Does caffeine enhance bowel recovery after elective colorectal resection? A prospective double-blinded randomized clinical trial.

BACKGROUND: Postoperative ileus is a common condition following abdominal surgery. Previous studies have shown the positive effects of coffee on gastrointestinal motility. The aim of this study was to assess whether caffeine is the stimulatory agent in coffee that triggers bowel motility and thus may reduce the duration of postoperative ileus. METHODS: This was a single-centered, prospective, randomized controlled, double-blinded clinical trial. Patients scheduled to undergo elective laparoscopic colectomy between November 2017 and March 2019 were randomly assigned to receive either oral caffeine (100 mg three times daily) or placebo following the procedure. Primary endpoints were time to first flatus and time to first bowel movement. Secondary endpoints were time to tolerate a solid, low-residue diet and length of hospital stay. Registration number: NCT03097900. RESULTS: Seventy patients were included, [35 males, median age 56 years (range 19-79 years)]. After the exclusion of 12 patients, there were 30 patients in the caffeine group and 28 patients in the placebo group. The first passage of stool in the caffeine group occurred 18 h earlier than in the placebo group (p = 0.012); other endpoints did not reach statistical significance. No caffeine-related adverse events were observed. CONCLUSION: Caffeine consumption following colectomy is safe, leads to a significantly shorter time to first bowel movement, and may thus potentially lead to a shorter postoperative hospital stay.

Differential Effect of Community Rehabilitation Reform on Hospitalizations of Patients with Chronic Psychotic Disorders With and Without Substance Use Disorder, Israel, 1991-2016.

The co-occurrence of schizophrenia and substance use disorder (SUD) is clinically challenging and increasingly prevalent. This study compares trends in hospitalization characteristics of chronic psychotic patients with and without SUD in Israel, before and after introduction of the Community Rehabilitation of Persons with Mental Disability Law in 2000. The National Psychiatric Case Registry provided data on 18,684 adults with schizophrenia/schizoaffective disorders, hospitalized in 1991-2016 (at least once in 2010-2015). Repeated-measures ANOVA was used to measure the effect (and interactions) of group (patients with and without co-occurring disorders (COD)), time-period (Period1: 1991-2000, Period2: 2001-2009, Period3: 2010-2016) and age, on hospitalization measures-average length of stay (LOS), annual number of hospitalizations and hospitalization days. Among non-COD patients hospitalized in all three periods, LOS declined by half from 133.3 days in Period1 to 63.2 in Period3, and the annual number of hospitalizations increased slightly from 0.45 to 0.56. Among COD patients, LOS declined moderately from 82.7 days to 58.3 days, while annual hospitalizations increased dramatically from 0.56 to 0.82. The annual average number of hospitalization days/capita declined from 49.7 in Period1 to 26.3 in Period3 among non-COD patients, yet remained virtually unchanged among COD patients-39.6 and 37.4 in the two periods, respectively. Since introduction of the law, a significant improvement in hospitalization characteristics of chronic psychotic non-COD patients has been noted, whereas the situation worsened somewhat for COD patients. Community rehabilitation services for COD patients in Israel have yet to develop as a suitable alternative to hospitalization, and additional rehabilitation services are urgently needed.

Psychiatric Hospitalizations of Chronic Psychotic Disorder Patients With and Without Dual Diagnosis, Israel, 1963-2016.

Objective: A significant proportion of patients with severe mental illness also experience substance use disorder. For these dual diagnosis (DD) patients, treatment is more complicated and prognosis is worse. Despite the introduction of the Community Rehabilitation of Persons With Mental Health Disability Law in 2000 and ongoing national mental health reforms, psychiatric services in Israel are not meeting the needs of an increasing number of DD patients. This study examines, for the first time in Israel, the prevalence of DD and patterns of psychiatric hospitalizations of chronic psychotic disorder patients with and without substance use disorder. Methods: The National Psychiatric Case Registry provided data on 18,684 persons with schizophrenia/schizoaffective disorders, aged 18-65, with a psychiatric hospitalization during the period 1963-2016 (with at least one hospitalization in 2010-15). Patients were considered as having DD if their substance use disorder was indicated in at least two, or 20%, of hospitalizations. Regression modeling predicted hospitalization measures (number of hospitalizations, total days hospitalized, length of stay). Results were also analyzed by legal status of admission (voluntary or involuntary; psychiatrist-ordered and court-ordered). Results: One-third of patients with chronic psychotic disorder met DD criteria, with a threefold higher rate among males (37.1%) than females (12.8%). Particularly high rates of DD (nearly 50%) were noted among male immigrants from Ethiopia. Compared with non-substance use disorder patients, DD patients had a significantly younger mean age at first hospitalization and shorter average length of stay per hospitalization but a greater number of hospitalizations and total hospital days (p < .0001 for all comparisons). The associations between DD status and hospitalization characteristics remained significant even after accounting for the effects of confounding factors. Hospitalization characteristics were also associated significantly with sex, population group, age, age at first hospitalization, and country of origin. The rate of court-ordered observation or hospitalization was threefold higher in the DD group. Conclusions: These findings, which broadly align with other countries, reflect a scarcity of outpatient services for DD patients with schizophrenia/schizoaffective disorder and substance use disorder. To achieve long-term mental health improvements, an expansion of community-based integrative treatment and rehabilitation services is needed in Israel.

Interaction with therapeutic soft contact lenses affects the intraocular efficacy of tropicamide and latanoprost in dogs.

Therapeutic soft contact lenses (TSCLs) are frequently used to support or protect the cornea during healing. Our aim was to quantitatively evaluate the efficacy of topical medications in TSCL-fitted dogs and determine whether it is affected by the presence of TSCLs. In Phase I, pupil diameter was measured in eyes treated with tropicamide and in eyes covered with TSCLs and then treated with tropicamide, with 1-week intervals between sessions. In Phase II, intraocular pressure (IOP) was measured in uncovered and TSCL-covered eyes treated with latanoprost, with 1-week intervals between sessions. Tropicamide caused significant mydriasis in both uncovered and TSCL-covered eyes (P = 0.005). On the other hand, latanoprost caused a significant decrease in IOP when applied to uncovered eyes (P = 0.002), but had no significant effect on IOP when applied to TSCL-covered eyes (P = 0.7). As we used the same dogs and identical TSCLs throughout the study, we conclude that the different outcomes of the two drugs are due to properties of the drugs themselves, or their formulations, affecting their interaction with the TSCLs. The clinical efficacy of topical drugs applied to TSCL-covered eyes may have to be determined for each drug and/or formulation.

Programmable bio-nanochip-based cytologic testing of oral potentially malignant disorders in Fanconi anemia.

Fanconi anemia (FA) is caused by mutations of DNA repair genes. The risk of oral squamous cell carcinoma (OSCC) among FA patients is 800-folds higher than in the general population. Early detection of OSCC, preferably at it precursor stage, is critical in FA patients to improve their survival. In an ongoing clinical trial, we are evaluating the effectiveness of the programmable bio-nanochip (p-BNC)-based oral cytology test in diagnosing oral potentially malignant disorders (OPMD) in non-FA patients. We used this test to compare cytomorphometric and molecular biomarkers in OSCC cell lines derived from FA and non-FA patients to brush biopsy samples of a FA patient with OPMD and normal mucosa of healthy volunteers. Our data showed that expression patterns of molecular biomarkers were not notably different between sporadic and FA-OSCC cell lines. The p-BNC assay revealed significant differences in cytometric parameters and biomarker MCM2 expression between cytobrush samples of the FA patient and cytobrush samples of normal oral mucosa obtained from healthy volunteers. Microscopic examination of the FA patient's OPMD confirmed the presence of dysplasia. Our pilot data suggests that the p-BNC brush biopsy test recognized dysplastic oral epithelial cells in a brush biopsy sample of a FA patient.

Evaluation of regional limb perfusion with chloramphenicol using the saphenous or cephalic vein in standing horses.

Regional limb perfusion (RLP) significantly decreases morbidity and mortality associated with distal limb injuries in horses. There is an urgent need for finding additional effective antimicrobial drugs for use in RLP. In this study, we tested the pharmacokinetics (PK) of chloramphenicol in RLP. Eight horses participated in the study, which was approved by the University Animal Care and Use Committee. The cephalic and the saphenous veins were used to perfuse the limbs. Synovial samples were collected from the metacarpo/metatarsophalangeal (MCP/MTP) joint. The Friedman Test was applied for assessing change in PK concentration over time, for all time points. The Wilcoxon Signed Ranks Test was used to test the difference between PK concentration in joint & serum as well as concentration in joint vs. MIC. The comparison of measurements between measurements taken on hind vs. front legs was carried out using the Mann-Whitney Test. A P-value of 5% or less was considered statistically significant. After RLP, the concentration of chloramphenicol in the synovial fluid of the MCP/MTP joint using either the cephalic or the saphenous vein was initially far above the minimal inhibitory concentration (MIC) of most susceptible pathogens and remained above the MIC for approximately 6 h. The results indicate that performing RLP using the cephalic and saphenous veins enables reaching concentrations of chloramphenicol in the MCP/MTP joint that are well above the MIC of most susceptible pathogens. The chloramphenicol concentrations achieved in the synovial fluid of the MCP/MTP joint in the current study were between 1.5 (MTP) and 7 (MCP) times the MIC of MRSA in horses. These results are encouraging since MRSA infections are becoming far more common, causing considerable morbidity. To the best of our knowledge, this is the first study to evaluate the pharmacokinetics of chloramphenicol following RLP in the horse and the results are positive.

Risk factors for bacteriuria with carbapenem-resistant Klebsiella pneumoniae and its impact on mortality: a case-control study.

BACKGROUND: The objective of this study was to evaluate the mortality of and risk factors for bacteriuria due to carbapenem-resistant Klebsiella pneumoniae (CRKp) versus carbapenem-susceptible K. pneumoniae (CSKp) producing extended spectrum ß lactamase (ESBL). METHODS: This was a retrospective case-control study in which 135 case-patients with bacteriuria due to CRKp were compared with 127 control patients with CSKp producing ESBL. In a first step, multivariate Cox regression and Kaplan-Meier survival analysis models were used to determine the difference in mortality between the two groups and risk factors for mortality. In a second step, a univariate analysis was used to identify risk factors for CRKp colonization. RESULTS: There were no significant demographic or clinical differences between the groups. In-hospital mortality in the study and control groups was 29 and 25 %, respectively (non-significant difference). Multivariate analysis revealed that the most important risk factor for mortality in both groups was being bed ridden [hazard ratio 2.2, 95 % confidence interval (CI) 1.23-3.93; P = 0.008]. Patients with CRKp bacteriuria had a longer hospitalization time with a mean ± standard deviation of 28 ± 33 days compared to 22 ± 28 days in the control group (P < 0.05). Several univariate risk factors for acquiring CRKp bacteriuria were identified: antibiotic use [odds ratio (OR) 1.93, 95 % CI 1.18-3.17, p = 0.008], especially colistin (OR 2.04, 95 % CI 1.04-4.02; P = 0.036), presence of a urinary catheter (OR 2.09, 95 % CI 1.2-3.63; P = 0.008), surgery (OR 3.94, 95 % CI 1.85-8.37; P = 0.0002), invasive procedures (OR 3.06, 95 % CI 1.61-5.8; P = 0.0004), and intensive care unit admission (OR 2.49, 95 % CI 1.18-5.37; P = 0.015). CONCLUSION: Bacteriuria caused by CRKp as compared that caused by CSKp was not found to be a risk factor for death.

Risk of sensorineural hearing loss in patients with vitiligo.

OBJECTIVE: The purpose of this study was to determine the prevalence of hearing loss and vestibular symptoms among Israeli vitiligo patients as compared with healthy controls. METHODS: 16 vitiligo patients and 16 healthy controls were enrolled in this prospective study. Vitiligo patients had undergone dermatologic evaluation and complete ENT evaluation. RESULTS: Vitiligo patients demonstrated a significantly higher prevalence of sensorineural hearing loss (SNHL) (p = 0.001). A 'notch'-shaped audiogram was the most frequent type of audiogram found among vitiligo patients (p = 0.021). Patients with mucosal involvement as the primary site of onset had a significantly more normal hearing level (p = 0.004). CONCLUSIONS: Due to the high prevalence of SNHL amongst vitiligo patients, it is recommended that these patients undergo a complete hearing evaluation, avoiding ototoxic hazards if possible.

Outcomes of pregnancy and delivery in women with cardiac disease compared to matched healthy controls.

OBJECTIVE: We compared pregnancy and delivery outcomes between women with cardiac disease versus matched healthy controls. The primary outcome was the frequency of unplanned cesarean delivery. METHODS: In this single-center retrospective case-control study, women with cardiac disease were identified and matched (1:2 ratio, according to maternal age, parity, number of prior cesareans, gestational age, delivery onset and fetal presentation) to healthy controls who delivered within the same year. Outcomes were frequency of unplanned cesarean delivery, complications during pregnancy and postpartum course, intensive care unit (ICU) admissions, and length of hospitalization. RESULTS: One hundred and twelve women with cardiac disease (exposed group, 225 deliveries) were identified and matched with 450 healthy women (controls, 2003-2014). The cohort comprised of 103 women (204 deliveries) with acquired heart disease (valve disease [n = 69], arrhythmia [n = 31], 3 with cardiomyopathy and peri/myocarditis, and 9 women (21 deliveries) with congenital heart disease. The frequency of unplanned cesarean was 14 (7.9%) for the exposed group as compared with 12 (3.4%) in controls with an odds ratio of 2.33 (95% CI = 1.0.2-5.32, p = .045). This difference was accentuated in a sub-group of women with severe cardiac disease (15% vs. 4.2% in matched control group, p = .028). Seventy-one (31.6%) exposed women exhibited obstetric and cardiovascular complications during pregnancy as compared with 65 (14.4%) controls, p < .001. Twenty-five (13.9%) exposed women experienced postpartum complications versus 26 (7.5%) in the control group (p = .019). Maternal ICU admission occurred in 13 (7.3%) of the exposed group as compared with only 2 (0.6%) in controls (p < .001). CONCLUSIONS: Women with a background cardiac condition, particularly those with severe disease, are at a higher risk for an unplanned cesarean delivery and other peripartum complications as compared with matched healthy controls.

Theoretical design of D-π-A system new dyes candidate for DSSC application.

Currently, dye-sensitized solar cells (DSSCs) are one of the energy technologies that has piqued the interest of researchers, due to their distinct characteristics such as excellent air stability, ease of synthesis and photovoltaic properties interesting. This work aims to study the optoelectronic properties and photovoltaic of six organic dyes based on phenothiazine (PTZ). The effects of bridging core modifications of recently synthesized PSB-4(R) molecule on structural, photovoltaic, electronic, and optical properties of D1-D6 are studied. Using the method Density Functional Theory (DFT) level of the B3LYP (Becke three-parameter Lee-Yang-Parr) exchange correlation functional with 6-31G (d, p) and time-dependent DFT (TD-DFT). According to the obtained results, optoelectronic properties and photovoltaic of the dyes, we can suggest that these designed molecules are better sensitizers as a candidate for the production of dye solar cells (DSSCs). This theoretical study paves the way for chemists to synthesize more efficient sensitizers for applications in dye solar cells.

Pulse oximeter perfusion index as an early indicator of sympathectomy after epidural anesthesia.

BACKGROUND: The pulse oximeter perfusion index (PI) has been used to indicate sympathectomy-induced vasodilatation. We hypothesized that pulse oximeter PI provides an earlier and clearer indication of sympathectomy following epidural anesthesia than skin temperature and arterial pressure. METHODS: Forty patients received lumbar epidural catheters. Patients were randomized to receive either 10 ml 0.5% bupivacaine or 10 ml 0.25% bupivacaine. PI in the toe, mean arterial pressure (MAP) and toe temperature were all assessed at baseline and at 5, 10 and 20 min following epidural anesthesia. The effect of epidural anesthesia over time was assessed by repeated measures analysis of variance. Additionally, we defined clinically evident sympathectomy criteria (a 100% increase in the PI, a 15% decrease in MAP and a 1 degrees C increase in toe temperature). The numbers of patients demonstrating these changes for each test were compared using the McNemar test for each time point. RESULTS: Twenty-nine subjects had photoplethysmography signals that met a priori signal quality criteria for analysis. By 20 min, PI increased by 326%, compared with a 10% decrease and a 3% increase in MAP and toe temperature, respectively. For PI 15/29, 26/29 and 29/29 of the subjects met the sympathectomy criteria at 5, 10 and 20 min, respectively, compared with 4/29, 6/29 and 18/29 for MAP changes and 3/29, 8/29 and 14/29 for toe temperature changes. CONCLUSIONS: PI was an earlier, clearer and more sensitive indicator of the development of epidural-induced sympathectomy than either skin temperature or MAP.

Surgical management of sand colic impactions in horses: a retrospective study of 41 cases.

OBJECTIVE: A retrospective review of the medical records of 41 horses requiring abdominal surgery for sand colic. RESULTS: The diagnosis of sand colic was made when sand was found to be the cause of impaction of the gastrointestinal tract during surgical exploration. The most common clinical signs at presentation were abdominal pain, abdominal distension and diarrhoea. A statistically significant association was found between the respiratory rate on arrival and short-term survival. Sand impaction at multiple locations was detected in one-third of the horses. Concurrent pathology was detected in half of the horses. Four horses were euthanased during surgery; of those that recovered from surgery, 35/37 (95%) were discharged from hospital. Short- and long-term complications were similar to those previously reported. Long-term (1 year) survival of the horses discharged was 100%. CONCLUSION: The good prognosis for horses undergoing surgery for the treatment of sand impaction supports early surgical intervention in cases where large amounts of sand are suspected.

Constant rate infusion vs. intermittent bolus administration of IV furosemide in 100 pets with acute left-sided congestive heart failure: A retrospective study.

The aim of this study was to determine whether the addition of constant rate infusion (CRI) to intermittent intravenous bolus (IVB) administration of furosemide resulted in an improvement in medical outcomes in dogs and cats with acute left-sided congestive heart failure (L-CHF). A total of 76 client-owned dogs and 24 client-owned cats admitted with acute L-CHF were retrospectively divided between an IVB group (43 dogs and 16 cats) and a CRI group (33 dogs and 8 cats). The median furosemide dose used in dogs in the CRI group (median 0.99mg/kg/h; range 0.025-3.73mg/kg/h) was lower than the dose used in dogs in the IVB group (median 1.19mg/kg/h; range 0.027-7.14mg/kg/h; P=0.008). Respiratory rates were lower in the IVB group (P=0.005) and the CRI group (P=0.039) compared to pre-treatment values. The overall short-term mortality was 15%. A trend of longer hospitalisation in the IVB group relative to the CRI group (P=0.07) was shown. Creatinine and total plasma protein concentrations increased more in the CRI group than in the IVB group, suggestive of a higher risk of dehydration and azotaemia. There may be safety profile differences between CRI and IVB, warranting a prospective study using a larger sample size.

Mercury in traditional Tibetan medicine - panacea or problem?

UNLABELLED: Symptoms of mercury toxicity, biochemical changes, and blood/urine mercury levels were evaluated in a small group of patients. Six patients attending Delek Hospital, Dharamsala, India, taking mercury-containing traditional Tibetan medicine (TTM) (Group I), were compared with three patients taking non-mercury containing TTM (Group II) and healthy volunteers(Group II). Quantitative estimation of mercury ingestion based on chemical analysis was compared with US regulatory standards. RESULTS: Group I were significantly older (mean 55 years+/-SE 6.4) range 26-69 years, than Group II (26.7 years+/-SE 5) range 17-34 years and Group III (32.5 years +/-SE 0.5) range 33-34 years (P =0.05). Group I took TTM on average for 51 months and had a mean of 2.5 non-specific, mercury-related symptoms. Group I had higher mean diastolic pressures (85 mmHg) than Group II (73 mmHg) (P=0.06) and more loose teeth. Mean daily mercury intake for Group I was 674 microg, estimated as 10 microg/kg per day. (Established reference dose for chronic oral exposure: 0.3 microg/kg per day.) Blood mercury levels were non-detectable, but mean urinary mercury levels for Group I were 67 microg/L (EPA levels <20 microg/L). Renal and liver function tests were not significantly different between groups and within normal clinical range. CONCLUSIONS: Prolonged ingestion of mercury containing TTM is associated with absent blood levels, but relatively high urinary levels. Further studies are needed to evaluate toxicity and therapeutic potential.

The renal effect of low-dose dopamine in high-risk patients undergoing coronary angiography.

OBJECTIVES: The purpose of the study was to examine the potential renal protective effect of low-dose dopamine in high-risk patients undergoing coronary angiography. BACKGROUND: Contrast nephropathy is prevalent in patients with chronic renal failure (CRF) and/or diabetes mellitus (DM). Decreased renal blood flow due to vasoconstriction was suggested as a contributory mechanism. Low-dose dopamine has a dilatory effect on the renal vasculature. METHODS: Sixty-six patients with mild or moderate CRF and/or DM undergoing coronary angiography were prospectively double-blindedly randomized, to either 120 ml/day of 0.9% saline plus dopamine 2 microg/kg/min (Dopamine group) or saline alone (Control group) for 48 h. RESULTS: Thirty-three Dopamine-treated (30 diabetics and 6 with CRF) and 33 Control (28 diabetics and 5 with CRF) patients were compared. Plasma creatinine (Cr) level increased in the Control group from 100.6+/-5.2 before to 112.3+/-8.0 micromol/liter within five days after angiography (p = 0.003), and in the Dopamine group from 100.3+/-5.4 before to 117.5+/-8.8 micromol/liter after angiography (p = 0.0001), respectively. There was no significant difference in the change of Cr level (deltaCr) between the two groups. However, in a subgroup of patients with peripheral vascular disease (PVD), deltaCr was -2.4+/-2.3 in the Control group and 30.0+/-12.0 micromol/liter in the Dopamine group (p = 0.01). No significant difference occurred in deltaCr between Control and Dopamine in subgroups of patients with preangiographic CRF or DM. CONCLUSIONS: Contrast material caused a small but significant increase in Cr blood level in high-risk patients. There is no advantage of dopamine over adequate hydration in patients with mild to moderate renal failure or DM undergoing coronary angiography. Dopamine should be avoided in patients with PVD exposed to contrast medium.

Characterisation of the TRIUMF neutron facility using a Monte Carlo simulation code.

Here, the characterisation of the high-energy neutron field at TRIUMF (The Tri Universities Meson Facility, Vancouver, British Columbia) with Monte Carlo simulation software is described. The package used is MCNPX version 2.6.0, with the neutron fluence rate determined at three locations within the TRIUMF Thermal Neutron Facility (TNF), including the exit of the neutron channel where users of the facility can test devices that may be susceptible to the effects of this form of radiation. The facility is often used to roughly emulate the field likely to be encountered at high altitudes due to radiation of galactic origin and thus the simulated information is compared with the energy spectrum calculated to be due to neutron radiation of cosmic origin at typical aircraft altitudes. The calculated values were also compared with neutron flux measurements that were estimated using the activation of various foils by the staff of the facility, showing agreement within an order of magnitude.

The prognostic value of cerebrospinal fluid characteristics in dogs without deep pain perception due to thoracolumbar disc herniation.

Providing a pre-operative prognosis for dogs presented with absent deep pain perception (DPP) is extremely challenging, as the overall recovery rates widely vary. This study assesses the possible correlation between the severity of spinal cord injury and CSF cytology in 31 paraplegic dogs presented with absent DPP due to acute thoracolumbar intervertebral disc herniation (TL-IVDH). All dogs underwent surgical decompression immediately following diagnosis. CSF TNCC, macrophage percentage and macrophage to monocyte (MΦ:M) ratio were significantly higher in dogs that failed to regain DPP within 10 days post-operatively and in dogs that failed to regain ambulation at the end of the study period (P< 0.05). MΦ:M of 0.73 and higher corresponded to a sensitivity of 54% and specificity of 100% for prediction of a negative long-term outcome. CSF TNCC, macrophage percentage and MΦ:M ratio effectively predicted regaining DPP and the long-term outcome in dogs that lost DPP due to acute TL-IVDH.

Leukotriene receptors on human pulmonary vascular endothelium.

1. Cysteinyl-leukotrienes cause contractions and/or relaxations of human isolated pulmonary vascular preparations. Although, the localization and nature of the receptors through which these effects are mediated have not been fully characterized, some effects are indirect and not mediated via the well-described LT1 receptor. 2. In human pulmonary veins (HPV) with an intact endothelium, leukotriene D4 (LTD4) induced contraction above basal tone. This response was observed at lower concentrations of LTD4 in the presence of nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NOARG). Contractions (in the absence and presence of L-NOARG) were partially blocked by the LT1 antagonists (MK 571 and ICI 198615). 3. LTD4 relaxed HPV previously contracted with noradrenaline. This relaxation was potentiated by LT1 antagonists, but was abolished by removal of the endothelium. LTD4 also relaxed human pulmonary arteries (HPA) precontracted with noradrenaline but this effect was not modified by LT1 antagonists. 4. The results suggest that contraction of endothelium-intact HPV by LTD4 is partially mediated via LT1 receptors. Further, in endothelium-intact HPV, this contraction was opposed by a relaxation induced by LTD4, dependent on the release of nitric oxide, which was mediated, at least in part, via a non-LT1 receptor. In addition, LTD4 relaxation on contracted HPA was not mediated by LT1 receptors. 5. The mechanical effects of LTD4 on human pulmonary vasculature are complex and involve both direct and indirect mechanisms mediated via at least two types of cysteinyl-leukotriene receptors.

The effects of a novel sulphidopeptide leukotriene antagonist, BAY x7195, against elicited bronchoconstriction in the anaesthetized guinea-pig.

1. The novel leukotriene antagonist Bay x7195, has been evaluated against bronchoconstriction induced by leukotriene D4 (LTD4), the thromboxane A2 (TXA2) mimetic U46619, histamine and antigen, in the guinea-pig in vivo by use of a modified Konzett-Rössler preparation. 2. LTD4, given intravenously (i.v.) at 1 or 3 microg kg(-1) in the presence of indomethacin and sotalol, caused a 50-70% maximal bronchoconstriction in most animals. 3. BAY x7195, given i.v., orally (p.o.), by aerosol or dry powder insufflation, in lactose, reduced LTD4-induced bronchoconstriction dose-dependently. The approximate ID50 values were 83 microg kg(-1), 3 mg kg(-1), 0.0003% w/v for 20 breaths and 20 microg respectively. 4. The action of BAY x7195 (10 mg kg(-1), p.o.) was long lasting, causing significant inhibition of the LTD4-induced response (88% reduction) 8 h after dosing. 5. When given intravenously, in the presence of selected antagonists, BAY x7195 caused a dose-related reduction in the antigen-induced response, with an approximate ID50 of 2 mg kg(-1). 6. At 3 mg kg(-1), i.v., a dose which abolished the response to LTD4, BAY x7195 had no effect on U46619- or histamine-induced bronchoconstriction. 7. BAY x7195 is a potent, selective and long acting antagonist of LTD4-induced bronchoconstriction, in an anaesthetized, ventilated guinea-pig model. It is therefore worthy of clinical evaluation in diseases believed to involve the sulphidopeptide leukotrienes, such as asthma.

The feasibility of high-dose chemotherapy in breast cancer patients with impaired left ventricular function.

Breast cancer patients with cardiac disease are usually excluded from clinical trials of high-dose chemotherapy. We treated 52 patients with inflammatory and/or metastatic disease with sequential high-dose melphalan and stem cell rescue followed by high-dose thiotepa and stem cell rescue. Stem cells were mobilized with cyclophosphamide and/or paclitaxel and filgrastim. Left ventricular ejection fraction (LVEF) was measured by equilibrium radionuclide angiocardiography (ERNA) at baseline, after each course of chemotherapy and 4 weeks after completing both transplants. The mean absolute decrease in LVEF after the two transplants was 3.6% (P = 0. 008 for the comparison with baseline LVEF), and most of this drop (-2.5%, P = 0.007) occurred after mobilization. Unexpectedly, paclitaxel was associated with a mean absolute decrease in LVEF of 3. 4% (P = 0.032, n = 19), cyclophosphamide alone was not associated with a significant change in LVEF (-1.3%, P = 0.23), but mobilization with sequential paclitaxel and cyclophosphamide resulted in a mean absolute drop of 4.9% in LVEF (P = 0.009). Twelve patients were found to have a reduced LVEF (<50%) at least once during treatment and had a mean absolute decrease in LVEF of 10% (P = 0.008) from baseline, compared with a drop of only 1.8% (P = 0. 176) in the patients without impaired LV function. Although two of these 12 patients developed symptomatic heart failure, their cardiac symptoms were easily treated and there were no cardiac deaths. We conclude that our protocol has acceptable cardiac toxicity and breast cancer patients with impaired LV function should not be denied high-dose chemotherapy if otherwise indicated.