PubMed Health⌕ Search

Biomedical subjects

William Carroll

Publications and source records attributed to William Carroll.

6 recordsLinked to original sources
PubMed2006

A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat.

ATP-sensitive P2X(7) receptors are localized on cells of immunological origin including glial cells in the central nervous system. Activation of P2X(7) receptors leads to rapid changes in intracellular calcium concentrations, release of the proinflammatory cytokine interleukin-1beta (IL-1beta), and following prolonged agonist exposure, cytolytic plasma membrane pore formation. P2X(7) knockout mice show reduced inflammation as well as decreased nociceptive sensitivity following peripheral nerve injury. A-740003 (N-(1-{[(cyanoimino)(5-quinolinylamino) methyl] amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide) is a novel competitive antagonist of P2X(7) receptors (IC(50) values = 40 nM for human and 18 nM for rat) as measured by agonist-stimulated changes in intracellular calcium concentrations. A-740003 showed weak or no activity (IC(50) > 10 muM) at other P2 receptors and an array of other neurotransmitter and peptide receptors, ion channels, reuptake sites, and enzymes. A-740003 potently blocked agonist-evoked IL-1beta release (IC(50) = 156 nM) and pore formation (IC(50) = 92 nM) in differentiated human THP-1 cells. Systemic administration of A-740003 produced dose-dependent antinociception in a spinal nerve ligation model (ED(50) = 19 mg/kg i.p.) in the rat. A-740003 also attenuated tactile allodynia in two other models of neuropathic pain, chronic constriction injury of the sciatic nerve and vincristine-induced neuropathy. In addition, A-740003 effectively reduced thermal hyperalgesia observed following intraplantar administration of carrageenan or complete Freund's adjuvant (ED(50) = 38-54 mg/kg i.p.). A-740003 was ineffective in attenuating acute thermal nociception in normal rats and did not alter motor performance at analgesic doses. These data demonstrate that selective blockade of P2X(7) receptors in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.

Acetamides↗
PubMed2006

Isolated CNS relapse of acute lymphoblastic leukemia treated with intensive systemic chemotherapy and delayed CNS radiation: a pediatric oncology group study.

PURPOSE: Prognosis and outcome of children with isolated CNS relapse of acute lymphoblastic leukemia (ALL) has depended on duration of first complete remission (CR1). This study intensified systemic therapy by delaying CNS radiation for 12 months and tailored CNS radiation by CR1 duration. PATIENTS AND METHODS: Seventy-six children with first isolated CNS relapse of ALL were treated with systemic chemotherapy that effectively penetrates into the CSF and intrathecal chemotherapy for 12 months. Patients with CR1 of less than 18 months received craniospinal radiation (24 Gy cranial/15 Gy spinal), whereas those with CR1 of 18 months or more received cranial radiation only (18 Gy), followed by maintenance chemotherapy. Additionally, asymptomatic patients were enrolled in a thiotepa up-front therapeutic window. RESULTS: Seventy-four (97.4%) of 76 eligible patients achieved a second remission. Overall 4-year event-free survival (EFS) for the 71 precursor B-cell patients was 70.1% +/- 5.8%. CR1 duration and National Cancer Institute (NCI; National Institutes of Health, Bethesda, MD) risk group at initial diagnosis predicted outcome. Patients with CR1 of less than 18 months and 18 months or more had a 4-year EFS of 51.6% +/- 11.3% and 77.7% +/- 6.4% (P = .027), respectively. NCI high- versus standard-risk 4-year EFS was 51.4% +/- 10.8% and 80.2% +/- 6.3% (P = .0018), respectively. A significant difference in EFS between standard risk/CR1 of at least 18 months and both high risk/CR1 of less than 18 months and high risk/CR1 of at least 18 months groups was detected (P = .0068 and .0314, respectively). Response rate to thiotepa was 78%. Most relapses involved the bone marrow, and three second malignancies were reported. CONCLUSION: Twelve months of intensive systemic chemotherapy with reduced dose cranial radiation (18 Gy) is highly effective for children with isolated CNS relapse and CR1 of 18 months or more. Novel strategies are needed for patients with CR1 of less than 18 months.

Adolescent↗
PubMed2006

Outcome of extremely preterm infants randomized at birth to different PaCO2 targets during the first seven days of life.

BACKGROUND: Ventilation with higher PaCO(2) goals may reduce lung injury and bronchopulmonary dysplasia (BPD). The effect may be enhanced by using a higher PaCO(2) goal than in previous trials. OBJECTIVE: To determine the clinical benefits and safety of higher PaCO(2) goals for ventilated preterm infants. STUDY DESIGN: Preterm infants with a gestational age between 23 and 28 completed weeks receiving mechanical ventilation within 6 h of birth were randomized to be managed with either a PaCO(2) target between 55 and 65 mm Hg (7.3- 8.7 kPa, minimal ventilation) or 35 and 45 mm Hg (4.7- 6.0 kPa, routine ventilation) for the first 7 days of life. The primary outcome measure was BPD, defined as need for mechanical ventilation or supplemental oxygen at 36 weeks postmenstrual age, or death. The neurodevelopmental status was assessed at 18-22 months corrected age. RESULTS: The trial was stopped early after enrolling 31% of the projected sample size. Enrolled infants had a median birth weight of 640 g. BPD or death occurred in 21/33 (64%) infants after minimal ventilation and 19/32 (59%) infants after routine ventilation. Minimal ventilation was associated with trends towards higher mortality and higher incidence of neurodevelopmental impairment, and a significantly increased combined outcome of mental impairment or death (p < 0.05). CONCLUSION: Minimal ventilation as performed in this study did not improve clinical outcome, and may have been associated with a worse neurodevelopmental outcome.

Algorithms↗
PubMed2004

Expression of proteolytic enzymes in head and neck cancer-associated fibroblasts.

OBJECTIVE: To elucidate tumor-stromal interactions during tumor invasion by assessing the expression of proteolytic enzymes by carcinoma-associated fibroblasts (CAFs) in vivo using complementary DNA (cDNA) array analysis. METHODS: Tumor-associated stroma was isolated from tumor and adjacent mucosal specimens of the same patient by laser capture microdissection, and the messenger RNA (mRNA) was assessed by cDNA microarray specific for proteolytic enzymes and their inhibitors. Protein overexpression was then analyzed by immunoblotting of primary fibroblast isolates derived from skin, mucosa, and tumor specimens. RESULTS: Array analysis of 4 tumor and 4 adjacent mucosal samples demonstrated significant (2.6-fold) overexpression of membrane type 1 matrix metalloproteinase (MT1-MMP) but not of serine proteases or other matrix metalloproteinases. Analysis of normal dermal fibroblasts, normal mucosal fibroblasts, and CAFs similarly demonstrated up-regulation of MT1-MMP. CONCLUSIONS: These results suggest that MT1-MMP mRNA is specifically up-regulated in CAFs in vivo whereas MT1-MMP protein is specifically up-regulated in CAFs in vitro. Known to induce tumor cell invasion when expressed in tumor cells, CAF expression of MT1-MMP may be important in the stromal response to tumor cells that characterizes the desmoplastic reaction.

Biomarkers, Tumor↗
PubMed2004

Simplifying head and neck microvascular reconstruction.

BACKGROUND: Free-tissue transfer has become the preferred method of head and neck reconstruction but is a technique that is considered to use excessive hospital resources. METHODS: This study is a retrospective review of 125 consecutive free flaps in 117 patients over a 16-month period at a tertiary care university hospital. RESULTS: Defects of the oral cavity/oropharynx (60%), midface (9%), hypopharynx (15%), or cervical and facial skin (16%) were reconstructed from three donor sites: forearm (70%), rectus (11%), and fibula (19%). Microvascular anastomoses were performed with a continuous suture technique or an anastomotic coupling device for end-to-end venous anastomoses. A single vein was anastomosed in 97% of tissue transfers. There were five flaps (4%) requiring exploration for vascular compromise, and the overall success rate was 97.6%. The major complication rate was 13%. Mean hospital stay was 7 days for all patients and 5 days for those with cutaneous defects. Combined ablative and reconstructive operative times were 6 hours 42 minutes, 7 hours 40 minutes, and 8 hours 32 minutes for forearm, rectus, and fibular free grafts, respectively. A subset of this patient series with oral cavity and oropharynx defects (76 patients; 58%) available for follow-up (74 patients) was assessed for deglutition. Forty-three patients (58%) had a regular diet, 22 patients (30%) had a limited diet or required supplemental tube feedings, and nine patients (12%) were dependent on tube feedings with a severely limited diet. CONCLUSIONS: This series suggests that most head and neck defects can be reconstructed by use of a simplified microvascular technique and a limited number of donor sites. Analysis of operative times and length of stay suggest improved efficiency with this approach to microvascular reconstruction. Complications and functional results are comparable to previously published results.

Adult↗