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Biomedical subjects

C Smith

Publications and source records attributed to C Smith.

At least 181 records · Page 10Linked to original sources
PubMed2000

A phase II study of paclitaxel, carboplatin, and hyperfractionated radiation therapy for locally advanced inoperable non-small-cell lung cancer (a Vanderbilt Cancer Center Affiliate Network Study).

PURPOSE: We conducted a prospective phase II study to determine the response rate, toxicity, and survival rate of concurrent weekly paclitaxel, carboplatin, and hyperfractionated radiation therapy (paclitaxel/carboplatin/HFX RT) followed by 2 cycles of paclitaxel and carboplatin for locally advanced unresectable non-small cell lung cancer (NSCLC). The weekly paclitaxel and carboplatin regimen was designed to optimize the radiosensitizing properties of paclitaxel during the concurrent phase of treatment. METHODS AND MATERIALS: Forty-three patients with unresectable stage IIIA and IIIB NSCLC from the Vanderbilt Cancer Center and Affiliate Network (VCCAN) institutions were entered onto the study from June 1996 until May 1997. Weekly intravenous (IV) paclitaxel (50 mg/m(2)/l-hour) and weekly carboplatin (AUC 2) plus concurrent hyperfractionated chest RT (1.2 Gy/BID/69.6 Gy) were delivered for 6 weeks followed by 2 cycles of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). RESULTS: Forty-two patients were evaluable for response and toxicities. Three patients achieved a complete response (7.2%) and 30 patients achieved a partial response (71.4%), for an overall response rate of 78.6% [95% C.I. (66.2%-91.0%)]. The 1- and 2-year overall and progression-free survival rates of all 43 patients were 61.6% and 35% respectively, with a median survival time of 14.3 months. The median follow-up time was 14 months. Esophagitis was the principal toxicity. Grade 3 or 4 esophagitis occurred in 11 patients (26%). There was an incidence of 7% grade 3 and 9.5% grade 4 pulmonary toxicities. CONCLUSIONS: Weekly paclitaxel, carboplatin, plus concurrent hyperfractionated RT is a well-tolerated outpatient regimen. The response rate from this regimen is encouraging and appears to be at least equivalent to the more toxic chemoradiation trials. These findings warrant further clinical evaluation of weekly paclitaxel/carboplatin/HFX RT in a phase III study.

Adenocarcinoma↗
PubMed2000

Selective ET(A) antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives.

The fifth paper in this series describes the culmination of our investigations into the development of a potent and selective ET(A) receptor antagonist for the treatment of diseases mediated by ET-1. Receptor site mapping of several ET(A) antagonists prepared previously identified a common cationic binding site which prompted synthesis of phenoxyphenylacetic acid derivative 13a, which showed good in vitro activity (IC(50) 59 nM, rat aortic ET(A)). Optimization of 13a led to the identification of 27b, which exhibited an IC(50) of 4 nM. Although this did not translate into the expected in vivo potency, a compound of comparable in vitro activity, 27a (RPR118031A), showed a far better pharmacokinetic profile and in vivo potency (75 micromol/kg) and was duly proposed and accepted as a development candidate.

Administration, Oral↗
PubMed2000

Mapping the collagen-binding site in the I domain of the glycoprotein Ia/IIa (integrin alpha(2)beta(1)).

The I domain present within the alpha2 chain of the integrin alpha(2)beta(1) (GPIa/IIa) contains the principal collagen-binding site. Based on the crystal structure of the alpha2-I domain, a hypothetical model was proposed in which collagen binds to a groove on the upper surface of the I domain (Emsley, J., King, S. L., Bergelson, J. M., and Liddington, R. C. (1997) J. Biol. Chem. 272, 28512-28517). We have introduced point mutations into 13 residues on the upper surface of the domain. Recombinant mutant proteins were assayed for binding to monoclonal antibodies 6F1 and 12F1, to collagen under static conditions, and for the ability to retain adhesive activity under flow conditions. The mutations to residues surrounding the metal ion-dependent adhesion site that caused the greatest loss of collagen binding under both static and flow conditions are N154S in the betaA-alpha1 turn, N190D in the betaB-betaC turn, D219R in the alpha3-alpha4 turn, and E256V and H258V in the betaD-alpha5 turn. Mutation in one of the residues that coordinate the metal binding, S155A, completely lost the adhesive activity under flow but bound normally under static conditions, whereas the mutation Y285F had the converse effect. We conclude that the upper surface of the domain, including the metal ion-dependent adhesion site motif, defines the collagen recognition site.

Antibodies, Monoclonal↗
PubMed2000

Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes.

BACKGROUND: Influenza is a highly infectious viral disease that is particularly common in the winter months. Conventional management options are limited to bed rest and treatment of complications such as secondary bacterial infections. Oscillococcinum is a patented, commercially available homoeopathic medicine. The rationale for its use in influenza comes from the homoeopathic principle of 'let like be cured by like'. The medicine is manufactured from wild duck heart and liver, a well-known reservoir for influenza viruses. OBJECTIVES: To determine whether homoeopathic Oscillococcinum or similar medicines are more effective than placebo in the prevention and treatment of influenza and influenza-like syndromes. SEARCH STRATEGY: The registry of randomised trials for the Cochrane Complementary Medicine Field was searched using the term "homeopathy" with "influenza", "respiratory tract", "infection", "cough", "virus" and "fever". The manufacturers of Oscillococcinum were contacted for information about other trials. Date of the most recent search: February 1999. SELECTION CRITERIA: Placebo-controlled trials of Oscillococcinum or homeopath-prepared influenza virus, influenza vaccine or avian liver in the prevention and treatment of influenza and influenza-like syndromes. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data and assessed methodological quality independently. MAIN RESULTS: Seven studies were included in the review, three prevention trials (n=2265) and four treatment trials (n=1194). Only for two studies was there sufficient information to complete data extraction fully. There was no evidence that ic treatment can prevent influenza-like syndrome (relative risk 0.64, 95% confidence interval 0.28 to 1.43). Oscillococcinum treatment reduced length of influenza illness by 0.28 days (95% confidence interval 0.50 to 0.06). Oscillococcinum also increased the chance of a patient considering treatment effective (relative risk 1.08; 95% CI 1.17, 1). REVIEWER'S CONCLUSIONS: Oscillococcinum probably reduces the duration of illness in patients presenting with influenza symptoms. Though promising, the data are not strong enough to make a general recommendation to use Oscillococcinum for first-line treatment of influenza and influenza-like syndrome. Further research is warranted but required sample sizes are large. Current evidence does not support a preventative effect of homeopathy in influenza and influenza-like syndromes.

Homeopathy↗
PubMed2000

Engagement of CD30 shapes the secretion of cytokines by human gamma delta T cells.

CD30 is a member of the TNF receptor superfamily, previously shown to be expressed on Hodgkin's lymphoma cells and on normal activated lymphocytes. We here show that CD30 is highly expressed on recently activated human gamma delta T cells. Elevated surface levels of this molecule persisted in long-term cultures of gamma delta cells, without further cell stimulation. CD30 acted as a co-stimulus in gamma delta T cells by potentiating the intracellular Ca(2+) fluxes induced by CD3 cross-linking. The engagement of CD30 enhanced the expression of several cytokines induced upon CD3 stimulation such as IL-4 and IFN-gamma but not IL-10. The CC chemokines RANTES and macrophage inflammatory protein-1beta were constitutively expressed and not affected by stimulation. The inducible expression of the neutrophil chemoattractant IL-8 was enhanced by CD30 co-stimulation, as well as that of the CC chemokines I-309 and MDC, whereas the secretion of the monocyte chemotactic protein-1 was not detected. Triggering of CD30 may therefore modulate the expression of several cytokines released by gamma delta cells; the expression of its physiologic ligand by APC and neutrophils at the site of infection may contribute to determine the outcome of an immune response.

Animals↗
PubMed2000

Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA) is a safe and effective medical therapy for most patients with primary biliary cirrhosis (PBC). However, some patients show an incomplete response to UDCA therapy. Treatment with corticosteroids may be of benefit although at the expense of systemic side effects. Budesonide, a corticosteroid with an extensive first-pass hepatic metabolism appeared promising for the treatment of PBC. The aim of this study was to evaluate the safety and estimate the efficacy of budesonide in patients with PBC, who have shown a suboptimal response to UDCA. Twenty-two patients with PBC, 16 women, median age of 50 who had been on UDCA (13-15 mg/kg/d) for a mean of 46 months (range 6-108 months) and had shown a persistent elevation of alkaline phosphatase activity at least 2 times the upper limit of normal were enrolled. Oral budesonide, 9 mg daily was administered for 1 year and patients continued on the same dosage of UDCA. There was a significant, but transitory improvement in serum levels of total bilirubin (P =.001) and a significant, but marginal improvement in serum alkaline phsophatase (P =.001) with combination therapy. The Mayo risk score increased significantly (P =.02) and there was a significant loss of bone mass (P <.001) of the lumbar spine. Budesonide-induced hyperglycemia and cosmetic adverse effects were noted in 2 patients. In conclusion, oral budesonide appears to add minimal, if any, additional benefit to UDCA, and it is associated with a significant worsening of osteoporosis in patients with PBC.

Administration, Oral↗
PubMed2000

Ethanol-mediated CYP1A1/2 induction in rat skeletal muscle tissue.

The causes of non-trauma-mediated rhabdomyolysis are not well understood. It has been speculated that ethanol-associated rhabdomyolysis may be attributed to ethanol induction of skeletal muscle cytochrome P450(s), causing drugs such as acetaminophen or cocaine to be metabolized to myotoxic compounds. To examine this possibility, the hypothesis that feeding ethanol induces cytochrome P450 in skeletal muscle was tested. To this end, rats were fed an ethanol-containing diet and skeletal muscle tissue was assessed for induction of CYP2E1 and CYP1A1/2 by immunohistochemical procedures; liver was examined as a positive control tissue. Enzymatic assays and Western blot analyses were also performed on these tissues. In one feeding system, ethanol-containing diets induced CYP1A1/2 in soleus, plantaris, and diaphragm muscles, with immunohistochemical staining predominantly localized to capillaries surrounding myofibers. Antibodies to CYP2E1 did not react with skeletal muscle tissue from animals receiving a control or ethanol-containing diet. However, neither skeletal muscle CYP1A1/2 nor CYP2E1 was induced when ethanol diets were administered by a different feeding system. Ethanol consumption can induce some cytochrome P450 isoforms in skeletal muscle tissue; however, the mechanism of CYP induction is apparently complex and appears to involve factors in addition to ethanol, per se.

Administration, Oral↗
PubMed2000

Patient delay in seeking care for heart attack symptoms: findings from focus groups conducted in five U.S. regions.

BACKGROUND: Patient delay in seeking health care for heart attack symptoms is a continuuing problem in the United States. METHODS: Investigators conducted focus groups (N = 34; 207 participants) in major U.S. regions (NE, NW, SE, SW, MW) as formative evaluation to develop a multi-center randomized community trial (the REACT Project). Target groups included adults with previous heart attacks, those at higher risk for heart attack, and bystanders to heart attacks. There were also subgroups reflecting gender and ethnicity (African-American, Hispanic-American, White). FINDINGS: Patients, bystanders, and those at higher risk expected heart attack symptoms to present as often portrayed in the movies, that is, as sharp, crushing chest pain rather than the more common onset of initially ambiguous but gradually increasing discomfort. Patients and those at higher risk also unrealistically judge their personal risk as low, understand little about the benefits of rapid action, are generally unaware of the benefits of using EMS/9-1-1 over alternative transport, and appear to need the "permission" of health care providers or family to act. Moreover, participants reported rarely discussing heart attack symptoms and appropriate responses in advance with health care providers, spouses, or family members. Women often described heart attack as a "male problem," an important aspect of their underestimation of personal risk. African-American participants were more likely to describe negative feelings about EMS/9-1-1, particularly whether they would be transported to their hospital of choice. CONCLUSIONS: Interventions to reduce patient delay need to address expectations about heart attack symptoms, educate about benefits and appropriate actions, and provide legitimacy for taking specific health care-seeking actions. In addition, strategy development must emphasize the role of health care providers in legitimizing the need and importance of taking rapid action in the first place.

Adaptation, Psychological↗
PubMed2000

Indomethacin and cyclosporin a inhibit in vitro ischemia-induced expression of ICAM-1 and chemokines in human brain endothelial cells.

Brain inflammation has been implicated in the development of brain edema and secondary brain damage in ischemia and trauma. Mechanisms involved in leukocyte infiltration across the blood-brain barrier are still unknown. In this study, we show that human cere-bromicrovascular endothelial cells (HCEC) subjected to a 4 h in vitro ischemia (hypoxia + glucose deprivation) followed by a 4-24 h recovery express elevated levels of ICAM-1, IL-8, and MCP-1 mRNAs (semi-quantitative RT-PCR) and secrete increased amounts of the immunoreactive chemokines IL-8 and MCP-1 (ELISA). The ischemia-induced expression of ICAM-1 in HCEC, and the expression/release of IL-8 and MCP-1 in HCEC were abolished by the non-steroid anti-inflammatory drug, indomethacin (100-300 microM). The immunosuppressant cyclosporin A (50 microM) partially reduced the ischemia-stimulated IL-8 and MCP-1 secretion by HCEC. Both indomethacin and cyclosporin A also inhibited the ischemia-induced neutrophil chemotaxis elicited by HCEC media. The study indicates that in vitro ischemia augments the expression of adhesion molecules and leukocyte chemoattractants at the site of the BBB. This ischemic pro-inflammatory activation of HCEC may constitute a key event in initiating post-ischemic inflammation, and it can be suppressed by the anti-inflammatory drugs, indomethacin and cyclosporin A.

Blood-Brain Barrier↗
PubMed2000

Glutathione homeostasis and leukotriene-induced permeability in human blood-brain barrier endothelial cells subjected to in vitro ischemia.

Ischemic alterations in the glutathione (GSH) redox system of the blood-brain barrier (BBB) may facilitate oxidative injury and formation of vasogenic brain edema. In this study, both the intra- and extracellular GSH contents of human cerebromicrovascular endothelial cells (HCEC) were reduced by 35% after exposing the cells to 4 h in vitro ischemia and 24 h-recovery. The intracellular/extracellular GSH ratio was not affected, indicating a constant rate of GSH efflux. The activities of the peroxide detoxifying enzymes, glutathione peroxidase and glutathione S-transferase, increased by 35%-50%, whereas the GSH regenerating enzyme, glutathione reductase, remained unchanged in ischemic HCEC. gamma-glutamyl transpeptidase (GGTP), a GSH catabolizing enzyme enriched in brain capillaries, was reduced by 30-50% in ischemic HCEC. The effect of in vitro ischemia on HCEC permeability was assessed by measuring sodium fluorescein clearance across a compartmentalized in vitro BBB model. Sodium fluorescein clearance across HCEC monolayers exposed to leukotriene C4 in the presence of the GGTP inhibitor, acivicin (1 microM), or after in vitro ischemia was increased by 60% and 30%, respectively, suggesting that oxidative stress and loss of GGTP may 'unmask' BBB permeabilizing actions of leukotrienes. These results indicate that oxidative stress and loss of GGTP activity in HCEC contribute to ischemic BBB disruption and vasogenic brain edema.

Blood-Brain Barrier↗
PubMed2000

Early infantile pertussis; increasingly prevalent and potentially fatal.

UNLABELLED: We report nine cases of severe early pertussis in infants less than 7 weeks of age. Clinical features at this age are atypical and may be confused with more common illnesses such as bronchiolitis. All were very difficult to manage. Ventilation was required for apnoeas in five cases, seizures in two or respiratory failure in two. Complications included hypotension in seven cases, pulmonary hypertension in one, pneumothoraces in two, seizures in five and co-infection in five. Two cases were referred for extracorporeal membrane oxygenation and six died. Infection was confirmed either at post mortem or by culture from pernasal swabs. The mother or other close family members were symptomatic at the time and thought to be the source of infection. CONCLUSION: The nine cases suggest a significant resurgence of the infection, which may be fatal in early life. If reporting continues to increase, the immunisation schedule will need to be reviewed and secondary transmission prevented where possible, to protect this vulnerable pre-immunisation group.

England↗
PubMed2000

MR imaging of simple bone cysts in children: not so simple.

OBJECTIVE: The unicameral bone cyst (UBC) is a common cystic bone lesion seen in children. We review and summarize its MR findings, focusing on their appearance following contrast enhancement, and correlating them to known histologic features of UBC. SUBJECTS AND METHODS: A retrospective review of 20 cases (13 boys, 7 girls; age range, 1-17 years; mean age, 8.9) diagnosed as UBC was conducted. Clinical histories, radiographic and MR features, follow-up data, and available pathologic findings were noted. RESULTS: At initial presentation 18 (90 %) of the patients with UBC had a history of acute or remote pathologic fracture. Cysts with history of fracture displayed heterogeneous fluid signals on T1-(n = 9, 50%), and T2-weighted (n = 15, 83 %) MR images. Gadolinium-enhanced images were obtained in 15 of the 18 UBC cases with history of previous fracture. All showed enhancement with focal, thick peripheral, heterogeneous, or subcortical patterns. Focal nodules of homogeneous enhancement (diameter > 1 cm) within the UBC (n = 5) correlated with areas of ground-glass opacification on plain film. Other interesting MR features were fluid-fluid levels (n = 11), "fallen-leaf" sign (n = 1), soft-tissue changes (n = 2), and detection of septations not seen on plain film (n = 2). CONCLUSION: UBCs frequently appear complicated on MR imaging, with heterogeneous fluid signals and regions of nodular and thick peripheral enhancement related to previous pathologic fracture and early healing.

Adolescent↗
PubMed2000

Global hypoxia per se is an unusual cause of axonal injury.

Irreversible hypoxic brain damage and axonal injury are present in over 90% of fatal blunt head injuries. Given the frequency of each, difficulties arise as to whether or not they are due to different mechanisms and, as such, can be separately recognised and quantified. Recent literature has raised the possible role of hypoxia in the formation of axonal bulbs. The present study of 17 cases of cardio-respiratory arrest, 12 of status epilepticus, 3 of carbon monoxide poisoning and 12 controls was designed to test the relationship between hypoxia and axonal injury and to test the hypothesis whether or not the two entities can be separated into primary and secondary forms of traumatic brain injury. Axonal damage was seen in 9/17 and 7/12 of the cases with cardiac arrest and status epilepticus, respectively, in most of whom there was also evidence of raised intracranial pressure (ICP). All 3 cases of carbon monoxide poisoning had evidence of white matter damage in keeping with the classical pattern of selective vulnerability. It is concluded that the great majority of axonal damage identified in cases dying after cardiac arrest and status epilepticus can be attributed to raised ICP and the vascular complications of internal herniation. However, in some cases, axonal damage was seen in the absence of an elevated ICP, although its amount and distribution were different from diffuse axonal injury. In many cases there was an increase in expression of neuronal beta amyloid precursor protein.

Adolescent↗
PubMed2000

ASW: a gene with conserved avian W-linkage and female specific expression in chick embryonic gonad.

Vertebrates exhibit a variety of sex determining mechanisms which fall broadly into two classes: environmental or genetic. In birds and mammals sex is determined by a genetic mechanism. In mammals males are the heterogametic sex (XY) with the Y chromosome acting as a dominant determiner of sex due to the action of the testis-determining factor, SRY. In birds females are the heterogametic sex (ZW); however, it is not known whether the W chromosome carries a dominant ovary-determining gene, or whether Z chromosome dosage determines sex. Using an experimental approach, which assumes only that the sex-determining event in birds is accompanied by sex-specific changes in gene expression, we have identified a novel gene, ASW (Avian Sex-specific W-linked). The putative protein for ASW is related to the HIT (histidine triad) family of proteins. ASW shows female-specific expression in genital ridges and maps to the chicken W chromosome. In addition, we show that, with the exception of ratites, ASW is linked to the W chromosome in each of 17 bird species from nine different families of the class Aves.

Amino Acid Sequence↗
PubMed2000

Office pediatric urologic procedures from a parental perspective.

OBJECTIVES: To determine the parent perception of discomfort (PPD) in children receiving local anesthesia for the lysis of labial adhesions, meatotomy, and newborn circumcision; the parents' perceived outcome of these procedures; and the overall satisfaction of parents when these procedures are performed in the office. METHODS: A confidential phone survey was given to 99 parent participants whose children had received local anesthesia for the lysis of labial adhesions (n = 14), meatotomy (n = 28), or newborn circumcision (n = 57). Parents in the labial adhesion and meatal stenosis groups were asked to rate their child's level of discomfort (PPD) during the procedure as mild (1), moderate (2), or severe (3), and those in the circumcision group were asked to use the same scale to rate their child's discomfort after the procedure. Parents were also asked whether they thought the procedure was successful and whether they were satisfied with their decision to have it done in the office using local anesthesia. RESULTS: Among the labial adhesion, meatotomy, and circumcision groups, the mean PPD +/- SD was 1.64 +/- 0.75, 1.54 +/- 0.69, and 1.21 +/- 0.53, respectively. The observed procedures, lysis of labial adhesions and meatotomy, had a significantly higher PPD score (P = 0.005) than the unobserved procedure (circumcision). Parents reported good outcomes in 94 (94.9%) of 99 children, with 4 girls experiencing recurrent labial adhesions and 1 boy experiencing recurrent meatal stenosis. Overall, 95 (96.0%) of 99 parents stated that they were satisfied with their decision to have the procedure done in the office with local anesthesia. Of the remaining 4 parents, 3 parents in the circumcision group stated they would have preferred general anesthesia, and 1 parent in the labial adhesion group was undecided. CONCLUSIONS: The PPD is greater if the parent observes their child's procedure. However, office procedures using local anesthesia for the lysis of labial adhesions, meatotomy, and newborn circumcision are well accepted among the parent population.

Ambulatory Surgical Procedures↗