Accumulation and metabolism of carbon-14 labeled benzene,naphthalene, and anthracene by young coho salmon (Oncorhynchus kisutch)

Carbon-14 labeled benzene, naphthalene, and anthracene were administered to young coho salmon (Oncorhynchus kisutch) in the food and by intraperitoneal injection. Regardless of the mode of application the accumulated carbon-14 (% administered dose) in key organs (e.g., liver and brain) increased in the order anthracene > naphthalene > benzene over various time periods. The metabolic fate of the hydrocarbons after intraperitoneal injection was studied. It was shown that the highest percentages of metabolites occurred in the gall bladder; however, significant amounts were also found in the liver, brain, flesh, and carcass. Solvent partition and thin-layer chromatographic techniques were developed to determine the structure of individual metabolites. In brain, liver, and gall bladder, 1-naphthol and 1-naphthyl glucuronic acid were major products of naphthalene metabolism; however, glycoside/sulfate fractions and mercapturic acid were indicated. The heart and flesh were rich in 1-naphthol and the former organ contained significant amounts of 1,2-dihydro-1,2-dihydroxynaphthalene. The findings indicated that the aromatic hydrocarbons in key organs increased in relation to the number of benzenoid rings. Further, it appears that aromatic metabolites are broadly distributed throughout fish exposed to polynuclear aromatic hydrocarbons.     

Postinjury treatment with magnesium chloride attenuates cortical damage after traumatic brain injury in rats

The neuroprotective effect of magnesium chloride (MgCl2), a compound previously demonstrated to improve behavioral and neurochemical outcome in several models of experimental brain injury, was evaluated in the present study. Male Sprague-Dawley rats were anesthetized and subjected to lateral fluid-percussion brain injury of moderate severity (2.5-2.8 atm). A cannula was implanted in the left femoral vein and at 1 h following injury, animals randomly received a 15 min i.v. infusion of either MgCl2 (125 micromol/rat) or saline. A second group of animals received anesthesia, surgery, and either MgCl2 or vehicle to serve as uninjured (sham) controls. Two weeks following brain injury, animals were sacrificed, brains removed, and coronal sections were taken for quantitative analysis of cortical lesion volume and hippocampal CA3 cell counts. Traumatic brain injury resulted in a lesion in the ipsilateral cortex and loss of pyramidal neurons in the CA3 region of the hippocampus in vehicle-treated animals (p < 0.01 vs. uninjured animals). Administration of MgCl2 significantly reduced the injury-induced damage in the cortex (p < 0.01) but did not alter posttraumatic cell loss in the CA3 region of the ipsilateral hippocampus. The present study demonstrates that, in addition to its beneficial effects on behavioral outcome, MgCl2 treatment attenuates cortical histological damage when administered following traumatic brain injury.     

Pain in the newborn, a possible new starting point

Received: 3 May 1996 and in revised form: 15 August 1996 / Accepted: 15 August 1996     

Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial. Pediatric AIDS Clinical Trials Group 338 Study Team

CONTEXT: Although protease inhibitors are used routinely in adults with human immunodeficiency virus (HIV) infection, the role of these drugs in the treatment of clinically stable HIV-infected children is not clear. OBJECTIVE: To evaluate the safety, tolerance, and virologic response produced by a change in antiretroviral therapy in HIV-infected children who were clinically and immunologically stable while receiving previous therapy. DESIGN: The Pediatric AIDS Clinical Trials Group 338, a multicenter, phase 2, randomized, open-label controlled trial conducted from February 6 to April 30, 1997 (patient entry period); patients were followed up for 48 weeks. SETTING: Pediatric HIV research clinics in the United States and Puerto Rico. PATIENTS: Two hundred ninety-seven antiretroviral-experienced, protease inhibitor-naive, clinically stable HIV-infected children aged 2 to 17 years. INTERVENTIONS: Children were randomized to receive zidovudine, 160 mg/m2 3 times per day, plus lamivudine, 4 mg/kg 2 times per day (n = 100); the same regimen plus ritonavir, 350 mg/m2 2 times per day (n = 100); or ritonavir, 350 mg/m2 2 times per day, and stavudine, 4 mg/kg 2 times per day (n = 97). MAIN OUTCOME MEASURE: Plasma HIV-1 RNA levels at study weeks 12 and 48, compared among the 3 treatment groups. RESULTS: At study week 12, 12% of patients in the zidovudine-lamivudine group had undetectable plasma HIV RNA levels (<400 copies/mL) compared with 52% and 54% of patients in the 2- and 3-drug ritonavir-containing groups, respectively (P<.001). Through study week 48, 70% of children continued receiving their ritonavir-containing regimen. At study week 48, 42% of children receiving ritonavir plus 2 nucleosides compared with 27% of those receiving ritonavir and a single nucleoside had undetectable HIV RNA levels (P = .04); however, similar proportions in each group continuing initial therapy had HIV RNA levels of less than 10000 copies/mL (58% vs 48%, respectively; P = .19). CONCLUSIONS: In our study, change in antiretroviral therapy to a ritonavir-containing regimen was associated with superior virologic response at study week 12 compared with change to a dual nucleoside analog regimen. More children receiving ritonavir in combination with 2 compared with 1 nucleoside analog had undetectable HIV RNA levels at study week 48.     

Brain trauma in aged transgenic mice induces regression of established abeta deposits

Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known if TBI affects the progression of AD. To address this question, we studied the neuropathological consequences of TBI in transgenic (TG) mice with a mutant human Abeta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter resulting in overexpression of mutant APP (V717F), elevated brain Abeta levels, and AD-like amyloidosis. Since brain Abeta deposits first appear in 6-month-old TG (PDAPP) mice and accumulate with age, 2-year-old PDAPP and wild-type (WT) mice were subjected to controlled cortical impact (CCI) TBI or sham treatment. At 1, 9, and 16 weeks after TBI, neuron loss, gliosis, and atrophy were most prominent near the CCI site in PDAPP and WT mice. However, there also was a remarkable regression in the Abeta amyloid plaque burden in the hippocampus ipsilateral to TBI compared to the contralateral hippocampus of the PDAPP mice by 16 weeks postinjury. Thus, these data suggest that previously accumulated Abeta plaques resulting from progressive amyloidosis in the AD brain also may be reversible.     

Neurofilament-rich intraneuronal inclusions exacerbate neurodegenerative sequelae of brain trauma in NFH/LacZ transgenic mice

Several neurodegenerative disorders are characterized by filamentous inclusions in neurons that selectively degenerate. The role these inclusions play in neuron degeneration is unclear, but this issue can be investigated experimentally in relevant animal models. The NFH/LacZ transgenic (TG) mice overexpress the high-molecular-weight neurofilament (NF) subunit (NFH) fused to beta-galactosidase, and these hybrid proteins aggregate into NF-rich, filamentous neuronal cytoplasmic inclusions (NCIs) that have been implicated in the progressive, age-dependent degeneration in subsets of affected neurons. Thus, these TG mice recapitulate some of the key pathology of neurodegenerative disorders with intraneuronal inclusions. To determine if the NCIs compromise neuron survival following traumatic brain injury (TBI), 3- to 6-month old TG and wild-type (WT) mice were subjected to TBI or sham injury. At 2 weeks post-TBI, the TG group showed increased TUNEL staining and activated caspase-3 immunoreactivity in cells of cerebral cortex, adjacent white matter, and hippocampus underlying the injury site, relative to control mice, but this labeling decreased at 4 weeks and was minimal thereafter. Compared to control mice, by 8 weeks postinjury, the TG mice showed a marked decrease in neuron density and increased gliosis in the hippocampal dentate gyrus and CA3 region as well as in the lateral thalamus, while the few remaining CA3 neurons exhibited cytoskeletal alterations, decreased synaptic protein immunoreactivity, and dissolution of NCIs. The more profound long-term neurodegenerative sequelae of TBI in the NFH/LacZ mice compared to WT mice suggest that the presence of intraneuronal inclusions may impair the recovery and long-term viability of injured neurons.     

Bilateral growth-related protein expression suggests a transient increase in regenerative potential following brain trauma

The potential of mature central nervous system (CNS) neurons to regenerate after injury represents a fundamental issue in neurobiology. The regional expression of proteins associated with axonal elongation, such as microtubule-associated protein 1B (MAP1B), its phosphorylated isoform (MAP1B-P), growth-associated protein 43 (GAP-43), and polysialylated neural cell-adhesion molecule (PSA-NCAM), was examined using immunohistochemistry from 24 hours to 2 months following lateral fluid percussion brain injury of moderate severity (2.4-2.6 atmospheres) in anesthetized rats. Uninjured (control) rats were subjected to anesthesia and surgery without injury or were subjected to anesthesia alone. Within the site of maximal injury, only increases in MAP1B and MAP1B-P were observed. Increased immunoreactivity was observed bilaterally for all growth-related proteins that were evaluated. By 24 hours postinjury, MAP1B and MAP1B-P increased within the cortex (P < 0.01) and the hippocampus (P < 0.001), whereas MAP1B-P also was elevated in the thalamus (P < 0.05). Within the dentate gyrus, increased immunoreactivity was observed for all proteins examined. By 48 hours postinjury, GAP-43 was elevated bilaterally within the inner molecular layers of the dentate gyrus (P < 0.005) and within the stratum lacunosum moleculare (P < 0.01), the stratum radiatum (P < 0. 005), and the stratum oriens (P < 0.05) of the hippocampus. Increased numbers of PSA-NCAM-labeled neurons were observed in the granule cell layers of the dentate gyrus from 48 hours through 2 weeks postinjury (P < 0.0005). The bilateral nature of increased expression of growth-related proteins differs from unilateral patterns of neuronal degeneration previously characterized for the lateral fluid-percussion model of brain injury. Taken together, these results suggest the existence of a temporary posttraumatic state in which the CNS may have increased regenerative potential. Enhancement of such a response may be one therapeutic strategy in treating CNS injury.     

Use of AcrySof acrylic foldable intraocular lens for secondary implantation in children.

PURPOSE: Secondary intraocular lens (IOL) implantation is an increasingly viable option in the management of pediatric aphakia. We report our experience of secondary IOL implantation in pediatric patients using the AcrySof (Alcon Surgical, Fort Worth, Texas) 3-piece foldable lenses through a small incision. METHODS: We reviewed the records of all our patients < 18 years undergoing secondary IOL implantation of the AcrySof lens from 1997 to 2001. All patients with a minimum of 6 months follow-up were included. Records were analyzed for age at surgery, postoperative acuity change, postoperative refractive error and anisometropia, surgical complications, and length of follow-up. RESULTS: Fifty-five eyes of 36 patients were included in the review. Mean age at surgery was 7.4 years (1.1 to 15.4), and mean follow-up was 28 months (6.3 months to 5 years). Vision decrease > 2 lines was noted in 3 eyes (5.8%) during the follow-up period. Complications included IOL decentration in 3 eyes (5%), wound leak in 3 eyes (5%), secondary membrane formation in 5 eyes (9%), pupillary block glaucoma in 1 eye (2%), and ptosis in 1 eye (2%). Four eyes (7%) required reoperation for complications. Mean postoperative refractive error was -0.1 +/- 3.2 diopters (D), and mean anisometropia was 2.01 +/- 1.44 D. Glaucoma subsequently developed in 6 eyes (11%), 2 of which required surgical correction. CONCLUSIONS: Secondary placement of the AcrySof IOL in the ciliary sulcus is a safe and effective method to correct aphakia in pediatric patients with adequate capsular support. The incidence of complications requiring reoperation is low.     

Randomized trial of two intravenous schedules of the topoisomerase I inhibitor liposomal lurtotecan in women with relapsed epithelial ovarian cancer: a trial of the national cancer institute of Canada clinical trials group.

PURPOSE: Liposomal lurtotecan (OSI-211) is a liposomal formulation of the water-soluble topoisomerase I inhibitor lurtotecan (GI147211), which demonstrated superior levels of activity compared with topotecan in preclinical models. We studied two schedules of OSI-211 in a randomized design in relapsed ovarian cancer to identify the more promising of the two schedules for further study. PATIENTS AND METHODS: Eligible patients had measurable epithelial ovarian, fallopian, or primary peritoneal cancer that was recurrent after one or two prior regimens of chemotherapy. Patients were randomly assigned to receive either arm A (OSI-211 1.8 mg/m(2)/d administered by 30-minute intravenous infusion on days 1, 2, and 3 every 3 weeks) or arm B (OSI-211 2.4 mg/m(2)/d administered by 30-minute intravenous infusion on days 1 and 8 every 3 weeks). The primary outcome measure was objective response, which was confirmed by independent radiologic review, and a pick the winner statistical design was used to identify the schedule most likely to be superior. RESULTS: Eighty-one patients were randomized between October 2000 and September 2001. The hematologic toxic effects were greater on arm A than on arm B (grade 4 neutropenia, 51% v 22%, respectively), as was febrile neutropenia (26% v 2.4%, respectively). Of the 80 eligible patients, eight patients (10%) had objective responses; six responders (15.4%; 95% CI, 6% to 30%) were in arm A and two responders (4.9%; 95% CI, 1% to 17%) were in arm B. CONCLUSION: The OSI-211 daily for 3 days intravenous schedule met the statistical criteria to be declared the winner in terms of objective response. This schedule was also associated with more myelosuppression than the schedule of OSI-211 administered in arm B.