Showing papers in "Annual Review of Medicine in 1995"

Advanced protein glycosylation in diabetes and aging

Abstract: Products of advanced protein glycosylation (advanced glycation end products, or AGEs) accumulate in tissues as a function of time and sugar concentration. AGEs induce permanent abnormalities in extracellular matrix component function, stimulate cytokine and reactive oxygen species production through AGE-specific receptors, and modify intracellular proteins. Pharmacologic inhibition of AGE formation in long-term diabetic animals prevents diabetic retinopathy, nephropathy, neuropathy, and arterial abnormalities in animal models. Clinical trials in humans are currently in progress.

Tissue factor pathway inhibitor and the revised theory of coagulation

Abstract: Tissue factor pathway inhibitor (TFPI) is a multivalent, Kunitz-type plasma proteinase inhibitor that regulates tissue factor-induced coagulation. TFPI directly inhibits activated factor X and, in a factor Xa-dependent fashion, produces feedback inhibition of the factor VIIa/tissue factor catalytic complex. The properties of this rediscovered inhibitor appear, at least in part, to explain the clinical requirement for both the extrinsic and intrinsic pathways of the cascade and waterfall theories of blood clotting and have led to a reformulation of the coagulation mechanism. In the revised hypothesis, factor VIIa/tissue factor is responsible for the initiation of coagulation, but owing to TFPI-mediated inhibition, sustained hemostasis requires the persistent and amplified procoagulant action of intrinsic factors VIII, IX, and XI.

Left ventricular remodeling after acute myocardial infarction

Abstract: ▪ Abstract The loss of myocytes as a consequence of myocardial infarction results in a prompt reduction in regional wall motion and often leads to more protracted and progressive changes in ventricular architecture. The recognition that the process of ventricular enlargement following myocardial infarction is modifiable provided the initial rationale for the use of angiotensin-converting enzyme (ACE) inhibitors as therapy to prevent deterioration in ventricular size and function following infarction. Experimental and clinical studies have documented the effectiveness of this therapy in preventing this late enlargement following infarction. Increasing clinical evidence indicates that this new use of ACE inhibitor therapy in survivors of acute myocardial infarction will lead to an improvement in clinical outcome.

The nuclear hormone receptor gene superfamily

Abstract: The nuclear hormone receptor gene superfamily encodes structurally related proteins that regulate transcription of target genes. These macromolecules include receptors for steroid and thyroid hormones, vitamins, and other proteins for which no ligands have been found. These receptors have modular domains. The DNA-binding domain directs the receptors to bind specific DNA sequences as monomers, homodimers, or heterodimers. The ligand-binding domain responds to binding of the cognate hormone; this domain and the amino terminal domain interact with other transcription factors. Nuclear receptor-specific actions are derived from a combination of diverse elements, including availability of ligand, receptors, and nonreceptor factors; target-site structure; interactions with other proteins, such as the general transcription factors; and influences of other signaling pathways. These interactions result in ligand-regulated and ligand-independent effects on initiation of transcription of the target genes. Understanding the mechanisms of nuclear receptor action will enhance our knowledge of transcription and hormone influences on disease and facilitate the design of drugs with greater therapeutic value.

Pharmacologic enhancement of wound healing

Abstract: The field of pharmacologic modulation of soft tissue repair is in its infancy. Although the soluble, cellular, and insoluble mediators that govern repair have not been elucidated, the application of pharmacologic concentrations of purified polypeptide growth factors, cytokines, and matrix molecules has nonetheless resulted in the acceleration of normal repair and the reversal of deficient repair in a wide variety of dermal wound models in animals. However, early clinical results using these factors have been less than encouraging, and their potential roles in the armamentarium of chronic wound therapies remain to be established.

Alcohol in the elderly

Abstract: Although older individuals drink less and report fewer alcohol-related problems than do younger individuals, alcohol use and abuse are significant health issues for older patients. The signs and symptoms of alcohol problems and dependence in the elderly may not only differ from those of young problem drinkers, but may also be present at lower levels of alcohol consumption. Older alcoholics do well in alcohol treatment. Therefore, discussion of alcohol consumption is a critical part of every history and physical examination for all patients, including older individuals.

Borderline hypothyroidism and depression

Abstract: This review defines subclinical hypothyroidism and examines its influence on the occurrence and course of major depression. Recommendations are presented for the identification and treatment of patients with coexisting mood disorders and borderline thyroid failure.

Genetics of colon cancer: Impact of inheritance on colon cancer risk

Abstract: The genes that are mutated in two of the rare syndromes of hereditary colon cancer were recently identified, and genetic diagnosis is already possible in some cases. Acquired mutations of these same genes also appear to be important in sporadic colon cancers. Familial clustering of sporadic cases is common and may likewise arise from inherited susceptibility. Screening strategies for both the rare syndromes and the common cases of colon cancer with familial risk have been suggested. Certain clinical features allow stratification of colon cancer risk among common cases. It is anticipated that continued genetic investigation will result in more precise screening and improved diagnostic and therapeutic options for colon cancer.

CLASSIFICATION OF EPSTEIN-BARR VIRUS-ASSOCIATED POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASES: Implications for Understanding their Pathogenesis and Developing Rational Treatment Strategies

Abstract: ▪ Abstract The Epstein-Barr virus (EBV) is associated with a spectrum of B-cell lymphoproliferative diseases (LPD) that develop following organ transplantation. A classification scheme for these disorders has been developed based on the clinical, histologic, immunologic cell-typing, cytogenetic, immunoglobulin gene-rearrangement, and virologic characteristics of these LPD. Four disease groups have been identified: (a) uncomplicated posttransplant infectious mononucleosis, (b) benign polyclonal polymorphic B-cell hyperplasia, (c) early malignant transformation in polyclonal polymorphic B-cell lymphoma, and (d) monoclonal polymorphic B-cell lymphoma. This classification has furthered our understanding of the pathogenesis of these diverse LPD and has allowed the development of rational treatment protocols.

Bone marrow transplantation in thalassemia.

Abstract: Early trials of allogeneic bone marrow transplantation (BMT) for homozygous beta-thalassemia and the analyses of results of transplantation in patients less than 16 years old have allowed us to identify three classes of risk based on the following criteria: (a) hepatomegaly, (b) presence of liver fibrosis at histological examination, and (c) quality of chelation treatment given before transplant Patients with none of these adverse criteria were assigned to Class 1; patients with either one or two adverse criteria comprised Class 2; and patients for whom all three criteria were adverse constituted Class 3 Most patients older than 16 years have disease characteristics that place them in Class 3, with very few falling into Class 2 All patients with a histocompatibility leukocyte antigen (HLA)-identical donor are actually assigned to one of two conditioning regimens on the basis of the class they belong to at the time of BMT and independently of age For Class 1, Class 2, and Class 3 patients, the probabilities of survival and event-free survival are 95 and 90%, 86 and 82%, and 87 and 63%, respectively For those patients older than 16 years at the time of transplant, the probabilities of survival and of event-free survival are 78 and 74%, respectively Allogeneic BMT is currently the only rational therapeutic modality for the eradication of beta-thalassemia

The modern version of adult respiratory distress syndrome

Abstract: Adult respiratory distress syndrome (ARDS) remains a highly lethal complication of autodestructive inflammation. This syndrome originally referred to a single organ failure but is now considered a component, usually the first, of the multisystem organ failure syndrome (MOFS). Cytokines, neutrophils, and endothelial adherence molecules initiate the disease process, with cell injury caused by oxidants and proteases released from inflammatory cells. ARDS, if progressive, will result in pulmonary fibrosis. Improved ventilatory support techniques have not been shown to decrease mortality. Pharmacologic manipulation of the inflammatory response is a more promising method of controlling the disease process.

Management of patients with zollinger-ellison syndrome

Abstract: ▪ Abstract Zollinger-Ellison syndrome (ZES) is caused by gastrin-secreting tumors called gastrinomas. Patients commonly present with peptic ulcer disease and may have recurrent, multiple, and atypically located ulcers, e.g. in the jejunum. Alternatively, severe diarrhea may be the only presenting symptom. Patients with multiple endocrine neoplasia Type I (MEN-I) and ZES become symptomatic at an earlier age than patients with sporadic ZES. Patients with ZES have elevated fasting serum gastrin concentrations (>100 pg/ml) and basal gastric acid hypersecretion (>15 mEq/h). The secretin stimulation test is the best test to distinguish ZES from other conditions resulting in elevated gastrin levels. Gastric acid hypersecretion can be controlled in virtually all patients with H2-receptor antagonists or omeprazole, thus rendering total gastrectomy unnecessary. Computed tomography (CT), magnetic resonance imaging (MRI), radionuclide octreotide scanning, endoscopic ultrasound, and the selective arterial secretin inj...

The changing face of tuberculosis.

Abstract: Tuberculosis (TB) remains an important public health problem worldwide, resulting in a estimated 8 to 10 million new cases and 2 to 3 million deaths each year. Between 1953 and 1985, the number of TB cases in the US declined by an average of 6% per year. However, since 1985, TB has been increasing in the US. Approximately 64,000 additional cases of the disease have been reported beyond the number expected had the rate of decline observed from 1980 to 1984 continued from 1985 through 1993. Increases in the number of TB cases have been significant in racial and ethnic minorities, in persons born outside the US, and in children less than 15 years of age. Infection with the human immunodeficiency virus (HIV) has also been recognized as a major risk factor for the development of active TB in persons with latent Mycobacterium tuberculosis infection. The unusual radiographic findings and the increased likelihood of extrapulmonary TB in HIV-infected persons make diagnosis of the disease problematic. Lastly, concomitant with the resurgence of TB has been the emergence of drug resistance. All of these factors make successful control of TB in the US difficult.

Molecular biology of diabetes insipidus

Abstract: The identification, characterization, and mutational analysis of three different genes, namely the prepro-arginine-vasopressin-neurophysin II gene ( preproAVP-NPII), the arginine-vasopressin receptor 2 gene ( AVPR2), and the vasopressin-sensitive water channel gene (aquaporin-2, AQP2), provide the basis for our understanding of three different hereditary forms of diabetes insipidus: autosomal dominant neurogenic diabetes insipidus, X-linked nephrogenic diabetes insipidus, and autosomal recessive nephrogenic diabetes insipidus, respectively. These advances provide diagnostic tools for physicians caring for these patients.

The transmissible spongiform encephalopathies

Abstract: The human transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of rapidly progressive disorders characterized by a spectrum of clinical abnormalities that include cognitive impairment, ataxia, myoclonus, and visual, pyramidal, and extrapyramidal signs. They share a spongiform (vacuolar) degeneration and variable amyloid plaque formation. Examples of TSEs are kuru, an infectious disease; Creutzfeldt-Jakob disease (CJD), which may take an infectious, genetic, or sporadic form; and Gerstmann-Straussler-Scheinker disease (GSS) and fatal familial insomnia (FFI), rare familial disorders. With the exception of FFI, all of these disorders have been experimentally transmitted to nonhuman primates and laboratory rodents. The pathogenic PrP protein accumulating in the brain of TSE patients is a protease-resistant and insoluble product of a precursor protein molecule of unknown function that is encoded by the PRNP gene on chromosome 20. Different mutations in this gene are responsible for various phenotypes of TSE in its familial form, and a polymorphism at codon 129 controls susceptibility to the infectious and perhaps sporadic forms of disease. TSEs are transmissible amyloidoses in which the host-encoded protein has the propensity to acquire a beta-sheet conformation and produce amyloid; the accumulation of amyloid eventually destroys the neurons and induces the deadly disease.

Diabetes control and complications.

Abstract: The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive treatment of patients with insulin-dependent diabetes mellitus (IDDM) can substantially reduce the onset and progression of diabetic retinopathy, nephropathy, and neuropathy. The major risk associated with intensive treatment is recurrent hypoglycemia. Implementation of intensive treatment recommendations is difficult but should be considered and probably recommended to most patients with IDDM. If intensive treatment is impractical, any improvement in glycemic control is probably beneficial. Improved glycemic control should be recommended to most patients with non-insulin-dependent diabetes mellitus (NIDDM). The use of insulin in patients with NIDDM is controversial, especially in patients who are overweight, overeating, and minimally symptomatic.

Brain imaging in schizophrenia.

Abstract: Neuroimaging provides an unprecedented means by which to study psychiatric disorders. Structural imaging methods, i.e. computerized tomography (CT) and magnetic resonance imaging (MRI), have revealed subtle differences in the brains of schizophrenic patients that appear to be present before symptom onset. Radionuclide functional methods such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) have led to hypotheses about dysfunction in specific neuronal networks in schizophrenia. New advances in MRI allow functional data to be obtained noninvasively in a single individual using conventional MRI scanners. This chapter discusses the parallels between the historical technical developments in neuroimaging and the deepening understanding of the etiology and manifestations of schizophrenia.

Class II antigens and disease susceptibility.

Abstract: The role for HLA typing in autoimmune disease is changing with the recognition that HLA markers can identify patients with poor prognosis in some autoimmune disease. Aggressive therapeutic intervention in patients with such HLA prognostic markers has the potential to improve or prevent progressive disease outcomes in a select group of patients.

Marrow transplantation from unrelated volunteer donors.

Abstract: Marrow transplants from human leukocyte antigen (HLA)-compatible unrelated volunteer donors have become feasible for more than 30% of patients without a family match and have allowed long-term, disease-free survival in 15-65% of patients with a variety of hematological disorders. However, unrelated donor transplants have a higher incidence of graft failure and graft versus host disease (GVHD) than do HLA-matched sibling transplants. This increase may be due to disparities between donor and recipient for undetected HLA determinants or for non-HLA histocompatibility genes. Because of the large number of HLA loci and their high degree of polymorphism, fully compatible donors will not be found for most patients. Fortunately, a limited degree of HLA mismatch does not necessarily impair long-term survival in patients with hematologic malignancy. Current studies are defining the risk associated with mismatching for each histocompatibility locus and are developing methods for marrow transplantation that can decrease morbidity and improve survival despite genetic disparity between donor and recipient.

The relationship of psychiatric illness with gastrointestinal disease.

Abstract: Higher rates of psychiatric comorbidity as well as more impaired psychosocial adjustment occur with the functional bowel disorders and are particularly high in self-selected referral patients compared with community populations. Reciprocally, some studies show higher rates of functional bowel disturbances in patients with psychiatric diagnoses. Remaining alert for and addressing coexisting psychiatric illness will enhance treatment outcome (increased patient compliance, functioning, and satisfaction). Additionally, psychological factors affect the clinical expression of structural disease. Resetting treatment goals from cure to coping with chronic illness and setting personal limits are important.

Transjugular intrahepatic portosystemic shunts

Abstract: Management of bleeding esophageal varices due to portal hypertension has traditionally relied on endoscopic sclerotherapy and operative intervention with placement of a portosystemic shunt. Although percutaneous decompression of portal hypertension was investigated 25 years ago, it was not clinically feasible until recently. With the advent of intravascular stents, the technique of creating a transjugular intrahepatic portosystemic shunt (TIPS) can now be effectively applied to treat the complications of portal hypertension, including variceal hemorrhage and refractory ascites. Since its introduction in 1989, TIPS has enjoyed widespread clinical application. The initial results with this procedure are encouraging and suggest that it is an effective means of reducing the frequency of variceal hemorrhage in patients with portal hypertension. The long-term patency rate and frequency of complications, however, have not been clearly defined. Similarly, the role of TIPS in the treatment of refractory ascites, Budd-Chiari syndrome, and hepatorenal syndrome remains unclear because sufficient data do not yet exist to support its general use in these settings.

Voltage-gated ion channelopathies: inherited disorders caused by abnormal sodium, chloride, and calcium regulation in skeletal muscle.

Abstract: The pathological genetic defects in the inherited myotonias and periodic paralyses were recently elucidated using molecular genetic studies. These disorders are usually transmitted as a dominant trait from an affected parent to a child. The many clinical symptoms include cold-induced uncontrollable contraction of muscle, potassium-induced contraction and paralysis, myotonia with dramatic muscular hypertrophy, muscle stiffness, and insulin-induced paralysis (in males). Horses afflicted with the disorder can suddenly collapse, despite an impressive physique. In the past three years, these clinically defined disorders have been shown to share a common etiology: subtle defects of ion channels in the muscle-fiber membrane. Although the specific ion channel involved varies depending on the disease, most patients have single amino acid changes in the channel proteins, with both normal and mutant channels present in each muscle fiber. For each patient, we can now establish a precise molecular diagnosis in the face of overlapping clinical symptoms and begin specific pharmacological treatment based on the primary problem. These studies have also provided insight into basic muscle biology and emphasize the careful regulation of ions in muscle excitation.

Treatment of osteoporosis

Abstract: Osteoporosis is a common disorder affecting the health of many adults. Strategies for fracture prevention include optimization of peak bone mass and prevention of bone loss at menopause and with aging. Genetic, nutritional, and life-style factors influence peak bone mass and may be used to focus preventive efforts. Once peak bone mass is reached, increased bone resorption may be the major pathogenetic factor. Calcium plus vitamin D, estrogen replacement therapy, calcitonin, and etidronate are agents currently available for treatment of osteoporosis; they act by inhibiting bone resorption. The failure of bone formation to keep pace with bone resorption also contributes to bone loss. Fluoride and intermittent parathyroid hormone therapy increase bone formation; however, more data are needed to determine efficacy. Insulin-like growth factors, transforming growth factor-beta (TGF-beta), and bone morphogenetic proteins may stimulate bone formation, but they have not yet been tested clinically. New approaches to treatment of osteoporosis will emerge as our understanding of the pathogenesis increases.

Repetitive motion injuries

Abstract: Repetitive motion injuries have presented clinicians with a significant challenge over the past two and a half decades. Acceptable treatment of inflammatory disorders is well established, but compressive neuropathies and nonspecific complaints of numbness, tingling, and discomfort in the upper extremity present vexing dilemmas. Current research and experience point to multilevel problems, including posturally induced muscular imbalance. Although surgical solutions to these problems are sometimes indicated, conservative approaches successfully treat many individuals and have narrowed the scope and indications for surgical intervention. These approaches include ergonomic changes at the workstation, postural changes, and muscle stretching and strengthening to correct imbalance.

FULMINANT HEPATIC FAILURE: Pathophysiology, Treatment, and Survival

Abstract: Fulminant hepatic failure is characterized by severe metabolic derangements, neurologic complications and, ultimately, multiorgan failure. In the past three decades, improved intensive care has increased mean survival from 15% to 50% in certain patient groups by providing metabolic support and management of specific, frequent, and potentially fatal complications. However, outcome remains highly dependent on etiology. While intensive care is sufficient therapy in some patients (Group I), those with irreparable hepatic damage (Group III) can only survive if transplanted. In intermediate cases (Group II), the liver retains the potential to regenerate if the patient receives hepatic functional support. Major areas of current research in this field include development of hepatic support devices, strategies to accelerate and maximize hepatic regeneration, and criteria for accurate prognostic classification of patients.

Hepatitis C: an overview.

Abstract: Hepatitis C virus (HCV) has been associated with acute and chronic posttransfusion and with sporadic non-A non-B (NANB) hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Cloning of the sequence encoding an antigenic component of HCV in 1989 led to the development of tests to detect antibody to HCV in serum. Viral HCV RNA can be detected and estimated with polymerase chain reaction (PCR) and branched-chain DNA (bDNA) signal amplification tests. The entire viral genome has been sequenced. The HCV envelope region varies considerably, and infections with mutant HCV have been described. Approximately 0.5-1.5% of healthy blood donors test positive, and HCV infection can be acquired by blood transfusion or i.v. drug abuse. Vertical and sexual transmission of the virus is rare, and the transmission mode remains obscure in a large group of patients. Acute hepatitis C is mild and often asymptomatic. Chronic hepatitis C has an indolent course but may progress to cirrhosis and HCC. Recombinant alpha interferon (IF) is used to treat chronic HCV disease, but no consensus has been reached on patient selection, dose, and duration of treatment. Approximately 50% of treated patients respond, but 50-80% of responders relapse over time. Liver transplantation in patients with end-stage, HCV-related liver disease is often followed by allograft infection. Short-term survival with reinfection is good, but the long-term consequences remain to be defined.

Molecular approaches to amyotrophic lateral sclerosis

Abstract: New discoveries are expanding our knowledge of mechanisms involved in amyotrophic lateral sclerosis (ALS) pathogenesis. Some recent advances in our understanding of motoneuron death in familial ALS (fALS) and sporadic ALS (sALS) are reviewed, with emphasis on molecular similarities that may further unite these phenotypically linked diseases.

Management of early nephropathy in diabetic patients

Abstract: Diabetic patients go through several stages of renal disease, moving from normo- to micro- to macroalbuminuria. Good metabolic control can prevent or postpone the development of microalbuminuria, the earliest sign of diabetic renal disease. Thus, efforts should focus on obtaining the best possible control before the onset of microalbuninuria. In patients with microalbuminuria, blood pressure starts to increase, and early antihypertensive treatment becomes important. Good glycemic control may be difficult to achieve. With overt nephropathy, defined as clinical proteinuria, a relentless decline in glomerular filtration rate (GFR) occurs unless patients are carefully treated with antihypertensive agents. Protein restriction may also be necessary, but a clear beneficial effect of optimized diabetes care is difficult to document. Early screening is recommended, with an emphasis on testing for albuminuria, including microalbuminuria, along with careful control of blood pressure.

Reduced-size hepatic allografts

Abstract: Reduced-size hepatic transplantation (RSHT) was developed to alleviate the mortality resulting from the scarcity of suitable cadaveric grafts. RSHT consists of various techniques that reduce a full liver to a smaller size. These techniques include reduced-size cadaveric liver transplantation (RLT), split liver transplantation (SLT), and living-related liver transplantation (LRLT). RLT utilizes part of a liver, while the rest is discarded; in SLT, the whole liver is used for two recipients after bipartition; and in LRLT, a portion of the liver retrieved from a living donor is transplanted. Whereas RLT only redistributes the pool of organs to the advantage of pediatric recipients, both SLT and LRLT increase the availability of grafts for transplantation. RSHT yields results comparable to full-liver allografting and drastically reduces the mortality of patients waiting for transplantation. The procedures involved are technically demanding and should be restricted to experienced liver centers.

Pancreas transplantation for diabetes mellitus

Abstract: Vascularized pancreas transplantation has assumed an increasing role in the treatment of diabetes mellitus. Through 1993, over 5500 pancreas transplants have been performed worldwide, with over 80% being combined pancreas-kidney transplants. Overall one-year patient survival exceeds 90% and graft survival (complete insulin independence) exceeds 70%. Although successful pancreas transplantation achieves euglycemia and complete insulin independence, this occurs at the expense of hyperinsulinemia and chronic immunosuppression. The net result of these changes on diabetic complications in the long term remains to be determined. In the short term, improvement in the quality of life and possible prevention of further morbidity associated with diabetes makes pancreas transplantation an important therapeutic option, particularly when combined with a kidney transplant, in appropriately selected diabetic patients.