Cytochrome P450 2C9 mediated metabolism in people with and without cancer.

OBJECTIVES: To compare cytochrome P450 activity in people with and without cancer and examine the relationship between CYP2C9 activity and serum cytokine levels. PATIENTS AND METHODS: 10 subjects with cancer who were currently receiving treatment and 10 additional subjects without cancer who were matched to the subjects with cancer based on gender and race were enrolled into the study. Serial blood samples were drawn to measure tolbutamide in the plasma before and after oral tolbutamide 500 mg. Total urine excreted was collected from 0 to 12 h following the dose. Tolbutamide and its metabolites were measured in plasma and urine by HPLC. CYP2C9 genotype was determined by PCR and pyrosequencing and cytokine values were determined by ELISA. RESULTS: The mean apparent oral clearance (cancer, 19.5 +/- 10.5 vs. non-cancer, 15.8 +/- 5.0 ml/min) and the mean urinary metabolic ratio from 0 to 12 h were similar (838 +/- 693 vs. 775 +/- 390). Neither age nor genotype statistically affected the outcomes. Mean interleukin-6 (7.2 +/- 9.4 vs. 1.5 +/- 1.3 pg/ml) and tissue necrosis factor-a (26.2 +/- 71.2 vs. 1.5 +/- 1.3 pg/ml) were 5- to 7-fold higher, respectively, in subjects with cancer. No statistically significant correlation between cytokine values and oral clearance or urinary metabolic ratio was found. CONCLUSIONS: CYP2C9 activity as measured by apparent oral clearance and urinary metabolic ratio following oral tolbutamide appear similar in people with and without cancer. Serum cytokine values appear higher in patients with cancer, although the differences did not reach statistical significance.

Pseudotumoural hemicerebellitis: imaging findings in two cases.

Pseudotumoural hemicerebellitis is exceedingly rare. It may closely resemble a tumour either clinically or on imaging, and a high index of suspicion is required to avoid unnecessary surgical procedures. MRI is the most useful diagnostic tool, and reveals a swollen cerebellar hemisphere, hyperintense in T(2) weighted images. A pattern of predominantly pial contrast enhancement, absence of a well-defined mass and regression of the abnormalities in follow up examinations help to rule out malignancy. We report two cases of pseudotumoural cerebellitis (an 11-year-old girl and a 9-year-old boy) studied with CT and MRI.

A reproducible method for injecting the mouse corneal stroma.

An improved delivery system for injecting the mouse corneal stroma was developed. This system incorporates the following features: a repeating dispenser that eliminates inaccuracies in depressing a syringe plunger, foot activation which frees both hands for manipulating the needle and permits constant observation of the injection site, and a flexible 30-cm, 32-gauge stainless steel needle with a 30 degrees bevel and a locking hub that resists pulsation due to back pressure while permitting freedom of motion by the operator. These injections were done while observing the cornea with a vertically mounted slit lamp, ideally suited for examining and photographing the eyes of laboratory animals. The reproducibility of the new delivery system, expressed in terms of the signal-to-noise ratio, was estimated and compared with that of a hand-held microsyringe by injecting a solution of radioactive chromium into the corneal stroma of A/J mice. The eyes were removed within 1 hr of injection, and the amount of chromium in each eye was determined in a gamma counter. The new delivery system had significantly (P less than 0.05) greater reproducibility than the hand-held syringe and could be calibrated to deliver up to 0.65 microliter to the mouse cornea.

The effect of collagen shields on rabbit corneal reepithelialization after chemical debridement.

We evaluated the effect of precarved collagen lenses on the kinetics of epithelial wound healing in an experimental model of corneal erosions. After induction of anesthesia, central corneal erosions of 5-mm diameter were created in New Zealand white rabbits using n-heptanol. Animals were randomly assigned either to the treatment group or to one of three control groups. Each animal in the treatment group received a precarved collagen shield made from porcine sclera. Immediately after creation of the corneal epithelial defects, topical fluorescein sodium was applied, and the corneas were photographed. Similar follow-up examinations were conducted at 5, 24, 30, 48, 72, and 96 hr after defect creation. Epithelial defect areas were calculated by projecting the photographic slides onto a computerized digitizing pad. Reepithelialization kinetics were compared for the four treatment groups. When initial wound size was taken into account, no significant difference between mean reepithelialization rates was noted. These results indicate that collagen lenses do not adversely affect the speed of corneal reepithelialization, and may, because of their documented biodegradibility and drug delivery capability, be useful in the clinical management of corneal epithelial erosions.

Ketamine suppresses ischemic injury in the rabbit retina.

Overstimulation of the N-methyl D-aspartate (NMDA) receptor has been implicated as a factor in the pathogenesis of ischemic injury in the central nervous system. The present study was undertaken to determine whether ketamine hydrochloride, a potent NMDA antagonist, could attenuate ischemic injury in the rabbit retina. Retinal ischemia was induced for 60 min in one eye of 18 albino rabbits by raising intraocular pressure above the systolic blood pressure. Three concentrations of ketamine, 0.5, 1.5, 5.0 mumol were dissolved in 20 microliters of saline solution and injected in the midvitreous in each eye of 14 rabbits 1 hr prior to ischemia. Four rabbits received saline solution as controls. The scotopic electroretinogram was monitored in each eye to assess the postischemic recovery of retinal function. A statistically significant reduction in the b-wave was detected in the eyes treated with saline (P less than 0.05), whereas the postischemic recovery of b-wave amplitude was enhanced by pretreatment with lower doses of ketamine. The highest dose depressed b-wave amplitude regardless of ischemia. Six rabbits underwent unilateral ocular ischemia under general anesthesia with ketamine. A small ameliorative effect was seen (P = 0.029). These results suggest that ketamine may alleviate ischemic injury in the rabbit retina, presumably by antagonizing the NMDA receptor-mediated toxicity. Thus, ketamine may have potential in the treatment of retinal vascular occlusive diseases. Moreover, a modified ischemic state may exist in experiments on ischemia conducted under general anesthesia with ketamine hydrochloride.

Ocular manifestations of leprosy in a noninstitutionalized community in the United States.

OBJECTIVE: Our goal was to delineate the epidemiologic and clinical patterns of ocular leprosy in an outpatient setting in the United States. DESIGN: Examinations were performed in 61 consecutive outpatients seen in a Midwestern leprosy clinic. PATIENTS: Forty-three male and 18 female patients were examined. The patients' origins included Southeast Asia (24 patients [39%]), Latin America (23 patients [38%]), India (nine patients [15%]), Europe or North America (two patients [3%]), Africa (two patients [3%]), and the Middle East (one patient [2%]). RESULTS: Thirty-nine percent of patients were classified as having polar lepromatous leprosy; 18%, borderline lepromatous leprosy; 3%, borderline borderline leprosy; 36%, borderline tuberculoid leprosy; 2%, polar tuberculoid leprosy; and 2%, indeterminate leprosy. Ninety-six percent of patients had a best-corrected visual acuity of 20/40 or better. Ocular findings included madarosis (28 patients [46%]), subconjunctival fibrosis (18 patients [30%]), punctate epithelial keratopathy (17 patients [28%]), posterior subcapsular cataract (10 patients [16%]), corneal hypesthesia (10 patients [16%]), lagophthalmos (seven patients [11%]), corneal pannus (six patients [10%]), entropion (five patients [8%]), prominent or beaded corneal nerves (four patients [7%]), iridocyclitis (four patients [7%]), focal avascular keratitis (three patients [5%]), scleritis (three patients [5%]), interstitial keratitis (two patients [3%]), iris pearls (two patients [3%]), and ocular clofazimine crystals (two patients [3%]). Madarosis, corneal hypesthesia, and posterior subcapsular cataracts were significantly associated with disease duration (P < .05). CONCLUSION: We report herein a relatively low frequency of visual impairment attributable to leprosy in our series compared with that seen among institutionalized leprous patients. However, since 48% of subjects had one or more sight-threatening complications as a result of their disease, a program of regular ophthalmic follow-up is strongly advocated for all patients with leprosy.

Evaluation of genotype data in clinical risk assessment: methods and application to BRCA1, BRCA2, and N-acetyl transferase-2 genotypes in breast cancer.

Associations of numerous susceptibility genes with disease risk have been reported. However, objective methods have not been developed to evaluate the conditions under which translation of knowledge about susceptibility genotypes may be clinically informative. We describe and apply a statistical approach to evaluate when genotype information may be clinically informative in disease risk assessment. We estimate an interval of cumulative cancer incidences where it may be appropriate to use these genes in disease risk assessment. We also estimate the magnitude of a log odds ratio (H) that measures genotype-disease association. We illustrate this method with three breast cancer susceptibility genotypes: population screening data evaluating the 185delAG mutation at BRCA1 and the 6174delT mutation at BRCA2 in a Ashkenazi Jewish population, and case control data for the slow acetylation genotype at the N-acetyl transferase 2 (NAT2) gene in combination with smoking. Knowledge of the 185delAG mutation in BRCA1 (HdelAG = 3.42; 95% CI: 3.04, 3.79) or the 6174delT mutation in BRCA2 (HdelT = 1.98; 95% CI: 1.16, 2.30) can be clinically informative in distinguishing individuals who are and are not at breast cancer risk in populations with cumulative breast cancer incidences of > or = 4% and > or = 13%, respectively. NAT2 genotypes alone are much less clinically informative in predicting breast cancer risk (HNAT2 = 0.10). However, knowledge of both heavy smoking 20 years ago and NAT2 genotype is a more clinically informative predictor of postmenopausal breast cancer risk with HNAT2 = 2.19, when the cumulative breast cancer incidence in the target population is at least 31%. These results indicate that knowledge of the 185delG mutation-status may be clinically informative even in populations with low cumulative breast cancer incidences, whereas the 6174delT mutation and NAT2 genotypes may only be clinically informative in a population with higher cumulative breast cancer incidence. The proposed approach can be used to objectively evaluate the conditions under which susceptibility genotypes may be applied for risk assessment or genetic screening.

Laryngeal electromyography: contribution to vocal fold immobility diagnosis.

Laryngeal Electromyography (LEMG) is a diagnostic test commonly used in patients with vocal fold movement disorder. The aim of this study is to describe LEMG in patients with vocal fold immobility. A total of 55 dysphonic patients with vocal fold immobility diagnosed by laryngeal endoscopy were grouped according to probable clinical cause: 1) unknown; 2) traumatic; or 3) tumoral compression. They were submitted to LEMG by percutaneous insertion of concentric needle electrode. LEMG was conclusive in all patients and showed a majority with peripheral nerve injury. LEMG diagnosed peripheral nerve damage in 25 group 1, 12 group 2, and 11 group 3 patients. LEMG was normal in 4 patients, suggesting cricoarytenoid joint fixation. Central nervous system disorders was suggested in 2 and myopathic pattern in 1. As the major cause of vocal fold immobility is peripheral nerve damage, LEMG is an important test to confirm diagnosis.

Laryngeal electromyography in normal Brazilian population.

Quantitative analysis of normal values of motor unit action potentials duration and amplitude of muscles tireoaritenoideus (TA), cricotireoideus (CT), cricoaritenoideus lateralis (CAL), and cricoaritenoideus posterioris (CAP) was performed in 14 adult normal Brazilian volunteers. The recordings were obtained by percutaneously inserted concentric needle electrode. Different motor unit action potentials were manually selected in each muscle for quantitative computerized analysis of duration and amplitude. The mean values for duration and amplitude were respectively 3.8 ms and 413 microV for TA, 4.9 ms and 585 microV for CT 4.1 ms and 388 microV for CAL and 4.5 ms and 475 microV in CAP. There were no similar reports of normal values of motor unit action potentials in Brazilian subjects.

Laryngeal electromyography: technical features.

Laryngeal Electromyography (LEMG) is an auxiliary diagnostic method used for the comprehension and diagnosis of different neurological diseases that compromise laryngeal function. The most common LEMG technique is the percutaneous insertion of needle electrodes guided by surface anatomical references. We describe techniques for inserting needle electrodes into the tireoaritenoideus (TA), cricotireoideus (CT), cricoaritenoideus lateralis (CAL) and cricoaritenoideus posterioris (CAP) muscles; these are used at UNICAMP laryngology ambulatory, we discuss difficulties found and their proposed solutions. All patients were submitted to otorhinolaryngological, phonoaudiological and laryngeal endoscopy before LEMG. The CAP approach, by digital rotation of the thyroid cartilage was found to be the most difficult, followed by the CAL approach. TA and CT approaches gave no major problems, except with some older and obese patients. A significant complication of the TA approach via thyroid cartilage was a hematoma in one patient which partially obstructed the laryngeal lumen.

Rhombencephalosynapsis: CT and MRI findings.

An unusual disorder of cerebellar development, rhombencephalosynapsis is a unique entity which presents with cerebellar fusion and absence of cerebellar vermis on imaging studies, often associated with supratentorial findings. No specific clinical syndrome has been described in these patients so far, and most cases are found in infancy and childhood. MRI and its multiplanar capabilities and high spatial and contrast resolution increased its recognition. Two cases are reported, with emphasis on imaging findings.

[De novo absence status: case report]. / Status epilepticus ausência de novo. Relato de caso.

There are few descriptions about middle-aged patients who have nonconvulsive status epilepticus, absence status. We reported the clinical case of a woman, 52-year-old, diabetic, referred to the emergency room in a confusional state. Initial electroencephalogram showed continuous typical, bilateral, symmetric and synchronous spike-and-wave discharges. Clinical and electroencephalogram normalization occurred immediately following intravenous injection of benzodiazepine. Computerized axial tomography was normal. The recognition of this entity is essential because of its similarity to psychiatric disturbance and its prompt response to proper treatment.

Genetic and clinical predictors of warfarin dose requirements in African Americans.

The objective of this study was to determine whether, in African-American patients, additional vitamin K oxidoreductase complex subunit 1 (VKORC1), cytochrome P450 2C9 (CYP2C9), CYP4F2, or apolipoprotein E (APOE) polymorphisms contribute to variability in the warfarin maintenance dose beyond what is attributable to the CYP2C9*2 and *3 alleles and the VKORC1 -1639G>A genotype. In a cohort of 226 African-American patients, weekly warfarin dose requirements were lower in those with the CYP2C9*8 allele (34 (30-47) mg; P = 0.023) and the CYP2C9 *2, *3, *5, *6, or *11 allele (33(28-40 mg); P < 0.001) as compared with those with the CYP2C9*1/*1 genotype (43 (35-56) mg). The combination of CYP2C9 alleles, VKORC1 -1639G>A genotype, and clinical variables explained 36% of the interpatient variability in warfarin dose requirements. By comparison, a model without the CYP2C9*5, *6, *8, and *11 alleles explained 30% of the variability in dose. No other VKORC1, CYP4F2, or APOE polymorphism contributed to the variance. The inclusion of additional CYP2C9 variants may improve the predictive ability of warfarin dosing algorithms for African Americans.

Effects of cashew nut shell liquid (CNSL) on the performance of broiler chickens / Efeitos do líquido da casca da castanha de caju (LCC) sobre o desempenho de frangos de corte

The effects of cashew nut shell liquid (CNSL) on growth performance, carcass yield, relative weight of internal organs and microbiology of digestive tract of broiler chickens were investigated. Five hundred and forty male broiler chicks at one day of age were arranged in a completely randomized design with six treatments and six repetitions with 15 broiler chicks each. The treatments were: control (T1 - without growth promoter virginiamycin and CNSL); inclusion levels of 0.10mL (T2), 0.20mL (T3), 0.30mL (T4) and 0.40mL (T5) of CNSL/kg of feed; and commercial promoter virginiamycin (T6). At 21 and 40 days of age, body weight, feed intake, feed conversion and viability of birds were similar in all treatments. Carcass yield was higher in the treatment with the growth promoter when compared to the control treatment. There was a linear increase in carcass yield when the level of CNSL was increased in the diet. The relative weight of the intestine was lower in the treatment containing virginiamycin when compared to the treatment without the inclusion of additives. The relative weight of the intestines decreased when the levels of inclusion of CNSL were increased. There was a gradual reduction of Escherichia coli concentration reaching the lowest number on the CNSL level of 0.30mL/kg. It was concluded that CNSL showed similar performance and slaughter yield as the growth promoter and reduced the concentration of Escherichia coli in the intestinal contents.

Um estudo foi conduzido para investigar os efeitos do líquido da casca da castanha de caju (LCC) sobre o desempenho, o rendimento de carcaça, o peso relativo dos órgãos internos e a microbiologia do trato digestivo de frangos de corte. Foram utilizados 540 pintos machos de um dia de idade, distribuídos num delineamento inteiramente casualizado, com seis tratamentos e seis repetições de 15 aves cada. Os tratamentos consistiram em: controle (T1 - sem promotor comercial e sem LCC), níveis de inclusão de 0,10mL (T2), 0,20mL (T3), 0,30mL (T4) e 0,40mL (T5) de LCC/kg de ração e T6 (promotor comercial - virginiamicina). Aos 21 e 40 dias de idade, o peso corporal, o consumo de ração, a conversão alimentar e a viabilidade das aves foram semelhantes em todos os tratamentos. O rendimento de carcaça foi superior no tratamento com promotor de crescimento em relação ao tratamento-controle. Ocorreu uma resposta linear de incremento no rendimento de carcaça com o aumento do nível de LCC na dieta. O peso relativo dos intestinos foi menor no tratamento com virginiamicina em relação ao tratamento-controle. O peso relativo dos intestinos diminuiu com o aumento do nível de inclusão do LCC. Houve uma redução gradual da concentração de Escherichia coli, cuja menor concentração atingiu o nível de 0,30mL/kg. Conclui-se que o LCC mostrou desempenho e rendimento de abate semelhantes ao promotor de crescimento e reduziu a concentração de Escherichia Coli no conteúdo intestinal.

Effects of cashew nut shell liquid (CNSL) on the performance of broiler chickens / Efeitos do líquido da casca da castanha de caju (LCC) sobre o desempenho de frangos de corte

The effects of cashew nut shell liquid (CNSL) on growth performance, carcass yield, relative weight of internal organs and microbiology of digestive tract of broiler chickens were investigated. Five hundred and forty male broiler chicks at one day of age were arranged in a completely randomized design with six treatments and six repetitions with 15 broiler chicks each. The treatments were: control (T1 - without growth promoter virginiamycin and CNSL); inclusion levels of 0.10mL (T2), 0.20mL (T3), 0.30mL (T4) and 0.40mL (T5) of CNSL/kg of feed; and commercial promoter virginiamycin (T6). At 21 and 40 days of age, body weight, feed intake, feed conversion and viability of birds were similar in all treatments. Carcass yield was higher in the treatment with the growth promoter when compared to the control treatment. There was a linear increase in carcass yield when the level of CNSL was increased in the diet. The relative weight of the intestine was lower in the treatment containing virginiamycin when compared to the treatment without the inclusion of additives. The relative weight of the intestines decreased when the levels of inclusion of CNSL were increased. There was a gradual reduction of Escherichia coli concentration reaching the lowest number on the CNSL level of 0.30mL/kg. It was concluded that CNSL showed similar performance and slaughter yield as the growth promoter and reduced the concentration of Escherichia coli in the intestinal contents.(AU)

Um estudo foi conduzido para investigar os efeitos do líquido da casca da castanha de caju (LCC) sobre o desempenho, o rendimento de carcaça, o peso relativo dos órgãos internos e a microbiologia do trato digestivo de frangos de corte. Foram utilizados 540 pintos machos de um dia de idade, distribuídos num delineamento inteiramente casualizado, com seis tratamentos e seis repetições de 15 aves cada. Os tratamentos consistiram em: controle (T1 - sem promotor comercial e sem LCC), níveis de inclusão de 0,10mL (T2), 0,20mL (T3), 0,30mL (T4) e 0,40mL (T5) de LCC/kg de ração e T6 (promotor comercial - virginiamicina). Aos 21 e 40 dias de idade, o peso corporal, o consumo de ração, a conversão alimentar e a viabilidade das aves foram semelhantes em todos os tratamentos. O rendimento de carcaça foi superior no tratamento com promotor de crescimento em relação ao tratamento-controle. Ocorreu uma resposta linear de incremento no rendimento de carcaça com o aumento do nível de LCC na dieta. O peso relativo dos intestinos foi menor no tratamento com virginiamicina em relação ao tratamento-controle. O peso relativo dos intestinos diminuiu com o aumento do nível de inclusão do LCC. Houve uma redução gradual da concentração de Escherichia coli, cuja menor concentração atingiu o nível de 0,30mL/kg. Conclui-se que o LCC mostrou desempenho e rendimento de abate semelhantes ao promotor de crescimento e reduziu a concentração de Escherichia Coli no conteúdo intestinal.(AU)

Combined maximum likelihood estimates for the equicorrelation coefficient.

Combined maximum likelihood estimates for equicorrelation covariance matrices are considered. The case of a common equicorrelation rho and possibly different standard deviations sigma 1, ..., sigma k among k experimental groups is examined first, and the estimation of (rho, sigma 1, ..., sigma k) is discussed. Second, under the assumption of a common standard deviation and possibly different equicorrelations, the estimation of (rho 1, ..., rho k, sigma) is considered. In each case, maximum likelihood solutions and corresponding large-sample variances are presented.