First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.

BACKGROUND: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. PATIENTS AND METHODS: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). RESULTS: With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61-0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation. CONCLUSIONS: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.

Metastatic spinal cord compression from basal cell carcinoma of the skin treated with surgical decompression and vismodegib: case report and review of Hedgehog signalling pathway inhibition in advanced basal cell carcinoma.

We report a case of a 66-year-old man with locally advanced and metastatic basal cell carcinoma (BCC) causing spinal cord compression, which was treated with spinal surgery and subsequent vismodegib. The patient presented with a large fungating chest wall lesion and a metastasis in T8 that was causing cord compression. He had neurosurgical decompression of the T8 lesion and fixation of the spine. Punch biopsy from the fungating chest wall lesion showed a BCC with some malignant squamous differentiation (basosquamous). Histopathological examination of the metastatic lesion in T8 at the time of surgical decompression identified features identical to the punch biopsy. The patient was referred to the oncology clinic for adjuvant treatment. In light of his metastatic disease and the large area over his chest wall that could not fully be covered by radiotherapy, he was treated with the novel oral Hedgehog signalling pathway (HHSP) inhibitor vismodegib, which led to marked improvement.

Organisational culture: variation across hospitals and connection to patient safety climate.

CONTEXT: Bureaucratic organisational culture is less favourable to quality improvement, whereas organisations with group (teamwork) culture are better aligned for quality improvement. OBJECTIVE: To determine if an organisational group culture shows better alignment with patient safety climate. DESIGN: Cross-sectional administration of questionnaires. Setting 40 Hospital Corporation of America hospitals. PARTICIPANTS: 1406 nurses, ancillary staff, allied staff and physicians. MAIN OUTCOME MEASURES: Competing Values Measure of Organisational Culture, Safety Attitudes Questionnaire (SAQ), Safety Climate Survey (SCSc) and Information and Analysis (IA). RESULTS: The Cronbach alpha was 0.81 for the group culture scale and 0.72 for the hierarchical culture scale. Group culture was positively correlated with SAQ and its subscales (from correlation coefficient r = 0.44 to 0.55, except situational recognition), ScSc (r = 0.47) and IA (r = 0.33). Hierarchical culture was negatively correlated with the SAQ scales, SCSc and IA. Among the 40 hospitals, 37.5% had a hierarchical dominant culture, 37.5% a dominant group culture and 25% a balanced culture. Group culture hospitals had significantly higher safety climate scores than hierarchical culture hospitals. The magnitude of these relationships was not affected after adjusting for provider job type and hospital characteristics. CONCLUSIONS: Hospitals vary in organisational culture, and the type of culture relates to the safety climate within the hospital. In combination with prior studies, these results suggest that a healthcare organisation's culture is a critical factor in the development of its patient safety climate and in the successful implementation of quality improvement initiatives.

The effects of viewing pro-eating disorder websites: a systematic review / Efectos de ver páginas web a favor del desorden alimentario: un estudio sistemático

OBJECTIVE: To determine health-related effects of viewing pro-eating disorder (Pro-ED) websites. METHODS: A systematic review was carried out addressing: 1. The effect of viewing pro-ED websites on 'eating disorder behaviour', 2. The effect of viewing pro-ED websites on viewers' negative and positive affect. RESULTS: Seven studies were included. Pro-ED viewers compared with controls showed higher levels of dieting and exercise (3 studies, 2 suggesting causation); higher levels of drive for thinness, body dissatisfaction and perfectionism (2 studies, both associative); a reduced likelihood of binging/purging (one study); increased negative affect (two studies); and a positive correlation between viewing pro-ED websites, disease duration and hospitalisations (one study). CONCLUSION: Viewing pro-ED websites may increase eating disorder behaviour but might not cause it. It may cause increased negative affect after a single short website exposure. For those with eating disorders, viewing is positively correlated with disease duration and hospitalisations. Professionals should be aware ofthese sites and their potential damage for health.

OBJETIVO: Determinar los efectos para la salud a consecuencia de ver páginas web a favor del desorden alimentario. MÉTODOS: Se llevó a cabo un estudio sistemático que abordó los siguientes asuntos: 1. El efecto de ver páginas web sobre "comportamientos de desorden alimentario "; 2. El efecto que ver páginas web a favor del desorden alimentario, tiene sobre el afecto negativo y positivo de los usuarios en cuestión. RESULTADOS: Se incluyeron siete estudios. Los usuarios que ven páginas pro-desorden alimentario mostraron niveles más altos de dieta y ejercicio, en comparación con los controles (3 estudios, 2 que sugieren causalidad); niveles más altos de compulsión a la delgadez, insatisfacción corporal y perfeccionismo (2 estudios, ambos asociativos); una probabilidad reducida de atracones/purga (un estudio); aumento del afecto negativo (dos estudios); y una correlación positiva entre ver páginas web prodesorden alimentario, duración de la enfermedad y hospitalización (un estudio). CONCLUSIÓN: Ver páginas Web pro-desorden alimentario puede aumentar los comportamientos de desorden alimentario pero podría no ser la causa. Puede producirse un aumento del afecto negativo luego de una sola exposición breve a la página Web. Para aquellas personas con desordenes alimentarios, el ver las páginas Web guarda una correlación positiva con la duración de la enfermedad y las hospitalizaciones. Los profesionales deben tener conciencia de estos sitios y su daño potencial para la salud.

The effects of viewing pro-eating disorder websites: a systematic review.

OBJECTIVE: To determine health-related effects of viewing pro-eating disorder (Pro-ED) websites. METHODS: A systematic review was carried out addressing: 1. The effect of viewing pro-ED websites on eating disorder behaviour 2. The effect of viewing pro-ED websites on viewers' negative and positive affect. RESULTS: Seven studies were included. Pro-ED viewers compared with controls showed higher levels of dieting and exercise (3 studies, 2 suggesting causation); higher levels of drive for thinness, body dissatisfaction and perfectionism (2 studies, both associative); a reduced likelihood of binging/purging (one study); increased negative affect (two studies); and a positive correlation between viewing pro-ED websites, disease duration and hospitalisations (one study). CONCLUSION: Viewing pro-ED websites may increase eating disorder behaviour but might not cause it. It may cause increased negative affect after a single short website exposure. For those with eating disorders, viewing is positively correlated with disease duration and hospitalisations. Professionals should be aware of these sites and their potential damage for health.

MRI in the classical MM1 and the atypical MV2 subtypes of sporadic CJD: an inter-observer agreement study.

BACKGROUND AND PURPOSE: To establish radiological features in the atypical MV2 subtype of sCJD compared with the classical MM1 subtype, as well as region- and sequence-dependent inter-observer correlation. METHODS: MRI hyperintensity of basal ganglia (BG), cortex and thalamus was evaluated in 31 MM1 and 32 MV2 patients. Each MR scan was analyzed independently by two neuroradiologists blinded to PRNP genotype/prion protein type. RESULTS: Cumulative T2-sensitivity for BG hyperintensity was higher in the MV2 subtype (84% for both observers versus 61% in observer 1/42% in observer 2 in MM1 patients). Significant inter-observer agreement was found for BG and thalamus on T2, FLAIR, PD and DWI, but for cortex only on DWI. Thalamic changes were significantly more frequent in MV2 than in MM1 patients (cumulative sensitivity 86% vs. 12.5% on DWI). DISCUSSION: The high frequency of thalamic hyperintensity in the MV2 subtype allowed differentiation from MM1 patients. Good inter-observer agreement was found for BG and thalamus in all sequences. DWI showed the highest inter-observer correlation independent of the investigated brain region and was therefore not only highly sensitive but also relatively independent of investigator bias. Since inter-observer correlation for cortical hyperintensity in T2, FLAIR and PD is relatively low, the cortical changes should not be over-interpreted with these sequences.

A revised sexual knowledge assessment tool for people with intellectual disabilities: is sexual knowledge related to sexual offending behaviour?

BACKGROUND: The aim of the current study was to update an existing short measure of sexual knowledge and generate some initial reliability and normative data. Comparisons of sexual knowledge across several groups were made to examine whether or not a lack of sexual knowledge is related to sexual offending. METHODS: The Bender Sexual Knowledge Questionnaire (BSKQ) was revised, and a new questionnaire, the General Sexual Knowledge Questionnaire (GSKQ), was created and administered to four groups of participants: (1) sex offenders with an intellectual disability (ID) and a history of engagement in treatment (n = 12); (2) sex offenders with an ID and no history of treatment (n = 13); (3) non-offenders with an ID (n = 28); and (4) non-offenders without an ID (n = 10). Between-group comparisons were made; internal consistency, split-half reliability and correlations were examined. RESULTS: The internal consistency and the split-half reliability of the entire questionnaire was good. Non-offenders without an ID scored significantly higher than non-offenders with an ID on all sections of the GSKQ. Sex offenders who had undergone treatment scored significantly higher than non-offenders with an ID on several sections of this questionnaire. CONCLUSIONS: The initial findings from this study suggest that the psychometric properties of the GSKQ are promising. The assumption that lower sexual knowledge may be related to the risk of committing a sexual offence by people with IDs is possibly erroneous, and further research is required to clarify this possibility.

Three-dimensional distributions of elements in biological samples by energy-filtered electron tomography.

By combining electron tomography with energy-filtered electron microscopy, we have shown the feasibility of determining the three-dimensional distributions of phosphorus in biological specimens. Thin sections of the nematode, Caenorhabditis elegans were prepared by high-pressure freezing, freeze-substitution and plastic embedding. Images were recorded at energy losses above and below the phosphorus L2,3 edge using a post-column imaging filter operating at a beam energy of 120 keV. The unstained specimens exhibited minimal contrast in bright-field images. After it was determined that the specimen was sufficiently thin to allow two-window ratio imaging of phosphorus, pairs of pre-edge and post-edge images were acquired in series over a tilt range of +/-55 degrees at 5 degrees increments for two orthogonal tilt axes. The projected phosphorus distributions were aligned using the pre-edge images that contained inelastic contrast from colloidal gold particles deposited on the specimen surface. A reconstruction and surface rendering of the phosphorus distribution clearly revealed features 15-20 nm in diameter, which were identified as ribosomes distributed along the stacked membranes of endoplasmic reticulum and in the cytoplasm. The sensitivity of the technique was estimated at < 35 phosphorus atoms per voxel based on the known total ribosomal phosphorus content of approximately 7000 atoms. Although a high electron dose of approximately 10(7)e/nm2 was required to record two-axis tilt series, specimens were sufficiently stable to allow image alignment and tomographic reconstruction.

Serologic evidence for West Nile virus infection in birds in the New York City vicinity during an outbreak in 1999.

As part of an investigation of an encephalitis outbreak in New York City, we sampled 430 birds, representing 18 species in four orders, during September 13-23, 1999, in Queens and surrounding counties. Overall, 33% were positive for West Nile (WN) virus-neutralizing antibodies, and 0.5% were positive for St. Louis encephalitis virus-neutralizing antibodies. By county, Queens had the most seropositive birds for WN virus (50%); species with the greatest seropositivity for WN virus (sample sizes were at least six) were Domestic Goose, Domestic Chicken, House Sparrow, Canada Goose, and Rock Dove. One sampled bird, a captive adult Domestic Goose, showed signs of illness; WN virus infection was confirmed. Our results support the concept that chickens and House Sparrows are good arbovirus sentinels. This study also implicates the House Sparrow as an important vertebrate reservoir host.

Crow deaths as a sentinel surveillance system for West Nile virus in the northeastern United States, 1999.

In addition to human encephalitis and meningitis cases, the West Nile (WN) virus outbreak in the summer and fall of 1999 in New York State resulted in bird deaths in New York, New Jersey, and Connecticut. From August to December 1999, 295 dead birds were laboratory-confirmed with WN virus infection; 262 (89%) were American Crows (Corvus brachyrhynchos). The New York State Department of Health received reports of 17,339 dead birds, including 5,697 (33%) crows; in Connecticut 1,040 dead crows were reported. Bird deaths were critical in identifying WN virus as the cause of the human outbreak and defining its geographic and temporal limits. If established before a WN virus outbreak, a surveillance system based on bird deaths may provide a sensitive method of detecting WN virus.

Expression of the 53 kD forked protein rescues F-actin bundle formation and mutant bristle phenotypes in Drosophila.

forked mutations affect bristle development in Drosophila pupae, resulting in short, thick, gnarled bristles in the adult. The forked proteins are components of 200-300-microm-long actin fiber bundles that are present transiently during pupal development [Petersen et al., 1994: Genetics 136:173-182]. These bundles are composed of segments of 3-10 microm long, and forked protein is localized along the actin fiber bundle segments and accumulates at the junctions connecting them longitudinally. In the forked mutants, f(36a) and f(hd), F-actin bundles are greatly reduced in number and size, and bundle segmentation is absent. The p-element, P[w(+), falter] contains a 5.3-kb fragment of the forked gene that encodes the 53-kD forked protein [Lankenau et al., 1996: Mol Cell Biol 16:3535-3544]. Expression of only the 53-kD forked protein is sufficient to rescue the actin bundle and bristle phenotypes of f(36a) and f(hd) mutant flies. The 5.3-kb forked sequence, although smaller than the 13-kb region previously shown to rescue forked mutants [Petersen et al., 1994: Genetics 136:173-182], does contain the core forked sequence that encodes actin binding and bundling domains in cultured mammalian cells [Grieshaber and Petersen, 1999: J Cell Sci 112:2203-2211]. These data show that the 53-kD forked protein is sufficient for normal bristle development and that the domains shown previously to be important for actin bundling in cell culture may be all that are required for normal actin bundle formation in developing Drosophila bristles.

Effect of argon laser irradiation on shear bond strength of orthodontic brackets: an in vitro study.

Argon lasers, due to their significant time savings over conventional curing lights, are being investigated for use in bonding orthodontic brackets. They are also being investigated for their ability to confer demineralization resistance on enamel. The purpose of this study was to evaluate the effects of argon laser irradiation on bond strength at 3 different laser energies (200, 230, and 300 mW) and at 3 unique time points of laser application (before, during, or after bracket placement). One hundred-fifty human posterior teeth were divided into 9 study groups and 1 control group. After debonding, the adhesive remnant index was scored for each tooth. There was no evidence of an effect of energy level on bond strength, P =.903, or of an interaction between timing of bracket placement and energy level, P =.858. When combining data across energy levels, the mean bond strength was significantly different between all 3 bracket placement groups, P <.001. In addition, the mean bond strength of teeth lased after bonding was significantly higher than the control group, P <.05. There were no statistically significant differences between adhesive remnant index scores among the 10 groups. Lasing the enamel before or after bonding does not adversely affect bond strength. Use of the argon laser to bond orthodontic brackets can yield excellent bond strengths in significantly less time than conventional curing lights, while possibly making the enamel more resistant to demineralization.

Evaluation of spatial filters to create smoothed maps of health data.

Spatial filters have been used as an easy and intuitive way to create smoothed disease maps. Birth weight data from New York State for 1994 and 1995 are used to compare the traditional filter type of fixed geographical size with a filter size of constant or nearly constant population size. The latter are more appropriate for mapping disease in geographic areas with widely varying population density, such as New York State. Issues such as the choice of population size for the filter, the scale of smoothing, the ability to detect true spatial variation and the ability to smooth over random spatial noise are evaluated and discussed.

Elucidating the pathophysiology of syringomyelia.

OBJECT: Syringomyelia causes progressive myelopathy. Most patients with syringomyelia have a Chiari I malformation of the cerebellar tonsils. Determination of the pathophysiological mechanisms underlying the progression of syringomyelia associated with the Chiari I malformation should improve strategies to halt progression of myelopathy. METHODS: The authors prospectively studied 20 adult patients with both Chiari I malformation and symptomatic syringomyelia. Testing before surgery included the following: clinical examination; evaluation of anatomy by using T1-weighted magnetic resonance (MR) imaging; evaluation of the syrinx and cerebrospinal fluid (CSF) velocity and flow by using phase-contrast cine MR imaging; and evaluation of lumbar and cervical subarachnoid pressure at rest, during the Valsalva maneuver, during jugular compression, and following removal of CSF (CSF compliance measurement). During surgery, cardiac-gated ultrasonography and pressure measurements were obtained from the intracranial, cervical subarachnoid, and lumbar intrathecal spaces and syrinx. Six months after surgery, clinical examinations, MR imaging studies, and CSF pressure recordings were repeated. Clinical examinations and MR imaging studies were repeated annually. For comparison, 18 healthy volunteers underwent T1-weighted MR imaging, cine MR imaging, and cervical and lumbar subarachnoid pressure testing. Compared with healthy volunteers, before surgery, the patients had decreased anteroposterior diameters of the ventral and dorsal CSF spaces at the foramen magnum. In patients, CSF velocity at the foramen magnum was increased, but CSF flow was reduced. Transmission of intracranial pressure across the foramen magnum to the spinal subarachnoid space in response to jugular compression was partially obstructed. Spinal CSF compliance was reduced, whereas cervical subarachnoid pressure and pulse pressure were increased. Syrinx fluid flowed inferiorly during systole and superiorly during diastole on cine MR imaging. At surgery, the cerebellar tonsils abruptly descended during systole and ascended during diastole, and the upper pole of the syrinx contracted in a manner synchronous with tonsillar descent and with the peak systolic cervical subarachnoid pressure wave. Following surgery, the diameter of the CSF passages at the foramen magnum increased compared with preoperative values, and the maximum flow rate of CSF across the foramen magnum during systole increased. Transmission of pressure across the foramen magnum to the spinal subarachnoid space in response to jugular compression was normal and cervical subarachnoid mean pressure and pulse pressure decreased to normal. The maximum syrinx diameter decreased on MR imaging in all patients. Cine MR imaging documented reduced velocity and flow of the syrinx fluid. Clinical symptoms and signs improved or remained stable in all patients, and the tonsils resumed a normal shape. CONCLUSIONS: The progression of syringomyelia associated with Chiari I malformation is produced by the action of the cerebellar tonsils, which partially occlude the subarachnoid space at the foramen magnum and act as a piston on the partially enclosed spinal subarachnoid space. This creates enlarged cervical subarachnoid pressure waves that compress the spinal cord from without, not from within, and propagate syrinx fluid caudally with each heartbeat, which leads to syrinx progression. The disappearance of the abnormal shape and position of the tonsils after simple decompressive extraarachnoidal surgery suggests that the Chiari I malformation of the cerebellar tonsils is acquired, not congenital. Surgery limited to suboccipital craniectomy, C-I laminectomy, and duraplasty eliminates this mechanism and eliminates syringomyelia and its progression without the risk of more invasive procedures.

Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.

BACKGROUND: Intravenous naloxone frequently ameliorates the pruritus of cholestasis, but its low oral bioavailability precludes its use as a long-term therapy. Nalmefene is an orally bioavailable opiate antagonist. OBJECTIVE: We assessed the efficacy of oral nalmefene in ameliorating the pruritus of cholestasis. METHODS: In a prospective controlled study conducted in a tertiary referral hospital, 11 patients with generalized pruritus complicating chronic liver disease were randomized to receive either nalmefene or placebo in a double-blinded fashion for 2-month periods. Scratching activity was measured continuously for 24-hour periods at baseline and at the end of each treatment period. RESULTS: Data on 8 patients who received at least 1 course of nalmefene were available for comparison with corresponding control data, which consisted of observations obtained during a course of placebo and/or at baseline. Nalmefene therapy was associated with a 75% reduction in the geometric mean hourly scratching activity (P <.01) and a decrease in the mean of a visual analogue score of the perception of pruritus in all 8 patients (mean decrease 77%, P <.01). CONCLUSION: Oral administration of nalmefene can ameliorate pruritus complicating chronic liver disease.

Acute hepatitis due to fluoxetine therapy.

Fluoxetine-induced hepatotoxicity is generally considered of minimal clinical importance and is not well recognized. Asymptomatic increases in liver enzyme values have been observed in 0.5% of patients who take long-term fluoxetine therapy. This report details 2 cases of acute hepatitis believed to be caused by fluoxetine. Three cases of acute hepatitis caused by fluoxetine have been reported previously. The mechanism of fluoxetine-induced hepatotoxicity is unknown. Although routine monitoring of liver function may not be cost-effective, physicians should be alert to the possibility of fluoxetine-associated hepatitis and consider early discontinuation of the drug if this condition is suspected.

Open-label trial of oral nalmefene therapy for the pruritus of cholestasis.

The aims of this study were to determine whether long-term oral administration of the opiate antagonist nalmefene is associated with any beneficial effects in patients with pruritus secondary to cholestatic liver disease and to assess the safety of long-term administration of this drug to these patients. Fourteen patients with unrelieved chronic pruritus of cholestasis were studied. Scratching activity, independent of limb movements, was recorded continuously for 24-hour periods before and during treatment with an initial ameliorating dose of nalmefene. Simultaneously, during these periods, visual analogue scores (VASs) of pruritus were recorded every 4 hours while patients were awake. The dose of nalmefene, which initially was 2 mg orally twice daily, was increased during the study, usually until a satisfactory clinical response was achieved. Five patients experienced a transient opioid withdrawal-like reaction that did not preclude continuing with nalmefene therapy. Serum biochemical indices of cholestasis did not change appreciably during treatment. Thirteen patients reported amelioration of the perception of pruritus on nalmefene. In 5 patients, exacerbations of pruritus occurred approximately 4 weeks after an initial ameliorating dose had been reached; these exacerbations were managed by increasing the dose. Baseline mean values for VAS and scratching activity were higher than corresponding means during nalmefene therapy in 13 (P = .002) and 12 (P = .013) patients, respectively. Possible tolerance to nalmefene occurred in 3 patients. Three patients experienced marked exacerbation of pruritus after nalmefene therapy was suddenly discontinued. Blood levels of nalmefene were consistent with normal pharmacokinetics of the drug. These results suggest that nalmefene may have a favorable risk-to-benefit ratio when it is administered orally long-term to patients with the pruritus of cholestasis.

Definition of a production specification for xenotransplantation. A European perspective.

In the absence of regulatory guidance on animal production for xenotransplantation and the need to conform to European, U.K. and international standards of animal health and welfare, Imutran set up a forum of experts in 1994 to assess the risks associated with the possible transmission of diseases from pig to man after transplantation of porcine tissue. This risk assessment set the specification for Qualified Pathogen-Free pig production and the animal testing required to demonstrate that the specification has been achieved. The invasive sampling required for detailed health monitoring of individual source animals is in conflict with the aim of producing healthy, normal animals that are not subject to undue stress, and produces predominantly retrospective data on a donor. Imutran has developed a sampling regime that qualifies age-class cohorts and the whole herd by the routine testing of representative sentinel animals. Imutran set up a pilot production unit in 1995 and this unit has remained populated beyond a 30-month period and has received in excess of 20 cohorts of animals by hysterectomy re-derivation. Rigorous testing of sentinels and noninvasive testing of individuals have demonstrated that this pilot unit has achieved the required specification on a routine basis in a system that has been designed to meet European ethical and animal welfare concerns, within the constraints of the strict U.K. animal research laws and an ISO 9001 quality environment.

Breast cancer risk and residence near industry or traffic in Nassau and Suffolk Counties, Long Island, New York.

A case-control interview study was used to evaluate the relationship between breast cancer risk and residential proximity to industrial facilities and traffic for pre- and postmenopausal women in Nassau and Suffolk Counties on Long Island, New York. A geographic information system was used to assign industry and traffic counts to 1-km2 grid cells (5-kM2 grid cells for traffic) and to assign potential exposure values to study subjects, based on 20-y residential histories. A significantly elevated risk of breast cancer was observed among postmenopausal subjects who were ever potentially exposed to chemical facilities (Nassau County adjusted odds ratio [OR] = 1.61, 95% confidence interval [95% CI] = 1.06-2.43; Suffolk County adjusted OR = 1.58, 95% CI = 0.71-3.51. This elevated risk, however, was not observed among premenopausal subjects. Risk increased for post-menopausal subjects as number of chemical facilities increased from one (adjusted OR = 1.45, 95% CI = 0.93-2.25) to two or more (adjusted OR = 3.47, 95% CI = 1.06-11.38). Crude and adjusted ORs for high traffic density were elevated among Nassau--but not Suffolk--county subjects and were not significant statistically.

Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial.

OBJECTIVE: To determine whether endogenous opioids contribute to the pruritus of cholestasis by studying the effect of the opiate antagonist naloxone on the perception of pruritus and on scratching activity in patients with this form of pruritus. DESIGN: Double-blind, placebo-controlled, crossover trial with four periods. SETTING: Clinical research referral center. PATIENTS: 29 pruritic patients with liver diseases of various causes. INTERVENTION: Each patient received as many as two naloxone and two placebo solution infusions consecutively in random order. Each infusion lasted 24 hours. MEASUREMENTS: During the infusions, visual analog scores of pruritus were recorded every 4 hours while patients were awake; scratching activity independent of limb movements was recorded continuously. RESULTS: One patient had a mild reaction consistent with a naloxone-precipitated syndrome similar to opiate withdrawal. A significant 24-hour rhythm of scratching activity was seen in 7 of 11 patients for whom complete 96-hour data were collected. The mean of a visual analog score of the perception of pruritus (maximum, 10.0) recorded during naloxone infusions was 0.582 lower than that recorded during placebo infusions (95% CI, 0.176 to 0.988; P < 0.01). Furthermore, the ratio of the geometric mean hourly scratching activity during naloxone infusions to that during placebo infusions was 0.727 (CI, 0.612 to 0.842; P < 0.001) and was greater than 1.0 in only five patients. CONCLUSIONS: Naloxone administration is associated with amelioration of the perception of pruritus and reduction of scratching activity in cholestatic patients. Because of the opioid receptor specificity of the action of naloxone, these findings support the hypothesis that a mechanism underlying the pruritus of cholestasis is modulated by endogenous opioids and suggest that opiate antagonists may have a role in the management of this complication of cholestasis.