New chemistry of 1,2-closo-P2B10H10 and 1,2-closo-As2B10H10; in silico and gas electron diffraction structures, and new metalladiphospha- and metalladiarsaboranes.

The molecular structures of 1,2-closo-P(2)B(10)H(10) (1) and 1,2-closo-As(2)B(10)H(10) (2) have been determined by gas electron diffraction and the results obtained compared with those from computation at the MP2/6-31G** level of theory. The level of agreement is good for 2 (root-mean-square [rms] misfit for As and B atoms 0.0297 Å) and very good for 1 (rms misfit for P and B atoms 0.0082 Å). In comparing the structures of 1 and 2 with that of 1,2-closo-C(2)B(10)H(12) (I) it is evident that expansion of the polyhedron from I to 1 to 2 is restricted only to the heteroatom vertices and the B(6) face to which these are bound. Following deboronation (at B3) and subsequent metallation, compounds 1 and 2 have been converted into the new metalladiheteroboranes 3-(η-C(9)H(7))-3,1,2-closo-CoAs(2)B(9)H(9) (4), 3-(η-C(10)H(14))-3,1,2-closo-RuAs(2)B(9)H(9) (5), 3-(η-C(5)H(5))-3,1,2-closo-CoP(2)B(9)H(9) (6), 3-(η-C(9)H(7))-3,1,2-closo-CoP(2)B(9)H(9) (7) and 3-(η-C(10)H(14))-3,1,2-closo-RuP(2)B(9)H(9) (8), the last three constituting the first examples of metalladiphosphaboranes. Together with the known compound 3-(η-C(5)H(5))-3,1,2-closo-CoAs(2)B(9)H(9) (3), compounds 4-8 have been analysed by NMR spectroscopy and (except for 8) single-crystal X-ray diffraction. The (11)B NMR spectra of analogous pairs of metalladiphosphaborane and metalladiarsaborane (6 and 3, 7 and 4, 8 and 5) reveal a consistently narrower (9-10 ppm) chemical shift range for the metalladiarsaboranes, the combined result of a deshielding of the lowest frequency resonance (B6) and an increased shielding of the highest frequency resonance (B8) via an antipodal effect. In crystallographic studies, compounds 3 and 5B (one of two crystallographically-independent molecules) suffer As/B disorder, but in both cases it was possible to refine distinct, ordered, components of the disorder, the first time this has been reported for metalladiarsaboranes. Moreover, whilst the Cp compounds 6 and 3 are disordered, their indenyl analogues 7 and 4 are either ordered or significantly less disordered, a consequence of both the reduced symmetry of an indenyl ligand compared to a Cp ligand and the preference of the former for a distinct conformation relative to the cage heteroatoms. Unexpectedly, whilst this conformation in the cobaltadiphosphaborane 7 is cis-staggered (similar to that previously established for the analogous cobaltadicarborane), in the cobaltadiarsaborane 4 the conformation is close to cis-eclipsed.

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.

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.

Disability management training for supervisors: a pilot intervention program.

Proactive disability management practices among employers have been associated with reduced frequency and duration of disability. Supervisors have a critical role in disability prevention. However, few studies have evaluated training efforts to modify supervisor responses in order to improve disability outcomes. In this study, 108 supervisors representing seven employers were provided a 1.5-h training session to reinforce a proactive and supportive response to work-related musculoskeletal symptoms and injuries among employees. Pre- and post training results showed improvements in supervisor confidence to investigate and modify job factors contributing to injury, to get medical advice, and to answer employees' questions related to injury and treatment (p < .05). More supervisors reported decreases (38.5%) than increases (9.6%) in lost work time within their departments. These data provide evidence that this approach may improve disability outcomes of work-related musculoskeletal disorders. Controlled trials with disability outcome data are needed to confirm these results.

Employer attitudes, training, and return-to-work outcomes: a pilot study.

This work was concerned with investigating and changing employer attitudes and practices that impede return to work and rehabilitation for injured workers. Prior studies have shown that employer responses to workers reporting work-related musculoskeletal discomfort have significant and independent effects on disability outcomes. Based on these findings, a pilot training program was developed by occupational rehabilitation specialists to improve the response of supervisors to employees reporting work-related injuries. The training was delivered to 108 supervisors at seven southeastern New Hampshire companies that volunteered to participate. A survey was developed and pilot-tested, then administered before the training. Survey participants were employees who had work-related injuries in the past year. The survey asked about types and onset of injury, specific supervisor responses, and overall impression of supervisor interaction at the time of injury. Employee responses before the intervention were compared with those collected from workers who reported injuries after the training. The postintervention results demonstrated significant decreases in supervisors (1) blaming employees for the injury, (2) not taking the condition seriously, and (3) discouraging the worker from filing a claim. Positive trends in confidentiality of discussions, access to medical care, and accommodation and work modifications were also noted. Although anecdotal reports from the companies indicated a consistent decrease in work-related lost time after the intervention, actual verification was not possible, and other components of the intervention may have accounted for this outcome. Small numbers of cases and possible lack of comparability of cases before and after the intervention are significant limitations. However, rehabilitation professionals may be able to improve disability management practices and accommodations through employer education, especially when training is directed toward front-line supervisors.

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.

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.

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.

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.

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.

Characterization and functional analysis of two common human cytochrome P450 1B1 variants.

Cytochrome P450 1B1 (CYP1B1) is a human extrahepatic P450 that activates procarinogens, metabolizes 17beta-estradiol, and may well have a role in the pathogenesis of some forms of cancer. Besides rare deleterious mutations reported for the CYP1B1 gene, six single-nucleotide polymorphisms have been reported, of which four cause amino acid exchanges. We have expressed two of the common CYP1B1 alleles in yeast cells and mammalian COS-1 cells in order to functionally characterize the alleles with respect to kinetic properties and protein stability. The CYP1B1.2 variant contains the two linked amino acid substitutions R48G and A119S compared to CYP1B1.1. The kinetic parameters of two structurally unrelated CYP1B1 substrates for the two variants were examined. No kinetic differences were seen of 17beta-estradiol hydroxylation activities between the two CYP1B1 variants and an only minor increase in the apparent Km for ethoxyresorufin was observed for CYP1B1.2. It therefore appears that they have very similar catalytic properties and the substitutions do not appear to alter CYP1B1 catalytic function. The two CYP1B1 variants were similarly stable when expressed in mammalian COS-1 cells, indicating that the substitutions have no effect on protein folding or stability. The combined results indicate that these two CYP1B1 variants show very similar properties with respect to catalytic activities and protein stability and do not alter CYP1B1 function.

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.

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.

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.

Prophylactic mastectomy and inherited predisposition to breast carcinoma.

Relative to her risk of breast carcinoma, the woman with a BRCA1 or BRCA2 gene mutation can be managed either by intensive screening (with or without chemoprevention) or by prophylactic mastectomy. Although it would be preferable to avoid prophylactic surgery, the current level of screening technology and the rudimentary state of chemoprevention do not guarantee a good outcome with intensive surveillance. A review of the currently available data was undertaken to determine the efficacy of prophylactic surgery, intensive screening, and chemoprevention. An attempt then was made to extrapolate the efficacy of the various approaches to the management of women who carry BRCA1 or BRCA2 gene mutations. Intensive surveillance may not detect breast carcinoma at an early, curable stage in young women with BRCA1 or BRCA2 gene mutations because the growth rate of the tumors in these women most likely will be rapid and the density of the breast tissue may compromise detection. Chemoprevention is in its infancy, and its efficacy in this population is unknown. Conversely, prophylactic surgery may not be completely effective in preventing breast carcinoma. The authors are hopeful that sometime in the next decade advances in chemoprevention, screening technology, or breast carcinoma treatment will make mastectomy obsolete. However, for the time being prophylactic mastectomy has attributes that make it an alternative for this population that must be considered. Careful discussion of all options is essential in the management of these women.

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.

Ultrasonic surgical aspiration for gynecologic disease.

Ultrasonic Surgical Aspiration (USA) is a technique which employs a hand-held instrument that selectively fragments and aspirates tissues of high-water content. The selectivity of the device permits preservation of underlying vital structures while the aspiration provides a tissue specimen for histologic analysis. Application of this device to neoplastic disease of the lower genital tract has been reported to provide durable success rates of 78% for conyloma acuminata and vulvar intraepithelial neoplasia (VIN) and 81% for vaginal intraepithelial neoplasia (VAIN).Employment of USA in patients with advanced ovarian cancer has been shown to improve surgical cytoreduction without increasing blood loss or complication rates.

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.