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Signal transducers and activators of transcription (STATs) are transcription factors activated in response to cytokines and growth factors. Constitutively active Stat3 has been shown to mediate oncogenic transformation in cultured cells and induce tumor formation in mice. An increasing number of tumor-derived cell lines as well as samples from human cancer have been reported to express constitutively active Stat3 protein. We previously demonstrated that ovarian cancer cell lines express high levels of constitutively active Stat3. In this study, we show that inhibition of the Stat3 signaling pathway using the Janus Kinase-selective inhibitor, AG490, and a dominant negative Stat3 (Stat3beta) significantly suppresses the growth of ovarian and breast cancer cell lines harboring constitutively active Stat3. In the ovarian cancer cell lines, AG490 also diminished the phosphorylation of Stat3, Stat3 DNA binding activity, and the expression of Bcl-x(L). Further, AG490 induced significant apoptosis in ovarian and breast cancer cell lines expressing high levels of constitutively active Stat3 but had a less profound effect on normal cells lacking constitutively active Stat3. AG490 also enhanced apoptosis induced by cisplatin in ovarian cancer cells. These results suggest that inhibition of Stat3 signaling may provide a potential therapeutic approach for treating ovarian and breast cancers.

A patient with type I Gaucher's disease had avascular necrosis of the right femoral head that resulted in an altered bony pelvis and marked restriction of right hip abduction. Enzyme replacement therapy with alglucerase prevented further deterioration and improved thrombocytopenia. Vaginal delivery was achieved with the patient in the left lateral position with exaggerated flexion at the contralateral hip.

The survey on our unit revealed that 80% of injection drug users (IDUs) had hepatitis B core antibody (HBcAB), and 90% had hepatitis C virus antibody (HCVAB). Less than half of each group did not know or were unsure of the mode of transmission and spread of HCV. These findings emphasize the need to focus on education, especially about transmission of hepatitis B and C infection in drug addicts, particularly IDUs.

We studied a population of high-risk drug users concerning their current sexual practices. They had a pattern of inconsistent or infrequent condom use. Only 11.5% reported always using condoms; 38.2% reported never using them; and 50.3% reported using them sometimes. Experimental educational programs have demonstrated the feasibility of changing sexual behaviors in illicit drug users by using innovative techniques targeted specifically at them. The application of sex and marital therapy techniques to changing high-risk behaviors is not widely discussed in the substance abuse literature. The hypothesis that the application of the techniques of sex and marital therapy in educational programs for drug users will improve outcomes of HIV prevention should be tested.

Connective tissue disorders (CTD) have a relatively high incidence of pulmonary complications but their delineation has been hampered by difficulties inherent in the diagnostic techniques. One fresh approach to this problem is based on a clustering method that uses data from 8 separate investigations to cluster the patients into 4 distinctly separate categories representing normal nonsmoker, normal smokers, those with active interstitial lung disease and those with bronchiolitis. Using this method, a large group of patients with CTD have been examined to assess the nature and extent of their pulmonary complications. Subjects in the first cluster had a normal test profile across all variables, and included no current active smokers. The normal smoking cluster contained only smokers who had a high total lavage cell number with a relative increase in macrophages and a decrease in lymphocytes. In this group, all respiratory variables were normal with the exception of a mildly depressed DLCO, also known to be associated with smoking. The general characteristics of the active interstitial lung disease cluster was a markedly depressed DLCO indicating impaired gas exchange, and elevated gallium index, bronchoalveolar lavage (BAL) cell number and neutrophil and lymphocyte percentages, all indicating an active inflammatory process. However more careful analysis of this group suggested the presence of 2 subgroups, one with a lymphocytic alveolitis, and another with a neutrophilic alveolitis. The bronchiolitis cluster characteristics were a markedly depressed maximal mid expiratory flow rate and raised BAL lymphocyte percentage and gallium index. The distribution of patients within the cluster groupings suggested that Sjögren's syndrome, often an accompaniment of other CTD, is most frequently associated with pulmonary disease.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanisms responsible for gallium uptake in chronic, non-infective, diffuse lung disease are not completely understood. This study attempted to clarify some of them. A lung/liver gallium index was calculated in 113 subjects, some normal and some with various interstitial lung diseases, predominantly those associated with connective tissue disease. The mean gallium index was significantly higher in the groups with active interstitial lung disease (5.7) and non-infective bronchiolitis (4.1) compared with non-smoking normals (3.0; P less than 0.05). To investigate the mechanisms responsible for gallium uptake, the gallium index was correlated with bronchoalveolar lavage findings, respiratory function tests and clinical features. Significant correlations (P less than 0.05) were found with age in non-smoking normals; lavage macrophages in smoking normals; age but no other parameter in bronchiolitis; lavage lymphocytes, lavage albumin and improvement in diffusion capacity for carbon monoxide in those with active interstitial lung disease. It is concluded that in normal smokers gallium uptake may be due to a macrophage-mediated process. Gallium uptake in active interstitial lung disease associated with connective tissue disease appears to be an immunological process in which transport and retention of gallium is associated with that of albumin.

Interstitial lung disorders associated with the connective tissue diseases are thought to be quite common, but their precise analysis is fraught with difficulty because of the absence of a Gold Standard that, short of open lung biopsy, is not available. Analysis is hampered by the biologic variability in test results, large overlap between the normal and the disease population for individual tests, the confounding effect of smoking, and the complexities of viewing multidimensional data. In order to better define the pattern of the lung involvement, an entirely different approach has been adopted that is based on the use of graphic and clustering techniques to define the multivariate structure inherent in the data, then discriminant analysis to assign patients into distinct clusters. Using this approach it has been possible to group patients into four distinct clusters based on the result of respiratory function studies, gallium lung scan, bronchoalveolar lavage, and smoking status. These clusters are a normal smoking cluster and a normal nonsmoking cluster, a cluster of patients with active ILD, and a cluster with bronchiolitis. The validity of this method has been verified, and an algorithm has been developed that allows the assignment of any new patient entering the study into one of these clusters. This type of analysis offers a valuable new approach to the categorization of patients into distinct groups based on the results of multiple investigations.

Results of routine thyroid function tests in heavy cocaine abusers at the time of treatment admission were not statistically different from normal values for our laboratory or from a similar group of other substance abuse patients in treatment. This suggests that heavy cocaine use per se does not affect thyroid function. Therefore, if the thyroid function tests are abnormal in a cocaine abuser, then a true thyroid dysfunction should be considered and completely evaluated. In addition, nonspecific alterations in thyroid function tests in nonthyroidal illnesses should be kept in mind.

The authors studied the pattern of benzoylecgonine excretion in 35 male veterans who had recently used large amounts of cocaine. Following admission to a drug-free environment, the veterans completed a short structured interview and gave daily urine samples for benzoylecgonine analysis. Eleven (31.4%) patients excreted benzoylecgonine at levels of 300 ng/mL or above for 120 hours or longer after admission. Eight (22.9%) patients whose enzyme-multiplied immunoassay test results were negative subsequently tested positive. These findings corroborate recent case reports of prolonged presence of benzoylecgonine in the urine and have important implications for drug treatment programs.

Alprazolam appears to have an abuse liability among opiate addicts, and detoxification can be prolonged. The authors describe experience with five methadone maintenance patients who were polysubstance abusers and were admitted specifically for detoxification from alprazolam dependence. Phenobarbital in tapering doses adequately suppressed withdrawal symptoms and shortened hospitalization.

A curriculum in community and family medicine at the University of Massachusetts Medical School, planned to include a primary care preceptorship as an integral unit, is described. The curriculum has been planned to allow for repeated and increasing exposure of medical students during their undergraduate years to a variety of health care settings within the state. An extensive program of courses is required for all students and consists of a three-week field clerkship in the first year, a field-oriented epidemiology course in the second year, and a six-week field clerkship in the third or fourth year. A preceptorship elective is available to all medical students after they have completed their first two years. Field visits by community and family medicine faculty to the preceptorship site provide overall guidance, facilitate the implementation of objectives, and provide opportunities to strengthen bonds between the practicing physicians of the Commonwealth of Massachusetts and the state medical school. The results to date are discussed.

The required first-year clerkship in family and community medicine at the University of Massachusetts Medical School is a major curricular innovation which has implications for physician education. Students have lived in communities and worked in health service settings with field sponsors, under full-time faculty guidance, in all regions of Massachusetts. This has been one answer to the school's mandate to address the physician maldistribution problem. The goals and objectives and the teaching methods used to implement the program are described. These lessons were drawn from the program experience: community medicine clerkships belong in the first year of the curriculum; full-time medical school faculty working with the field sponsor promotes an optimal learning environment; long-term evaluation remains an important consideration. The first eight years of experience with the clerkship have demonstrated its value, and it should be considered for inclusion in the curriculum of other medical schools.

As a prelude to a study of severe ischemic heart failure, the therapeutic response of the ischemic ventricle to epinephrine and acetylstrophanthidin in nontoxic doses was determined in 24 intact anesthetized dogs undergoing a first episode of acute regional ischemia. A thrombotic obstruction was produced in the left ventricular dysfunction. The elevation of end-diastolic pressure and reduced stroke volume in control dogs were not significantly altered by administration of strophanthidin. Epinephrine (0.05 mug/kg per min) elicited a significant reduction in end-diastolic pressure and increase in stroke volume. The latter was not attended by an increased incidence of ventricular fibrillation, whereas fibrillation occurred in half of the group given strophantihidin. Thus, the catecholamine was selected to study pump failure. Severe ischemic heart failure was assessed in two groups with scar from previous infarction for up to 4 hours. By 60 minutes of ischemia the increase in end-diastolic pressure and volume and decrease in stroke volume and ejection fraction were comparable in both groups. Thereafter, alternate animals received small doses of epinephrine (0.05 to 0.15 mug/kg per min) with graded increments at 60 minute intervals to counter tachyphylaxis and findings were compared with those in control dogs. Over the subsequent 3 hours, there was progressive deterioration of left anterior descending coronary artery, affecting ventricular function in the untreated group with an increase in end-diastolic pressure from 10 plus or minus 1 to 33 plus or minus 2.4 mm Hg. End-diastolic volume increased by 63 percent; stroke volume and ejection fraction decreased by 48 and 66 percent, respectively. The infusion of epinephrine was attended by a significantly lower end-diastolic pressure of 20 plus or minus 2.5 mm Hg, whereas end-diastolic volume, stroke volume and ejection fraction were restored to control levels after 4 hours of ischemia. Mortality in the untreated group was 62 percent by 4 hours; all seven animals in the treated group survived.

Worcester, MA, experienced an outbreak of hepatitis during 1969-1970, an expected event which had occurred previously at eight-year intervals since reporting of the disease began in 1950. Other Massachusetts communities of similar character and the nation did not experience an epidemic during that same period. An extensive epidemiologic study of the disease illustrated that the epidemic followed the classical pattern in which individuals 5-14 years old were most affected irrespective of sex. During the interepidemic years from 1968-1972 in Worcester, and in all years (1968-1972) in both New Bedford and Springfield, MA, those primarily affected were young adults 15-30 years old, with male cases predominating. Sociodemographic statistical analyses also indicated the classical pattern of the less affluent, less educated, and sometimes the more crowded populations being at greater risk of contracting the disease. This outbreak of hepatitis was comparable to another in Greenland two years later in which immunologic methods differentiated between type A and type B viral infections. The data from both studies support the conclusion that the type B virus, often associated with parenteral drug use, is the predominate infectious agent during the interepidemic (endemic) periods. The type A virus is most likely responsible for the periodic epidemics.

A comparison of "Technegas" and xenon-133 was performed in 50 patients presenting with a clinical diagnosis of pulmonary embolus. All patients underwent studies with xenon inhalation, Technegas inhalation, and macroaggregated albumin perfusion. Technegas is a new ultrafine ventilatory agent with a particle size of 50 to 200A produced from technetium pertechnetate and graphite in an argon environment. Although particulate in nature, Technegas is transported and diffuses like a gaseous agent. Its production results in a high specific activity yield with high efficiency. There is no significant deposition in the central airways, and good peripheral visualization of the lung is obtained. The study was designed to assess whether Technegas could be used as a ventilatory agent to obtain high-quality diagnostic images. All studies were reported as in normal clinical practice, and no statistical analysis was performed. The aim of the study was simply to see what role Technegas had in a busy clinical department and how well it reflected ventilation by comparison with xenon. Patient compliance with Technegas was 100 percent and for xenon was 94 percent. Technegas enables one to obtain high-quality ventilatory images and has an important role to play in the assessment of pulmonary ventilation.

To assess the relation of ventricular arrhythmias to myocardial K(+) movement during ischemia, we placed an electrode catheter in the left anterior descending coronary artery for thrombus production in intact anesthetized dogs. (85)Kr injections distal to the thrombus permitted serial coronary blood flow measurements. Animals of Group I with a moderate flow reduction exhibited no arrhythmia or myocardial egress of K(+). In Group II, marked flow reduction was accompanied by an injury potential and loss of K(+) from the ischemic site, before and during ventricular tachycardia. Therapeutic interventions were performed in animals having the same degree of ischemia as Group II. Systemic procaine amide in Group III interrupted the tachycardia and egress of K(+), despite persistent ischemia. Group IV did not respond to intracoronary insulin with K(+) uptake, as did normal dogs, and progressed to fibrillation. During the production of hyperglycemia in Group V, myocardial loss of K(+) ceased with maintenance of sinus rhythm. Hemodynamic factors did not appear to have a major role in the genesis of the arrhythmia.Since intracoronary infusion of K(+) in normal dogs similarly altered repolarization and produced fibrillation, it would appear that during ischemia egress of K(+) before development of the arrhythmia indicates a major role of the ion in pathogenesis. This view is supported by the myocardial loss of K(+) and arrhythmia induced in normal dogs by strophanthidin and by the fact that pharmacologic regulation of K(+) loss is associated with correction of the arrhythmia, despite persistence of low blood flow.