Characterization and opioid modulation of inflammatory temporomandibular joint pain in the rat.

PURPOSE: Experimental inflammation of the rat temporomandibular joint (TMJ) is commonly used to study trigeminal nociceptive processing. This study describes spontaneous pain-related behaviors following TMJ inflammation in the rat. The ability of preemptive systemic morphine to attenuate behaviors as well as immediate-early gene expression in the trigeminal nucleus is described. MATERIALS AND METHODS: Adult male Sprague-Dawley rats received an intra-articular injection of mustard oil (0% to 20%, 50 microL) and were observed for behavioral changes. Morphine sulfate (0 to 10 mg/kg SC) was given 30 minutes before mustard oil; this was reversed in one group with naltrexone hydrochloride (5 mg/kg SC). Two hours after injection rats were killed and perfused. Immunohistochemistry for the protein product of the immediate-early gene c-fos was performed, and brain stem sections including the trigeminal subnucleus caudalis were examined for positive nuclei. RESULTS: Mustard oil inflammation of the rat TMJ induces dose-dependent, morphine-sensitive behaviors. Behaviors observed included excessive grooming of the region, a chewing-like behavior, and head shaking. Fos expression in the trigeminal subnucleus caudalis parallels changes in behaviors. Morphine dose dependently attenuates the number of behaviors, as well as Fos expression; this effect is reversed by the micro-opioid receptor antagonist naltrexone. CONCLUSIONS: Mustard oil inflammation of the rat TMJ causes reliable behavioral changes, which may be quantified and, together with Fos expression, used to assess various experimental TMJ treatment modalities.     

Anticipatory nausea and emesis, and psychological morbidity: assessment of prevalence among out-patients on mild to moderate chemotherapy regimens.

The prevalence of nausea and emesis among a series of out-patients (n = 95) receiving mainly mild-to moderately-emetic cytotoxics, was assessed, along with levels of psychological morbidity. Particular focus was given to the rates of psychologically-based (anticipatory) nausea and emesis. Results indicated that 23% of patients experienced anticipatory nausea and the majority reported that this occurred before at least half of the previous treatment cycles. Both emetic challenge of chemotherapy regimen and younger age were linked to this anticipatory effect. The data clearly indicated that nausea and emesis, both post-treatment and in anticipation of treatment, carried a psychological cost with anxiety being highest in those experiencing anticipatory nausea and/or emesis. The role of anxiety in the aetiology of psychologically-based nausea and emesis was not evaluated and it is considered that a prospective study is needed to clarify the exact contribution of psychological factors in the incidence of both post-treatment and anticipatory side-effects.     

Risk analysis in resection of squamous cell carcinoma of the esophagus

A study of risk factors that affect morbidity and mortality in 523 patients with squamous cell cancer of the esophagus who had one-stage resection was undertaken. The 30-day and hospital mortality rates were 5.0% and 15.5%, respectively. Pulmonary complications, malignant cachexia, and surgical complications accounted for 42%, 25%, and 21% of hospital deaths, respectively. Major pulmonary complications occurred in 23% of patients. Multivariate analysis identified six factors that predicted major pulmonary complications: age, mid-arm circumference, percent of predicted FEV₁, abnormal chest radiograph, amount of blood loss, and palliative resection. Three risk groups of pulmonary complications were identified: low, median, and high risk group with complications in 3%, 17%, and 43% of patients, respectively. Significantly, patients with curative resection had a lower hospital mortality rate (9%) than those with palliative resection (20%), p=0.001. Patients with stage I, IIa, or IIb disease had a lower hospital mortality rate (9%) than those with stage III or IV disease (18%), p=0.026. Multivariate analysis identified six factors that predicted hospital death: age, mid-arm circumference, history of smoking, incentive spirometry, number of stairs climbed, and amount of blood loss. Three risk groups of hospital death were identified: low, median, and high risk groups with death in 7%, 30%, and 38%, respectively. Anastomotic leakage rate was 4%. Technical faults were identified in 53% of patients with leakage. Together with other surgical complications, a presumed or apparent technical error was noted in 63% of patients. The identification of high-risk patients and prevention of technical faults can help improve surgical outcome.

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Resumen Se emprendió un estudio sobre los factores de riesgo que afectaron la mortalidad en 523 pacientes con carcinoma escamocelular del esófago sometidos a resección en una etapa en nuestra institución.Las tasas de mortalidad a 30 días y de mortalidad hospitalaria fueron 5% y 15%. Las complicaciones pulmonares, caquexia maligna y quirúrgica representaron 42%, 25% y 21% de las muertes hospitalarias, respectivamente. Complicaciones pulmonares mayores fueron registradas en 23% de los pacientes.El análisis multivariado identificó seis factores que predicen complicaciones pulmonares mayores: edad, circunferencia del brazo, porcentaje del FEV1 predecible, radiografía de tórax anormal, pérdida de sangre durante la operación y resección de tipo paliativo. Se identificaron tres grupos de riesgo de desarrollar complicaciones pulmonares: bajo, medio y alto, con tasas de 3%, 17% y 43% de los pacientes, respectivamente. Los pacientes que recibieron resección curative exhibieron una significativamente menor tasa de mortalidad hospitalaria (9%) en comparación con los que recibieron resección paliativa (20%), p=0.001. Los pacientes con enfermedad en estados I, IIa, IIb exhibieron menor mortalidad hospitalaria (9%) en comparación con los estados III o IV (18%), p=0.026. El análisis multivariado identificó seis factores que predicen mortalidad hospitalaria: edad, circunferencia del brazo, historia de tabaquismo, espirometría de incentivo, número de escalones que puede ascender y pérdida de sangre durante la operación. Se identificaron tres grupos de riesgo de mortalidad hospitalaria: bajo, medio y alto, con tasas de 7%, 30% y 38% respectivamente.La tasa de fuga anastomótica fue 4% y se identificaron defectos técnicos en 53% de los pacientes. Junto con otras complicaciones quirúrgicas, se observó un error técnico presumible o aparente en 63% de los pacientes.La identificación de los pacientes de alto riesgo y la prevención de los errores técnicos pueden ayudar a mejorar el pronóstico.

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Résumé Dans cette étude, on a étudié les facteurs de risque influençant la morbidité et la mortalité chez 523 patients ayant un cancer épidermoïde de l'oesophage et ayant eu une résection en un seul temps. La mortalité à 30 jours et la mortalité hospitalière ont été respectivement de 5% et de 15.5%. Les complications pulmonaires, la cachexie maligne et les complications chirurgicales ont été responsable respectivement de 42%, 25% et 21% des décès hospitaliers. Une analyse multifactorielle a permis d'identifier six facteurs prédictifs des complications pulmonaires: l'âge, la circonférence brachiale, la prévision du volume expiratoire forcé en une seconde, les anomalies de la radiographie thoracique, la quantité de sang perdu, et le caractère palliatif de la résection. Trois groupes, dont le risque de complications pulmonaires a été classé faible, moyen et élevé, ont été identifiés. Le taux de complications dans ces groupes ont été respectivement de 3%, 17% et 43%. Les patients ayant eu une résection à visée curative avaient une mortalité hospitalière significativement plus basse (9%) comparée à celle des patients ayant eu une résection à visée palliative (20%) (p=0.001). Les patients ayant des maladies de stades I, IIa, IIb avaient une mortalité plus basse (9%) que ceux qui avaient des stades III ou IV (18%), (p=0.026). L'analyse multifactorielle a permis d'identifier six facteurs prédictifs de la mortalité hospitalière: l'âge, la circonférence brachial, des antécédents de consommation excessive du tabac, la spirométrie, le nombre d'escaliers que le patient peut monter, et la quantité de sang perdu. Trois groupes de patients, dont le risque de mortalité hospitalière a été classé faible, moyen, et élevé, ont eu des décès dans respectivement 7%, 30% et 38% des cas. Le taux de fistule a été de 4%. Une faute technique a été identifiée chez 53% des patients ayant eu une fistule. Une faute technique apparente ou présumée a été identifie chez 63% des patients ayant eu soit une fistule soit une complication chirurgicale. L'identification des patients à haut risque et la prévention des fautes techniques peuvent contribuer à améliorer le pronostic après chirurgie.

     

Pharmacokinetic and pharmacodynamic studies with mitoxantrone in the treatment of patients with nasopharyngeal carcinoma.

The pharmacokinetics and pharmacodynamics of mitoxantrone were studied in 15 patients with advanced nasopharyngeal carcinoma (NPC) after single intravenous rapid infusion (12 to 14 mg/m2). Mitoxantrone plasma concentrations and urinary excretion were measured specifically with the use of a high-performance liquid chromatographic method with ultraviolet detection at 242 and 658 nm. The pharmacokinetic parameters are described adequately by a three-compartment model with a terminal half-life of 71.5 +/- 40.1 hours and a volume of distribution of 5037 +/- 2377 l. The total plasma clearance was 743 +/- 462 ml/minute, and the renal clearance was 18.8 +/- 8.49 ml/minute. Within 72 hours, 1.8 +/- 0.6% of the administration dose was excreted in urine as mitoxantrone parent compound. From the urinary excretion rate data, glomerular filtration and possible tubular reabsorption were the mechanisms involved in the urinary excretion of mitoxantrone. The values for unbound fraction (%) in plasma at time 0 and 5 minutes were 2.88 +/- 0.91% and 3.25 +/- 1.19%, with an average of 3.04 +/- 1.01%. The degree of protein binding of mitoxantrone was not affected by concentration (P greater than 0.05) in Chinese patients with NPC. The response rate for mitoxantrone was poor in this study. Clinical studies have demonstrated that mitoxantrone was generally well tolerated. Only very low incidences of nausea, vomiting, and alopecia were observed. The mild and rapidly reversible dose-limiting hematologic toxic effects have proven leukopenia. Although the toxicities reported here were tolerated for most patients, other combination regimens including mitoxantrone or other administration routes may be considered and need to be evaluated carefully.     

Prognostic factors in hormone-resistant progressing cancer of the prostate.

In 224 consecutive patients with hormone-resistant prostatic cancer referred to 2 European Cancer Centres for palliation of painful bone metastases the one year survival for all patients was 24% (2-year survival: 7%). The median survival was 8 months. In univariate analyses the following prognostic factors were identified: performance status, serum creatinine, alkaline phosphatase, duration of response to primary hormone treatment, degree of bone scan involvement and hemoglobin. Multivariate analyses confirmed the four first parameters to be independent factors. A prognostic model was established (no or one risk factors vs 2 risk factors vs 3 or 4 risk factors) based on performance status, creatinine, alkaline phosphatase and hormone response duration. The median survival of these groups was 10 months, 6 months and 3 months, respectively. This model proved to be discriminative in an external data set of 214 patients with hormone-resistant prostatic cancer entered in two prospective trials. The above differences in outcome between readily and simply defined prognostic groups are greater than the differences one can realistically hope to produce using new treatment strategies. These prognostic factors should be taken into account both in the design and interpretation of clinical studies dealing with the treatment of hormone-resistant progressing prostatic cancer and painful bone metastases.     

Incidence of childhood diabetes mellitus in Yorkshire, northern England, is associated with nitrate in drinking water: an ecological analysis

Summary The relationship between the incidence of childhood-onset insulin-dependent diabetes mellitus and levels of nitrate in drinking water in the former Yorkshire Regional Health Authority was investigated by means of an ecological analysis. A population-based register contributed 1797 0–16-year-olds diagnosed with diabetes between 1978 and 1994. Nitrate data were based on 9330 samples of drinking water tested between 1990 and 1995 in 148 water supply zones, for which 1991 census small area statistics were taken on population density, ethnicity and socio-economic status. Diabetes incidence was positively associated with raised mean nitrate levels with a standardised incidence ratio of 115 in zones with greater than 14.85 mg · l^–1 (χ² = 26.81, 1 df, p < 0.001). Significant negative trends were found between standardised incidence ratios and proportion of non-whites in the population (χ² = 33.57, 1 df, p < 0.001), childhood population density (χ² = 30.81, 1 df, p < 0.001) and the Townsend deprivation score (χ² = 33.89, 1 df, p < 0.001). Poisson regression modelling, adjusting for the other factors, showed a significant increase in relative incidence rate ratio from a baseline of 1 at nitrate levels below 3.22 mg · l^–1 to 1.27 (95 % confidence interval 1.09,1.48) for mean nitrate levels above 14.85 mg · l^–1. An association between higher nitrate levels in domestic drinking water and incidence of childhood diabetes has been demonstrated. This was not explained by the ethnic composition of the population, population density or socioeconomic status. Nitrate in drinking water may be a precursor of chemicals which are toxic to the pancreas. [Diabetologia (1997) 40: 550–556] Received: 24 October 1996 and in revised form: 20 December 1996     

Reactive hemophagocytic syndrome: a study of 7 fatal cases

Reactive hemophagocytic syndrome is a clinico-pathologic entity characterized by systemic proliferation of non-neoplastic histiocytes showing phagocytosis of hemopoietic cells, resulting in blood cytopenia. It is best known to be associated with virus infection, but other associated diseases have also been implicated. The clinical and pathological findings of 7 fatal cases are described. The syndrome affected both sexes of a wide age range, and all patients had fever. Significant laboratory findings were blood cytopenia, abrupt drop in the blood cell counts, deranged liver function tests and abnormal coagulation profile. The associated diseases were diverse: two patients had bacterial infection; two had peripheral T-cell lymphoma; one had disseminated undifferentiated carcinoma of the ovary; one had both tuberculosis and disseminated nasopharyngeal carcinoma, and one had no obvious underlying disease. It is postulated that lymphokines secreted by lymphoid cells or tumor cells may be responsible for the systemic activation of histiocytes. The differential diagnosis from malignant histiocytosis is discussed.     

Cloning and expression of the major secreted cathepsin B-like protein from juvenile Fasciola hepatica and analysis of immunogenicity following liver fluke infection

The functions of the cathepsin B-like proteases in liver flukes are unknown and analysis has been hindered by a lack of protein for study, since the protein is produced in small amounts by juvenile flukes. To circumvent this, we isolated and characterized a cDNA encoding the major secreted cathepsin B from Fasciola hepatica. The predicted preproprotein is 339 amino acids in length, with the mature protease predicted to be 254 amino acids long, and shows significant similarity to parasite and mammalian cathepsin B. Only one of the two conserved histidine residues required for cathepsin B exopeptidase activity is predicted to be present. Recombinant preproprotein was produced in yeast, and it was shown that the recombinant proprotein can undergo a degree of self-processing in vitro to the mature form, which is active against gelatin and synthetic peptide substrates. The recombinant protein is antigenic in vaccinated rats, and antibodies to the protein are detected early after infection of rats and sheep with F. hepatica. The kinetics of the response to cathepsin B and cathepsin L after infection of sheep and rats confirm the temporal expression of these proteins during the life cycle of the parasite.