Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway

Oncogenic forms of the Abl and Src tyrosine kinases trigger the destruction of the Abi proteins, a family of Abl-interacting proteins that antagonize the oncogenic potential of Abl after overexpression in fibroblasts. The destruction of the Abi proteins requires tyrosine kinase activity and is dependent on the ubiquitin–proteasome pathway. We show that degradation of the Abi proteins occurs through a Ras-independent pathway. Significantly, expression of the Abi proteins is lost in cell lines and bone marrow cells isolated from patients with aggressive Bcr–Abl-positive leukemias. These findings suggest that loss of Abi proteins may be a component in the progression of Bcr–Abl-positive leukemias and identify a novel pathway linking activated nonreceptor protein tyrosine kinases to the destruction of specific target proteins through the ubiquitin–proteasome pathway.     

Cystic fibrosis and the phenotypic expression of autosomal dominant polycystic kidney disease

Recent experiments in cultured cyst epithelial cells from kidneys of patients with autosomal dominant polycystic kidney disease (ADPKD) have shown that the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is present in the apical surface of these cells and mediates chloride (Cl-) and fluid secretion in vitro. To determine whether the presence of CF with the expression of mutated CFTR proteins modifies cyst formation in ADPKD, we studied a large family with both inherited diseases. ADPKD in this family is linked to PKD1. The family is composed of 26 members; 11 members with ADPKD, 4 members with CF, and 2 members with both diseases. Renal volumes measured by computerized tomography (CT), calculated creatinine clearances, and other clinical parameters in the family members with ADPKD and CF were compared with those in the family members with ADPKD alone, as well as to a large population of patients with ADPKD. The patients with CF and ADPKD, but not the CF heterozygote carriers with ADPKD, had less severe polycystic kidney and liver disease, as indicated by normal renal function; smaller renal volume, even when corrected for height and body surface area; and the absence of hypertension and liver cysts. These observations suggest that the coexistence of CF may reduce the severity of ADPKD.     

HIV/AIDS infection control enforcement: a comparison between Nigeria and the United States

We examined differences in approaches to HIV-related infection control practices in two university teaching hospitals in the United States and Nigeria. Health care workers (n = 202 in Nigeria and 186 in the USA) responded to a previously validated measure of infection control practices. There were significant differences in the estimated probability of treating a person with HIV disease (higher in USA), and a greater probability of peer ridicule as a way of enforcing group norms on infection control in Nigeria. Peer enforcement of norms was significantly lower in the USA. In both countries, more precautions would be taken if it was known that the patient was HIV infected. Infection control practices were more likely to be followed in the USA compared with Nigeria if they were praised for this activity, if appropriate facilities (sharps containers, gloves, etc.) were nearby, and if they felt that infection control procedures were effective. These data point to the importance of normative social pressures in Nigeria and of knowing the patient is HIV infected in the USA and feeling that infection control procedures are effective ways of avoiding occupational HIV infection. The role of normative pressures and assumptions about HIV infection status as well as cues and availability of facilities for infection control appear to differ between these health care workers in Nigeria and the USA.     

Iopamidol and meglumine diatrizoate: comparison of effects on patient discomfort during aortofemoral arteriography

Iopamidol was compared with Renografin-60 (meglumine diatrizoate, Squibb) in a controlled, randomized double-blind study of 40 patients undergoing peripheral arteriography for arteriosclerotic occlusive disease to determine which agent caused less discomfort. Each patient was evaluated for objective signs of discomfort and subjective feelings of pain and heat. Monitoring was achieved by multiple physical examinations, chemical tests, electrocardiograms, and intra-arterial pressure recordings. It is concluded that iopamidol is safe and causes significantly less patient discomfort than Renografin-60.     

Pulmonary arteriovenous malformations: techniques and long-term outcome of embolotherapy

Over a 10-year period, 276 pulmonary arteriovenous malformations (PAVMs) were occluded with balloon embolotherapy in 76 patients, 67 (88%) of whom had hereditary hemorrhagic telangiectasia. Eleven patients (14%) were discovered by means of family screening with measurement of arterial blood gases and chest radiography. Epistaxis, dyspnea, hemoptysis, and hemothorax occurred in 79%, 71%, 13%, and 9% of patients, respectively. Clinical histories of strokes and transient ischemic attacks were present in 18% and 37% of patients, respectively. Computed tomographic scans of 59 patients showed stroke in 36%. Sixty-five percent of PAVMs were located in the lower lobes, which correlated with the finding of more pronounced hypoxemia in the upright position. After embolotherapy, symptomatic hypoxemia was corrected, and serial values have remained constant for 5 years. Complications were minimal, and no patient required surgery. Balloon embolotherapy is effective long-term therapy for PAVMs, and family screening should be pursued because of the possibility of a higher frequency of paradoxical embolization (stroke) than previously recognized.