Reperfusion following lower-torso ischemia in humans leads to respiratory failure manifest by pulmonary hypertension, hypoxemia, and noncardiogenic pulmonary edema. The mechanism of injury has been studied in the sheep lung lymph preparation, where it has been demonstrated that the reperfusion resulting in pulmonary edema is due to an increase in microvascular permeability of the lung to protein. This respiratory failure caused by reperfusion appears to be an inflammatory reaction associated with intravascular release of the chemoattractants leukotriene B4 and thromboxane. Histological studies of the lung in experimental animals revealed significant accumulation of neutrophils but not platelets in alveolar capillaries. We conclude that thromboxane generated and released from the ischemic tissue is responsible for the transient pulmonary hypertension. Second, it is likely that the chemoattractants are responsible for leukosequestration, and, third, neutrophils, oxygen-derived free radicals, and thromboxane moderate the altered lung permeability.

Osteoporosis is a devastating, morbid, and costly condition whose ravages are felt most profoundly by women over age 70 years. Yet most research on its prevention and treatment has focused on perimenopausal women, although there are significant differences between perimenopausal and older women in factors related to bone mineral metabolism, rates of bone loss, the structural integrity of remaining bone, risk factors for fractures, and the types of fractures sustained. Currently recommended therapies, which slow bone loss in perimenopausal women, may be of less benefit for older women whose loss of bone has already slowed or ceased and whose remaining bone may be of inadequate quantity and quality to prevent fracture. Thus, the application of currently available modalities is unlikely to mitigate significantly the consequences of osteoporosis in this population. Further research is urgently needed, and some directions for future investigation are suggested.

Pediatricians face clinical and ethical dilemmas about therapy to augment growth in short children who do not meet classic criteria for growth hormone (GH) deficiency. Biologic norms of health are unhelpful because of the uncertain relationship between stature, GH secretion, health, and disease. Instead, we suggest that GH therapy be evaluated from the perspective of cultural norms. We compare GH therapy for short normal children with currently accepted therapies for non--life-threatening pediatric conditions such as well-child care, cosmetic therapy, treatment of psychological problems, and invasive outpatient therapy for chronic conditions. Based on this analysis, we argue that the burdens of therapy, the uncertainty about long-term risks and benefits, the unclear therapeutic end point, and the implications for child health policy place routine GH therapy for children without documented deficiency of GH secretion outside current pediatric ethical norms. Such therapy is properly administered within a comprehensive clinical research protocol.

The complex detection system leading to the discovery and treatment of precancerous lesions and early cancer of the uterine cervix is described in detail and discussed. By far the most difficult and underestimated component of this system is the screening and interpretation of cervical (Papanicolaou) smears. Cytologic case finding may fail because of inadequate samples, insufficient time devoted to screening, or human fatigue. Other weak points of the system, such as an inadequate clinical component, inadequate patient compliance, poor reproducibility of diagnoses, and ineffective aftercare, are also described. For example, obtaining a second smear to confirm or refute a diagnosis of cellular atypia is often a misleading practice. Although this cancer detection system has been shown to be effective in reducing the rate of morbidity and mortality from invasive cervical cancer in appropriately screened populations, there is no evidence that the Papanicolaou test has succeeded anywhere in complete eradication of this theoretically preventable disease. It is important to inform the public about the potential failures of the system and the reasons for them.

Child sexual abuse is a serious, pervasive problem with clinical, social, moral, and legal implications. Between 100,000 and 500,000 children in the United States are thought to be sexually molested annually. Physicians in all specialties may detect sexual exploitation of youngsters and are mandated to report such cases. Failure to diagnose child molestation and pedophilia and to treat their cause can have serious, long-lasting consequences for innocent victims and continued distress for the perpetrator and for the professional who missed the diagnosis. A single child molester may commit hundreds of sexual acts on hundreds of children. The etiology of paraphilic syndromes is multifactorial. There are substantial differences among sexual abusers of children in their personalities and psychopathologies. Although available interventions are symptomatically palliative rather than curative, many pedophiles can benefit from appropriate treatment. Primary prevention may be the key to reducing the frequency of child sexual abuse.

Colorectal cancer is the second most common cause of cancer in the United States. The overall mortality rate approaches 60%. However, the detection of early lesions results in a mortality rate of 20% or less. Therefore, if improvement in survival is to occur, increased efforts need to be focused not only on primary prevention but also on early detection of malignant lesions and the eradication of potentially malignant lesions. There is no universal consensus as to how this can be accomplished. The purpose of this article is to serve as a guideline, providing a practical basis for improving early detection and management of colorectal cancer and its precursors.

Magnetic resonance imaging (MRI) of the abdomen presents greater inherent difficulties than other anatomic regions. However, new techniques now allow imaging comparable in quality to computed tomography (CT). Magnetic resonance imaging offers the advantages of greater tissue contrast, multiplanar imaging, and lack of ionizing radiation or risk of toxic reactions from iodinated contrast media. Its use remains limited by high cost, limited availability, lack of a bowel contrast agent, and long imaging time, which some patients cannot tolerate. In many areas of abdominal imaging, MRI is now comparable to CT, but because of the greater availability and lesser cost, CT remains the procedure of choice. Magnetic resonance imaging is more accurate for staging neoplasms of the liver, adrenal glands, kidneys, bladder, prostate, uterus, and cervix and may aid in diagnosis of hepatic, adrenal, and uterine masses. In selected patients, especially those in whom CT is inconclusive or those who cannot tolerate iodinated contrast material, MRI can provide valuable information. Development of faster scanning techniques and MRI contrast agents and wider availability will probably increase the usefulness of abdominal MRI. At this time, MRI complements other abdominal imaging procedures. In a small number of patients, however, it can provide unique information in a virtually risk-free manner.

Resolution 43 (1987 Annual Meeting), adopted by the House of Delegates, resolved that the American Medical Association study the dangers associated with clove cigarettes, that policy recommendations regarding regulation of clove and other tobacco additives be developed, and that this information be made available to physicians and the public. Clove cigarettes are tobacco products. They therefore possess all the hazards associated with smoking all-tobacco cigarettes. In addition, inhaling clove cigarette smoke has been associated with severe lung injury in a few susceptible individuals with prodromal respiratory infection. Some individuals with normal respiratory tracts have apparently suffered aspiration pneumonitis as the result of a diminished gag reflex induced by a local anesthetic action of eugenol (the active component of cloves), which is volatilized into the smoke. The American Medical Association has an existing policy vigorously opposing the use of any tobacco product; no exemption from this policy is made for clove-containing cigarettes.

Increasingly high levels of absenteeism for minor illnesses and injuries have created serious problems for American schools and industries. Short-term absenteeism also creates serious ethical and professional dilemmas for primary care physicians who routinely perform school and work release evaluations. Through an inductive analysis of three typical cases, these problems are identified. The major ethical issues involved are discussed, including truth-telling, confidentiality, and a confusion of the professional boundaries of medicine, education, and industry. Through a deductive analysis, it is shown that the conventional approaches to school and work release evaluations fail to achieve satisfactory results. To circumvent these problems, three solutions are proposed: primary care physicians can refuse to do such evaluations, inform the patient of the purpose and rules of the encounter, or perform evaluations only in the context of treatment.

Two cases of pediatric accidental ingestion of an acetonitrile-containing cosmetic are reported. One of the children, a 16-month-old boy, was found dead in bed the morning after ingesting the product. No therapy had been undertaken, as the product was mistakenly assumed to be an acetone-containing nail polish remover. The second child, a 2-year-old boy, experienced signs of severe cyanide poisoning, but survived with vigorous supportive care. Both children had blood cyanide levels in the potentially lethal range. The observed delayed onset of severe toxic reactions supports the proposed mechanism of acetonitrile conversion to inorganic cyanide via hepatic microsomal enzymes. Physicians and poison centers should be alerted to the existence of this highly toxic product, sold for removal of sculptured nails and likely to be confused with the less toxic acetone-containing nail polish removers. We urge regulatory agencies to reconsider the wisdom of marketing a cosmetic that poses such an extreme health hazard.

Magnetic resonance imaging (MRI) has many bona fide applications in the head and neck region. The major strengths of its current conventional use include excellent soft-tissue contrast, multiplanar capabilities, noninvasiveness, and lack of ionizing radiation. Newer advances, including gradient-echo techniques, three-dimensional fourier transformation, paramagnetic contrast, and more efficient receiver coils, will improve images and expand indications for MRI. The technology, however, remains relatively expensive, and the additional information compared with that of other techniques might not always justify the difference in cost. Moreover, MRI's insensitivity to calcifications, lack of depiction of fine bone detail, and, in some areas, degradation caused by motion and other artifacts make computed tomography and other noninvasive studies more appropriate as a primary imaging tool in many circumstances. Continued careful clinical research should clarify the relative role of MRI and other imaging tools during the next several years.

The splicing of long transcripts of RNA (copied from DNA in the cell nucleus) into smaller, specific mRNA (ready for export to the protein-producing machinery in the cytoplasm) is an important event in the regulation of gene expression in eukaryotic cells. The splicing reaction occurs as a late step in the nuclear pathway for synthesis of mRNAs. This pathway commences with initiation of transcription by RNA polymerase II and probably involves an integrated series of steps each dependent on previous events. Splicing of precursors to mRNAs involves the formation of a spliceosome complex containing the 5' and 3' splice sites. This complex contains the evolutionarily highly conserved small nuclear RNAs (snRNAs) U2, U4, U5, and U6. The most abundant snRNA, U1, is required to form the spliceosome and may be a part of the spliceosome. Analogues of these snRNAs have been identified in yeast. Assembly of the spliceosome probably involves the binding of a multi-snRNA complex containing U4, U5, and U6 snRNAs. Several observations suggest that the association of snRNAs in such complexes is quite dynamic. It is argued that the snRNAs in the spliceosome form a catalytic RNA structure that is responsible for the cleavage and ligation steps during splicing.

Clinical success in rehabilitation of heroin addicts with maintenance treatment requires stability of the blood level in a pharmacologically effective range (optimally, 150 to 600 ng/mL)-a phenomenon that emphasizes the central importance of narcotic receptor occupation. It is postulated that the high rate of relapse of addicts after detoxification from heroin use is due to persistent derangement of the endogenous ligand-narcotic receptor system and that methadone in an adequate daily dose compensates for this defect. Some patients with long histories of heroin use and subsequent rehabilitation on a maintenance program do well when the treatment is terminated. The majority, unfortunately, experience a return of symptoms after maintenance is stopped. The treatment, therefore, is corrective but not curative for severely addicted persons. A major challenge for future research is to identify the specific defect in receptor function and to repair it. Meanwhile, methadone maintenance provides a safe and effective way to normalize the function of otherwise intractable narcotic addicts.

Certain RNA molecules can mediate their own cleavage or splicing or act as enzymes to promote reactions on substrate RNA molecules. Thus, RNA is not restricted to being a passive carrier of genetic information but can have an active role in directing cellular biochemistry. These findings suggest the possibility that other cellular RNAs, including the RNA components of small nuclear ribonucleoproteins, of the ribosome, and of various ribonucleoprotein enzymes, are catalysts. RNA enzymes (ribozymes) can be used as sequence-specific RNA cleavage agents in vitro, providing useful tools for biochemical studies of RNA. On a more speculative note, ribozymes directed against viral RNAs have the potential of serving as therapeutic agents. Finally, some infectious agents, including hepatitis delta virus and perhaps poliovirus and rhinoviruses, are themselves ribozymes, providing potential targets for pharmaceuticals.