninvestigated dyspeptic patients who are H. pylori infected based on a non-invasive test, empiric anti–H. pylori therapy is a reasonable and probably cost-effective option. In documented non-ulcer dyspepsia, prokinetics are superior to placebo while antisecretory therapy is of less certain efficacy.