Effective analgesia and decreased length of stay for patients undergoing radical prostatectomy: Effectiveness of a clinical pathway.

OBJECTIVES: To assess the impact of a clinical pathway (CP) on length of stay (LOS), complications, readmission rates, and patient satisfaction for patients undergoing a radical retropubic prostatectomy (RRP). MATERIALS AND METHODS: A standardized CP for all patients undergoing RRP was developed and implemented. Post-operatively, patients enrolled in the CP received oral ibuprofen and acetaminophen analgesia, with oral and subcutaneous narcotics available for breakthrough pain. Patients enrolled in the CP were compared to a pre-CP historical cohort. Patients were asked to complete a short, validated satisfaction questionnaire 10 days post-operatively. RESULTS: Sixty-eight consecutive patients underwent a RRP following CP implementation and were compared to a historical cohort of 147 pre-CP patients. Median LOS decreased by 50% (4 days versus 2 days, p < 0.0001) while complication and readmission rates were unchanged. Patient satisfaction was high in all domains. Overall, 29.4% of patients treated within the CP required no narcotic analgesia during their admission. CONCLUSIONS: The implementation of a CP for patients undergoing a RRP is a simple and effective method for reducing LOS without compromising complication, readmission rates or patient satisfaction.

Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment.

Approximately 40% of human P450-dependent drug metabolism is carried out by polymorphic enzymes, which can cause abolished, quantitatively or qualitatively altered or enhanced drug metabolism. The latter situation is due to stable duplication, multiduplication or amplification of active genes, most likely in response to dietary components that have resulted in a selection of alleles with multiple non-inducible genes. Several examples exist where subjects carrying certain alleles suffer from a lack of drug efficacy due to ultrarapid metabolism or, alternatively, adverse effects from the drug treatment due to the presence of defective alleles. Knowledge in this field has grown rapidly and can now be applied to both drug development and clinical practice. This is facilitated by the recent development of high-throughput methods for mutation detection and oligonucleotide chips array technology for the identification of a multitude of mutations in the genes encoding drug-metabolizing enzymes. The outcome will allow for safer and more efficient drug therapies.

Somatic mutation of PTEN in vulvar cancer.

PTEN, a candidate tumor suppressor gene located at chromosome 10q23.3, has been shown to be mutated in approximately 40% of endometrial cancers. Such mutations have also been identified in endometrial hyperplasia, indicating that inactivation of the PTEN tumor suppressor gene is an early event in the genesis of some endometrial cancers. In this study, we have extended the analysis of PTEN in gynecological cancer to include adenocarcinoma of the cervix and vulvar carcinomas. Microdissected tissue (including normal tissues), preneoplastic, and neoplastic lesions were analyzed from 9 patients with cervical cancer and 10 patients with vulvar cancer. Only 1 cervical adenocarcinoma displayed a PTEN mutation. In contrast, five of eight vulvar carcinomas studied harbored PTEN mutations. Alterations were identified in carcinoma in situ as well as squamous cell carcinoma of the vulva. In two patients, PTEN mutations were identified in mucosal regions with mild or focal dysplasia. These results suggest that PTEN is frequently altered in vulvar carcinomas and can be found associated with early dysplastic changes in vulvar mucosa.

Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians.

The polymorphic cytochrome P450 2D6 (CYP2D6) causing poor, extensive or ultrarapid metabolism of several clinically important drugs exhibits pronounced interethnic variation. Ultrarapid metabolism is caused by multiple copies of active CYP2D6 genes and recently 29% of an Ethiopian population has been shown to carry duplicated or multiduplicated CYP2D6 genes, whereas the corresponding frequency in other black, Oriental and European populations investigated is 1-2%. In order to characterize the distribution of alleles with multiple CYP2D6 copies in a neighbouring population and to characterize the CYP2D locus in general among Saudi Arabians, the CYP2D6 genotype of a Saudi Arabian population was examined using restriction fragment length polymorphism (RFLP) analysis and allele-specific polymerase chain reaction (PCR) amplification. Of 101 Saudi Arabians studied, 21 subjects had an EcoRI fragment indicative of CYP2D6 gene duplication. In contrast, only two individuals were heterozygous for a deletion of the whole gene (CYP2D6*5). The allele frequency of CYP2D6*4, the most common defective allele among Caucasians, was only 3.5% in the Saudi population. Two other alleles, CYP2D6*10 and *17, common in certain populations and which cause diminished enzyme activity, were found only at low allele frequencies of 3.0% each. These findings are in agreement with earlier Saudi Arabian phenotyping studies which reported a low frequency (1-2%) of poor metabolizers for CYP2D6 probe drugs. In conclusion, the Saudi Arabian population studied exhibited very few defective alleles and a large number of subjects carried duplicated CYP2D6 genes, implying a high conservation on functional CYP2D6 genes possibly due to dietary reasons and reveal the Saudi Arabians as an unique population in comparison with others examined.

Norfloxacin interferes with cyclosporine disposition in pediatric patients undergoing renal transplantation.

Prophylactic treatment with norfloxacin was initiated in a group of pediatric patients undergoing renal transplantation who were receiving cyclosporine and were susceptible to recurrent urinary tract infections. At discharge from the hospital, the mean daily dose of cyclosporine needed to maintain trough cyclosporine blood levels of 150 to 400 ng/ml was 4.5 mg/kg/day for the patients who received norfloxacin compared with 7.4 mg/kg/day for patients who did not receive the antibiotic. This observation suggested that the clearance of cyclosporine was decreased by the concomitant use of norfloxacin. The effect of norfloxacin on specific drug-metabolizing cytochrome P450 isozymes in vitro was examined to determine if the metabolism and subsequent clearance of cyclosporine and possibly other drugs are altered through a metabolic interaction with norfloxacin. In human liver microsomes, the activity of cytochrome P4503A4, the isozyme that metabolizes cyclosporine in humans, was inhibited by norfloxacin. In rat liver microsomes, norfloxacin inhibited the activity of cytochrome P4503A2, the isozyme responsible for cyclosporine metabolism in this species, but did not alter the activity of the rat cytochrome P450 isozymes 1A, 2E1, and 4A1. The in vitro studies suggest that the lower cyclosporine dose required by pediatric patients who were given norfloxacin was caused by inhibition of the metabolism of cyclosporine.

Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism.

The polymorphic human cytochrome P450 2A6 (CYP2A6) metabolises a number of drugs, activates a variety of precarcinogens and constitutes the major nicotine C-oxidase. A relationship between CYP2A6 genotype and smoking habits, as well as incidence of lung cancer, has been proposed. Two defective alleles have hitherto been identified, one of which is very common in Asian populations. Among Caucasians, an additional defective and frequently distributed allele (CYP2A6*3) has been suggested to play a protective role against nicotine addiction and cigarette consumption. Here, we have re-evaluated the genotyping method used for the CYP2A6*3 allele and found that a gene conversion in the 3' flanking region of 30-40% of CYP2A6*1 alleles results in genotype misclassification. In fact, no true CYP2A6*3 alleles were found among 100 Spaniards and 96 Chinese subjects. In one Spanish poor metaboliser of the CYP2A6 probe drug coumarin, we found two novel defective alleles. One, CYP2A6*5, encoded an unstable enzyme having a G479L substitution and the other was found to carry a novel type of CYP2A6 gene deletion (CYP2A6*4D). The results imply the presence of numerous defective as well as active CYP2A6 alleles as a consequence of CYP2A6/CYP2A7 gene conversion events. We conclude that molecular epidemiological studies concerning CYP2A6 require validated genotyping methods for accurate detection of all known defective CYP2A6 alleles.

Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population.

Cytochrome P450 2A6 is an important human hepatic P450 which activates pre-carcinogens, oxidises some drugs and constitutes the major nicotine C-oxidase. In fact, results have been presented in the literature which suggested a relationship between the distribution of defective CYP2A6 alleles and smoking behaviour as well as cigarette consumption. In the present report, we describe the structure of a novel CYP2A locus where the whole CYP2A6 gene has been deleted, resulting in an abolished cytochrome P450 2A6-dependent metabolism. The origin of this locus is apparently due to an unequal crossover event between the 3'-flanking region of the CYP2A6 and CYP2A7 genes. A rapid PCR-based method for the detection of the CYP2A6del allele was developed and the allele frequency was 15.1% among 96 Chinese subjects, but only 1.0% in Finns (n=100) and 0.5% in Spaniards (n=100). In the Chinese population, we did not detect any CYP2A6*2 alleles using an improved genotyping procedure, in contrast to the 11-20% previously reported. It is concluded that genotyping for the CYP2A6del allele is of great importance in studies correlating, for example, smoking behaviour, pre-carcinogen activation or drug metabolism to the CYP2A6 genotype, in particular when oriental populations are investigated.

Differential effect of pentoxifylline on lipopolysaccharide-induced downregulation of cytochrome P450.

It is now established that inflammatory stimuli such as lipopolysaccharides (LPS) and polyinosinic acid:polycytidylic (polyIC) suppress hepatic expression of cytochrome P450 (P450) genes in rat liver. Previous studies have suggested that LPS- or polyIC-induced downregulation of P450 was due to endogenously released inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1, interleukin-6, and interferons (IFNs). To improve our understanding of the role of inflammatory cytokines in mediating P450 depression, we investigated the possibility of preventing P450 downregulation with pentoxifylline. Pentoxifylline has been shown to inhibit LPS-induced TNF-alpha production by suppression of TNF-alpha gene expression. The present study shows that in uninduced male rats pentoxifylline selectively prevents the downregulation of microsomal P4501A2 and P4502B caused by LPS. No protective effect of pentoxifylline on the downregulation of P4502E1 and P4503A1/2 was observed. PolyIC-induced downregulation of P4501A2, P4502B, P4502E1, and P4503A1/2 was not affected by pentoxifylline. These results suggest that the LPS-induced downregulation of P4501A2 and P4502B is mediated to a large extent by TNF-alpha. Other cytokines might be involved in the suppression of P4502E1 and P4503A1/2. The fact that polyIC-induced downregulation is not protected by pentoxifylline is further evidence that this agent acts via a selective induction of IFNs.

Placental site trophoblastic tumor in a postmenopausal woman.

Placental site trophoblastic tumor is a rare neoplasm that arises in the trophoblastic tissue of the placental bed. This case report is unusual because of the patient's advanced age at the time of diagnosis and the favorable response of the disease to chemotherapy. Although the clinical course is benign for most patients with placental site trophoblastic tumor, the malignant variant of the disease is characterized by recurrence, relative insensitivity to radiation and chemotherapy, and death. To the authors' knowledge, the 53-year-old woman reported is the oldest patient with histologically confirmed placental site trophoblastic tumor. Initially, surgery, radiation, and multiagent chemotherapy failed to control vaginal and pulmonary metastatic disease. After administration of four treatment cycles of a "second-line" chemotherapeutic regimen consisting of cyclophosphamide and cisplatin, complete clinical and radiologic remission was achieved. The patient's serum level of human chorionic gonadotropin has remained undetectable, and she has been without measurable evidence of disease for 16 months.

MK-801 and male odours induce c-fos expression in the AOB of juvenile female mice.

The odours of adult males, which accelerate the timing of puberty of female mice, activate c-fos in the accessory olfactory bulb (AOB). To test the hypothesis that NMDA receptors are involved in the male odour-induced increase in c-fos expression, we studied the effects of the non-competitive NMDA receptor agonist MK-801 on male odour-induced c-fos expression in the AOB of juvenile female mice. Surprisingly, MK-801 increased FOS-like immunoreactivity (FLI) within the AOB in the absence of male odour and had no effect on male odour-induced c-fos expression. We suggest that MK-801 increases AOB mitral cell activity by disinhibiting GABAergic granule cells, resulting in increased c-fos expression throughout the AOB.

Ovarian carcinoma and paraneoplastic cerebellar degeneration.

A case of paraneoplastic cerebellar degeneration complicating ovarian cancer is presented. This rare disorder is characterized by vertigo, nystagmus, diplopia, and ataxia. Neurologic sequelae are progressive, ultimately culminating in complete incapacitation and death. Symptoms of paraneoplastic cerebellar degeneration precede the diagnosis of malignancy in the majority of cases. Marked elevation in the anti-Purkinje cell antibody titer together with immunofluorescent staining techniques suggest that an autoimmune mechanism plays a role in the etiology of this disorder.

The clinical diagnosis of trichomoniasis.

Two hundred twenty-six consecutive women attending an inner-city clinic for sexually transmitted diseases were evaluated. Problem-directed histories and physical examinations were conducted and vaginal specimens for wet preparation and Trichomonas vaginalis culture were obtained from each patient. One hundred patients were found to be infected. Patients with multiple sex partners were found to be at increased risk of trichomoniasis (P less than .05). Those with abnormal discharge noted on examination had a higher frequency of positive cultures for T vaginalis (P less than .001). Only 50% of patients with trichomoniasis had an abnormal discharge. Patients with greater than 10 white blood cells per high power field on wet preparation, regardless of whether trichomonads were visualized, had a higher incidence of trichomoniasis (P less than .01). Factors that were not associated with Trichomonas infection included patient age, frequency of coitus, date of most recent coitus, day of menstrual cycle on which patient was examined, recent antibiotic use, use of contraceptives or specific contraceptive methods, symptoms of discharge or pruritus, or the finding of Leptothrix on wet preparation. These data support the contention that the classic description of trichomoniasis cannot be uniformly relied upon for diagnosis, but that patients with multiple sex partners, abnormal vaginal discharge and/or greater than 10 white blood cells per high power field on wet preparation are at increased risk of infection by T vaginalis.

Cannabinoid modulation of rat pup ultrasonic vocalizations.

The present study investigated the effects of the cannabinoid receptor agonist CP 55,940 (1-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) and the cannabinoid receptor antagonist SR 141716A (N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide hydrochloride) on ultrasonic vocalizations, body temperature and activity in 11-13-day-old rat pups. Testing occurred in a 5-min session 30 min following drug administration. CP 55,940 produced a dose-dependent decrease in ultrasonic vocalizations, with a 1000-micrograms/kg dose causing an almost complete inhibition of calls. Doses of 100 and 1000 micrograms/kg of CP 55,940, but not 10 micrograms/kg, caused significant hypothermia in the pups and the 1000 micrograms/kg dose also inhibited activity. The cannabinoid receptor antagonist SR 141716A (20 mg/kg) reversed the effects of 1000 micrograms/kg CP 55,940 on ultrasonic vocalizations and body temperature, but the benzodiazepine receptor antagonist flumazenil (20 mg/kg), the dopamine D1 receptor antagonist SCH 23390 (0.5 mg/kg) and the opioid receptor antagonist naloxone (1 mg/kg) did not. When administered alone, SR 141716A (20 mg/kg) increased pup ultrasonic vocalizations without affecting body temperature or activity. These results indicate that cannabinoids modulate ultrasonic vocalization production in rat pups in a manner that is independent of hypothermia. The increase in ultrasonic vocalizations produced by SR 141716A is one of the first reported behavioural effects of this drug and suggests that the endogenous cannabinoid ligand anandamide may be involved in the regulation of ultrasonic vocalizations.

Peritoneal cytology in endometrial cancer: a review.

Utilization of literature review to evaluate peritoneal cytology as a test for the detection of malignant cells in the peritoneal cavity is limited by the size of the study populations, varied use of preoperative radiation, the lack of consistent methodology for specimen retrieval and processing, and the inherent subjectivity of cytologic interpretation. A standardized methodology for retrieval and processing of peritoneal cytologic specimens should be developed to allow meaningful comparisons of future studies. However, certain conclusions are permitted from published data: 1. The incidence of positive peritoneal cytology is 11.4 per cent among 3091 patients with FIGO stage I endometrial cancer. 2. The depth of the uterus does not influence the incidence of positive peritoneal cytology. 3. Positive peritoneal cytology is predictive of other known prognostic factors including advanced histologic grade, depth of myometrial invasion, and pelvic/periaortic lymph node metastases. 4. The presence of malignant cells in the peritoneal washings from some patients with no myometrial invasion and the high incidence of lymph node metastases in other patients with positive peritoneal cytology suggest that malignant cells gain access to the peritoneal cavity in a variety of ways. It is unclear whether each of these modes of access result in viable tumor cells with the potential for viable metastasis. The high incidence of lymph node metastasis in such patients suggests that lymphatic dissemination of malignant cells plays a significant role in the development of positive peritoneal cytology. In this setting positive peritoneal cytology clearly identifies that individual at high risk for recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)

Amlodipine inhibits rat microsomal cytochrome P450-mediated drug biotransformation.

Calcium channel antagonists have been shown to inhibit cytochrome P-450-mediated metabolism both in vitro and in vivo. The purpose of the present study was to examine the effect of amlodipine on a suite of rat hepatic microsomal cytochrome P-450 activities to determine the potential for drug interactions. In this study, amlodipine (0.05 and 0.5 mM) decreased CYP1A-mediated ethoxyresorufin O-deethylase activity in microsomes prepared from noninduced (56 and 73% inhibition) and pyridine-induced (30 and 51% inhibition) rats. Amlodipine reduced pentoxyresorufin O-deethylase activity (a marker for CYP2B) to 15% of control in incubations utilizing microsomes from phenobarbital-treated rats, but had no effect on this enzyme reaction in noninduced microsomes. The para-nitrophenol hydroxylase, erythromycin N-demethylase, and lauric acid omega and omega-1 hydroxylase activities were significantly inhibited by 1 mM amlodipine in both noninduced and induced microsomes. These results suggest that amlodipine inhibits a number of different P450 forms and therefore has the potential to inhibit the metabolism of a large number of drugs.

Epidemiologic basis for an occupational and environmental policy on environmental tobacco smoke.

ETS contains numerous toxins. Robust epidemiologic evidence implicates ETS as a cause of lung cancer and as a primary cause and source of exacerbation of excess respiratory disease. There is also increasing evidence that ETS may be associated with other outcomes, including heart disease. There is currently little doubt that ETS is an important and avoidable health hazard. Unfortunately, ETS is frequently encountered in the workplace--where it is no safer than in other environments and where it presents hazards to exposed workers and to others. A unique aspect of workplace ETS is that exposure is rarely an outcome of essential manufacturing, extraction, or service delivery processes. Moreover, ETS exposure, with its growing list of known hazards, is preventable by engineering or policy means. Implementation of policies to prevent workplace ETS can be highly effective while entailing low costs and yielding primary and secondary benefits to employers and employees. ACOEM strongly supports an increase in the scope and effectiveness of policies and efforts that protect against exposure to ETS in the workplace and elsewhere. To that end, ACOEM supports voluntary, regulatory, and legislative initiatives to eliminate ETS from the workplace, including public spaces such as bars, casinos, restaurants, schools, day-care centers, and public transportation. ACOEM also encourages employers to provide employee training concerning the health hazards of ETS and voluntary personal smoking-cessation programs.

Gestational trophoblastic disease.

Gestational trophoblastic disease consists of a broad spectrum of conditions ranging from an uncomplicated partial hydatidiform molar pregnancy to stage IV choriocarcinoma with cerebral metastases. Fortunately, with the advent of combination chemotherapy, the patient with advanced-stage disease has a significant chance of achieving complete remission. In addition, several studies have demonstrated that patients with a history of gestational trophoblastic neoplasia do not experience an increased risk of complications with future pregnancies. Patients who have undergone chemotherapy do not seem to experience an increase in the risk for congenital anomalies in their offspring. Patients with a history of hydatidiform molar pregnancy should be advised that they are at increased risk of future molar pregnancies, with a risk of 1% in subsequent gestations after one molar pregnancy and a risk as high as 23% after two molar gestations. Although patients should be reassured regarding their reproductive future, they should be advised to seek prompt medical attention once gestation is suspected so that an early work-up can be initiated if pregnancy is confirmed.

Primary extranodal lymphoma of the scrotum.

Primary extranodal lymphomatous involvement of the skin or genitourinary tract is rare. We report a case of primary scrotal diffuse large cell non-Hodgkin's lymphoma in a 78 year-old male.

Perinephric abscess presenting as chronic diarrhea.

Perinephric abscess is an uncommon diagnosis with a variable presentation and high mortality. We report an unusual case of a patient with a perinephric abscess who presented with chronic diarrhea and weight loss.

Trends in the incidence of bladder cancer in Nova Scotia: a twenty-year perspective.

INTRODUCTION: Bladder cancer is the most common malignant tumor of the urinary system. Tobacco smoking has been implicated as a major risk factor for the development of bladder cancer and Nova Scotia has some of the highest smoking rates in Canada. We examined trends in the incidence of bladder cancer in Nova Scotia between 1980 and 1999. MATERIALS AND METHODS: Data on incident cases of bladder cancer diagnosed in Nova Scotia over a twenty-year period (1980 - 1999) were obtained from the Nova Scotia Cancer Registry. The age- standardized incidence and mortality due to bladder cancer was calculated for both genders. Trends in the incidence of bladder cancer during the study period were analyzed for three different age groups in each gender as an estimate of birth cohort. The average annual percent change (AAPC) in incidence of bladder cancer was calculated. RESULTS: Between 1980 and 1999, 3569 cases of bladder cancer were reported (male: female = 2.9:1). The overall incidence of bladder cancer increased in both males (27.5 to 39.5 cases per 100 000) and females (7.0 to 10.7 cases per 100 000). Mortality rates were stable. There was a trend towards an increase in bladder cancer rates for all age groups analyzed, with a substantial rise occurring in females less than 65 years of age. The AAPC in incidence of bladder cancer was +1.5 for males and +2.6 for females. CONCLUSIONS: We hypothesize that the rising incidence of bladder cancer in Nova Scotia, particularly in individuals less than 65 years of age, is related to changes in cigarette smoking practices during the past century. As the population ages, we are likely to see an increased incidence of bladder cancer in females.