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PubMedDate not supplied

Breast cancer screening among women younger than age 50: a current assessment of the issues.

In the hope of resolving underlying policy questions related to the value of breast cancer screening with mammography for women younger than 50 years of age, the National Institutes of Health and the National Cancer Institute in 1997 jointly sponsored a consensus conference on the subject. While the panel concluded that the data were insufficient to endorse mammography for this age group apart from individual choice, the conclusion was not the "consensus" sought by many of those with strong opinions on both sides of this issue, and the debate raged on. Prior to the 1997 conference, and since, meta-analyses of trial data and assessments of service screening programs have indicated that breast cancer screening with mammography for women between 40 and 49 meets recommended levels of performance compared with performance in women 50 years and older, especially if programs achieve high quality and screen at 12-to-18 month intervals. Because the detectable preclinical phase is shorter in younger women who develop breast cancer compared with that in women 50 years of age or older, a key component of any screening program for those younger than 50 is an appropriate screening interval. Many of the screening programs that had historically been developed for women in their forties--and whose disappointing results contributed to the confusion and controversy about the efficacy of mammography in younger women--had a 24-month screening interval, which was not found to be of significant benefit for early detection of breast cancer in this age group. While a new emphasis of this controversy has focused on the balance of benefits and harms in women ages 40 to 49, women of all ages need to be fully informed about the benefits and limitations of breast cancer screening--more specifically, what to expect at the time of screening, and what to expect from screening. There are differences in the performance and effectiveness of mammography in different age groups of women aged 40 and older, but these differences are not so great to question the value of screening in any one group. While some questions remain unresolved, the efficacy of mammography in women ages 40 to 49 should no longer be considered controversial.

Adult↗
PubMed1990

Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy.

Septic shock is the commonest cause of death in intensive care units. Although sepsis usually produces a low systemic vascular resistance and elevated cardiac output, strong evidence (decreased ejection fraction and reduced response to fluid administration) suggests that the ventricular myocardium is depressed and the ventricle dilated. In survivors, these abnormalities are reversible. Failure to develop ventricular dilatation in nonsurvivors suggests that dilatation is a compensatory mechanism needed to maintain adequate cardiac output. With a canine model of septic shock that is very similar to human sepsis, myocardial depression was confirmed using load-independent measures of ventricular performance. Endotoxin administration to humans simulates the qualitative, cardiovascular abnormalities of sepsis. The pathogenesis of septic shock is extraordinarily complex. Diverse microorganisms can generate toxins, stimulating release of potent mediators that act on vasculature and myocardium. A circulating myocardial depressant substance has been closely associated with the myocardial depression of human septic shock. Therapy has emphasized early use of antibiotics, critical care monitoring, aggressive volume resuscitation, and, if shock continues, use of inotropic agents and vasopressors. Pharmacologic or immunologic antagonism of endotoxin or other mediators may prove to enhance survival in this highly lethal syndrome.

Animals↗
PubMed1994

Clinical uses of insulin-like growth factor I.

Insulin-like growth factor I (IGF-I) has acute insulin-like metabolic effects and long-term anabolic actions. The therapeutic potential of recombinant human IGF-I treatment is being investigated in various growth hormone-resistant and insulin-resistant disorders. Recent studies have shown that IGF-I may substitute for growth hormone in promoting linear growth in children with growth hormone insensitivity. The anabolic, protein-sparing action of IGF-I is being evaluated as a potential therapy for adults with catabolic diseases. Patients with insulin-dependent diabetes mellitus have reduced endogenous IGF-I production, and studies are in progress to determine whether treatment with IGF-I in addition to insulin may improve their metabolic/anabolic status. Insulin-like growth factor I treatment may reduce glucose and triglyceride levels in adults with non-insulin-dependent diabetes mellitus and in some patients with extreme insulin resistance. Further studies are needed to evaluate the efficacy and safety of IGF-I treatment in these and other conditions and to provide a better understanding of this hormone's normal physiologic role(s) and complex relations with growth hormone and insulin.

Diabetes Mellitus, Type 1↗
PubMed1995

Insulin-like growth factors and cancer.

The insulin-like growth factor (IGF) family of peptides, binding proteins, and receptors are important for normal human growth and development and are involved in the specialized functions of most physiologic systems. Most members of the IGF system are expressed by different cancer cells and may play an important role in the propagation of these malignancies. New therapies aimed at modulating various components of the IGF system could affect the progression and metastasis of cancer.

Animals↗
PubMed1995

Functional magnetic resonance imaging of the brain.

This conference reviewed the potential scope of application of recently developed techniques for functional magnetic resonance imaging (fMRI) of the brain. The most successful technique is based on the sensitivity of magnetic resonance imaging (MRI) to magnetic effects caused by the modulation of the oxygenation state of hemoglobin, which is induced by local variations in blood flow during task activation. Typically, the MRI signal increases by a few percentage points during brain activation because blood flow and oxygen supply sharply increase. Brain activation images with excellent combined spatial and temporal resolution have been obtained noninvasively using visual, sensorimotor, or auditory stimuli, or during higher-order cognitive processes such as language or mental imagery. Although sensitive to misregistration artifacts and macroscopic vessels, MRI permits both the direct correlation of function with underlying anatomy and repeated studies on the same person. It may become the method of choice for studies of mental and cognitive processes, presurgical mapping, monitoring recovery from stroke or head injuries, exploration of seizure disorders, or monitoring the effects of neuropharmaceuticals.

Animals↗
PubMed1996

The laboratory evaluation of opportunistic pulmonary infections.

The patient population at risk for opportunistic pulmonary infections has increased during the last decade. The spectrum of organisms causing opportunistic infections has also grown. With an ever broader list of potential diagnosis, a specific diagnosis of the cause of pulmonary disease becomes more important. Recent microbiologic advances have helped to facilitate the laboratory diagnosis of some of these agents. Immunoassays are available for the detection of antigen in nasopharyngeal secretions (respiratory syncytial virus, influenza) in serum (Cryptococcus species), and in urine (Legionella or Histoplasma species). Rapid-culture techniques are available for the culture and detection of various viruses, including cytomegalovirus. Molecular probes can now assist in the rapid identification of Mycobacterium tuberculosis and some fungi. In the near future, polymerase chain reaction-based techniques may assist in the detection of Pneumocystis carinii and Legionella, Chlamydia, Mycoplasma, and Mycobacteria species. An expeditious evaluation of pulmonary disease requires an understanding of the differential diagnosis of likely causes of pulmonary disease in specific immunosuppressed patient populations, an understanding of the most appropriate specimens to process for these diagnoses, and an understanding of the limitations (sensitivity and specificity) of these diagnostic tests. An understanding of the most appropriate specimens and tests in a given institution should allow for early, relatively specific treatment of many potentially life-threatening infections.

Clinical Laboratory Techniques↗
PubMed1996

Immunopathogenic mechanisms of HIV infection.

A complex array of multiphasic and multifactorial immunopathogenic mechanisms are involved in the establishment and progression of human immunodeficiency virus (HIV) disease. After primary infection, acute viremia occurs with wide dissemination of HIV. During this early viremic phase, the virus is trapped within the processes of follicular dendritic cells in the germinal centers of lymphoid tissue. Also, during this phase of primary infection, some patients show major expansions of certain subsets of CD8+ T cells that are identified by the expression of a particular variable region of the beta chain of the T-cell receptor. These expansions are manifestations of responses to HIV that may be important in controlling the progression of HIV infection. In addition, inappropriate immune activation and elevated secretion of certain proinflammatory cytokines occur during HIV infection; these cytokines play a role in the regulation of HIV expression in the tissues. Infection of progenitor cells in bone marrow and the thymus contribute to the lack of regeneration of immunocompetent cells. Dendritic cells are involved in the initiation and propagation of HIV infection in CD4+ T cells. In studies of long-term nonprogressors - persons who have stable CD4+ T-cell counts and no HIV disease progression despite years of HIV infection - preserved lymph node architecture, low viral burden, and viral expression were found.

Dendritic Cells↗
PubMed1998

The pathophysiologic roles of interleukin-6 in human disease.

Interleukin-6, an inflammatory cytokine, is characterized by pleiotropy and redundancy of action. Apart from its hematologic, immune, and hepatic effects, it has many endocrine and metabolic actions. Specifically, it is a potent stimulator of the hypothalamic-pituitary-adrenal axis and is under the tonic negative control of glucocorticoids. It acutely stimulates the secretion of growth hormone, inhibits thyroid-stimulating hormone secretion, and decreases serum lipid concentrations. Furthermore, it is secreted during stress and is positively controlled by catecholamines. Administration of interleukin-6 results in fever, anorexia, and fatigue. Elevated levels of circulating interleukin-6 have been seen in the steroid withdrawal syndrome and in the severe inflammatory, infectious, and traumatic states potentially associated with the inappropriate secretion of vasopressin. Levels of circulating interleukin-6 are also elevated in several inflammatory diseases, such as rheumatoid arthritis. Interleukin-6 is negatively controlled by estrogens and androgens, and it plays a central role in the pathogenesis of the osteoporosis seen in conditions characterized by increased bone resorption, such as sex-steroid deficiency and hyperparathyroidism. Overproduction of interleukin-6 may contribute to illness during aging and chronic stress. Finally, administration of recombinant human interleukin-6 may serve as a stimulation test for the integrity of the hypothalamic-pituitary-adrenal axis.

Aging↗
PubMed1998

Use of cytotoxic agents and cyclosporine in the treatment of autoimmune disease. Part 2: Inflammatory bowel disease, systemic vasculitis, and therapeutic toxicity.

When cytotoxic agents were introduced, their ability to disrupt nucleic acid and protein synthesis led to their effective use for the treatment of neoplastic disease. During the course of this use, however, it became apparent that these agents also suppress the immune system. This usually unwelcome effect was subsequently studied and beneficially directed toward the treatment of non-neoplastic diseases in which autoimmune mechanisms were considered important to pathogenesis. As a result of these investigations, cytotoxic agents and, more recently, cyclosporine have emerged to become an important part of the therapeutic regimen for many autoimmune diseases. Nonetheless, these medications may still cause treatment-induced illness or even death. It is therefore particularly important to weigh the benefits and risks of cytotoxic therapy when treating a non-neoplastic disease. This two-part Clinical Staff Conference reviews data on the efficacy and toxicity of cytotoxic drugs and cyclosporine in selected autoimmune diseases. In part 2, we focus on the role of these agents in treating inflammatory bowel disease and systemic vasculitis and review the toxic effects of these agents.

Cyclosporine↗
PubMed1998

Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system: clinical implications.

The hypothalamic-pituitary-adrenal axis exerts profound, multilevel inhibitory effects on the female reproductive system. Corticotropin-releasing hormone (CRH) and CRH-induced proopiomelanocortin peptides inhibit hypothalamic gonadotropin-releasing hormone secretion, whereas glucocorticoids suppress pituitary luteinizing hormone and ovarian estrogen and progesterone secretion and render target tissues resistant to estradiol. The hypothalamic-pituitary-adrenal axis is thus responsible for the "hypothalamic" amenorrhea of stress, which is also seen in melancholic depression, malnutrition, eating disorders, chronic active alcoholism, chronic excessive exercise, and the hypogonadism of the Cushing syndrome. Conversely, estrogen directly stimulates the CRH gene promoter and the central noradrenergic system, which may explain adult women's slight hypercortisolism; preponderance of affective, anxiety, and eating disorders; and mood cycles and vulnerability to autoimmune and inflammatory disease, both of which follow estradiol fluctuations. Several components of the hypothalamic-pituitary-adrenal axis and their receptors are present in reproductive tissues as autacoid regulators. These include ovarian and endometrial CRH, which may participate in the inflammatory processes of the ovary (ovulation and luteolysis) and endometrium (blastocyst implantation and menstruation), and placental CRH, which may participate in the physiology of pregnancy and the timing of labor and delivery. The hypercortisolism of the latter half of pregnancy can be explained by high levels of placental CRH in plasma. This hypercortisolism causes a transient postpartum adrenal suppression that, together with estrogen withdrawal, may partly explain the depression and autoimmune phenomena of the postpartum period.

Corticotropin-Releasing Hormone↗
PubMed1998

Treating histologically mild chronic hepatitis C: monotherapy, combination therapy, or tincture of time?

The recent National Institutes of Health Consensus Conference on hepatitis C solidified the justification for a selective approach to treatment. Nevertheless, the high profile of chronic hepatitis C has led to a sense of urgency about treating "all-comers" and thus has caused the variable natural history of this disease to be overlooked. The debate about whom to treat has failed to focus attention on the alternative approach of waiting for better emerging therapies for the subset of patients with histologically mild chronic hepatitis C. Practitioners should be more confident about postponing treatment in less symptomatic patients if liver biopsy specimens show no more than grade 1 necroinflammatory activity or stage 1 fibrosis. Patients with these lesions, in the absence of clinical signs of advancing disease, are much less likely than patients with higher grades or stages to progress to cirrhosis. A "cure" for chronic hepatitis C remains elusive. End points of treatment depend on the achievement of sustained clearance of serum hepatitis C virus RNA, which is influenced, in turn, by the patient's viral replication and immune balance. Treatment of histologically mild chronic hepatitis C may ultimately mimic that of HIV infection.

Alanine Transaminase↗
PubMed1998

Multiple endocrine neoplasia type 1: clinical and genetic topics.

Multiple endocrine neoplasia type 1 (MEN1) consists of benign, and sometimes malignant, tumors (often multiple in a tissue) of the parathyroids, enteropancreatic neuroendocrine system, anterior pituitary, and other tissues. Skin angiofibromas and skin collagenomas are common. Typically, MEN1 tumors begin two decades earlier than sporadic tumors. Because of tumor multiplicity and the tendency for postoperative tumor recurrence, specialized methods have been developed for preoperative and intraoperative localization of many MEN1-associated tumors. The MEN1 gene was recently isolated by positional cloning. This strategy progressively narrows the size of the candidate MEN1 gene interval on the chromosome and then finds and tests many or, if needed, all genes within that interval. The MEN1 gene was finally identified because it was the one gene that contained mutations in most DNAs from a test panel of MEN1 cases. It has been suggested that MEN1, like many hereditary cancer syndromes, is caused by mutation in a tumor suppressor gene that contributes to neoplasia when both gene copies in a tumor precursor cell have been sequentially inactivated ("two-hit" oncogenesis mechanism). Germline MEN1 mutations were found in most families with MEN1 and in most cases of sporadic MEN1. In addition, the MEN1 gene was the gene most likely to show acquired mutation in several sporadic or nonhereditary tumors-parathyroid adenomas, gastrinomas, insulinomas, and bronchial carcinoids. Most germline or acquired MEN1 mutations predicted truncation (and thus likely inactivation) of the encoded protein, supporting expectations for the "first hit" to a tumor suppressor gene. Testing for MEN1 germline mutation is possible in a research setting. Candidates for MEN1 mutation testing include patients with MEN1 or its phenocopies and first-degree relatives of persons with MEN1.

Chromosome Mapping↗
PubMed2000

Pathogenesis, natural history, treatment, and prevention of hepatitis C.

Approximately 4 million persons in the United States and probably more than 100 million persons worldwide are infected with hepatitis C virus. The virus has the unique ability to cause persistent infection in susceptible hosts after parenteral or percutaneous transmission, and its underlying mechanisms are not well understood. The immunologic correlates of protection and viral clearance and the pathogenesis of liver injury are yet to be defined, but recent studies suggest the importance of cell-mediated immune responses. Although 70% to 80% of infected persons become chronic carriers, most have relatively mild disease with slow progression. However, chronic and progressive hepatitis C carries significant morbidity and mortality and is a major cause of cirrhosis, end-stage liver disease, and liver cancer. Development of an effective hepatitis C virus vaccine is not imminent, but recent advances in technology and basic knowledge of molecular virology and immunology have engendered novel approaches to the fundamental problems encountered in vaccine development. Current therapy for hepatitis C, although effective in some patients, is problematic and still evolving. Advances in modern biology and immunology promise new therapies for this important disease.

Antibody Formation↗
PubMed2000

Osteoarthritis: new insights. Part 1: the disease and its risk factors.

Osteoarthritis is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors (such as genetics, dietary intake, estrogen use, and bone density) and of local biomechanical factors (such as muscle weakness, obesity, and joint laxity). These risk factors are particularly important in weight-bearing joints, and modifying them may present opportunities for prevention of osteoarthritis-related pain and disability. Major advances in management to reduce pain and disability are yielding a panoply of available treatments ranging from nutriceuticals to chondrocyte transplantation, new oral anti-inflammatory medications, and health education. This article is part 1 of a two-part summary of a National Institutes of Health conference. The conference brought together experts on osteoarthritis from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. Part 1 focuses on a new understanding of what osteoarthritis is and on risk factors that predispose to disease occurrence. It concludes with a discussion of the impact of osteoarthritis on disability.

Age Distribution↗
PubMed2000

Osteoarthritis: new insights. Part 2: treatment approaches.

Osteoarthritis is the most common form of arthritis, affecting millions of people in the United States. It is a complex disease whose etiology bridges biomechanics and biochemistry. Evidence is growing for the role of systemic factors, such as genetics, diet, estrogen use, and bone density, and local biomechanical factors, such as muscle weakness, obesity, and joint laxity. These risk factors are particularly important in the weight-bearing joints, and modifying them may help prevent osteoarthritis-related pain and disability. Major advances in management to reduce pain and disability are yielding a panoply of available treatments ranging from nutriceuticals to chondrocyte transplantation, new oral anti-inflammatory medications, and health education. This article is part 2 of a two-part summary of a National Institutes of Health conference that brought together experts in osteoarthritis from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. Part 2 focuses on treatment approaches; evidence for the efficacy of commonly used oral therapies is reviewed and information on alternative therapies, including nutriceuticals and acupuncture, is presented. Biomechanical interventions, such as exercise and bracing, and behavioral interventions directed toward enhancing self-management are reviewed. Current surgical approaches are described and probable future biotechnology-oriented approaches to treatment are suggested.

Acupuncture Therapy↗
PubMed2001

Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma.

Pheochromocytoma is a rare but important tumor of chromaffin cells that is frequently considered in the evaluation of hypertension, arrhythmias, or panic disorder and in the follow-up of patients with particular genetic diseases. This report provides an update about the genetics, neurochemical diagnosis, localization by imaging, and surgical management of pheochromocytoma. Specific mutations of the RET proto-oncogene cause familial predisposition to pheochromocytoma in multiple endocrine neoplasia type II, and mutations in the von Hippel-Lindau tumor suppressor gene cause familial disposition to pheochromocytoma in von Hippel-Lindau disease. Recent findings demonstrating extraordinarily high sensitivity of plasma levels of metanephrines for detecting pheochromocytoma have led to an algorithm for clinical diagnostic steps. Nuclear imaging approaches, such as(123) I-metaiodobenzylguanidine scintigraphy and 6-[(18) F]fluorodopamine positron emission tomography, enhance both diagnosis and localization of the tumor, as described in an algorithm for patients with positive biochemical test results. Since pheochromocytoma is often benign, surgical resection by laparoscopic adrenalectomy can be curative. Areas requiring further work include determining appropriate follow-up of patients with familial pheochromocytoma, elucidating the bases for phenotypic differences, improving both specificity and sensitivity of biochemical tests, optimizing cost-effectiveness of diagnostic imaging, and testing the risk for tumor recurrence after partial adrenalectomy.

Adrenal Gland Neoplasms↗