Cushing's syndrome is usually caused by the secretion of corticotropin or cortisol by a pituitary or adrenal tumor, respectively, or by ectopic secretion of corticotropin. It is possible to determine the specific abnormality in most patients, but it can sometimes be difficult to decide whether the patient has hypercortisolism and whether it is primary or due to major depressive disorder or to the stress of other diseases. Determining the cause of the hypercortisolism involves performing multiple tests in a logical sequence; the results should all be consistent with the same diagnosis. Treatment should aim to cure the hypercortisolism and to eliminate any tumor that threatens the patient's health, while minimizing the chance of an endocrine deficiency or long-term dependence on medications.

Radiotherapy remains an important component of the management of malignant disease. Especially when combined with cytotoxic chemotherapy, limited surgical excision, or both, irradiation has been shown to control disease in the primary site and regional nodes without the need for surgical extirpation as frequently as in past years. New developments in three-dimensional treatment planning and the precise delivery of high-dose radiation promise to increase the benefit of radiation treatment. Finally, molecular studies of the cell's response to radiation and the phenomena of DNA damage and repair are providing explanations for heretofore unexplained radiobiologic observations. Such research is laying the groundwork for targeted manipulation of the cell's response to radiation, which will be tested in the near future.

Both osteoblasts and osteoclasts are derived from progenitors that reside in the bone marrow; osteoblasts belong to the mesenchymal lineage of the marrow stroma, and osteoclasts to the hematopoietic lineage. The development of osteoclasts from their progenitors is dependent on stromal-osteoblastic cells, which are a major source of cytokines that are critical in osteoclastogenesis, such as interleukin-6 and interleukin-11. The production of interleukin-6 by stromal osteoblastic cells, as well as the responsiveness of bone marrow cells to cytokines such as interleukin-6 and interleukin-11, is regulated by sex steroids. When gonadal function is lost, the formation of osteoclasts as well as osteoblasts increases in the marrow, both changes apparently mediated by an increase in the production of interleukin-6 and perhaps by an increase in the responsiveness of bone marrow progenitor cells not only to interleukin-6 but also to other cytokines with osteoclastogenic and osteoblastogenic properties. The cellular activity of the bone marrow is also altered by the process of aging. Specifically, senescence may decrease the ability of the marrow to form osteoblast precursors. The association between the dysregulation of osteoclast or osteoblast development in the marrow and the disruption of the balance between bone resorption and bone formation, resulting in the loss of bone, leads to the following notion. Like homeostasis of other regenerating tissues, homeostasis of bone depends on the orderly replenishment of its cellular constituents. Excessive osteoclastogenesis and inadequate osteoblastogenesis are responsible for the mismatch between the formation and resorption of bone in postmenopausal and age-related osteopenia. The recognition that changes in the numbers of bone cells, rather than changes in the activity of individual cells, form the pathogenetic basis of osteoporosis is a major advance in understanding the mechanism of this disease.

Randomized clinical trials have proved that warfarin therapy decreases the risk of stroke in patients with nonvalvular atrial fibrillation and in those who have had a myocardial infarction. In patients who are not candidates for long-term anticoagulant therapy, aspirin is beneficial, but the reduction in risk is smaller with aspirin than with warfarin. In patients with cerebral ischemic symptoms of noncardiac origin, aspirin and ticlopidine reduce the risk of stroke, but the benefit is modest. Given alone, neither dipyridamole nor sulfinpyrazone prevents stroke. The question remains whether either of these drugs plus aspirin is better than aspirin alone. The optimal dose of aspirin for stroke prevention has not been established. Carotid endarterectomy reduces the risk of stroke in symptomatic patients with at least 70 percent stenosis, as determined by arteriography. Current trials are addressing the question of whether endarterectomy is beneficial for patients with moderate degrees of carotid stenosis. The benefit of endarterectomy for patients with asymptomatic carotid lesions remains unclear.

ARDS is a complex response of the lung to direct (inhalational) and indirect (hematogenous) insults. It is easy to be pessimistic about the benefit of the approaches we have described, but there is evidence that overall survival has improved in recent years. To maintain this progress, new therapies for ARDS must be rigorously evaluated, and their routine use should be recommended only after careful scrutiny of the evidence. Such a course will eliminate the unnecessary risks and costs often associated with unproved therapies.