Bleomycin inhibition of angiotensin-converting enzyme activity from serum, lungs, and cultured pulmonary artery endothelial cells

The interaction between bleomycin (BLM) and angiotensin-converting enzyme (ACE) from bovine lungs, serum, and cultured pulmonary artery endothelial cells was examined. ACE activity from all sources was inhibited by metal-free BLM but not by metal-complexed BLM. The metal-free deamide metabolite of BLM, which is nontoxic, also inhibited ACE activity from bovine endothelial cell homogenates and serum. Incubation of intact cultured pulmonary artery endothelial cells for 1 h with metal-free BLM produced a concentration-dependent inhibition of cellular ACE activity, which was persistent, lasting at least 24 h after drug removal. In addition, the enzyme activity released into the culture medium was decreased. The inhibition of cellular ACE activity occurred in the absence of (1) cell death as measured by dye exclusion, (2) inhibition of total protein synthesis as measured by [3H]leucine incorporation, and (3) decreased cellular enzyme content as assayed using a monoclonal antibody against the enzyme. These results indicate that a brief exposure of intact cultured pulmonary endothelial cells to BLM can produce direct and prolonged inhibition of ACE activity. The inhibition of ACE activity does not relate directly to cell death but rather appears to result from metal chelation by BLM.     

Management of scaphoid nonunions

Scaphoid nonunions can exist with or without avascular necrosis of the proximal pole, and waist fractures may have an associated humpback deformity. CT best shows the deformity and bone loss, whereas MRI will show avascular necrosis. Operative treatment should be directed at correcting the deformity with open reduction and internal fixation and bone grafting. Vascularized bone grafts should be used in cases of avascular necrosis.     

Down-regulation of early ionotrophic glutamate receptor subunit developmental expression as a mechanism for observed plasticity deficits following gestational exposure to benzo(a)pyrene

The focus of this study was to characterize the impact of gestational exposure to benzo(a)pyrene [B(a)P] on modulation of glutamate receptor subunit expression that is critical for the maintenance of synaptic plasticity mechanisms during hippocampal or cortical development in offspring. Previous studies have demonstrated that hippocampal and/or cortical synaptic plasticity (as measured by long-term potentiation and S1-cortex spontaneous/evoked neuronal activity) and learning behavior (as measured by fixed-ratio performance operant testing) is significantly impaired in polycyclic aromatic or halogenated aromatic hydrocarbon-exposed offspring as compared to controls. These previous studies have also revealed that brain to body weight ratios are greater in exposed offspring relative to controls indicative of intrauterine growth retardation which has been shown to manifest as low birth weight in offspring. Recent epidemiological studies have identified an effect of prenatal exposure to airborne polycyclic aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner-city children [Perera FP, Rauh V, Whyatt RM, Tsai WY, Tang D, Diaz D, et al. Effect of prenatal exposure to airborne polycyclic aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner-city children. Environ Health Perspect 2006;114:1287-92]. The present study utilizes a well-characterized animal model to test the hypothesis that gestational exposure to B(a)P causes dysregulation of developmental ionotropic glutamate receptor subunit expression, namely the N-methyl-d-aspartate receptor (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptor (AMPAR) both critical to the expression of synaptic plasticity mechanisms. To mechanistically ascertain the basis of B(a)P-induced plasticity perturbations, timed pregnant Long-Evans rats were exposed in an oral subacute exposure regimen to 0, 25 and 150mug/kg BW B(a)P on gestation days 14-17. The first sub-hypothesis tested whether gestational exposure to B(a)P would result in significant disposition in offspring. The second sub-hypothesis tested whether gestational exposure to B(a)P would result in down-regulation of early developmental expression of NMDA and AMPA receptor subunits in the hippocampus of offspring as well as in primary neuronal cultures. The results of these studies revealed significant: (1) disposition to the hippocampus and cortex, (2) down-regulation of developmental glutamate receptor mRNA and protein subunit expression and (3) voltage-dependent decreases in the amplitude of inward currents at negative potentials in B(a)P-treated cortical neuronal membranes. These results suggest that plasticity and behavioral deficits produced as a result of gestational B(a)P exposure are at least, in part, a result of down-regulation of early developmental glutamate receptor subunit expression and function at a time when excitatory synapses are being formed for the first time in the developing central nervous system. The results also predict that in B(a)P-exposed offspring with reduced early glutamate receptor subunit expression, a parallel deficit in behaviors that depend on normal hippocampal or cortical functioning will be observed and that these deficits will be present throughout life.     

Displaced scaphoid fractures treated with open reduction and internal fixation with a cannulated screw

BACKGROUND: This study was performed to determine if the accuracy of screw placement was improved with use of the Herbert-Whipple cannulated screw compared with use of the AO/ASIF cannulated screw and also to evaluate the functional results in patients with an acute displaced fracture of the waist of the scaphoid treated with open reduction and internal fixation with a cannulated screw. METHODS: We retrospectively reviewed the results for thirty-five patients in whom an acute displaced fracture of the waist of the scaphoid had been treated with internal fixation with use of a cannulated screw. The patients were divided into two groups; Group 1 consisted of nineteen patients managed with a 3.5-millimeter cannulated AO/ASIF screw from 1990 through 1997, and Group 2 consisted of sixteen patients managed with a Herbert-Whipple screw from 1993 through 1997. RESULTS: There were no clinical or radiographic differences between the two groups. The average time to union (and standard deviation), confirmed with tomography, was 4.2 +/- 1.2 months for Group 1 and 4.0 +/- 1.2 months for Group 2. Both screws significantly improved the alignment of the scaphoid and decreased carpal collapse (p < 0.01). Importantly, the use of either cannulated screw improved the height-to-length ratio and the lateral intrascaphoid angle, which were correlated with an increase in the range of motion of the wrist (r = 0.584 and 0.625). In addition, both screws allowed for accurate placement in the central portion of the proximal pole. Regardless of the type of screw used, the time to union increased with increasing age of the patient (r = 0.665) and with increasing initial displacement of the fracture (r = 0.541). Within both groups, the time to union was longer for the patients who smoked (p < 0.01). CONCLUSIONS: Within both groups, cannulated screw fixation maintained the corrected fracture alignment and promoted healing and return of function. Our study shows cannulated screws to be a safe and effective method of treatment.     

Serologic and cellular assays to monitor therapy with murine monoclonal antibodies

The emergence of new therapeutic modalities frequently requires development of relevant laboratory assays. This is especially true for the clinical uses of newly developed reagents such as murine monoclonal antibodies. We have described immunofluorescence, immunohistochemical, and enzyme-linked immunosorbent assays (ELISA) for monitoring anticancer therapy with monoclonal antibodies. Immunofluorescence assays performed on single cell suspensions and immunohistochemical assays performed on freshly frozen biopsy tissue have confirmed tissue reactivity of the monoclonal antibody prior to infusion and have been used to measure in vivo antibody binding to target cells as well as antigenic modulation during therapy. An ELISA has been used to measure the serum concentrations of monoclonal antibodies; another ELISA has been used to detect the presence of human antibodies reactive with murine monoclonal antibody. These reproducible assays can be performed with commercially available reagents and provide an important data base for making clinical decisions concerning therapy with monoclonal antibodies.